Cardiology

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

 

 

Noninvasive imaging-based diagnostic methods 

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

 

 

Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; Anne_Mounsey@med.unc.edu

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

 

 

Noninvasive imaging-based diagnostic methods 

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

 

 

Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; Anne_Mounsey@med.unc.edu

One of the most concerning and challenging patient complaints presented to physicians is chest pain. Chest pain is a ubiquitous complaint in primary care settings and in the emergency department (ED), accounting for 8 million ED visits and 0.4% of all primary care visits in North America annually.^1,2

Acute coronary syndrome is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chestpain patients seen in ambulatory care.

Despite the great number of chest-pain encounters, early identification of life-threatening causes and prompt treatment remain a challenge. In this article, we examine how the approach to a complaint of chest pain in a primary care practice (and, likewise, in the ED) must first, rest on the clinical evaluation and second, employ risk-stratification tools to aid in evaluation, appropriate diagnosis, triage, and treatment.

Chest pain by the numbers

Acute coronary syndrome (ACS) is the cause of chest pain in 5.1% of patients with chest pain who present to the ED, compared with 1.5% to 3.1% of chest-pain patients seen in ambulatory care.^1,3 “Nonspecific chest pain” is the most frequent diagnosis of chest pain in the ED for all age groups (47.5% to 55.8%).³ In contrast, the most common cause of chest pain in primary care is musculoskeletal (36%), followed by gastrointestinal disease (18% to 19%); serious cardiac causes (15%), including ACS (1.5%); nonspecific causes (16%); psychiatric causes (8%); and pulmonary causes (5% to 10%).⁴ Among patients seen in the ED because of chest pain, 57.4% are discharged, 30.6% are admitted for further evaluation, and 0.4% die in the ED or after admission.³

IMAGE: © KIMBERLY MARTENS-KIEFER

First challenge: The scale of the differential Dx

The differential diagnosis of chest pain is broad. It includes life-threatening causes, such as ACS (from ST-segment elevation myocardial infarction [STEMI], Type 1 non-STEMI, and unstable angina), acute aortic dissection, pulmonary embolism (PE), esophageal rupture, and tension pneumothorax, as well as non-life-threatening causes (TABLE 1).

History and physical exam guide early decisions

Triage assessment of the patient with chest pain, including vital signs, general appearance, and basic symptom questions, can guide you as to whether they require transfer to a higher level of care. Although an individual’s findings cannot, alone, accurately exclude or diagnose ACS, the findings can be used in combination in clinical decision tools to distinguish noncardiac chest pain from ACS.

History. Features in the history (TABLE 2^5-9) that are most helpful at increasing the probability (ie, a positive likelihood ratio [LR] ≥ 2) of chest pain being caused by ACS are:

• pain radiating to both arms or the right arm
• pain that is worse upon exertion
• a history of peripheral artery disease or coronary artery disease (CAD)
• a previously abnormal stress test.

The presence of any prior normal stress test is unhelpful: Such patients have a similar risk of a 30-day adverse cardiac event as a patient who has never had a stress test.⁵

Continue to: A history of tobacco use...

A history of tobacco use, hyperlipidemia, hypertension, obesity, acute myocardial infarction (AMI), coronary artery bypass grafting, or a family history of CAD does not significantly increase the risk of ACS.⁶ However, exploring each of these risk factors further is important, because genetic links between these risk factors can lead to an increased risk of CAD (eg, familial hypercholesterolemia).⁷

A history of normal or near-normal coronary angiography (< 25% stenosis) is associated with a lower likelihood of ACS, because 98% of such patients are free of AMI and 90% are without single-vessel coronary disease nearly 10 years out.⁶ A history of coronary artery bypass grafting is not necessarily predictive of ACS (LR = 1-3).^5,6

Historical features classically associated with ACS, but that have an LR < 2, are pain radiating to the neck or jaw, nausea or vomiting, dyspnea, and pain that is relieved with nitroglycerin.^5,6 Pain described as pleuritic, sharp, positional, or reproduced with palpation is less likely due to AMI.⁵

Physical exam findings are not independently diagnostic when evaluating chest pain. However, a third heart sound is the most likely finding associated with AMI and hypotension is the clinical sign most likely associated with ACS.⁵

Consider the diagnosis of PE in all patients with chest pain. In PE, chest pain might be associated with dyspnea, presyncope, syncope, or hemoptysis.⁸ On examination, 40% of patients have tachycardia.⁸ If PE is suspected; the patient should be risk-stratified using a validated prediction rule (see the discussion of PE that follows).

Continue to: Other historical features...

Other historical features or physical exam findings correlate with aortic dissection, pneumonia, and psychiatric causes of chest pain (TABLE 2^5-9).

Useful EKG findings

Among patients in whom ACS or PE is suspected, 12-lead electrocardiography (EKG) should be performed.

AMI. EKG findings most predictive of AMI are new ST-segment elevation or depression > 1 mm (LR = 6-54), new left bundle branch block (LR = 6.3), Q wave (positive LR = 3.9), and prominent, wide-based (hyperacute) T wave (LR = 3.1).¹⁰

ACS. Useful EKG findings to predict ACS are ST-segment depression (LR = 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia, defined as ST-segment depression, T-wave inversion, or Q wave (LR = 3.6 [95% CI, 1.6-5.7]).¹⁰

PE. The most common abnormal finding on EKG in the setting of PE is sinus tachycardia.

Continue to: Right ventricular strain

Right ventricular strain. Other findings that reflect right ventricular strain, but are much less common, are complete or incomplete right bundle branch block, prominent S wave in lead I, Q wave in lead III, and T-wave inversion in lead III (S1Q3T3; the ­McGinn-White sign) and in leads V₁-V₄.⁸

The utility of troponin and high-sensitivity troponin testing

Clinical evaluation and EKG findings are unable to diagnose or exclude ACS without the use of the cardiac biomarker troponin. In the past decade, high-sensitivity troponin assays have been used to stratify patients at risk of ACS.^11,12 Many protocols now exist using short interval (2-3 hours), high-sensitivity troponin testing to identify patients at low risk of myocardial infarction who can be safely discharged from the ED after 2 normal tests of the troponin level.^13-16

An elevated troponin value alone, however, is not a specific indicator of ACS; troponin can be elevated in the settings of myocardial ischemia related to increased oxygen demand (Type 2 non-STEMI) and decreased renal clearance. Consideration of the rate of rising and falling levels of troponin, its absolute value > 99th percentile, and other findings is critical to interpreting an elevated troponin level.¹⁷ Studies in which the HEART score (History, Electrocardiography, Age, Risk factors, Troponin) was combined with high-sensitivity troponin measurement show that this pairing is promising in reducing unnecessary admissions for chest pain.¹⁸ (For a description of this tool, see the discussion of the HEART score that follows.) Carlton and colleagues¹⁸ showed that a HEART score ≤ 3 and a negative high-sensitivity troponin I level had a negative predictive value of ≥ 99.5% for AMI.

Clinical decision tools: Who needs care? Who can go home?

Given the varied presentations of patients with life-threatening causes of chest pain, it is challenging to confidently determine who is safe to send home after initial assessment. Guidance in 2014 from the American Heart Association and American College of Cardiology recommends risk-stratifying patients for ACS using clinical decision tools to help guide management.^19,20 The American College of Physicians, in its 2015 guidelines, also recommends using a clinical decision tool to assess patients when there is suspicion of PE.²¹ Clinical application of these tools identifies patients at low risk of life-threatening conditions and can help avoid unnecessary intervention and a higher level of care. 

Tools for investigating ACS

The Marburg Heart Score²² assesses the likelihood of CAD in ambulatory settings while the HEART score assesses the risk of major adverse cardiac events in ED patients.²³ The Diamond Forrester criteria can be used to assess the pretest probability of CAD in both settings.²⁴

Continue to: Marburg Heart Score

Marburg Heart Score. Validated in patients older than 35 years of age in 2 different outpatient populations in 2010²² and 2012,²⁵ the Marburg score is determined by answering 5 questions:

• Female ≥ 65 years? Or male ≥ 55 years of age? (No, 0; Yes, +1)
• Known CAD, cerebrovascular disease, or peripheral vascular disease? (No, 0; Yes, +1)
• Is pain worse with exercise? (No, 0; Yes, +1)
• Is pain reproducible with palpation? (No, +1, Yes, 0)
• Does the patient assume that the pain is cardiac in nature? (No, 0; Yes, +1)

A Marburg Heart Score of 0 or 1 means CAD is highly unlikely in a patient with chest pain (negative predictive value = 99%-100%; positive predictive value = 0.6%)⁴ (TABLE 3^4,26-28). A score of ≤ 2 has a negative predictive value of 98%. A Marburg Heart Score of 4 or 5 has a relatively low positive predictive value (63%).⁴

The most common causes of chest pain in primary care? In descending order, musculoskeletal, GI, serious cardiac, nonspecific, psychiatric, and pulmonary causes.

This tool does not accurately diagnose acute MI, but it does help identify patients at low risk of ACS, thus reducing unnecessary subsequent testing. Although no clinical decision tool can rule out AMI with absolute certainty, the Marburg Heart Score is considered one of the most extensively tested and sensitive tools to predict low risk of CAD in outpatient primary care.²⁹

INTERCHEST rule (in outpatient primary care) is a newer prediction rule using data from 5 primary care–based studies of chest pain.³⁰ For a score ≤ 2, the negative predictive value for CAD causing chest pain is 97% to 98% and the positive predictive value is 43%. INTERCHEST incorporates studies used to validate the Marburg Heart Score, but has not been validated beyond initial pooled studies. Concerns have been raised about the quality of these pooled studies, however, and this rule has not been widely accepted for clinical use at this time.²⁹

The HEART score has been validated in patients older than 12 years in multiple institutions and across multiple ED populations.^23,31,32 It is widely used in the ED to assess a patient’s risk of major adverse cardiac events (MACE) over the next 6 weeks. MACE is defined as AMI, percutaneous coronary intervention, coronary artery bypass grafting, or death.

Continue to: The HEART score...

The HEART score is calculated based on 5 components:

• History of chest pain (slightly [0], moderately [+1], or highly [+2]) suspicious for ACS)
• EKG (normal [0], nonspecific ST changes [+1], significant ST deviations [+2])
• Age (< 45 y [0], 45-64 y [+1], ≥ 65 y [+2])
• Risk factors (none [0], 1 or 2 [+1], ≥ 3 or a history of atherosclerotic disease [+2]) ^a
• Initial troponin assay, standard sensitivity (≤ normal [0], 1-3× normal [+1], > 3× normal [+2]).

For patients with a HEART score of 0-3 (ie, at low risk), the pooled positive predictive value of a MACE was determined to be 0.19 (95% CI, 0.14-0.24), and the negative predictive value was 0.99 (95% CI, 0.98-0.99)—making it an effective tool to rule out a MACE over the short term²⁶ (TABLE 3^4,26-28).

Because the HEART Score was published in 2008, multiple systematic reviews and meta-analyses have compared it to the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores for predicting short-term (30-day to 6-week) MACE in ED patients.^27,28,33,34 These studies have all shown that the HEART score is relatively superior to the TIMI and GRACE tools.

Characteristics of these tools are summarized in TABLE 3.^4,26-28

Diamond Forrester classification (in ED and outpatient settings). This tool uses 3 criteria—substernal chest pain, pain that increases upon exertion or with stress, and pain relieved by nitroglycerin or rest—to classify chest pain as typical angina (all 3 criteria), atypical angina (2 criteria), or noncardiac chest pain (0 criteria or 1 criterion).²⁴ Pretest probability (ie, the likelihood of an outcome before noninvasive testing) of the pain being due to CAD can then be determined from the type of chest pain and the patient’s gender and age¹⁹ (TABLE 4¹⁹). Recent studies have found that the Diamond Forrester criteria might overestimate the probability of CAD.³⁵

Continue to: Noninvasive imaging-based diagnostic methods

 

 

Noninvasive imaging-based diagnostic methods 

Positron-emission tomography stress testing, stress echocardiography, myocardial perfusion scanning, exercise treadmill testing. The first 3 of these imaging tests have a sensitivity and specificity ranging from 74% to 87%³⁶; exercise treadmill testing is less sensitive (68%) and specific (77%).³⁷

In a patient with a very low (< 5%) probability of CAD, a positive stress test (of any modality) is likely to be a false-positive; conversely, in a patient with a very high (> 90%) probability of CAD, a negative stress test is likely to be a false-negative.¹⁹ The American Heart Association, therefore, does not recommend any of these modalities for patients who have a < 5% or > 90% probability of CAD.¹⁹

Triage assessment of the chestpain patient, including vital signs, general appearance, and basic symptom questions, can clarify whether they need transfer to a higher level of care.

Noninvasive testing to rule out ACS in low- and intermediate-risk patients who present to the ED with chest pain provides no clinical benefit over clinical evaluation alone.³⁸ Therefore, these tests are rarely used in the initial evaluation of chest pain in an acute setting.

Coronary artery calcium score (CACS), coronary computed tomography angiography (CCTA). These tests have demonstrated promise in the risk stratification of chest pain, given their high sensitivity and negative predictive value in low- and intermediate-risk patients.^39,40 However, their application remains unclear in the evaluation of acute chest pain: Appropriate-use criteria do not favor CACS or CCTA alone to evaluate acute chest pain when there is suspicion of ACS.⁴¹ The Choosing Wisely initiative (for “avoiding unnecessary medical tests, treatments, and procedures”; www.choosingwisely.org) recommends against CCTA for high-risk patients presenting to the ED with acute chest pain.⁴²

Cardiac magnetic resonance imaging does not have an established role in the evaluation of patients with suspected ACS.⁴³

Continue to: Tools for investigating PE

 

 

Tools for investigating PE

Three clinical decision tools have been validated to predict the risk of PE: the Wells score, the Geneva score, and Pulmonary Embolism Rule Out Criteria (PERC).^44,45

Wells score is more sensitive than the Geneva score and has been validated in ambulatory¹ and ED^46-48 settings. Based on Wells criteria, high-risk patients need further evaluation with imaging. In low-risk patients, a normal D-dimer level effectively excludes PE, with a < 1% risk of subsequent thromboembolism in the following 3 months. Positive predictive value of the Wells decision tool is low because it is intended to rule out, not confirm, PE.

PERC can be used in a low-probability setting (defined as the treating physician arriving at the conclusion that PE is not the most likely diagnosis and can be excluded with a negative D-dimer test). In that setting, if the patient meets the 8 clinical variables in PERC, the diagnosis of PE is, effectively, ruled out.⁴⁸

Summing up: Evaluation of chest pain guided by risk of CAD

Patients who present in an outpatient setting with a potentially life-threatening cause of chest pain (TABLE 1) and patients with unstable vital signs should be sent to the ED for urgent evaluation. In the remaining outpatients, use the Marburg Heart Score or Diamond Forrester classification to assess the likelihood that pain is due to CAD (in the ED, the HEART score can be used for this purpose) (FIGURE).

When the risk is low. No further cardiac testing is indicated in patients with a risk of CAD < 5%, based on a Marburg score of 0 or 1, or on Diamond Forrester criteria; an abnormal stress test is likely to be a false-positive.¹⁹

Continue to: Moderate risk

Moderate risk. However, further testing is indicated, with a stress test (with or without myocardial imaging), in patients whose risk of CAD is 5% to 70%, based on the Diamond Forrester classification or an intermediate Marburg Heart Score (ie, a score of 2 or 3 but a normal EKG). This further testing can be performed urgently in patients who have multiple other risk factors that are not assessed by the Marburg Heart Score.

High risk. In patients whose risk is > 70%, invasive testing with angiography should be considered.^35,49

EKG abnormalities. Patients with a Marburg Score of 2 or 3 and an abnormal EKG should be sent to the ED (FIGURE). There, patients with a HEART score < 4 and a negative 2-3–hour troponin test have a < 1% chance of ACS and can be safely discharged.³¹

CORRESPONDENCE
Anne Mounsey, MD, UNC Family Medicine, 590 Manning Drive, Chapel Hill, NC 27599; Anne_Mounsey@med.unc.edu

Percutaneous coronary intervention (PCI) guided by quantitative flow ratio (QFR) lesion assessment provided better clinical outcomes than visual assessment of the angiogram in the sham-controlled FAVOR III China study.

PCI success rates were about 95% with both strategies; however, QFR guidance was associated with fewer major adverse cardiac events (MACE) at 1 year, use of fewer stents, less contrast medium exposure, and fewer procedural complications.

“The simplicity and safety of QFR compared with wire-based physiologic measurements should facilitate the adoption of physiologic lesion assessment into routine clinical practice,” co–primary investigator Bo Xu, MBBS, Fuwai Hospital, Beijing, said.

The results were presented at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held online and in Orlando, and published simultaneously in The Lancet.

Although pressure wire–based physiological assessment with fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR) more accurately identify flow-limiting lesions than standard angiography and have been shown to improve outcomes after PCI, the authors note that it’s underused in practice because of prolonged procedural time, potential pressure wire complications, and side effects from hyperemic agents.

QFR, however, is derived from 3-dimensional coronary artery reconstruction and computational fluid dynamics from the angiogram, so FFR can be estimated without the need for a pressure wire or hyperemic drugs.

FAVOR III China was designed statistically for superiority and enrolled 3,847 patients with stable or unstable angina or a myocardial infarction (MI) at least 72 hours before screening if they had at least one coronary lesion with a diameter stenosis of 50% to 90% and a reference vessel diameter of at least 2.5 mm. The intention-to-treat population included 3,825 patients (mean age, 62.7 years; 29.4% female).

In the QFR group, QFR was measured in all coronary arteries with a lesion but PCI performed only in lesions with a QFR of at least 0.80 or diameter stenosis greater than 90%. Two angiographic imaging runs were taken and the data transmitted to the AngioPlus system (Pulse Medical Imaging Technology) by a local network of sites for QFR calculation.

PCI in the angiography-guided group was performed on the basis of visual angiographic assessment only. A 10-minute delay was used in both groups to preserve masking.

The primary endpoint of 1-year MACE, a composite of all-cause death, MI, or ischemia-driven revascularization, occurred in 5.8% of the QFR-guided group and 8.8% of the angiography-guided group (hazard ratio, 0.65; 95% CI, 0.51-0.83; P = .0004).

The curves separated within 48 hours, driven largely by fewer MIs (3.4% vs. 5.7%; P = .0008) and ischemia-driven revascularizations (2.0% vs. 3.1%; P = .0078) in the QFR-guided group, Mr. Xu said.

The major secondary endpoint of MACE excluding periprocedural MI occurred in 3.1% of QFR-guided patients and 4.8% of angiography-guided patients (HR, 0.64; 95% CI, 0.46-0.89; P = .0073).

The prerandomization revascularization plan was changed in 23.3% of patients with QFR and only 6.2% in the angiography group (P < .0001), mainly due to deferral of treatment of at least one vessel originally planned for PCI (19.6% vs. 5.2%; P < .0001).

“I think in the next guideline they will change the recommendation, not just to include FFR and IFR, but also to include QFR,” Giuseppe Tarantini, MD, PhD, University of Padua, Italy, said during a press briefing on the study.

“This is a milestone in our community, not only because it is easier to use compared to the other lesion-specific indexes like FFR, IFR, but also for the need to expand the use of physiology in the setting of interventional cardiology,” he added.

In an accompanying commentary, Robert A. Byrne, MBBCh, PhD, and Laurna McGovern, MBBCh, both from the Cardiovascular Research Institute Dublin, say the results are “relevant for cardiovascular disease researchers and clinicians and an important step forward for the field of angiography-derived flow measurements for guidance of PCI.”

They point out, however, that the control group did not receive pressure wire–guided PCI, which is the standard of care in contemporary practice and out of step with clinical practice guidelines, thus limiting external validity.

They also note that experiences to date suggest that up to 20% of patients may be unsuitable for the algorithm analysis because of coronary anatomy, presence of overlapping vessels, and insufficient image quality.

Commenting for this news organization, David E. Kandzari, MD, chief of the Piedmont Heart Institute, Atlanta, said “the technology isn’t readily available in catheterization labs today. Could it be assimilated into the cath labs at one point in the near term? I think absolutely, and that would be a welcome addition to expedite the procedure itself.”

Nevertheless, he said the results “need to be externally validated too, with what is the gold standard today of FFR in a larger experience.”

Session moderator Gregg W. Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said FAVOR III China has “advanced our knowledge” but pointed out that the ongoing randomized FAVOR III Europe Japan study is directly comparing QFR with invasive pressure-wire assessed FFR. The estimated primary completion date for that study is Dec. 31.

The study was supported by grants from the Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital. Dr. Byrne reported institutional research or educational funding from Abbott Vascular, Biosensors, Biotronik, and Boston Scientific. Ms. McGovern has disclosed no relevant financial relationships. Dr. Kandzari reported minor consulting honoraria from the interventional device industry and institutional research grant support.

A version of this article first appeared on Medscape.com.

Percutaneous coronary intervention (PCI) guided by quantitative flow ratio (QFR) lesion assessment provided better clinical outcomes than visual assessment of the angiogram in the sham-controlled FAVOR III China study.

PCI success rates were about 95% with both strategies; however, QFR guidance was associated with fewer major adverse cardiac events (MACE) at 1 year, use of fewer stents, less contrast medium exposure, and fewer procedural complications.

“The simplicity and safety of QFR compared with wire-based physiologic measurements should facilitate the adoption of physiologic lesion assessment into routine clinical practice,” co–primary investigator Bo Xu, MBBS, Fuwai Hospital, Beijing, said.

The results were presented at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held online and in Orlando, and published simultaneously in The Lancet.

Although pressure wire–based physiological assessment with fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR) more accurately identify flow-limiting lesions than standard angiography and have been shown to improve outcomes after PCI, the authors note that it’s underused in practice because of prolonged procedural time, potential pressure wire complications, and side effects from hyperemic agents.

QFR, however, is derived from 3-dimensional coronary artery reconstruction and computational fluid dynamics from the angiogram, so FFR can be estimated without the need for a pressure wire or hyperemic drugs.

FAVOR III China was designed statistically for superiority and enrolled 3,847 patients with stable or unstable angina or a myocardial infarction (MI) at least 72 hours before screening if they had at least one coronary lesion with a diameter stenosis of 50% to 90% and a reference vessel diameter of at least 2.5 mm. The intention-to-treat population included 3,825 patients (mean age, 62.7 years; 29.4% female).

In the QFR group, QFR was measured in all coronary arteries with a lesion but PCI performed only in lesions with a QFR of at least 0.80 or diameter stenosis greater than 90%. Two angiographic imaging runs were taken and the data transmitted to the AngioPlus system (Pulse Medical Imaging Technology) by a local network of sites for QFR calculation.

PCI in the angiography-guided group was performed on the basis of visual angiographic assessment only. A 10-minute delay was used in both groups to preserve masking.

The primary endpoint of 1-year MACE, a composite of all-cause death, MI, or ischemia-driven revascularization, occurred in 5.8% of the QFR-guided group and 8.8% of the angiography-guided group (hazard ratio, 0.65; 95% CI, 0.51-0.83; P = .0004).

The curves separated within 48 hours, driven largely by fewer MIs (3.4% vs. 5.7%; P = .0008) and ischemia-driven revascularizations (2.0% vs. 3.1%; P = .0078) in the QFR-guided group, Mr. Xu said.

The major secondary endpoint of MACE excluding periprocedural MI occurred in 3.1% of QFR-guided patients and 4.8% of angiography-guided patients (HR, 0.64; 95% CI, 0.46-0.89; P = .0073).

The prerandomization revascularization plan was changed in 23.3% of patients with QFR and only 6.2% in the angiography group (P < .0001), mainly due to deferral of treatment of at least one vessel originally planned for PCI (19.6% vs. 5.2%; P < .0001).

“I think in the next guideline they will change the recommendation, not just to include FFR and IFR, but also to include QFR,” Giuseppe Tarantini, MD, PhD, University of Padua, Italy, said during a press briefing on the study.

“This is a milestone in our community, not only because it is easier to use compared to the other lesion-specific indexes like FFR, IFR, but also for the need to expand the use of physiology in the setting of interventional cardiology,” he added.

In an accompanying commentary, Robert A. Byrne, MBBCh, PhD, and Laurna McGovern, MBBCh, both from the Cardiovascular Research Institute Dublin, say the results are “relevant for cardiovascular disease researchers and clinicians and an important step forward for the field of angiography-derived flow measurements for guidance of PCI.”

They point out, however, that the control group did not receive pressure wire–guided PCI, which is the standard of care in contemporary practice and out of step with clinical practice guidelines, thus limiting external validity.

They also note that experiences to date suggest that up to 20% of patients may be unsuitable for the algorithm analysis because of coronary anatomy, presence of overlapping vessels, and insufficient image quality.

Commenting for this news organization, David E. Kandzari, MD, chief of the Piedmont Heart Institute, Atlanta, said “the technology isn’t readily available in catheterization labs today. Could it be assimilated into the cath labs at one point in the near term? I think absolutely, and that would be a welcome addition to expedite the procedure itself.”

Nevertheless, he said the results “need to be externally validated too, with what is the gold standard today of FFR in a larger experience.”

Session moderator Gregg W. Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said FAVOR III China has “advanced our knowledge” but pointed out that the ongoing randomized FAVOR III Europe Japan study is directly comparing QFR with invasive pressure-wire assessed FFR. The estimated primary completion date for that study is Dec. 31.

The study was supported by grants from the Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital. Dr. Byrne reported institutional research or educational funding from Abbott Vascular, Biosensors, Biotronik, and Boston Scientific. Ms. McGovern has disclosed no relevant financial relationships. Dr. Kandzari reported minor consulting honoraria from the interventional device industry and institutional research grant support.

A version of this article first appeared on Medscape.com.

Percutaneous coronary intervention (PCI) guided by quantitative flow ratio (QFR) lesion assessment provided better clinical outcomes than visual assessment of the angiogram in the sham-controlled FAVOR III China study.

PCI success rates were about 95% with both strategies; however, QFR guidance was associated with fewer major adverse cardiac events (MACE) at 1 year, use of fewer stents, less contrast medium exposure, and fewer procedural complications.

“The simplicity and safety of QFR compared with wire-based physiologic measurements should facilitate the adoption of physiologic lesion assessment into routine clinical practice,” co–primary investigator Bo Xu, MBBS, Fuwai Hospital, Beijing, said.

The results were presented at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held online and in Orlando, and published simultaneously in The Lancet.

Although pressure wire–based physiological assessment with fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR) more accurately identify flow-limiting lesions than standard angiography and have been shown to improve outcomes after PCI, the authors note that it’s underused in practice because of prolonged procedural time, potential pressure wire complications, and side effects from hyperemic agents.

QFR, however, is derived from 3-dimensional coronary artery reconstruction and computational fluid dynamics from the angiogram, so FFR can be estimated without the need for a pressure wire or hyperemic drugs.

FAVOR III China was designed statistically for superiority and enrolled 3,847 patients with stable or unstable angina or a myocardial infarction (MI) at least 72 hours before screening if they had at least one coronary lesion with a diameter stenosis of 50% to 90% and a reference vessel diameter of at least 2.5 mm. The intention-to-treat population included 3,825 patients (mean age, 62.7 years; 29.4% female).

In the QFR group, QFR was measured in all coronary arteries with a lesion but PCI performed only in lesions with a QFR of at least 0.80 or diameter stenosis greater than 90%. Two angiographic imaging runs were taken and the data transmitted to the AngioPlus system (Pulse Medical Imaging Technology) by a local network of sites for QFR calculation.

PCI in the angiography-guided group was performed on the basis of visual angiographic assessment only. A 10-minute delay was used in both groups to preserve masking.

The primary endpoint of 1-year MACE, a composite of all-cause death, MI, or ischemia-driven revascularization, occurred in 5.8% of the QFR-guided group and 8.8% of the angiography-guided group (hazard ratio, 0.65; 95% CI, 0.51-0.83; P = .0004).

The curves separated within 48 hours, driven largely by fewer MIs (3.4% vs. 5.7%; P = .0008) and ischemia-driven revascularizations (2.0% vs. 3.1%; P = .0078) in the QFR-guided group, Mr. Xu said.

The major secondary endpoint of MACE excluding periprocedural MI occurred in 3.1% of QFR-guided patients and 4.8% of angiography-guided patients (HR, 0.64; 95% CI, 0.46-0.89; P = .0073).

The prerandomization revascularization plan was changed in 23.3% of patients with QFR and only 6.2% in the angiography group (P < .0001), mainly due to deferral of treatment of at least one vessel originally planned for PCI (19.6% vs. 5.2%; P < .0001).

“I think in the next guideline they will change the recommendation, not just to include FFR and IFR, but also to include QFR,” Giuseppe Tarantini, MD, PhD, University of Padua, Italy, said during a press briefing on the study.

“This is a milestone in our community, not only because it is easier to use compared to the other lesion-specific indexes like FFR, IFR, but also for the need to expand the use of physiology in the setting of interventional cardiology,” he added.

In an accompanying commentary, Robert A. Byrne, MBBCh, PhD, and Laurna McGovern, MBBCh, both from the Cardiovascular Research Institute Dublin, say the results are “relevant for cardiovascular disease researchers and clinicians and an important step forward for the field of angiography-derived flow measurements for guidance of PCI.”

They point out, however, that the control group did not receive pressure wire–guided PCI, which is the standard of care in contemporary practice and out of step with clinical practice guidelines, thus limiting external validity.

They also note that experiences to date suggest that up to 20% of patients may be unsuitable for the algorithm analysis because of coronary anatomy, presence of overlapping vessels, and insufficient image quality.

Commenting for this news organization, David E. Kandzari, MD, chief of the Piedmont Heart Institute, Atlanta, said “the technology isn’t readily available in catheterization labs today. Could it be assimilated into the cath labs at one point in the near term? I think absolutely, and that would be a welcome addition to expedite the procedure itself.”

Nevertheless, he said the results “need to be externally validated too, with what is the gold standard today of FFR in a larger experience.”

Session moderator Gregg W. Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said FAVOR III China has “advanced our knowledge” but pointed out that the ongoing randomized FAVOR III Europe Japan study is directly comparing QFR with invasive pressure-wire assessed FFR. The estimated primary completion date for that study is Dec. 31.

The study was supported by grants from the Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital. Dr. Byrne reported institutional research or educational funding from Abbott Vascular, Biosensors, Biotronik, and Boston Scientific. Ms. McGovern has disclosed no relevant financial relationships. Dr. Kandzari reported minor consulting honoraria from the interventional device industry and institutional research grant support.

A version of this article first appeared on Medscape.com.

More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.

“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”

Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).

The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.

Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)

In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.

When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.

But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.

And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.

Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.

The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.

“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.

As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.

“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”

In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.

“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”

Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.

A version of this article first appeared on Medscape.com.

More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.

“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”

Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).

The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.

Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)

In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.

When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.

But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.

And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.

Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.

The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.

“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.

As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.

“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”

In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.

“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”

Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.

A version of this article first appeared on Medscape.com.

More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.

“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”

Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).

The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.

Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)

In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.

When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.

But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.

And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.

Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.

The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.

“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.

As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.

“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”

In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.

“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”

Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.

A version of this article first appeared on Medscape.com.

Certain antihypertensive medications, particularly diuretics, are linked to lower Alzheimer’s disease neuropathology and other brain disease processes, new research shows.

Investigators found that use of any antihypertensive was associated with an 18% decrease in Alzheimer’s disease neuropathology, a 22% decrease in Lewy bodies, and a 40% decrease in TAR DNA-binding protein 43 (TDP-43), a protein relevant to several neurodegenerative diseases. Diuretics in particular appear to be driving the association.

Although diuretics might be a better option for preventing brain neuropathology, it’s too early to make firm recommendations solely on the basis of these results as to what blood pressure–lowering agent to prescribe a particular patient, said study investigator Ahmad Sajjadi, MD, assistant professor of neurology, University of California, Irvine.

“This is early stages and preliminary results,” said Dr. Sajjadi, “but it’s food for thought.”

The findings were presented at the 2021 annual meeting of the American Neurological Association.
 

Autopsy data

The study included 3,315 individuals who had donated their brains to research. The National Alzheimer’s Coordinating Center maintains a database that includes data from 32 Alzheimer’s disease research centers in the United States. Participants in the study must have visited one of these centers within 4 years of death. Each person whose brain was included in the study underwent two or more BP measurements on at least 50% of visits.

The mean age at death was 81.7 years, and the mean time between last visit and death was 13.1 months. About 44.4% of participants were women, 57.0% had at least a college degree, and 84.7% had cognitive impairment.

Researchers defined hypertension as systolic BP of at least 130 mm Hg, diastolic BP of at least 80 mm Hg, mean arterial pressure of at least 100 mm Hg, and pulse pressure of at least 60 mm Hg.

Antihypertensive medications that were evaluated included antiadrenergic agents, ACE inhibitors, angiotensin II receptor blockers, beta blockers, calcium channel blockers, diuretics, vasodilators, and combination therapies.

The investigators assessed the number of neuropathologies. In addition to Alzheimer’s disease neuropathology, which included amyloid-beta, tau, Lewy bodies, and TDP-43, they also assessed for atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, frontotemporal lobar degeneration, and hippocampal sclerosis.

Results showed that use of any antihypertensive was associated with a lower likelihood of Alzheimer’s disease neuropathology (odds ratio, 0.822), Lewy bodies (OR, 0.786), and TDP 43 (OR, 0.597). Use of antihypertensives was also associated with increased odds of atherosclerosis (OR, 1.217) (all P < .5.)

The study showed that hypertensive systolic BP was associated with higher odds of Alzheimer’s disease neuropathology (OR, 1.28; P < .5).

Differences by drug type

Results differed in accordance with antihypertensive class. Angiotensin II receptor blockers decreased the odds of Alzheimer’s disease neuropathology by 40% (OR, 0.60; P < .5). Diuretics decreased the odds of Alzheimer’s disease by 36% (OR, 0.64; P < .001) and of hippocampal sclerosis by 32% (OR, 0.68; P < .5).

“We see diuretics are a main driver, especially for lower odds of Alzheimer’s disease and lower odds of hippocampal sclerosis,” said lead author Hanna L. Nguyen, a first-year medical student at the University of California, Irvine.

The results indicate that it is the medications, not BP levels, that account for these associations, she added.

One potential mechanism linking antihypertensives to brain pathology is that with these agents, BP is maintained in the target zone. Blood pressure that’s too high can damage blood vessels, whereas BP that’s too low may result in less than adequate perfusion, said Ms. Nguyen.

These medications may also alter pathways leading to degeneration and could, for example, affect the apo E mechanism of Alzheimer’s disease, she added.

The researchers plan to conduct subset analyses using apo E genetic status and age of death.

Although this is a “massive database,” it has limitations. For example, said Dr. Sajjadi, it does not reveal when patients started taking BP medication, how long they had been taking it, or why.

“We don’t know the exact the reason they were taking these medications. Was it just hypertension, or did they also have heart disease, stroke, a kidney problem, or was there another explanation,” he said.

Following the study presentation, session comoderator Krish Sathian, MBBS, PhD, professor of neurology, neural, and behavioral sciences, and psychology and director of the Neuroscience Institute, Penn State University, Hershey, called this work “fascinating. It provides a lot of data that really touches on everyday practice,” inasmuch as clinicians often prescribe antihypertensive medications and see patients with these kinds of brain disorders.

The investigators and Dr. Sathian reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Certain antihypertensive medications, particularly diuretics, are linked to lower Alzheimer’s disease neuropathology and other brain disease processes, new research shows.

Investigators found that use of any antihypertensive was associated with an 18% decrease in Alzheimer’s disease neuropathology, a 22% decrease in Lewy bodies, and a 40% decrease in TAR DNA-binding protein 43 (TDP-43), a protein relevant to several neurodegenerative diseases. Diuretics in particular appear to be driving the association.

Although diuretics might be a better option for preventing brain neuropathology, it’s too early to make firm recommendations solely on the basis of these results as to what blood pressure–lowering agent to prescribe a particular patient, said study investigator Ahmad Sajjadi, MD, assistant professor of neurology, University of California, Irvine.

“This is early stages and preliminary results,” said Dr. Sajjadi, “but it’s food for thought.”

The findings were presented at the 2021 annual meeting of the American Neurological Association.
 

Autopsy data

The study included 3,315 individuals who had donated their brains to research. The National Alzheimer’s Coordinating Center maintains a database that includes data from 32 Alzheimer’s disease research centers in the United States. Participants in the study must have visited one of these centers within 4 years of death. Each person whose brain was included in the study underwent two or more BP measurements on at least 50% of visits.

The mean age at death was 81.7 years, and the mean time between last visit and death was 13.1 months. About 44.4% of participants were women, 57.0% had at least a college degree, and 84.7% had cognitive impairment.

Researchers defined hypertension as systolic BP of at least 130 mm Hg, diastolic BP of at least 80 mm Hg, mean arterial pressure of at least 100 mm Hg, and pulse pressure of at least 60 mm Hg.

Antihypertensive medications that were evaluated included antiadrenergic agents, ACE inhibitors, angiotensin II receptor blockers, beta blockers, calcium channel blockers, diuretics, vasodilators, and combination therapies.

The investigators assessed the number of neuropathologies. In addition to Alzheimer’s disease neuropathology, which included amyloid-beta, tau, Lewy bodies, and TDP-43, they also assessed for atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, frontotemporal lobar degeneration, and hippocampal sclerosis.

Results showed that use of any antihypertensive was associated with a lower likelihood of Alzheimer’s disease neuropathology (odds ratio, 0.822), Lewy bodies (OR, 0.786), and TDP 43 (OR, 0.597). Use of antihypertensives was also associated with increased odds of atherosclerosis (OR, 1.217) (all P < .5.)

The study showed that hypertensive systolic BP was associated with higher odds of Alzheimer’s disease neuropathology (OR, 1.28; P < .5).

Differences by drug type

Results differed in accordance with antihypertensive class. Angiotensin II receptor blockers decreased the odds of Alzheimer’s disease neuropathology by 40% (OR, 0.60; P < .5). Diuretics decreased the odds of Alzheimer’s disease by 36% (OR, 0.64; P < .001) and of hippocampal sclerosis by 32% (OR, 0.68; P < .5).

“We see diuretics are a main driver, especially for lower odds of Alzheimer’s disease and lower odds of hippocampal sclerosis,” said lead author Hanna L. Nguyen, a first-year medical student at the University of California, Irvine.

The results indicate that it is the medications, not BP levels, that account for these associations, she added.

One potential mechanism linking antihypertensives to brain pathology is that with these agents, BP is maintained in the target zone. Blood pressure that’s too high can damage blood vessels, whereas BP that’s too low may result in less than adequate perfusion, said Ms. Nguyen.

These medications may also alter pathways leading to degeneration and could, for example, affect the apo E mechanism of Alzheimer’s disease, she added.

The researchers plan to conduct subset analyses using apo E genetic status and age of death.

Although this is a “massive database,” it has limitations. For example, said Dr. Sajjadi, it does not reveal when patients started taking BP medication, how long they had been taking it, or why.

“We don’t know the exact the reason they were taking these medications. Was it just hypertension, or did they also have heart disease, stroke, a kidney problem, or was there another explanation,” he said.

Following the study presentation, session comoderator Krish Sathian, MBBS, PhD, professor of neurology, neural, and behavioral sciences, and psychology and director of the Neuroscience Institute, Penn State University, Hershey, called this work “fascinating. It provides a lot of data that really touches on everyday practice,” inasmuch as clinicians often prescribe antihypertensive medications and see patients with these kinds of brain disorders.

The investigators and Dr. Sathian reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Certain antihypertensive medications, particularly diuretics, are linked to lower Alzheimer’s disease neuropathology and other brain disease processes, new research shows.

Investigators found that use of any antihypertensive was associated with an 18% decrease in Alzheimer’s disease neuropathology, a 22% decrease in Lewy bodies, and a 40% decrease in TAR DNA-binding protein 43 (TDP-43), a protein relevant to several neurodegenerative diseases. Diuretics in particular appear to be driving the association.

Although diuretics might be a better option for preventing brain neuropathology, it’s too early to make firm recommendations solely on the basis of these results as to what blood pressure–lowering agent to prescribe a particular patient, said study investigator Ahmad Sajjadi, MD, assistant professor of neurology, University of California, Irvine.

“This is early stages and preliminary results,” said Dr. Sajjadi, “but it’s food for thought.”

The findings were presented at the 2021 annual meeting of the American Neurological Association.
 

Autopsy data

The study included 3,315 individuals who had donated their brains to research. The National Alzheimer’s Coordinating Center maintains a database that includes data from 32 Alzheimer’s disease research centers in the United States. Participants in the study must have visited one of these centers within 4 years of death. Each person whose brain was included in the study underwent two or more BP measurements on at least 50% of visits.

The mean age at death was 81.7 years, and the mean time between last visit and death was 13.1 months. About 44.4% of participants were women, 57.0% had at least a college degree, and 84.7% had cognitive impairment.

Researchers defined hypertension as systolic BP of at least 130 mm Hg, diastolic BP of at least 80 mm Hg, mean arterial pressure of at least 100 mm Hg, and pulse pressure of at least 60 mm Hg.

Antihypertensive medications that were evaluated included antiadrenergic agents, ACE inhibitors, angiotensin II receptor blockers, beta blockers, calcium channel blockers, diuretics, vasodilators, and combination therapies.

The investigators assessed the number of neuropathologies. In addition to Alzheimer’s disease neuropathology, which included amyloid-beta, tau, Lewy bodies, and TDP-43, they also assessed for atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, frontotemporal lobar degeneration, and hippocampal sclerosis.

Results showed that use of any antihypertensive was associated with a lower likelihood of Alzheimer’s disease neuropathology (odds ratio, 0.822), Lewy bodies (OR, 0.786), and TDP 43 (OR, 0.597). Use of antihypertensives was also associated with increased odds of atherosclerosis (OR, 1.217) (all P < .5.)

The study showed that hypertensive systolic BP was associated with higher odds of Alzheimer’s disease neuropathology (OR, 1.28; P < .5).

Differences by drug type

Results differed in accordance with antihypertensive class. Angiotensin II receptor blockers decreased the odds of Alzheimer’s disease neuropathology by 40% (OR, 0.60; P < .5). Diuretics decreased the odds of Alzheimer’s disease by 36% (OR, 0.64; P < .001) and of hippocampal sclerosis by 32% (OR, 0.68; P < .5).

“We see diuretics are a main driver, especially for lower odds of Alzheimer’s disease and lower odds of hippocampal sclerosis,” said lead author Hanna L. Nguyen, a first-year medical student at the University of California, Irvine.

The results indicate that it is the medications, not BP levels, that account for these associations, she added.

One potential mechanism linking antihypertensives to brain pathology is that with these agents, BP is maintained in the target zone. Blood pressure that’s too high can damage blood vessels, whereas BP that’s too low may result in less than adequate perfusion, said Ms. Nguyen.

These medications may also alter pathways leading to degeneration and could, for example, affect the apo E mechanism of Alzheimer’s disease, she added.

The researchers plan to conduct subset analyses using apo E genetic status and age of death.

Although this is a “massive database,” it has limitations. For example, said Dr. Sajjadi, it does not reveal when patients started taking BP medication, how long they had been taking it, or why.

“We don’t know the exact the reason they were taking these medications. Was it just hypertension, or did they also have heart disease, stroke, a kidney problem, or was there another explanation,” he said.

Following the study presentation, session comoderator Krish Sathian, MBBS, PhD, professor of neurology, neural, and behavioral sciences, and psychology and director of the Neuroscience Institute, Penn State University, Hershey, called this work “fascinating. It provides a lot of data that really touches on everyday practice,” inasmuch as clinicians often prescribe antihypertensive medications and see patients with these kinds of brain disorders.

The investigators and Dr. Sathian reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The applicability of the results of the ISCHEMIA trial to real-world clinical practice in the United States has been called into question by a new study showing that less than a third of U.S. patients with stable ischemic heart disease (IHD) who currently undergo intervention would meet the trial’s inclusion criteria.

The ISCHEMIA trial, first reported in 2019, showed that, for stable patients with moderate to severe ischemia, an invasive approach using percutaneous coronary intervention (PCI) did not significantly reduce major cardiovascular events after a median 3.2 years of follow-up, compared with a conservative medical strategy.

For the current study, a group of interventionalists analyzed contemporary U.S. data on patients undergoing PCI and found that a large proportion of patients receiving PCI for stable ischemic heart disease in the United States would not have met criteria of the ISCHEMIA trial population.

The study was published online Nov. 1 in JACC: Cardiovascular Interventions).  

“While ISCHEMIA was a very well-conducted trial, our results show that it only applies to about one-third of stable IHD patients undergoing intervention in U.S. clinical practice in the real world. In this group, while ISCHEMIA did not show a reduction in event rate in the intervention group, there was a reduction in symptoms,” lead author Saurav Chatterjee, MD, Long Island Jewish Medical Center, New York, told this news organization.

“But ISCHEMIA did not really answer the question for 67% of stable IHD in current U.S. practice. We may be abIe to defer PCI in these patients, but we don’t know that from the ISCHEMIA trial, as these patients were not included in the trial,” Chatterjee said.  

“There is some concern that people will accept the ISCHEMIA results as being universal, but we cannot apply these results to all stable IHD patients who currently undergo intervention,” he added. “We believe that patients who do not fall into the ISCHEMIA population need a nuanced individual approach, taking into account symptom burden and patient preferences.”

In the new report, Dr. Chatterjee and associates note that the applicability of the ISCHEMIA findings to contemporary practice has been questioned by some, because of the exclusion of a significant proportion of patients that are routinely considered for revascularization, both within and outside of the United States.

They point out that the ISCHEMIA trial recruited 16.5% of its participants from the United States, and the proportion of patients in contemporary U.S. practice that would have qualified for the trial is not clear.

They therefore examined the proportion of stable IHD patients meeting inclusion criteria for the ISCHEMIA trial in a U.S. nationwide PCI registry.

The researchers used data from the National Cardiovascular Data Registry (NCDR) CathPCI Registry, which includes patients undergoing PCI at 1,662 institutions and accounts for more than 90% of PCI-capable hospitals in the United States.

All PCI procedures performed at institutions participating in the NCDR CathPCI Registry from October 2017 to June 2019 were identified. Patients presenting with acute coronary syndrome (ACS), cardiogenic shock, or cardiac arrest were excluded, as there is significant evidence in favor of revascularization in these groups, and they were not included in the ISCHEMIA trial.

Subsequently, all remaining stable IHD patients were classified into one of four groups.

• ISCHEMIA-like: These patients had intermediate- or high-risk findings on a stress test but no high-risk features that would have excluded enrollment into the ISCHEMIA trial
• High risk: This group comprised patients with stable IHD and left ventricular ejection fraction less than 35%, significant unprotected left main stenosis (>50%), preexisting dialysis, recent heart-failure exacerbation, or heart transplant. These patients would have met exclusion criteria for the ISCHEMIA trial
• Low risk: This group included patients with stable and negative or low-risk findings on stress test and would have met exclusion criteria for the ISCHEMIA trial
• Not classifiable: This group comprised patients with stable IHD not fitting any of the other cohorts, including no stress test or extent of ischemia not reported on stress testing. These patients would have not had enough information to clearly meet inclusion or exclusion criteria for the ISCHEMIA trial

Results showed that during the study period 927,011 patients underwent PCI as recorded in the NCDR CathPCI Registry. Of these, 58% had ACS, cardiogenic shock, or cardiac arrest and were excluded; the remaining 388,212 patients who underwent PCI for stable IHD comprised the study population.

Of these, 125,302 (32.28%) had a moderate- or high-risk stress test without high-risk anatomic or clinical features and met ISCHEMIA trial inclusion criteria.

Among stable IHD patients not meeting ISCHEMIA trial inclusion criteria, 71,852 (18.51%) had high-risk criteria that would have excluded them from the ISCHEMIA trial, a total of 67,159 (17.29%) patients had low-risk criteria that would have excluded them from the ISCHEMIA trial, and 123,899 (31.92%) were unclassifiable, either owing to lack of stress testing or the extent of ischemia not being reported on stress testing.

The authors suggest that the unclassifiable patients appear to represent a “higher-risk” population than those closely resembling the ISCHEMIA trial population, with more prior myocardial infarction and heart failure.
 

ISCHEMIA investigators respond

In an accompanying editorial, ISCHEMIA investigators David J. Maron, MD, Stanford (Calif.) University, and Sripal Bangalore, MD, and Judith S. Hochman, MD, New York University, argue that many of the patients highlighted by Dr. Chatterjee and associates were excluded from the ISCHEMIA trial for good reason.

They explain that ISCHEMIA was designed under the premise that prior stable IHD strategy trials such as COURAGE and BARI 2D included lower-risk patients, and the remaining gap was to evaluate the utility of invasive management in those at higher risk with moderate or severe stress-induced ischemia.

They point out that, among the NCDR patients with stable IHD in the current study by Dr. Chatterjee and associates who did not meet ISCHEMIA entry criteria, 18.5% had high-risk features, including 35.2% with left main coronary artery disease, 43.7% with left ventricular systolic dysfunction, and 16.8% with end-stage renal disease.

Although ISCHEMIA results do not apply to patients who were excluded from the trial, there is little controversy regarding the benefit of revascularization in patients with stable IHD with left main coronary artery disease or left ventricular ejection fraction <35%, which is why they were excluded from ISCHEMIA, the editorialists note.  

They also report that patients with end-stage renal disease, who were also designated as not meeting ISCHEMIA inclusion criteria, were included in the companion ISCHEMIA CKD trial.

They further point out that, at the other end of the risk spectrum, 17.3% of stable IHD patients in the current analysis had negative or low-risk functional testing, and these patients were excluded from ISCHEMIA because they were shown in COURAGE and BARI 2D to not benefit from revascularization, and they do not meet guideline recommendations for elective PCI in the absence of symptoms.

Of the 31.9% of stable IHD patients who had missing data on ischemic burden, the ISCHEMIA investigators say that some of these would have qualified for the trial, although it is not possible to say how many. They suggest a conservative estimate of 50%.

Taking these arguments into account, the editorialists recalculated the proportion of NCDR PCI patients with stable IHD who would have been included in ISCHEMIA as between 62.1% and 68.6% of patients.

They say the current NCDR analysis by Dr. Chatterjee and associates should be interpreted as indicating, at worst, that the ISCHEMIA trial results apply to only 32% of patients undergoing elective PCI in the United States, and at best “that the results apply to a far higher proportion, excluding only those at high risk (18.5%) or with unacceptable symptoms despite maximal medical therapy (percentage unknown), for whom PCI is clearly indicated.”

The editorialists conclude: “The purpose of the analysis by Chatterjee et al. is to inform the cardiovascular community of the proportion of patients with stable IHD in clinical practice who would have been excluded from ISCHEMIA without regard for the logic of each exclusion criterion. The purpose of this editorial is to provide context for the analysis, admittedly from the perspective of ISCHEMIA investigators, with the hope that this helps readers clearly see the relevance of the trial to patients under their care.”

They add: “For practical and ethical reasons, ISCHEMIA excluded stable patients with high-risk features, angina inadequately controlled by medication, and low-risk features who do not meet evidence-based guidelines for revascularization. That leaves a large percentage of patients for whom the ISCHEMIA trial is highly relevant; exactly what percentage on the basis of NCDR data is hard to say.”

The ISCHEMIA trial was supported by the National Heart, Lung, and Blood Institute.

A version of this article first appeared on Medscape.com.

The applicability of the results of the ISCHEMIA trial to real-world clinical practice in the United States has been called into question by a new study showing that less than a third of U.S. patients with stable ischemic heart disease (IHD) who currently undergo intervention would meet the trial’s inclusion criteria.

The ISCHEMIA trial, first reported in 2019, showed that, for stable patients with moderate to severe ischemia, an invasive approach using percutaneous coronary intervention (PCI) did not significantly reduce major cardiovascular events after a median 3.2 years of follow-up, compared with a conservative medical strategy.

For the current study, a group of interventionalists analyzed contemporary U.S. data on patients undergoing PCI and found that a large proportion of patients receiving PCI for stable ischemic heart disease in the United States would not have met criteria of the ISCHEMIA trial population.

The study was published online Nov. 1 in JACC: Cardiovascular Interventions).  

“While ISCHEMIA was a very well-conducted trial, our results show that it only applies to about one-third of stable IHD patients undergoing intervention in U.S. clinical practice in the real world. In this group, while ISCHEMIA did not show a reduction in event rate in the intervention group, there was a reduction in symptoms,” lead author Saurav Chatterjee, MD, Long Island Jewish Medical Center, New York, told this news organization.

“But ISCHEMIA did not really answer the question for 67% of stable IHD in current U.S. practice. We may be abIe to defer PCI in these patients, but we don’t know that from the ISCHEMIA trial, as these patients were not included in the trial,” Chatterjee said.  

“There is some concern that people will accept the ISCHEMIA results as being universal, but we cannot apply these results to all stable IHD patients who currently undergo intervention,” he added. “We believe that patients who do not fall into the ISCHEMIA population need a nuanced individual approach, taking into account symptom burden and patient preferences.”

In the new report, Dr. Chatterjee and associates note that the applicability of the ISCHEMIA findings to contemporary practice has been questioned by some, because of the exclusion of a significant proportion of patients that are routinely considered for revascularization, both within and outside of the United States.

They point out that the ISCHEMIA trial recruited 16.5% of its participants from the United States, and the proportion of patients in contemporary U.S. practice that would have qualified for the trial is not clear.

They therefore examined the proportion of stable IHD patients meeting inclusion criteria for the ISCHEMIA trial in a U.S. nationwide PCI registry.

The researchers used data from the National Cardiovascular Data Registry (NCDR) CathPCI Registry, which includes patients undergoing PCI at 1,662 institutions and accounts for more than 90% of PCI-capable hospitals in the United States.

All PCI procedures performed at institutions participating in the NCDR CathPCI Registry from October 2017 to June 2019 were identified. Patients presenting with acute coronary syndrome (ACS), cardiogenic shock, or cardiac arrest were excluded, as there is significant evidence in favor of revascularization in these groups, and they were not included in the ISCHEMIA trial.

Subsequently, all remaining stable IHD patients were classified into one of four groups.

• ISCHEMIA-like: These patients had intermediate- or high-risk findings on a stress test but no high-risk features that would have excluded enrollment into the ISCHEMIA trial
• High risk: This group comprised patients with stable IHD and left ventricular ejection fraction less than 35%, significant unprotected left main stenosis (>50%), preexisting dialysis, recent heart-failure exacerbation, or heart transplant. These patients would have met exclusion criteria for the ISCHEMIA trial
• Low risk: This group included patients with stable and negative or low-risk findings on stress test and would have met exclusion criteria for the ISCHEMIA trial
• Not classifiable: This group comprised patients with stable IHD not fitting any of the other cohorts, including no stress test or extent of ischemia not reported on stress testing. These patients would have not had enough information to clearly meet inclusion or exclusion criteria for the ISCHEMIA trial

Results showed that during the study period 927,011 patients underwent PCI as recorded in the NCDR CathPCI Registry. Of these, 58% had ACS, cardiogenic shock, or cardiac arrest and were excluded; the remaining 388,212 patients who underwent PCI for stable IHD comprised the study population.

Of these, 125,302 (32.28%) had a moderate- or high-risk stress test without high-risk anatomic or clinical features and met ISCHEMIA trial inclusion criteria.

Among stable IHD patients not meeting ISCHEMIA trial inclusion criteria, 71,852 (18.51%) had high-risk criteria that would have excluded them from the ISCHEMIA trial, a total of 67,159 (17.29%) patients had low-risk criteria that would have excluded them from the ISCHEMIA trial, and 123,899 (31.92%) were unclassifiable, either owing to lack of stress testing or the extent of ischemia not being reported on stress testing.

The authors suggest that the unclassifiable patients appear to represent a “higher-risk” population than those closely resembling the ISCHEMIA trial population, with more prior myocardial infarction and heart failure.
 

ISCHEMIA investigators respond

In an accompanying editorial, ISCHEMIA investigators David J. Maron, MD, Stanford (Calif.) University, and Sripal Bangalore, MD, and Judith S. Hochman, MD, New York University, argue that many of the patients highlighted by Dr. Chatterjee and associates were excluded from the ISCHEMIA trial for good reason.

They explain that ISCHEMIA was designed under the premise that prior stable IHD strategy trials such as COURAGE and BARI 2D included lower-risk patients, and the remaining gap was to evaluate the utility of invasive management in those at higher risk with moderate or severe stress-induced ischemia.

They point out that, among the NCDR patients with stable IHD in the current study by Dr. Chatterjee and associates who did not meet ISCHEMIA entry criteria, 18.5% had high-risk features, including 35.2% with left main coronary artery disease, 43.7% with left ventricular systolic dysfunction, and 16.8% with end-stage renal disease.

Although ISCHEMIA results do not apply to patients who were excluded from the trial, there is little controversy regarding the benefit of revascularization in patients with stable IHD with left main coronary artery disease or left ventricular ejection fraction <35%, which is why they were excluded from ISCHEMIA, the editorialists note.  

They also report that patients with end-stage renal disease, who were also designated as not meeting ISCHEMIA inclusion criteria, were included in the companion ISCHEMIA CKD trial.

They further point out that, at the other end of the risk spectrum, 17.3% of stable IHD patients in the current analysis had negative or low-risk functional testing, and these patients were excluded from ISCHEMIA because they were shown in COURAGE and BARI 2D to not benefit from revascularization, and they do not meet guideline recommendations for elective PCI in the absence of symptoms.

Of the 31.9% of stable IHD patients who had missing data on ischemic burden, the ISCHEMIA investigators say that some of these would have qualified for the trial, although it is not possible to say how many. They suggest a conservative estimate of 50%.

Taking these arguments into account, the editorialists recalculated the proportion of NCDR PCI patients with stable IHD who would have been included in ISCHEMIA as between 62.1% and 68.6% of patients.

They say the current NCDR analysis by Dr. Chatterjee and associates should be interpreted as indicating, at worst, that the ISCHEMIA trial results apply to only 32% of patients undergoing elective PCI in the United States, and at best “that the results apply to a far higher proportion, excluding only those at high risk (18.5%) or with unacceptable symptoms despite maximal medical therapy (percentage unknown), for whom PCI is clearly indicated.”

The editorialists conclude: “The purpose of the analysis by Chatterjee et al. is to inform the cardiovascular community of the proportion of patients with stable IHD in clinical practice who would have been excluded from ISCHEMIA without regard for the logic of each exclusion criterion. The purpose of this editorial is to provide context for the analysis, admittedly from the perspective of ISCHEMIA investigators, with the hope that this helps readers clearly see the relevance of the trial to patients under their care.”

They add: “For practical and ethical reasons, ISCHEMIA excluded stable patients with high-risk features, angina inadequately controlled by medication, and low-risk features who do not meet evidence-based guidelines for revascularization. That leaves a large percentage of patients for whom the ISCHEMIA trial is highly relevant; exactly what percentage on the basis of NCDR data is hard to say.”

The ISCHEMIA trial was supported by the National Heart, Lung, and Blood Institute.

A version of this article first appeared on Medscape.com.

The applicability of the results of the ISCHEMIA trial to real-world clinical practice in the United States has been called into question by a new study showing that less than a third of U.S. patients with stable ischemic heart disease (IHD) who currently undergo intervention would meet the trial’s inclusion criteria.

The ISCHEMIA trial, first reported in 2019, showed that, for stable patients with moderate to severe ischemia, an invasive approach using percutaneous coronary intervention (PCI) did not significantly reduce major cardiovascular events after a median 3.2 years of follow-up, compared with a conservative medical strategy.

For the current study, a group of interventionalists analyzed contemporary U.S. data on patients undergoing PCI and found that a large proportion of patients receiving PCI for stable ischemic heart disease in the United States would not have met criteria of the ISCHEMIA trial population.

The study was published online Nov. 1 in JACC: Cardiovascular Interventions).  

“While ISCHEMIA was a very well-conducted trial, our results show that it only applies to about one-third of stable IHD patients undergoing intervention in U.S. clinical practice in the real world. In this group, while ISCHEMIA did not show a reduction in event rate in the intervention group, there was a reduction in symptoms,” lead author Saurav Chatterjee, MD, Long Island Jewish Medical Center, New York, told this news organization.

“But ISCHEMIA did not really answer the question for 67% of stable IHD in current U.S. practice. We may be abIe to defer PCI in these patients, but we don’t know that from the ISCHEMIA trial, as these patients were not included in the trial,” Chatterjee said.  

“There is some concern that people will accept the ISCHEMIA results as being universal, but we cannot apply these results to all stable IHD patients who currently undergo intervention,” he added. “We believe that patients who do not fall into the ISCHEMIA population need a nuanced individual approach, taking into account symptom burden and patient preferences.”

In the new report, Dr. Chatterjee and associates note that the applicability of the ISCHEMIA findings to contemporary practice has been questioned by some, because of the exclusion of a significant proportion of patients that are routinely considered for revascularization, both within and outside of the United States.

They point out that the ISCHEMIA trial recruited 16.5% of its participants from the United States, and the proportion of patients in contemporary U.S. practice that would have qualified for the trial is not clear.

They therefore examined the proportion of stable IHD patients meeting inclusion criteria for the ISCHEMIA trial in a U.S. nationwide PCI registry.

The researchers used data from the National Cardiovascular Data Registry (NCDR) CathPCI Registry, which includes patients undergoing PCI at 1,662 institutions and accounts for more than 90% of PCI-capable hospitals in the United States.

All PCI procedures performed at institutions participating in the NCDR CathPCI Registry from October 2017 to June 2019 were identified. Patients presenting with acute coronary syndrome (ACS), cardiogenic shock, or cardiac arrest were excluded, as there is significant evidence in favor of revascularization in these groups, and they were not included in the ISCHEMIA trial.

Subsequently, all remaining stable IHD patients were classified into one of four groups.

• ISCHEMIA-like: These patients had intermediate- or high-risk findings on a stress test but no high-risk features that would have excluded enrollment into the ISCHEMIA trial
• High risk: This group comprised patients with stable IHD and left ventricular ejection fraction less than 35%, significant unprotected left main stenosis (>50%), preexisting dialysis, recent heart-failure exacerbation, or heart transplant. These patients would have met exclusion criteria for the ISCHEMIA trial
• Low risk: This group included patients with stable and negative or low-risk findings on stress test and would have met exclusion criteria for the ISCHEMIA trial
• Not classifiable: This group comprised patients with stable IHD not fitting any of the other cohorts, including no stress test or extent of ischemia not reported on stress testing. These patients would have not had enough information to clearly meet inclusion or exclusion criteria for the ISCHEMIA trial

Results showed that during the study period 927,011 patients underwent PCI as recorded in the NCDR CathPCI Registry. Of these, 58% had ACS, cardiogenic shock, or cardiac arrest and were excluded; the remaining 388,212 patients who underwent PCI for stable IHD comprised the study population.

Of these, 125,302 (32.28%) had a moderate- or high-risk stress test without high-risk anatomic or clinical features and met ISCHEMIA trial inclusion criteria.

Among stable IHD patients not meeting ISCHEMIA trial inclusion criteria, 71,852 (18.51%) had high-risk criteria that would have excluded them from the ISCHEMIA trial, a total of 67,159 (17.29%) patients had low-risk criteria that would have excluded them from the ISCHEMIA trial, and 123,899 (31.92%) were unclassifiable, either owing to lack of stress testing or the extent of ischemia not being reported on stress testing.

The authors suggest that the unclassifiable patients appear to represent a “higher-risk” population than those closely resembling the ISCHEMIA trial population, with more prior myocardial infarction and heart failure.
 

ISCHEMIA investigators respond

In an accompanying editorial, ISCHEMIA investigators David J. Maron, MD, Stanford (Calif.) University, and Sripal Bangalore, MD, and Judith S. Hochman, MD, New York University, argue that many of the patients highlighted by Dr. Chatterjee and associates were excluded from the ISCHEMIA trial for good reason.

They explain that ISCHEMIA was designed under the premise that prior stable IHD strategy trials such as COURAGE and BARI 2D included lower-risk patients, and the remaining gap was to evaluate the utility of invasive management in those at higher risk with moderate or severe stress-induced ischemia.

They point out that, among the NCDR patients with stable IHD in the current study by Dr. Chatterjee and associates who did not meet ISCHEMIA entry criteria, 18.5% had high-risk features, including 35.2% with left main coronary artery disease, 43.7% with left ventricular systolic dysfunction, and 16.8% with end-stage renal disease.

Although ISCHEMIA results do not apply to patients who were excluded from the trial, there is little controversy regarding the benefit of revascularization in patients with stable IHD with left main coronary artery disease or left ventricular ejection fraction <35%, which is why they were excluded from ISCHEMIA, the editorialists note.  

They also report that patients with end-stage renal disease, who were also designated as not meeting ISCHEMIA inclusion criteria, were included in the companion ISCHEMIA CKD trial.

They further point out that, at the other end of the risk spectrum, 17.3% of stable IHD patients in the current analysis had negative or low-risk functional testing, and these patients were excluded from ISCHEMIA because they were shown in COURAGE and BARI 2D to not benefit from revascularization, and they do not meet guideline recommendations for elective PCI in the absence of symptoms.

Of the 31.9% of stable IHD patients who had missing data on ischemic burden, the ISCHEMIA investigators say that some of these would have qualified for the trial, although it is not possible to say how many. They suggest a conservative estimate of 50%.

Taking these arguments into account, the editorialists recalculated the proportion of NCDR PCI patients with stable IHD who would have been included in ISCHEMIA as between 62.1% and 68.6% of patients.

They say the current NCDR analysis by Dr. Chatterjee and associates should be interpreted as indicating, at worst, that the ISCHEMIA trial results apply to only 32% of patients undergoing elective PCI in the United States, and at best “that the results apply to a far higher proportion, excluding only those at high risk (18.5%) or with unacceptable symptoms despite maximal medical therapy (percentage unknown), for whom PCI is clearly indicated.”

The editorialists conclude: “The purpose of the analysis by Chatterjee et al. is to inform the cardiovascular community of the proportion of patients with stable IHD in clinical practice who would have been excluded from ISCHEMIA without regard for the logic of each exclusion criterion. The purpose of this editorial is to provide context for the analysis, admittedly from the perspective of ISCHEMIA investigators, with the hope that this helps readers clearly see the relevance of the trial to patients under their care.”

They add: “For practical and ethical reasons, ISCHEMIA excluded stable patients with high-risk features, angina inadequately controlled by medication, and low-risk features who do not meet evidence-based guidelines for revascularization. That leaves a large percentage of patients for whom the ISCHEMIA trial is highly relevant; exactly what percentage on the basis of NCDR data is hard to say.”

The ISCHEMIA trial was supported by the National Heart, Lung, and Blood Institute.

A version of this article first appeared on Medscape.com.

Coronary stenting guided by fractional flow reserve (FFR) readings, considered to reflect the targeted lesion’s functional impact, was no match for coronary bypass surgery (CABG) in patients with multivessel disease (MVD) in a major international randomized trial.

M. Alexander Otto/MDedge News

Indeed, FFR-guided percutaneous coronary intervention (PCI) using one of the latest drug-eluting stents (DES) seemed to perform poorly in the trial, compared with surgery, apparently upping the risk for clinical events by 50% over 1 year.

Designed statistically for noninferiority, the third Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME 3) trial, with 1,500 randomized patients, showed that FFR-guided PCI was “not noninferior” to CABG. Of those randomized to PCI, 10.6% met the 1-year primary endpoint of major adverse cardiac or cerebrovascular events (MACCE), compared with only 6.9% of patients assigned to CABG.

The trial enrolled only patients with three-vessel coronary disease with no left-main coronary artery involvement, who were declared by their institution’s multidisciplinary heart team to be appropriate for either form of revascularization.

One of the roles of FFR for PCI guidance is to identify significant lesions “that are underrecognized by the angiogram,” which is less likely to happen in patients with very complex coronary anatomy, study chair William F. Fearon, MD, Stanford (Calif.) University, said in an interview.

“That’s what we saw in a subgroup analysis based on SYNTAX score,” an index of lesion complexity. “In patients with very high SYNTAX scores, CABG outperformed FFR-guided PCI. But if you look at patients with low SYNTAX scores, actually, FFR-guided PCI outperformed CABG for 1-year MACCE.”

Dr. Fearon is lead author on the study’s Nov. 4, 2021, publication in the New England Journal of Medicine, its release timed to coincide with his presentation of the trial at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation.

He noted that FAME-3 “wasn’t designed or powered to test for superiority,” so its results do not imply CABG is superior to FFR-PCI in patients with MVD, and remains “inconclusive” on that question.

“I think what this study does is provide both the physician and patients more contemporary data and information on options and expected outcomes in multivessel disease. So if you are a patient who has less complex disease, I think you can feel comfortable that you will get an equivalent result with FFR-guided PCI.” But, at least based on FAME-3, Dr. Fearon said, CABG provides better outcomes in patients with more complex disease.

“I think there are still patients that look at trade-offs. Some patients will accept a higher event rate in order to avoid a long recovery, and vice versa.” So the trial may allow patients and physicians to make more informed decisions, he said.

A main message of FAME-3 “is that we’re getting very good results with three-vessel PCI, but better results with surgery,” Ran Kornowski, MD, Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, said as a discussant following Dr. Fearon’s presentation of the trial. The subanalysis by SYNTAX score, he agreed, probably could be used as part of shared decision-making with patients.

Not all that surprising

“It’s a well-designed study, with a lot of patients,” said surgeon Frank W. Sellke, MD, of Rhode Island Hospital, Miriam Hospital, and Brown University, all in Providence.

“I don’t think it’s all that surprising,” he said in an interview. “It’s very consistent with what other studies have shown, that for three-vessel disease, surgery tends to have the edge,” even when pitted against FFR-guided PCI.

Indeed, pressure-wire FFR-PCI has a spotty history, even as an alternative to standard angiography-based PCI. For example, it has performed well in registry and other cohort studies but showed no advantage in the all-comers RIPCORD-2 trial or in the setting of complete revascularization PCI for acute MI in FLOWER-MI. And it emitted an increased-mortality signal in the prematurely halted FUTURE trial.

In FAME-3, “the 1-year follow-up was the best chance for FFR-PCI to be noninferior to CABG. The CABG advantage is only going to get better with time if prior experience and pathobiology is true,” Sanjay Kaul, MD, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

Overall, “the quality and quantity of evidence is insufficient to support FFR-guided PCI” in patients with complex coronary artery disease (CAD), he said. “I would also argue that the evidence for FFR-guided PCI for simple CAD is also not high quality.”

Dr. Kaul also blasted the claim that FFR-PCI was seen to perform better against CABG in patients with low SYNTAX scores. “In general, one cannot use a positive subgroup in a null or negative trial, as is the case with FAME-3, to ‘rescue’ the treatment intervention.” Such a positive subgroup finding, he said, “would at best be deemed hypothesis-generating and not hypothesis validating.”

Dr. Fearon agreed that the subgroup analysis by SYNTAX score, though prespecified, was only hypothesis generating. “But I think that other studies have shown the same thing – that in less complex disease, the two strategies appear to perform in a similar fashion.”

The FAME-3 trial’s 1,500 patients were randomly assigned at 48 centers to undergo standard CABG or FFR-guided PCI with Resolute Integrity (Medtronic) zotarolimus-eluting DES. Lesions with a pressure-wire FFR of 0.80 or less were stented and those with higher FFR readings were deferred.

The 1-year hazard ratio for the primary endpoint—a composite of death from any cause, MI, stroke, or repeat revascularization – was 1.5 (95% confidence interval, 1.1-2.2) with a noninferiority P value of .35 for the comparison of FFR-PCI versus CABG.

FFR-guided PCI fared significantly better than CABG for some safety endpoints, including major bleeding (1.6% vs 3.8%, P < .01), arrhythmia including atrial fibrillation (2.4% vs. 14.1%, P < .001), acute kidney injury (0.1% vs 0.9%, P < .04), and 30-day rehospitalization (5.5% vs 10.2%, P < .001).
 

Did the primary endpoint favor CABG?

At a media briefing prior to Dr. Fearon’s TCT 2021 presentation of the trail, Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, proposed that the inclusion of repeat revascularization in the trial’s composite primary endpoint tilted the outcome in favor of CABG. “To me, the FAME-3 results are predictable because repeat revascularization is in the equation.”

M. Alexander Otto, MDedge News

It’s well recognized that the endpoint is less likely after CABG than PCI. The latter treats focal lesions that are a limited part of a coronary artery in which CAD is still likely progressing. CABG, on the other hand, can bypass longer segments of diseased artery.

Indeed, as Dr. Fearon reported, the rates of death, MI, or stroke excluding repeat revascularization were 7.3% with FFR-PCI and 5.2% for CABG, for an HR of 1.4 (95% CI, 0.9-2.1).

Dr. Mehran also proposed that intravascular-ultrasound (IVUS) guidance, had it been part of the trial, could potentially have boosted the performance of FFR-PCI.

Repeat revascularization, Dr. Kaul agreed, “should not have been included” in the trial’s primary endpoint. It had been added “to amplify events and to minimize sample size. Not including revascularization would render the sample size prohibitive. There is always give and take in designing clinical trials.”

And he agreed that “IVUS-based PCI optimization would have further improved PCI outcomes.” However, “IVUS plus FFR adds to the procedural burden and limited resources available.” Dr. Fearon said when interviewed that the trial’s definition of procedural MI, a component of the primary endpoint, might potentially be seen as controversial. Procedural MIs in both the PCI and CABG groups were required to meet the standards of CABG-related type-5 MI according to the third and fourth Universal Definitions. The had also had to be accompanied by “a significant finding like new Q waves or a new wall-motion abnormality on echocardiography,” he said.

“That’s fairly strict. Because of that, we had a low rate of periprocedural MI and it was similar between the two groups, around 1.5% in both arms.”

FAME-3 was funded by Medtronic and Abbott Vascular. Dr. Kaul disclosed no relevant financial relationships. Dr. Kornowsky receives royalties from or holds intellectual property rights with CathWorks. Dr. Mehran disclosed financial ties to numerous pharmaceutical and device companies, and that she, her spouse, or her institution hold equity in Elixir Medical, Applied Therapeutics, and ControlRad.

A version of this article first appeared on Medscape.com.

Coronary stenting guided by fractional flow reserve (FFR) readings, considered to reflect the targeted lesion’s functional impact, was no match for coronary bypass surgery (CABG) in patients with multivessel disease (MVD) in a major international randomized trial.

M. Alexander Otto/MDedge News

Indeed, FFR-guided percutaneous coronary intervention (PCI) using one of the latest drug-eluting stents (DES) seemed to perform poorly in the trial, compared with surgery, apparently upping the risk for clinical events by 50% over 1 year.

Designed statistically for noninferiority, the third Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME 3) trial, with 1,500 randomized patients, showed that FFR-guided PCI was “not noninferior” to CABG. Of those randomized to PCI, 10.6% met the 1-year primary endpoint of major adverse cardiac or cerebrovascular events (MACCE), compared with only 6.9% of patients assigned to CABG.

The trial enrolled only patients with three-vessel coronary disease with no left-main coronary artery involvement, who were declared by their institution’s multidisciplinary heart team to be appropriate for either form of revascularization.

One of the roles of FFR for PCI guidance is to identify significant lesions “that are underrecognized by the angiogram,” which is less likely to happen in patients with very complex coronary anatomy, study chair William F. Fearon, MD, Stanford (Calif.) University, said in an interview.

“That’s what we saw in a subgroup analysis based on SYNTAX score,” an index of lesion complexity. “In patients with very high SYNTAX scores, CABG outperformed FFR-guided PCI. But if you look at patients with low SYNTAX scores, actually, FFR-guided PCI outperformed CABG for 1-year MACCE.”

Dr. Fearon is lead author on the study’s Nov. 4, 2021, publication in the New England Journal of Medicine, its release timed to coincide with his presentation of the trial at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation.

He noted that FAME-3 “wasn’t designed or powered to test for superiority,” so its results do not imply CABG is superior to FFR-PCI in patients with MVD, and remains “inconclusive” on that question.

“I think what this study does is provide both the physician and patients more contemporary data and information on options and expected outcomes in multivessel disease. So if you are a patient who has less complex disease, I think you can feel comfortable that you will get an equivalent result with FFR-guided PCI.” But, at least based on FAME-3, Dr. Fearon said, CABG provides better outcomes in patients with more complex disease.

“I think there are still patients that look at trade-offs. Some patients will accept a higher event rate in order to avoid a long recovery, and vice versa.” So the trial may allow patients and physicians to make more informed decisions, he said.

A main message of FAME-3 “is that we’re getting very good results with three-vessel PCI, but better results with surgery,” Ran Kornowski, MD, Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, said as a discussant following Dr. Fearon’s presentation of the trial. The subanalysis by SYNTAX score, he agreed, probably could be used as part of shared decision-making with patients.

Not all that surprising

“It’s a well-designed study, with a lot of patients,” said surgeon Frank W. Sellke, MD, of Rhode Island Hospital, Miriam Hospital, and Brown University, all in Providence.

“I don’t think it’s all that surprising,” he said in an interview. “It’s very consistent with what other studies have shown, that for three-vessel disease, surgery tends to have the edge,” even when pitted against FFR-guided PCI.

Indeed, pressure-wire FFR-PCI has a spotty history, even as an alternative to standard angiography-based PCI. For example, it has performed well in registry and other cohort studies but showed no advantage in the all-comers RIPCORD-2 trial or in the setting of complete revascularization PCI for acute MI in FLOWER-MI. And it emitted an increased-mortality signal in the prematurely halted FUTURE trial.

In FAME-3, “the 1-year follow-up was the best chance for FFR-PCI to be noninferior to CABG. The CABG advantage is only going to get better with time if prior experience and pathobiology is true,” Sanjay Kaul, MD, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

Overall, “the quality and quantity of evidence is insufficient to support FFR-guided PCI” in patients with complex coronary artery disease (CAD), he said. “I would also argue that the evidence for FFR-guided PCI for simple CAD is also not high quality.”

Dr. Kaul also blasted the claim that FFR-PCI was seen to perform better against CABG in patients with low SYNTAX scores. “In general, one cannot use a positive subgroup in a null or negative trial, as is the case with FAME-3, to ‘rescue’ the treatment intervention.” Such a positive subgroup finding, he said, “would at best be deemed hypothesis-generating and not hypothesis validating.”

Dr. Fearon agreed that the subgroup analysis by SYNTAX score, though prespecified, was only hypothesis generating. “But I think that other studies have shown the same thing – that in less complex disease, the two strategies appear to perform in a similar fashion.”

The FAME-3 trial’s 1,500 patients were randomly assigned at 48 centers to undergo standard CABG or FFR-guided PCI with Resolute Integrity (Medtronic) zotarolimus-eluting DES. Lesions with a pressure-wire FFR of 0.80 or less were stented and those with higher FFR readings were deferred.

The 1-year hazard ratio for the primary endpoint—a composite of death from any cause, MI, stroke, or repeat revascularization – was 1.5 (95% confidence interval, 1.1-2.2) with a noninferiority P value of .35 for the comparison of FFR-PCI versus CABG.

FFR-guided PCI fared significantly better than CABG for some safety endpoints, including major bleeding (1.6% vs 3.8%, P < .01), arrhythmia including atrial fibrillation (2.4% vs. 14.1%, P < .001), acute kidney injury (0.1% vs 0.9%, P < .04), and 30-day rehospitalization (5.5% vs 10.2%, P < .001).
 

Did the primary endpoint favor CABG?

At a media briefing prior to Dr. Fearon’s TCT 2021 presentation of the trail, Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, proposed that the inclusion of repeat revascularization in the trial’s composite primary endpoint tilted the outcome in favor of CABG. “To me, the FAME-3 results are predictable because repeat revascularization is in the equation.”

M. Alexander Otto, MDedge News

It’s well recognized that the endpoint is less likely after CABG than PCI. The latter treats focal lesions that are a limited part of a coronary artery in which CAD is still likely progressing. CABG, on the other hand, can bypass longer segments of diseased artery.

Indeed, as Dr. Fearon reported, the rates of death, MI, or stroke excluding repeat revascularization were 7.3% with FFR-PCI and 5.2% for CABG, for an HR of 1.4 (95% CI, 0.9-2.1).

Dr. Mehran also proposed that intravascular-ultrasound (IVUS) guidance, had it been part of the trial, could potentially have boosted the performance of FFR-PCI.

Repeat revascularization, Dr. Kaul agreed, “should not have been included” in the trial’s primary endpoint. It had been added “to amplify events and to minimize sample size. Not including revascularization would render the sample size prohibitive. There is always give and take in designing clinical trials.”

And he agreed that “IVUS-based PCI optimization would have further improved PCI outcomes.” However, “IVUS plus FFR adds to the procedural burden and limited resources available.” Dr. Fearon said when interviewed that the trial’s definition of procedural MI, a component of the primary endpoint, might potentially be seen as controversial. Procedural MIs in both the PCI and CABG groups were required to meet the standards of CABG-related type-5 MI according to the third and fourth Universal Definitions. The had also had to be accompanied by “a significant finding like new Q waves or a new wall-motion abnormality on echocardiography,” he said.

“That’s fairly strict. Because of that, we had a low rate of periprocedural MI and it was similar between the two groups, around 1.5% in both arms.”

FAME-3 was funded by Medtronic and Abbott Vascular. Dr. Kaul disclosed no relevant financial relationships. Dr. Kornowsky receives royalties from or holds intellectual property rights with CathWorks. Dr. Mehran disclosed financial ties to numerous pharmaceutical and device companies, and that she, her spouse, or her institution hold equity in Elixir Medical, Applied Therapeutics, and ControlRad.

A version of this article first appeared on Medscape.com.

Coronary stenting guided by fractional flow reserve (FFR) readings, considered to reflect the targeted lesion’s functional impact, was no match for coronary bypass surgery (CABG) in patients with multivessel disease (MVD) in a major international randomized trial.

M. Alexander Otto/MDedge News

Indeed, FFR-guided percutaneous coronary intervention (PCI) using one of the latest drug-eluting stents (DES) seemed to perform poorly in the trial, compared with surgery, apparently upping the risk for clinical events by 50% over 1 year.

Designed statistically for noninferiority, the third Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME 3) trial, with 1,500 randomized patients, showed that FFR-guided PCI was “not noninferior” to CABG. Of those randomized to PCI, 10.6% met the 1-year primary endpoint of major adverse cardiac or cerebrovascular events (MACCE), compared with only 6.9% of patients assigned to CABG.

The trial enrolled only patients with three-vessel coronary disease with no left-main coronary artery involvement, who were declared by their institution’s multidisciplinary heart team to be appropriate for either form of revascularization.

One of the roles of FFR for PCI guidance is to identify significant lesions “that are underrecognized by the angiogram,” which is less likely to happen in patients with very complex coronary anatomy, study chair William F. Fearon, MD, Stanford (Calif.) University, said in an interview.

“That’s what we saw in a subgroup analysis based on SYNTAX score,” an index of lesion complexity. “In patients with very high SYNTAX scores, CABG outperformed FFR-guided PCI. But if you look at patients with low SYNTAX scores, actually, FFR-guided PCI outperformed CABG for 1-year MACCE.”

Dr. Fearon is lead author on the study’s Nov. 4, 2021, publication in the New England Journal of Medicine, its release timed to coincide with his presentation of the trial at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation.

He noted that FAME-3 “wasn’t designed or powered to test for superiority,” so its results do not imply CABG is superior to FFR-PCI in patients with MVD, and remains “inconclusive” on that question.

“I think what this study does is provide both the physician and patients more contemporary data and information on options and expected outcomes in multivessel disease. So if you are a patient who has less complex disease, I think you can feel comfortable that you will get an equivalent result with FFR-guided PCI.” But, at least based on FAME-3, Dr. Fearon said, CABG provides better outcomes in patients with more complex disease.

“I think there are still patients that look at trade-offs. Some patients will accept a higher event rate in order to avoid a long recovery, and vice versa.” So the trial may allow patients and physicians to make more informed decisions, he said.

A main message of FAME-3 “is that we’re getting very good results with three-vessel PCI, but better results with surgery,” Ran Kornowski, MD, Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, said as a discussant following Dr. Fearon’s presentation of the trial. The subanalysis by SYNTAX score, he agreed, probably could be used as part of shared decision-making with patients.

Not all that surprising

“It’s a well-designed study, with a lot of patients,” said surgeon Frank W. Sellke, MD, of Rhode Island Hospital, Miriam Hospital, and Brown University, all in Providence.

“I don’t think it’s all that surprising,” he said in an interview. “It’s very consistent with what other studies have shown, that for three-vessel disease, surgery tends to have the edge,” even when pitted against FFR-guided PCI.

Indeed, pressure-wire FFR-PCI has a spotty history, even as an alternative to standard angiography-based PCI. For example, it has performed well in registry and other cohort studies but showed no advantage in the all-comers RIPCORD-2 trial or in the setting of complete revascularization PCI for acute MI in FLOWER-MI. And it emitted an increased-mortality signal in the prematurely halted FUTURE trial.

In FAME-3, “the 1-year follow-up was the best chance for FFR-PCI to be noninferior to CABG. The CABG advantage is only going to get better with time if prior experience and pathobiology is true,” Sanjay Kaul, MD, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

Overall, “the quality and quantity of evidence is insufficient to support FFR-guided PCI” in patients with complex coronary artery disease (CAD), he said. “I would also argue that the evidence for FFR-guided PCI for simple CAD is also not high quality.”

Dr. Kaul also blasted the claim that FFR-PCI was seen to perform better against CABG in patients with low SYNTAX scores. “In general, one cannot use a positive subgroup in a null or negative trial, as is the case with FAME-3, to ‘rescue’ the treatment intervention.” Such a positive subgroup finding, he said, “would at best be deemed hypothesis-generating and not hypothesis validating.”

Dr. Fearon agreed that the subgroup analysis by SYNTAX score, though prespecified, was only hypothesis generating. “But I think that other studies have shown the same thing – that in less complex disease, the two strategies appear to perform in a similar fashion.”

The FAME-3 trial’s 1,500 patients were randomly assigned at 48 centers to undergo standard CABG or FFR-guided PCI with Resolute Integrity (Medtronic) zotarolimus-eluting DES. Lesions with a pressure-wire FFR of 0.80 or less were stented and those with higher FFR readings were deferred.

The 1-year hazard ratio for the primary endpoint—a composite of death from any cause, MI, stroke, or repeat revascularization – was 1.5 (95% confidence interval, 1.1-2.2) with a noninferiority P value of .35 for the comparison of FFR-PCI versus CABG.

FFR-guided PCI fared significantly better than CABG for some safety endpoints, including major bleeding (1.6% vs 3.8%, P < .01), arrhythmia including atrial fibrillation (2.4% vs. 14.1%, P < .001), acute kidney injury (0.1% vs 0.9%, P < .04), and 30-day rehospitalization (5.5% vs 10.2%, P < .001).
 

Did the primary endpoint favor CABG?

At a media briefing prior to Dr. Fearon’s TCT 2021 presentation of the trail, Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, proposed that the inclusion of repeat revascularization in the trial’s composite primary endpoint tilted the outcome in favor of CABG. “To me, the FAME-3 results are predictable because repeat revascularization is in the equation.”

M. Alexander Otto, MDedge News

It’s well recognized that the endpoint is less likely after CABG than PCI. The latter treats focal lesions that are a limited part of a coronary artery in which CAD is still likely progressing. CABG, on the other hand, can bypass longer segments of diseased artery.

Indeed, as Dr. Fearon reported, the rates of death, MI, or stroke excluding repeat revascularization were 7.3% with FFR-PCI and 5.2% for CABG, for an HR of 1.4 (95% CI, 0.9-2.1).

Dr. Mehran also proposed that intravascular-ultrasound (IVUS) guidance, had it been part of the trial, could potentially have boosted the performance of FFR-PCI.

Repeat revascularization, Dr. Kaul agreed, “should not have been included” in the trial’s primary endpoint. It had been added “to amplify events and to minimize sample size. Not including revascularization would render the sample size prohibitive. There is always give and take in designing clinical trials.”

And he agreed that “IVUS-based PCI optimization would have further improved PCI outcomes.” However, “IVUS plus FFR adds to the procedural burden and limited resources available.” Dr. Fearon said when interviewed that the trial’s definition of procedural MI, a component of the primary endpoint, might potentially be seen as controversial. Procedural MIs in both the PCI and CABG groups were required to meet the standards of CABG-related type-5 MI according to the third and fourth Universal Definitions. The had also had to be accompanied by “a significant finding like new Q waves or a new wall-motion abnormality on echocardiography,” he said.

“That’s fairly strict. Because of that, we had a low rate of periprocedural MI and it was similar between the two groups, around 1.5% in both arms.”

FAME-3 was funded by Medtronic and Abbott Vascular. Dr. Kaul disclosed no relevant financial relationships. Dr. Kornowsky receives royalties from or holds intellectual property rights with CathWorks. Dr. Mehran disclosed financial ties to numerous pharmaceutical and device companies, and that she, her spouse, or her institution hold equity in Elixir Medical, Applied Therapeutics, and ControlRad.

A version of this article first appeared on Medscape.com.

Designed to show noninferiority for treatment of coronary artery disease (CAD) in patients with diabetes, a head-to-head comparison of contemporary stents ended up showing that one was superior to the for the primary endpoint of target lesion failure (TLF).

HandmadePictures/Thinkstock

In the superiority analysis, the 35% relative reduction in the risk of TLF at 1 year for the Cre8 EVO (Alvimedica) stent relative to the Resolute Onyx (Medtronic) device reached significance, according to Rafael Romaguera, MD, PhD, an interventional cardiologist at the Bellvitge University Hospital, Barcelona.

At 1 year, the rates of TLF were 7.2% and 10.5% for the Cre8 EVO and Resolute Onyx stents, respectively. On the basis of noninferiority, the 3.73% reduction in TLF at 1 year among those receiving the Cre8 EVO device provided a highly significant confirmation of noninferiority (P < .001) and triggered the preplanned superiority analysis.

When the significant advantage on the TLF endpoint (P = .03) was broken down into its components, the Cre8 EVO stent was linked to numerically lower rates of cardiac death (2.1% vs. 2.7%), target vessel MI (5.3% vs. 7.2%), and target lesion revascularization (2.4% vs. 3.9%), according to the SUGAR (Second-Generation Drug-Eluting Stents in Diabetes) trial results presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation.

In a previous study comparing these devices, called the ReCre8 trial, the rates of TLF in an all-comer CAD population were similar at 1 year. When an updated 3-year analysis was presented earlier in 2021 at the Cardiovascular Research Technologies meeting, they remained similar.
 

Diabetes-centered trial was unmet need

The rationale for conducting a new trial limited to patients with diabetes was based on the greater risk in this population, according to Dr. Romaguera. He cited data that indicate the risk of major adverse cardiac events are about two times higher 2 years after stent implantation in patients with diabetes relative to those without, even when contemporary drug-eluting stents are used.

Both the Cre8 EVO and Resolute Onyx stent are drug eluting and employ contemporary architecture that provides the basis for marketing claims that they are suitable for complex patients; but they have differences.

“There are three features that I think differentiate the Cre8 EVO stent,” Dr. Romaguera reported at the meeting, sponsored by the Cardiovascular Research Foundation.

One is the absence of polymer, which contrasts with the permanent polymer of the Resolute device. This feature affects the dissolution of the anti-inflammatory drug and might be one explanation for the greater protection from ischemic events, according to Dr. Romaguera.

Another is the thickness of the struts, which range from 70 to 80 mm for the Cre8 EVO device and from 92 to 102 mm for the Resolute Onyx device. In experimental studies, strut thickness has been associated with greater risk of thrombus formation, although it is unclear if this modest difference is clinically significant.

Also important, the Cre8 EVO device employs sirolimus for an anti-inflammatory effect, while the Resolute Onyx elutes zotarolimus. Again, experimental evidence suggests a greater anti-inflammatory effect reduces the need for dual-antiplatelet therapy (DAPT); that might offer a relative advantage in patients with an elevated risk of bleeding.

It is not clear whether all of these features contribute to the better results observed in this trial in diabetes patients, but Dr. Romaguera indicated that the lower risk of TLF with Cre8 EVO is not just statistically significant but also clinically meaningful.

In SUGAR, which included 23 centers in Spain, 1,175 patients with confirmed diabetes scheduled for percutaneous intervention (PCI) were randomized to one of the two stents. The study was purposely designed with very few exclusion criteria.
 

SUGAR trial employed all-comer design

“This was an all-comer design and there was no limitation in regard to clinical presentation, complexity, number of lesions, or other disease features,” said Dr. Romaguera. The major exclusions were a life expectancy of less than 2 years and a contraindication to taking DAPT for at least 1 month,

The patients were almost equally divided between those who had a non–ST-segment elevation MI) and those with chronic coronary artery disease, but patients with a STEMI, representing about 12% of the population, were included. Almost all of the patients (about 95%) had type 2 diabetes; nearly one-third were on insulin at the time of randomization.

According to Dr. Romaguera, “SUGAR is the first powered trial to compare new-generation drug-eluting stents in patients with diabetes,” and he emphasized the all-comer design in supporting its clinical relevance.

Several of those participating in discussion of the trial during the late-breaker session agreed. Although the moderator, Gregg Stone, MD, of the Icahn School of Medicine at Mount Sinai, New York, expressed surprise that the trial “actually demonstrated superiority” given the difficulty of showing a difference between modern stents, he called the findings “remarkable.”

Others seemed to suggest that it would alter their practice.

“This study is sweet like sugar for us, because now we have a stent that is dedicated and fitted for the diabetic population,” said Gennaro Sardella, MD, of Sapienza University of Rome.

For Marc Etienne Jolicoeur, MD, an interventional cardiologist associated with Duke University, Durham, N.C., one of the impressive findings was the early separation of the curves in favor of Cre8 EVO. Calling SUGAR a “fantastic trial,” he indicated that the progressive advantage over time reinforced his impression that the difference is real.

However, David Kandzari, MD, director of interventional cardiology, Piedmont Hart Institute, Atlanta, was more circumspect. He did not express any criticisms of the trial, but he called for “a larger evidence base” before declaring the Cre8 EVO device a standard of care for patients with diabetes undergoing PCI.

The SUGAR results were published in the European Heart Journal at the time of presentation at the meeting.

The trial was funded by the Spanish Society of Cardiology. Dr. Romaguera reported financial relationships with Biotronik and Boston Scientific. Dr. Stone, has financial relationships with more than 10 pharmaceutical companies, including those developing devices used in PCI. Dr. Sardella and Dr. Jolicoeur reported no financial relationships relevant to this topic. Dr. Kandzari reported financial relationships with Ablative Solutions and Medtronic.

Designed to show noninferiority for treatment of coronary artery disease (CAD) in patients with diabetes, a head-to-head comparison of contemporary stents ended up showing that one was superior to the for the primary endpoint of target lesion failure (TLF).

HandmadePictures/Thinkstock

In the superiority analysis, the 35% relative reduction in the risk of TLF at 1 year for the Cre8 EVO (Alvimedica) stent relative to the Resolute Onyx (Medtronic) device reached significance, according to Rafael Romaguera, MD, PhD, an interventional cardiologist at the Bellvitge University Hospital, Barcelona.

At 1 year, the rates of TLF were 7.2% and 10.5% for the Cre8 EVO and Resolute Onyx stents, respectively. On the basis of noninferiority, the 3.73% reduction in TLF at 1 year among those receiving the Cre8 EVO device provided a highly significant confirmation of noninferiority (P < .001) and triggered the preplanned superiority analysis.

When the significant advantage on the TLF endpoint (P = .03) was broken down into its components, the Cre8 EVO stent was linked to numerically lower rates of cardiac death (2.1% vs. 2.7%), target vessel MI (5.3% vs. 7.2%), and target lesion revascularization (2.4% vs. 3.9%), according to the SUGAR (Second-Generation Drug-Eluting Stents in Diabetes) trial results presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation.

In a previous study comparing these devices, called the ReCre8 trial, the rates of TLF in an all-comer CAD population were similar at 1 year. When an updated 3-year analysis was presented earlier in 2021 at the Cardiovascular Research Technologies meeting, they remained similar.
 

Diabetes-centered trial was unmet need

The rationale for conducting a new trial limited to patients with diabetes was based on the greater risk in this population, according to Dr. Romaguera. He cited data that indicate the risk of major adverse cardiac events are about two times higher 2 years after stent implantation in patients with diabetes relative to those without, even when contemporary drug-eluting stents are used.

Both the Cre8 EVO and Resolute Onyx stent are drug eluting and employ contemporary architecture that provides the basis for marketing claims that they are suitable for complex patients; but they have differences.

“There are three features that I think differentiate the Cre8 EVO stent,” Dr. Romaguera reported at the meeting, sponsored by the Cardiovascular Research Foundation.

One is the absence of polymer, which contrasts with the permanent polymer of the Resolute device. This feature affects the dissolution of the anti-inflammatory drug and might be one explanation for the greater protection from ischemic events, according to Dr. Romaguera.

Another is the thickness of the struts, which range from 70 to 80 mm for the Cre8 EVO device and from 92 to 102 mm for the Resolute Onyx device. In experimental studies, strut thickness has been associated with greater risk of thrombus formation, although it is unclear if this modest difference is clinically significant.

Also important, the Cre8 EVO device employs sirolimus for an anti-inflammatory effect, while the Resolute Onyx elutes zotarolimus. Again, experimental evidence suggests a greater anti-inflammatory effect reduces the need for dual-antiplatelet therapy (DAPT); that might offer a relative advantage in patients with an elevated risk of bleeding.

It is not clear whether all of these features contribute to the better results observed in this trial in diabetes patients, but Dr. Romaguera indicated that the lower risk of TLF with Cre8 EVO is not just statistically significant but also clinically meaningful.

In SUGAR, which included 23 centers in Spain, 1,175 patients with confirmed diabetes scheduled for percutaneous intervention (PCI) were randomized to one of the two stents. The study was purposely designed with very few exclusion criteria.
 

SUGAR trial employed all-comer design

“This was an all-comer design and there was no limitation in regard to clinical presentation, complexity, number of lesions, or other disease features,” said Dr. Romaguera. The major exclusions were a life expectancy of less than 2 years and a contraindication to taking DAPT for at least 1 month,

The patients were almost equally divided between those who had a non–ST-segment elevation MI) and those with chronic coronary artery disease, but patients with a STEMI, representing about 12% of the population, were included. Almost all of the patients (about 95%) had type 2 diabetes; nearly one-third were on insulin at the time of randomization.

According to Dr. Romaguera, “SUGAR is the first powered trial to compare new-generation drug-eluting stents in patients with diabetes,” and he emphasized the all-comer design in supporting its clinical relevance.

Several of those participating in discussion of the trial during the late-breaker session agreed. Although the moderator, Gregg Stone, MD, of the Icahn School of Medicine at Mount Sinai, New York, expressed surprise that the trial “actually demonstrated superiority” given the difficulty of showing a difference between modern stents, he called the findings “remarkable.”

Others seemed to suggest that it would alter their practice.

“This study is sweet like sugar for us, because now we have a stent that is dedicated and fitted for the diabetic population,” said Gennaro Sardella, MD, of Sapienza University of Rome.

For Marc Etienne Jolicoeur, MD, an interventional cardiologist associated with Duke University, Durham, N.C., one of the impressive findings was the early separation of the curves in favor of Cre8 EVO. Calling SUGAR a “fantastic trial,” he indicated that the progressive advantage over time reinforced his impression that the difference is real.

However, David Kandzari, MD, director of interventional cardiology, Piedmont Hart Institute, Atlanta, was more circumspect. He did not express any criticisms of the trial, but he called for “a larger evidence base” before declaring the Cre8 EVO device a standard of care for patients with diabetes undergoing PCI.

The SUGAR results were published in the European Heart Journal at the time of presentation at the meeting.

The trial was funded by the Spanish Society of Cardiology. Dr. Romaguera reported financial relationships with Biotronik and Boston Scientific. Dr. Stone, has financial relationships with more than 10 pharmaceutical companies, including those developing devices used in PCI. Dr. Sardella and Dr. Jolicoeur reported no financial relationships relevant to this topic. Dr. Kandzari reported financial relationships with Ablative Solutions and Medtronic.

Designed to show noninferiority for treatment of coronary artery disease (CAD) in patients with diabetes, a head-to-head comparison of contemporary stents ended up showing that one was superior to the for the primary endpoint of target lesion failure (TLF).

HandmadePictures/Thinkstock

In the superiority analysis, the 35% relative reduction in the risk of TLF at 1 year for the Cre8 EVO (Alvimedica) stent relative to the Resolute Onyx (Medtronic) device reached significance, according to Rafael Romaguera, MD, PhD, an interventional cardiologist at the Bellvitge University Hospital, Barcelona.

At 1 year, the rates of TLF were 7.2% and 10.5% for the Cre8 EVO and Resolute Onyx stents, respectively. On the basis of noninferiority, the 3.73% reduction in TLF at 1 year among those receiving the Cre8 EVO device provided a highly significant confirmation of noninferiority (P < .001) and triggered the preplanned superiority analysis.

When the significant advantage on the TLF endpoint (P = .03) was broken down into its components, the Cre8 EVO stent was linked to numerically lower rates of cardiac death (2.1% vs. 2.7%), target vessel MI (5.3% vs. 7.2%), and target lesion revascularization (2.4% vs. 3.9%), according to the SUGAR (Second-Generation Drug-Eluting Stents in Diabetes) trial results presented at the Transcatheter Cardiovascular Therapeutics annual meeting, held virtually and live in Orlando and sponsored by the Cardiovascular Research Foundation.

In a previous study comparing these devices, called the ReCre8 trial, the rates of TLF in an all-comer CAD population were similar at 1 year. When an updated 3-year analysis was presented earlier in 2021 at the Cardiovascular Research Technologies meeting, they remained similar.
 

Diabetes-centered trial was unmet need

The rationale for conducting a new trial limited to patients with diabetes was based on the greater risk in this population, according to Dr. Romaguera. He cited data that indicate the risk of major adverse cardiac events are about two times higher 2 years after stent implantation in patients with diabetes relative to those without, even when contemporary drug-eluting stents are used.

Both the Cre8 EVO and Resolute Onyx stent are drug eluting and employ contemporary architecture that provides the basis for marketing claims that they are suitable for complex patients; but they have differences.

“There are three features that I think differentiate the Cre8 EVO stent,” Dr. Romaguera reported at the meeting, sponsored by the Cardiovascular Research Foundation.

One is the absence of polymer, which contrasts with the permanent polymer of the Resolute device. This feature affects the dissolution of the anti-inflammatory drug and might be one explanation for the greater protection from ischemic events, according to Dr. Romaguera.

Another is the thickness of the struts, which range from 70 to 80 mm for the Cre8 EVO device and from 92 to 102 mm for the Resolute Onyx device. In experimental studies, strut thickness has been associated with greater risk of thrombus formation, although it is unclear if this modest difference is clinically significant.

Also important, the Cre8 EVO device employs sirolimus for an anti-inflammatory effect, while the Resolute Onyx elutes zotarolimus. Again, experimental evidence suggests a greater anti-inflammatory effect reduces the need for dual-antiplatelet therapy (DAPT); that might offer a relative advantage in patients with an elevated risk of bleeding.

It is not clear whether all of these features contribute to the better results observed in this trial in diabetes patients, but Dr. Romaguera indicated that the lower risk of TLF with Cre8 EVO is not just statistically significant but also clinically meaningful.

In SUGAR, which included 23 centers in Spain, 1,175 patients with confirmed diabetes scheduled for percutaneous intervention (PCI) were randomized to one of the two stents. The study was purposely designed with very few exclusion criteria.
 

SUGAR trial employed all-comer design

“This was an all-comer design and there was no limitation in regard to clinical presentation, complexity, number of lesions, or other disease features,” said Dr. Romaguera. The major exclusions were a life expectancy of less than 2 years and a contraindication to taking DAPT for at least 1 month,

The patients were almost equally divided between those who had a non–ST-segment elevation MI) and those with chronic coronary artery disease, but patients with a STEMI, representing about 12% of the population, were included. Almost all of the patients (about 95%) had type 2 diabetes; nearly one-third were on insulin at the time of randomization.

According to Dr. Romaguera, “SUGAR is the first powered trial to compare new-generation drug-eluting stents in patients with diabetes,” and he emphasized the all-comer design in supporting its clinical relevance.

Several of those participating in discussion of the trial during the late-breaker session agreed. Although the moderator, Gregg Stone, MD, of the Icahn School of Medicine at Mount Sinai, New York, expressed surprise that the trial “actually demonstrated superiority” given the difficulty of showing a difference between modern stents, he called the findings “remarkable.”

Others seemed to suggest that it would alter their practice.

“This study is sweet like sugar for us, because now we have a stent that is dedicated and fitted for the diabetic population,” said Gennaro Sardella, MD, of Sapienza University of Rome.

For Marc Etienne Jolicoeur, MD, an interventional cardiologist associated with Duke University, Durham, N.C., one of the impressive findings was the early separation of the curves in favor of Cre8 EVO. Calling SUGAR a “fantastic trial,” he indicated that the progressive advantage over time reinforced his impression that the difference is real.

However, David Kandzari, MD, director of interventional cardiology, Piedmont Hart Institute, Atlanta, was more circumspect. He did not express any criticisms of the trial, but he called for “a larger evidence base” before declaring the Cre8 EVO device a standard of care for patients with diabetes undergoing PCI.

The SUGAR results were published in the European Heart Journal at the time of presentation at the meeting.

The trial was funded by the Spanish Society of Cardiology. Dr. Romaguera reported financial relationships with Biotronik and Boston Scientific. Dr. Stone, has financial relationships with more than 10 pharmaceutical companies, including those developing devices used in PCI. Dr. Sardella and Dr. Jolicoeur reported no financial relationships relevant to this topic. Dr. Kandzari reported financial relationships with Ablative Solutions and Medtronic.

Increased mental health needs, higher acuity from delayed appointments, and added questions and conversations surrounding COVID-19 are forcing primary care offices to rethink priorities in office visits.

Evidence of this came from the latest Primary Care Collaborative (PCC) survey, which found that primary care clinicians are seeing more complex patients requiring longer appointments in the wake of COVID-19.

The PCC with the Larry A. Green Center regularly surveys primary care clinicians. This round of questions came August 14-17 and included 1,263 respondents from 49 states, the District of Columbia, and two territories.

More than 7 in 10 (71%) respondents said their patients are more complex and nearly the same percentage said appointments are taking more time.

Ann Greiner, president and CEO of the PCC, said in an interview that 55% of respondents reported that clinicians are struggling to keep up with pent-up demand after patients have delayed or canceled care. Sixty-five percent in the survey said they had seen a rise in children’s mental health issues, and 58% said they were unsure how to help their patients with long COVID.

In addition, primary care clinicians are having repeated conversations with patients on why they should get a vaccine and which one.

“I think that’s adding to the complexity. There is a lot going on here with patient trust,” Ms. Greiner said.
 

‘We’re going to be playing catch-up’

Jacqueline Fincher, MD, an internist in Thompson, Ga., said in an interview that appointments have gotten longer and more complex in the wake of the pandemic – “no question.”

The immediate past president of the American College of Physicians is seeing patients with chronic disease that has gone untreated for sometimes a year or more, she said.

“Their blood pressure was not under good control, they were under more stress, their sugars were up and weren’t being followed as closely for conditions such as congestive heart failure,” she said.

Dr. Fincher, who works in a rural practice 40 miles from Augusta, Ga., with her physician husband and two other physicians, said patients are ready to come back in, “but I don’t have enough slots for them.”

She said she prioritizes what to help patients with first and schedules the next tier for the next appointment, but added, “honestly, over the next 2 years we’re going to be playing catch-up.”

At the same time, the CDC has estimated that 45% of U.S. adults are at increased risk for complications from COVID-19 because of cardiovascular disease, diabetes, respiratory disease, hypertension, or cancer. Rates ranged from 19.8% for people 18-29 years old to 80.7% for people over 80 years of age.
 

Long COVID could overwhelm existing health care capacity

Primary care physicians are also having to diagnose sometimes “invisible” symptoms after people have recovered from acute COVID-19 infection. Diagnosing takes intent listening to patients who describe symptoms that tests can’t confirm.

As this news organization has previously reported, half of COVID-19 survivors report postacute sequelae of COVID-19 (PASC) lasting longer than 6 months.

“These long-term PASC effects occur on a scale that could overwhelm existing health care capacity, particularly in low- and middle-income countries,” the authors wrote.
 

Anxiety, depression ‘have gone off the charts’

Danielle Loeb, MD, MPH, associate professor of internal medicine at the University of Colorado in Denver, who studies complexity in primary care, said in the wake of COVID-19, more patients have developed “new, serious anxiety.”

Courtesy Dr. Danielle Loeb

“That got extremely exacerbated during the pandemic. Anxiety and depression have gone off the charts,” said Dr. Loeb, who prefers the pronoun “they.”

Dr. Loeb cares for a large number of transgender patients. As offices reopen, some patients are having trouble reintegrating into the workplace and resuming social contacts. The primary care doctor says appointments can get longer because of the need to complete tasks, such as filling out forms for Family Medical Leave Act for those not yet ready to return to work.

COVID-19–related fears are keeping many patients from coming into the office, Dr. Loeb said, either from fear of exposure or because they have mental health issues that keep them from feeling safe leaving the house.

“That really affects my ability to care for them,” they said.

Loss of employment in the pandemic or fear of job loss and subsequent changing of insurance has complicated primary care in terms of treatment and administrative tasks, according to Dr. Loeb.

To help treat patients with acute mental health issues and manage other patients, Dr. Loeb’s practice has brought in a social worker and a therapist.

Team-based care is key in the survival of primary care practices, though providing that is difficult in the smaller clinics because of the critical mass of patients needed to make it viable, they said.

“It’s the only answer. It’s the only way you don’t drown,” Dr. Loeb added. “I’m not drowning, and I credit that to my clinic having the help to support the mental health piece of things.”
 

Rethinking workflow

Tricia McGinnis, MPP, MPH, executive vice president of the nonprofit Center for Health Care Strategies (CHCS) says complexity has forced rethinking workflow.

“A lot of the trends we’re seeing in primary care were there pre-COVID, but COVID has exacerbated those trends,” she said in an interview.

“The good news ... is that it was already becoming clear that primary care needed to provide basic mental health services and integrate with behavioral health. It had also become clear that effective primary care needed to address social issues that keep patients from accessing health care,” she said.

Expanding care teams, as Dr. Loeb mentioned, is a key strategy, according to Ms. McGinnis. Potential teams would include the clinical staff, but also social workers and community health workers – people who come from the community primary care is serving who can help build trust with patients and connect the patient to the primary care team.

“There’s a lot that needs to happen that the clinician doesn’t need to do,” she said.

Telehealth can be a big factor in coordinating the team, Ms. McGinnis added.

“It’s thinking less about who’s doing the work, but more about the work that needs to be done to keep people healthy. Then let’s think about the type of workers best suited to perform those tasks,” she said.

As for reimbursing more complex care, population-based, up-front capitated payments linked to high-quality care and better outcomes will need to replace fee-for-service models, according to Ms. McGinnis.

That will provide reliable incomes for primary care offices, but also flexibility in how each patient with different levels of complexity is managed, she said.

Ms. Greiner, Dr. Fincher, Dr. Loeb, and Ms. McGinnis have no relevant financial relationships.

Increased mental health needs, higher acuity from delayed appointments, and added questions and conversations surrounding COVID-19 are forcing primary care offices to rethink priorities in office visits.

Evidence of this came from the latest Primary Care Collaborative (PCC) survey, which found that primary care clinicians are seeing more complex patients requiring longer appointments in the wake of COVID-19.

The PCC with the Larry A. Green Center regularly surveys primary care clinicians. This round of questions came August 14-17 and included 1,263 respondents from 49 states, the District of Columbia, and two territories.

More than 7 in 10 (71%) respondents said their patients are more complex and nearly the same percentage said appointments are taking more time.

Ann Greiner, president and CEO of the PCC, said in an interview that 55% of respondents reported that clinicians are struggling to keep up with pent-up demand after patients have delayed or canceled care. Sixty-five percent in the survey said they had seen a rise in children’s mental health issues, and 58% said they were unsure how to help their patients with long COVID.

In addition, primary care clinicians are having repeated conversations with patients on why they should get a vaccine and which one.

“I think that’s adding to the complexity. There is a lot going on here with patient trust,” Ms. Greiner said.
 

‘We’re going to be playing catch-up’

Jacqueline Fincher, MD, an internist in Thompson, Ga., said in an interview that appointments have gotten longer and more complex in the wake of the pandemic – “no question.”

The immediate past president of the American College of Physicians is seeing patients with chronic disease that has gone untreated for sometimes a year or more, she said.

“Their blood pressure was not under good control, they were under more stress, their sugars were up and weren’t being followed as closely for conditions such as congestive heart failure,” she said.

Dr. Fincher, who works in a rural practice 40 miles from Augusta, Ga., with her physician husband and two other physicians, said patients are ready to come back in, “but I don’t have enough slots for them.”

She said she prioritizes what to help patients with first and schedules the next tier for the next appointment, but added, “honestly, over the next 2 years we’re going to be playing catch-up.”

At the same time, the CDC has estimated that 45% of U.S. adults are at increased risk for complications from COVID-19 because of cardiovascular disease, diabetes, respiratory disease, hypertension, or cancer. Rates ranged from 19.8% for people 18-29 years old to 80.7% for people over 80 years of age.
 

Long COVID could overwhelm existing health care capacity

Primary care physicians are also having to diagnose sometimes “invisible” symptoms after people have recovered from acute COVID-19 infection. Diagnosing takes intent listening to patients who describe symptoms that tests can’t confirm.

As this news organization has previously reported, half of COVID-19 survivors report postacute sequelae of COVID-19 (PASC) lasting longer than 6 months.

“These long-term PASC effects occur on a scale that could overwhelm existing health care capacity, particularly in low- and middle-income countries,” the authors wrote.
 

Anxiety, depression ‘have gone off the charts’

Danielle Loeb, MD, MPH, associate professor of internal medicine at the University of Colorado in Denver, who studies complexity in primary care, said in the wake of COVID-19, more patients have developed “new, serious anxiety.”

Courtesy Dr. Danielle Loeb

“That got extremely exacerbated during the pandemic. Anxiety and depression have gone off the charts,” said Dr. Loeb, who prefers the pronoun “they.”

Dr. Loeb cares for a large number of transgender patients. As offices reopen, some patients are having trouble reintegrating into the workplace and resuming social contacts. The primary care doctor says appointments can get longer because of the need to complete tasks, such as filling out forms for Family Medical Leave Act for those not yet ready to return to work.

COVID-19–related fears are keeping many patients from coming into the office, Dr. Loeb said, either from fear of exposure or because they have mental health issues that keep them from feeling safe leaving the house.

“That really affects my ability to care for them,” they said.

Loss of employment in the pandemic or fear of job loss and subsequent changing of insurance has complicated primary care in terms of treatment and administrative tasks, according to Dr. Loeb.

To help treat patients with acute mental health issues and manage other patients, Dr. Loeb’s practice has brought in a social worker and a therapist.

Team-based care is key in the survival of primary care practices, though providing that is difficult in the smaller clinics because of the critical mass of patients needed to make it viable, they said.

“It’s the only answer. It’s the only way you don’t drown,” Dr. Loeb added. “I’m not drowning, and I credit that to my clinic having the help to support the mental health piece of things.”
 

Rethinking workflow

Tricia McGinnis, MPP, MPH, executive vice president of the nonprofit Center for Health Care Strategies (CHCS) says complexity has forced rethinking workflow.

“A lot of the trends we’re seeing in primary care were there pre-COVID, but COVID has exacerbated those trends,” she said in an interview.

“The good news ... is that it was already becoming clear that primary care needed to provide basic mental health services and integrate with behavioral health. It had also become clear that effective primary care needed to address social issues that keep patients from accessing health care,” she said.

Expanding care teams, as Dr. Loeb mentioned, is a key strategy, according to Ms. McGinnis. Potential teams would include the clinical staff, but also social workers and community health workers – people who come from the community primary care is serving who can help build trust with patients and connect the patient to the primary care team.

“There’s a lot that needs to happen that the clinician doesn’t need to do,” she said.

Telehealth can be a big factor in coordinating the team, Ms. McGinnis added.

“It’s thinking less about who’s doing the work, but more about the work that needs to be done to keep people healthy. Then let’s think about the type of workers best suited to perform those tasks,” she said.

As for reimbursing more complex care, population-based, up-front capitated payments linked to high-quality care and better outcomes will need to replace fee-for-service models, according to Ms. McGinnis.

That will provide reliable incomes for primary care offices, but also flexibility in how each patient with different levels of complexity is managed, she said.

Ms. Greiner, Dr. Fincher, Dr. Loeb, and Ms. McGinnis have no relevant financial relationships.

Increased mental health needs, higher acuity from delayed appointments, and added questions and conversations surrounding COVID-19 are forcing primary care offices to rethink priorities in office visits.

Evidence of this came from the latest Primary Care Collaborative (PCC) survey, which found that primary care clinicians are seeing more complex patients requiring longer appointments in the wake of COVID-19.

The PCC with the Larry A. Green Center regularly surveys primary care clinicians. This round of questions came August 14-17 and included 1,263 respondents from 49 states, the District of Columbia, and two territories.

More than 7 in 10 (71%) respondents said their patients are more complex and nearly the same percentage said appointments are taking more time.

Ann Greiner, president and CEO of the PCC, said in an interview that 55% of respondents reported that clinicians are struggling to keep up with pent-up demand after patients have delayed or canceled care. Sixty-five percent in the survey said they had seen a rise in children’s mental health issues, and 58% said they were unsure how to help their patients with long COVID.

In addition, primary care clinicians are having repeated conversations with patients on why they should get a vaccine and which one.

“I think that’s adding to the complexity. There is a lot going on here with patient trust,” Ms. Greiner said.
 

‘We’re going to be playing catch-up’

Jacqueline Fincher, MD, an internist in Thompson, Ga., said in an interview that appointments have gotten longer and more complex in the wake of the pandemic – “no question.”

The immediate past president of the American College of Physicians is seeing patients with chronic disease that has gone untreated for sometimes a year or more, she said.

“Their blood pressure was not under good control, they were under more stress, their sugars were up and weren’t being followed as closely for conditions such as congestive heart failure,” she said.

Dr. Fincher, who works in a rural practice 40 miles from Augusta, Ga., with her physician husband and two other physicians, said patients are ready to come back in, “but I don’t have enough slots for them.”

She said she prioritizes what to help patients with first and schedules the next tier for the next appointment, but added, “honestly, over the next 2 years we’re going to be playing catch-up.”

At the same time, the CDC has estimated that 45% of U.S. adults are at increased risk for complications from COVID-19 because of cardiovascular disease, diabetes, respiratory disease, hypertension, or cancer. Rates ranged from 19.8% for people 18-29 years old to 80.7% for people over 80 years of age.
 

Long COVID could overwhelm existing health care capacity

Primary care physicians are also having to diagnose sometimes “invisible” symptoms after people have recovered from acute COVID-19 infection. Diagnosing takes intent listening to patients who describe symptoms that tests can’t confirm.

As this news organization has previously reported, half of COVID-19 survivors report postacute sequelae of COVID-19 (PASC) lasting longer than 6 months.

“These long-term PASC effects occur on a scale that could overwhelm existing health care capacity, particularly in low- and middle-income countries,” the authors wrote.
 

Anxiety, depression ‘have gone off the charts’

Danielle Loeb, MD, MPH, associate professor of internal medicine at the University of Colorado in Denver, who studies complexity in primary care, said in the wake of COVID-19, more patients have developed “new, serious anxiety.”

Courtesy Dr. Danielle Loeb

“That got extremely exacerbated during the pandemic. Anxiety and depression have gone off the charts,” said Dr. Loeb, who prefers the pronoun “they.”

Dr. Loeb cares for a large number of transgender patients. As offices reopen, some patients are having trouble reintegrating into the workplace and resuming social contacts. The primary care doctor says appointments can get longer because of the need to complete tasks, such as filling out forms for Family Medical Leave Act for those not yet ready to return to work.

COVID-19–related fears are keeping many patients from coming into the office, Dr. Loeb said, either from fear of exposure or because they have mental health issues that keep them from feeling safe leaving the house.

“That really affects my ability to care for them,” they said.

Loss of employment in the pandemic or fear of job loss and subsequent changing of insurance has complicated primary care in terms of treatment and administrative tasks, according to Dr. Loeb.

To help treat patients with acute mental health issues and manage other patients, Dr. Loeb’s practice has brought in a social worker and a therapist.

Team-based care is key in the survival of primary care practices, though providing that is difficult in the smaller clinics because of the critical mass of patients needed to make it viable, they said.

“It’s the only answer. It’s the only way you don’t drown,” Dr. Loeb added. “I’m not drowning, and I credit that to my clinic having the help to support the mental health piece of things.”
 

Rethinking workflow

Tricia McGinnis, MPP, MPH, executive vice president of the nonprofit Center for Health Care Strategies (CHCS) says complexity has forced rethinking workflow.

“A lot of the trends we’re seeing in primary care were there pre-COVID, but COVID has exacerbated those trends,” she said in an interview.

“The good news ... is that it was already becoming clear that primary care needed to provide basic mental health services and integrate with behavioral health. It had also become clear that effective primary care needed to address social issues that keep patients from accessing health care,” she said.

Expanding care teams, as Dr. Loeb mentioned, is a key strategy, according to Ms. McGinnis. Potential teams would include the clinical staff, but also social workers and community health workers – people who come from the community primary care is serving who can help build trust with patients and connect the patient to the primary care team.

“There’s a lot that needs to happen that the clinician doesn’t need to do,” she said.

Telehealth can be a big factor in coordinating the team, Ms. McGinnis added.

“It’s thinking less about who’s doing the work, but more about the work that needs to be done to keep people healthy. Then let’s think about the type of workers best suited to perform those tasks,” she said.

As for reimbursing more complex care, population-based, up-front capitated payments linked to high-quality care and better outcomes will need to replace fee-for-service models, according to Ms. McGinnis.

That will provide reliable incomes for primary care offices, but also flexibility in how each patient with different levels of complexity is managed, she said.

Ms. Greiner, Dr. Fincher, Dr. Loeb, and Ms. McGinnis have no relevant financial relationships.

In a new scientific statement on diet and lifestyle recommendations, the American Heart Association is highlighting, for the first time, structural challenges that impede the adoption of heart-healthy dietary patterns.

American Heart Association

This is in addition to stressing aspects of diet that improve cardiovascular health and reduce cardiovascular risk, with an emphasis on dietary patterns and food-based guidance beyond naming individual foods or nutrients.

The 2021 Dietary Guidance to Improve Cardiovascular Health scientific statement, developed under Alice H. Lichtenstein, DSc, chair of the AHA writing group, provides 10 evidence-based guidance recommendations to promote cardiometabolic health.

“The way to make heart-healthy choices every day,” said Dr. Lichtenstein, of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, in a statement, “is to step back, look at the environment in which you eat, whether it be at home, at work, during social interaction, and then identify what the best choices are. And if there are no good choices, then think about how you can modify your environment so that there are good choices.”

The statement, published in Circulation, underscores growing evidence that nutrition-related chronic diseases have maternal-nutritional origins, and that prevention of pediatric obesity is a key to preserving and prolonging ideal cardiovascular health.

The features are as follows:

• Adjust energy intake and expenditure to achieve and maintain a healthy body weight. To counter the shift toward higher energy intake and more sedentary lifestyles over the past 3 decades, the statement recommends at least 150 minutes of moderate physical activity per week, adjusted for individual’s age, activity level, sex, and size.
• Eat plenty of fruits and vegetables; choose a wide variety. Observational and intervention studies document that dietary patterns rich in varied fruits and vegetables, with the exception of white potatoes, are linked to a lower risk of cardiovascular disease (CVD). Also, whole fruits and vegetables, which more readily provide fiber and satiety, are preferred over juices.
• Choose whole grain foods and products made mostly with whole grains rather than refined grains. Evidence from observational, interventional, and clinical studies confirm the benefits of frequent consumption of whole grains over infrequent consumption or over refined grains in terms of CVD risk, coronary heart disease (CHD), stroke, metabolic syndrome, cardiometabolic risk factors, laxation, and gut microbiota.
• Choose healthy sources of protein, mostly from plants (legumes and nuts).
• Higher intake of legumes, which are rich in protein and fiber, is associated with lower CVD risk, while higher nut intake is associated with lower risks of CVD, CHD, and stroke mortality/incidence. Replacing animal-source foods with plant-source whole foods, beyond health benefits, lowers the diet’s carbon footprint. Meat alternatives are often ultraprocessed and evidence on their short- and long-term health effects is limited. Unsaturated fats are preferred, as are lean, nonprocessed meats.
• Use liquid plant oils rather than tropical oils (coconut, palm, and palm kernel), animal fats (butter and lard), and partially hydrogenated fats. Saturated and trans fats (animal and dairy fats, and partially hydrogenated fat) should be replaced with nontropical liquid plant oils. Evidence supports cardiovascular benefits of dietary unsaturated fats, especially polyunsaturated fats primarily from plant oils (e.g. soybean, corn, safflower and sunflower oils, walnuts, and flax seeds).
• Choose minimally processed foods instead of ultraprocessed foods. Because of their proven association with adverse health outcomes, including overweight and obesity, cardiometabolic disorders (type 2 diabetes, CVD), and all-cause mortality, the consumption of many ultraprocessed foods is of concern. Ultraprocessed foods include artificial colors and flavors and preservatives that promote shelf stability, preserve texture, and increase palatability. A general principle is to emphasize unprocessed or minimally processed foods.
• Minimize intake of beverages and foods with added sugars. Added sugars (commonly glucose, dextrose, sucrose, corn syrup, honey, maple syrup, and concentrated fruit juice) are tied to elevated risk for type 2 diabetes, high cholesterol, and excess body weight. Findings from meta-analyses on body weight and metabolic outcomes for replacing added sugars with low-energy sweeteners are mixed, and the possibility of reverse causality has been raised.
• Choose and prepare foods with little or no salt. In general, the effects of sodium reduction on blood pressure tend to be higher in Black people, middle-aged and older people, and those with hypertension. In the United States, the main combined sources of sodium intake are processed foods, those prepared outside the home, packaged foods, and restaurant foods. Potassium-enriched salts are a promising alternative.
• If you don’t drink alcohol, don’t start; if you choose to drink, limit intake.
• While relationships between alcohol intake and cardiovascular outcomes are complex, the 2020 Dietary Guidelines Advisory Committee recently concluded that those who do drink should consume no more than one drink per day and should not drink alcohol in binges; the 2020 Dietary Guidelines for Americans con­tinues to recommend no more than one drink per day for women and two drinks per day for men.
• Adhere to the guidance regardless in all settings. Food-based dietary guidance applies to all foods and beverages, regardless of where prepared, procured, and consumed. Policies should be enacted that encourage healthier default options (for example, whole grains, minimized sodium and sugar content).

Recognizing impediments

The AHA/ASA scientific statement closes with the declaration: “Creating an environment that facilitates, rather than impedes, adherence to heart-healthy dietary patterns among all individuals is a public health imperative.” It points to the National Institutes of Health’s 2020-2030 Strategic Plan for National Institutes of Health Nutrition Research, which focuses on precision nutrition as a means “to determine the impact on health of not only what individuals eat, but also of why, when, and how they eat throughout the life course.”

Ultimately, precision nutrition may provide personalized diets for CVD prevention. But the “food environment,” often conditioned by “rampant nutrition misinformation” through local, state, and federal practices and policies, may impede the adoption of heart-healthy dietary patterns. Factors such as targeted food marketing (for example, of processed food and beverages in minority neighborhoods), structural racism, neighborhood segregation, unhealthy built environments, and food insecurity create environments in which unhealthy foods are the default option.”

These factors compound adverse dietary and health effects, and underscore a need to “directly combat nutrition misinformation among the public and health care professionals.” They also explain why, despite widespread knowledge of heart-healthy dietary pattern components, little progress has been made in achieving dietary goals in the United States.

Dr. Lichtenstein’s office, in response to a request regarding AHA advocacy and consumer programs, provided the following links: Voices for Healthy Kids initiative site and choosing healthier processed foods and one on fresh, frozen, and canned fruits and vegetables.

Dr. Lichtenstein had no disclosures. Disclosures for the writing group members are included in the statement.

In a new scientific statement on diet and lifestyle recommendations, the American Heart Association is highlighting, for the first time, structural challenges that impede the adoption of heart-healthy dietary patterns.

American Heart Association

This is in addition to stressing aspects of diet that improve cardiovascular health and reduce cardiovascular risk, with an emphasis on dietary patterns and food-based guidance beyond naming individual foods or nutrients.

The 2021 Dietary Guidance to Improve Cardiovascular Health scientific statement, developed under Alice H. Lichtenstein, DSc, chair of the AHA writing group, provides 10 evidence-based guidance recommendations to promote cardiometabolic health.

“The way to make heart-healthy choices every day,” said Dr. Lichtenstein, of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, in a statement, “is to step back, look at the environment in which you eat, whether it be at home, at work, during social interaction, and then identify what the best choices are. And if there are no good choices, then think about how you can modify your environment so that there are good choices.”

The statement, published in Circulation, underscores growing evidence that nutrition-related chronic diseases have maternal-nutritional origins, and that prevention of pediatric obesity is a key to preserving and prolonging ideal cardiovascular health.

The features are as follows:

• Adjust energy intake and expenditure to achieve and maintain a healthy body weight. To counter the shift toward higher energy intake and more sedentary lifestyles over the past 3 decades, the statement recommends at least 150 minutes of moderate physical activity per week, adjusted for individual’s age, activity level, sex, and size.
• Eat plenty of fruits and vegetables; choose a wide variety. Observational and intervention studies document that dietary patterns rich in varied fruits and vegetables, with the exception of white potatoes, are linked to a lower risk of cardiovascular disease (CVD). Also, whole fruits and vegetables, which more readily provide fiber and satiety, are preferred over juices.
• Choose whole grain foods and products made mostly with whole grains rather than refined grains. Evidence from observational, interventional, and clinical studies confirm the benefits of frequent consumption of whole grains over infrequent consumption or over refined grains in terms of CVD risk, coronary heart disease (CHD), stroke, metabolic syndrome, cardiometabolic risk factors, laxation, and gut microbiota.
• Choose healthy sources of protein, mostly from plants (legumes and nuts).
• Higher intake of legumes, which are rich in protein and fiber, is associated with lower CVD risk, while higher nut intake is associated with lower risks of CVD, CHD, and stroke mortality/incidence. Replacing animal-source foods with plant-source whole foods, beyond health benefits, lowers the diet’s carbon footprint. Meat alternatives are often ultraprocessed and evidence on their short- and long-term health effects is limited. Unsaturated fats are preferred, as are lean, nonprocessed meats.
• Use liquid plant oils rather than tropical oils (coconut, palm, and palm kernel), animal fats (butter and lard), and partially hydrogenated fats. Saturated and trans fats (animal and dairy fats, and partially hydrogenated fat) should be replaced with nontropical liquid plant oils. Evidence supports cardiovascular benefits of dietary unsaturated fats, especially polyunsaturated fats primarily from plant oils (e.g. soybean, corn, safflower and sunflower oils, walnuts, and flax seeds).
• Choose minimally processed foods instead of ultraprocessed foods. Because of their proven association with adverse health outcomes, including overweight and obesity, cardiometabolic disorders (type 2 diabetes, CVD), and all-cause mortality, the consumption of many ultraprocessed foods is of concern. Ultraprocessed foods include artificial colors and flavors and preservatives that promote shelf stability, preserve texture, and increase palatability. A general principle is to emphasize unprocessed or minimally processed foods.
• Minimize intake of beverages and foods with added sugars. Added sugars (commonly glucose, dextrose, sucrose, corn syrup, honey, maple syrup, and concentrated fruit juice) are tied to elevated risk for type 2 diabetes, high cholesterol, and excess body weight. Findings from meta-analyses on body weight and metabolic outcomes for replacing added sugars with low-energy sweeteners are mixed, and the possibility of reverse causality has been raised.
• Choose and prepare foods with little or no salt. In general, the effects of sodium reduction on blood pressure tend to be higher in Black people, middle-aged and older people, and those with hypertension. In the United States, the main combined sources of sodium intake are processed foods, those prepared outside the home, packaged foods, and restaurant foods. Potassium-enriched salts are a promising alternative.
• If you don’t drink alcohol, don’t start; if you choose to drink, limit intake.
• While relationships between alcohol intake and cardiovascular outcomes are complex, the 2020 Dietary Guidelines Advisory Committee recently concluded that those who do drink should consume no more than one drink per day and should not drink alcohol in binges; the 2020 Dietary Guidelines for Americans con­tinues to recommend no more than one drink per day for women and two drinks per day for men.
• Adhere to the guidance regardless in all settings. Food-based dietary guidance applies to all foods and beverages, regardless of where prepared, procured, and consumed. Policies should be enacted that encourage healthier default options (for example, whole grains, minimized sodium and sugar content).

Recognizing impediments

The AHA/ASA scientific statement closes with the declaration: “Creating an environment that facilitates, rather than impedes, adherence to heart-healthy dietary patterns among all individuals is a public health imperative.” It points to the National Institutes of Health’s 2020-2030 Strategic Plan for National Institutes of Health Nutrition Research, which focuses on precision nutrition as a means “to determine the impact on health of not only what individuals eat, but also of why, when, and how they eat throughout the life course.”

Ultimately, precision nutrition may provide personalized diets for CVD prevention. But the “food environment,” often conditioned by “rampant nutrition misinformation” through local, state, and federal practices and policies, may impede the adoption of heart-healthy dietary patterns. Factors such as targeted food marketing (for example, of processed food and beverages in minority neighborhoods), structural racism, neighborhood segregation, unhealthy built environments, and food insecurity create environments in which unhealthy foods are the default option.”

These factors compound adverse dietary and health effects, and underscore a need to “directly combat nutrition misinformation among the public and health care professionals.” They also explain why, despite widespread knowledge of heart-healthy dietary pattern components, little progress has been made in achieving dietary goals in the United States.

Dr. Lichtenstein’s office, in response to a request regarding AHA advocacy and consumer programs, provided the following links: Voices for Healthy Kids initiative site and choosing healthier processed foods and one on fresh, frozen, and canned fruits and vegetables.

Dr. Lichtenstein had no disclosures. Disclosures for the writing group members are included in the statement.

In a new scientific statement on diet and lifestyle recommendations, the American Heart Association is highlighting, for the first time, structural challenges that impede the adoption of heart-healthy dietary patterns.

American Heart Association

This is in addition to stressing aspects of diet that improve cardiovascular health and reduce cardiovascular risk, with an emphasis on dietary patterns and food-based guidance beyond naming individual foods or nutrients.

The 2021 Dietary Guidance to Improve Cardiovascular Health scientific statement, developed under Alice H. Lichtenstein, DSc, chair of the AHA writing group, provides 10 evidence-based guidance recommendations to promote cardiometabolic health.

“The way to make heart-healthy choices every day,” said Dr. Lichtenstein, of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, in a statement, “is to step back, look at the environment in which you eat, whether it be at home, at work, during social interaction, and then identify what the best choices are. And if there are no good choices, then think about how you can modify your environment so that there are good choices.”

The statement, published in Circulation, underscores growing evidence that nutrition-related chronic diseases have maternal-nutritional origins, and that prevention of pediatric obesity is a key to preserving and prolonging ideal cardiovascular health.

The features are as follows:

• Adjust energy intake and expenditure to achieve and maintain a healthy body weight. To counter the shift toward higher energy intake and more sedentary lifestyles over the past 3 decades, the statement recommends at least 150 minutes of moderate physical activity per week, adjusted for individual’s age, activity level, sex, and size.
• Eat plenty of fruits and vegetables; choose a wide variety. Observational and intervention studies document that dietary patterns rich in varied fruits and vegetables, with the exception of white potatoes, are linked to a lower risk of cardiovascular disease (CVD). Also, whole fruits and vegetables, which more readily provide fiber and satiety, are preferred over juices.
• Choose whole grain foods and products made mostly with whole grains rather than refined grains. Evidence from observational, interventional, and clinical studies confirm the benefits of frequent consumption of whole grains over infrequent consumption or over refined grains in terms of CVD risk, coronary heart disease (CHD), stroke, metabolic syndrome, cardiometabolic risk factors, laxation, and gut microbiota.
• Choose healthy sources of protein, mostly from plants (legumes and nuts).
• Higher intake of legumes, which are rich in protein and fiber, is associated with lower CVD risk, while higher nut intake is associated with lower risks of CVD, CHD, and stroke mortality/incidence. Replacing animal-source foods with plant-source whole foods, beyond health benefits, lowers the diet’s carbon footprint. Meat alternatives are often ultraprocessed and evidence on their short- and long-term health effects is limited. Unsaturated fats are preferred, as are lean, nonprocessed meats.
• Use liquid plant oils rather than tropical oils (coconut, palm, and palm kernel), animal fats (butter and lard), and partially hydrogenated fats. Saturated and trans fats (animal and dairy fats, and partially hydrogenated fat) should be replaced with nontropical liquid plant oils. Evidence supports cardiovascular benefits of dietary unsaturated fats, especially polyunsaturated fats primarily from plant oils (e.g. soybean, corn, safflower and sunflower oils, walnuts, and flax seeds).
• Choose minimally processed foods instead of ultraprocessed foods. Because of their proven association with adverse health outcomes, including overweight and obesity, cardiometabolic disorders (type 2 diabetes, CVD), and all-cause mortality, the consumption of many ultraprocessed foods is of concern. Ultraprocessed foods include artificial colors and flavors and preservatives that promote shelf stability, preserve texture, and increase palatability. A general principle is to emphasize unprocessed or minimally processed foods.
• Minimize intake of beverages and foods with added sugars. Added sugars (commonly glucose, dextrose, sucrose, corn syrup, honey, maple syrup, and concentrated fruit juice) are tied to elevated risk for type 2 diabetes, high cholesterol, and excess body weight. Findings from meta-analyses on body weight and metabolic outcomes for replacing added sugars with low-energy sweeteners are mixed, and the possibility of reverse causality has been raised.
• Choose and prepare foods with little or no salt. In general, the effects of sodium reduction on blood pressure tend to be higher in Black people, middle-aged and older people, and those with hypertension. In the United States, the main combined sources of sodium intake are processed foods, those prepared outside the home, packaged foods, and restaurant foods. Potassium-enriched salts are a promising alternative.
• If you don’t drink alcohol, don’t start; if you choose to drink, limit intake.
• While relationships between alcohol intake and cardiovascular outcomes are complex, the 2020 Dietary Guidelines Advisory Committee recently concluded that those who do drink should consume no more than one drink per day and should not drink alcohol in binges; the 2020 Dietary Guidelines for Americans con­tinues to recommend no more than one drink per day for women and two drinks per day for men.
• Adhere to the guidance regardless in all settings. Food-based dietary guidance applies to all foods and beverages, regardless of where prepared, procured, and consumed. Policies should be enacted that encourage healthier default options (for example, whole grains, minimized sodium and sugar content).

Recognizing impediments

The AHA/ASA scientific statement closes with the declaration: “Creating an environment that facilitates, rather than impedes, adherence to heart-healthy dietary patterns among all individuals is a public health imperative.” It points to the National Institutes of Health’s 2020-2030 Strategic Plan for National Institutes of Health Nutrition Research, which focuses on precision nutrition as a means “to determine the impact on health of not only what individuals eat, but also of why, when, and how they eat throughout the life course.”

Ultimately, precision nutrition may provide personalized diets for CVD prevention. But the “food environment,” often conditioned by “rampant nutrition misinformation” through local, state, and federal practices and policies, may impede the adoption of heart-healthy dietary patterns. Factors such as targeted food marketing (for example, of processed food and beverages in minority neighborhoods), structural racism, neighborhood segregation, unhealthy built environments, and food insecurity create environments in which unhealthy foods are the default option.”

These factors compound adverse dietary and health effects, and underscore a need to “directly combat nutrition misinformation among the public and health care professionals.” They also explain why, despite widespread knowledge of heart-healthy dietary pattern components, little progress has been made in achieving dietary goals in the United States.

Dr. Lichtenstein’s office, in response to a request regarding AHA advocacy and consumer programs, provided the following links: Voices for Healthy Kids initiative site and choosing healthier processed foods and one on fresh, frozen, and canned fruits and vegetables.

Dr. Lichtenstein had no disclosures. Disclosures for the writing group members are included in the statement.

According to the latest meta-analysis of sham-controlled randomized trials, catheter-based renal sympathetic denervation produces clinically meaningful reductions in blood pressure with acceptable safety, but the strategy is not yet regarded as ready for prime time, according to a summary of the results to be presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

This meta-analysis was based on seven blinded trials, all of which associated denervation with a reduction in systolic ambulatory BP, according to Yousif Ahmad, BMBS, PhD, an interventional cardiologist at Yale University, New Haven, Conn.

Although the BP-lowering advantage in two of these studies did not reach statistical significance, the other five did, and all the data moved in the same direction.

For ambulatory diastolic pressure, the effect was more modest. One of the studies showed essentially a neutral effect. The reductions were statistically significant in only two, but, again, the data moved in the same direction in six of the studies, and a random-effects analysis suggested that the reductions, although modest, were potentially meaningful, according to Dr. Ahmad.

Overall, at a mean follow-up of 4.5 months, the reductions in ambulatory systolic and diastolic BPs were 3.61 and 1.85 mm Hg, respectively. The benefit was about the same whether renal denervation was or was not performed on the background of antihypertensive drugs, which was permitted in five of the seven trials. In the other two, all patients were off hypertensive medication.
 

Office-based systolic reduction: 6 mm Hg

When the same analysis was performed for office-based BP reductions, which were available for five of the seven trials, the overall reductions based on the meta-analysis were 5.86 and 3.63 mm Hg for the systolic and diastolic pressures, respectively. Again, background antihypertensive therapy was not a factor.

Of the seven trials, three randomized fewer than 100 patients. The largest, SYMPLICITY HTN-3, randomized 491 patients in 2:1 ratio to denervation or sham.

Three of the studies in the meta-analysis were trials of the Symplicity flex device. Another two evaluated the Symplicity Spyral catheter. Both deliver radiofrequency energy to for denervation. The Paradise device, the focus of the remaining two trials, employs energy in the form of ultrasound.

According to Dr. Ahmad, adverse events regardless of device were rare and not more common among those in the active treatment arm than in those treated with a sham procedure. Although one of these trials, RADIANCE-HTN SOLO associated denervation with efficacy and safety out to 12 months , Dr. Ahmad concluded that the mean follow-up of 4.5 months is not sufficient to consider long-term effects.

More than 20 meta-analyses published so far

By one count, there have been more than 20 meta-analyses of renal denervation published previously yet this intervention is still considered “controversial,” according to Dr. Ahmad. Relative to the previous meta-analyses, this included the RADIANCE-HTN TRIO trial, which is the latest such sham-controlled study and added 136 patients to the dataset of high-quality trials.

Basically, the results led Dr. Ahmad to conclude that, although the treatment effect is modest, it could be valuable in specific groups of patients, such as those reluctant or unable to take multiple medications or any medications at all. In addition to generating more data on efficacy and safety, he said longer follow-up is also needed for calculations of cost-effectiveness. Larger-scale observational studies might be one way of collecting these data, he reported.

The results of this study were published online in JACC Cardiovascular Interventions with an accompanying editorial by David E. Kandzari, MD, director of interventional cardiology, Piedmont Hart Institute, Atlanta.

Commenting on the large pile of meta-analyses, sometimes published months apart, Dr. Kandzari explained that their “short half-life” is a product of the continuous updating of data with new trials. For a procedure that remains controversial, he said these constant relooks are inevitable.

“My point is that, with more studies, we can expect to see more meta-analyses. It is just the way this is going to work,” Dr. Kandzari said in an interview.
 

Individual study data also relevant

Even as the authors of these analyses attempt to cull the best data from the most rigorously performed trials, “we are also going to have to look at the individual studies, because of the differences in the trial designs, particularly the devices used,” according to Dr. Kandzari, who was the principle investigator of the sham-controlled SPYRAL HTN-ON MED trial.

So far, the data, despite some inconsistencies, have supported “clinically meaningful” BP reductions and acceptable safety regardless of the device used, according to Dr. Kandzari. Although he also agrees with the basic premise that more long-term data are needed to better determine how renal denervation should be applied in management of hypertension, he does think it will eventually find a role that is “complimentary to, rather than a replacement for, drugs.”

“The effect is modest, but keep in mind that the effect size is similar to that of a single oral medication, and there are some features, such as an always-on 24-hour effect that could be useful,” he said.

“We have enough of a signal to start thinking of how this will be enveloped into routine care,” he said.

But it is not ready yet. This was the point made by Dr. Ahmad, and it was seconded by Dr. Kandzari. One of the senior authors of the meta-analysis, Deepak Bhatt, MD, executive director of interventional cardiovascular programs, Brigham and Women’s Health, Boston, was also asked to weigh on when it will be ready for prime time.

“At a minimum, I would recommend completion of ongoing sham-controlled randomized trials before considering clinical use of renal denervation. Longer term safety and durability data, as well as data on cost-effectiveness, are all still needed – preferably from randomized trials as opposed to registries,” he said.

“Ideally, larger sham-controlled trials with longer follow-up and clinical endpoints, as opposed to only blood pressure measurements, would be performed, although I am not aware of any plans at present,” he added.

Dr. Ahmad reported no financial relationships relevant to this research. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, including those developing products relevant to hypertension and renal denervation. Dr. Kandzari reported financial relationships with Ablative Solutions and Medtronic.

According to the latest meta-analysis of sham-controlled randomized trials, catheter-based renal sympathetic denervation produces clinically meaningful reductions in blood pressure with acceptable safety, but the strategy is not yet regarded as ready for prime time, according to a summary of the results to be presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

This meta-analysis was based on seven blinded trials, all of which associated denervation with a reduction in systolic ambulatory BP, according to Yousif Ahmad, BMBS, PhD, an interventional cardiologist at Yale University, New Haven, Conn.

Although the BP-lowering advantage in two of these studies did not reach statistical significance, the other five did, and all the data moved in the same direction.

For ambulatory diastolic pressure, the effect was more modest. One of the studies showed essentially a neutral effect. The reductions were statistically significant in only two, but, again, the data moved in the same direction in six of the studies, and a random-effects analysis suggested that the reductions, although modest, were potentially meaningful, according to Dr. Ahmad.

Overall, at a mean follow-up of 4.5 months, the reductions in ambulatory systolic and diastolic BPs were 3.61 and 1.85 mm Hg, respectively. The benefit was about the same whether renal denervation was or was not performed on the background of antihypertensive drugs, which was permitted in five of the seven trials. In the other two, all patients were off hypertensive medication.
 

Office-based systolic reduction: 6 mm Hg

When the same analysis was performed for office-based BP reductions, which were available for five of the seven trials, the overall reductions based on the meta-analysis were 5.86 and 3.63 mm Hg for the systolic and diastolic pressures, respectively. Again, background antihypertensive therapy was not a factor.

Of the seven trials, three randomized fewer than 100 patients. The largest, SYMPLICITY HTN-3, randomized 491 patients in 2:1 ratio to denervation or sham.

Three of the studies in the meta-analysis were trials of the Symplicity flex device. Another two evaluated the Symplicity Spyral catheter. Both deliver radiofrequency energy to for denervation. The Paradise device, the focus of the remaining two trials, employs energy in the form of ultrasound.

According to Dr. Ahmad, adverse events regardless of device were rare and not more common among those in the active treatment arm than in those treated with a sham procedure. Although one of these trials, RADIANCE-HTN SOLO associated denervation with efficacy and safety out to 12 months , Dr. Ahmad concluded that the mean follow-up of 4.5 months is not sufficient to consider long-term effects.

More than 20 meta-analyses published so far

By one count, there have been more than 20 meta-analyses of renal denervation published previously yet this intervention is still considered “controversial,” according to Dr. Ahmad. Relative to the previous meta-analyses, this included the RADIANCE-HTN TRIO trial, which is the latest such sham-controlled study and added 136 patients to the dataset of high-quality trials.

Basically, the results led Dr. Ahmad to conclude that, although the treatment effect is modest, it could be valuable in specific groups of patients, such as those reluctant or unable to take multiple medications or any medications at all. In addition to generating more data on efficacy and safety, he said longer follow-up is also needed for calculations of cost-effectiveness. Larger-scale observational studies might be one way of collecting these data, he reported.

The results of this study were published online in JACC Cardiovascular Interventions with an accompanying editorial by David E. Kandzari, MD, director of interventional cardiology, Piedmont Hart Institute, Atlanta.

Commenting on the large pile of meta-analyses, sometimes published months apart, Dr. Kandzari explained that their “short half-life” is a product of the continuous updating of data with new trials. For a procedure that remains controversial, he said these constant relooks are inevitable.

“My point is that, with more studies, we can expect to see more meta-analyses. It is just the way this is going to work,” Dr. Kandzari said in an interview.
 

Individual study data also relevant

Even as the authors of these analyses attempt to cull the best data from the most rigorously performed trials, “we are also going to have to look at the individual studies, because of the differences in the trial designs, particularly the devices used,” according to Dr. Kandzari, who was the principle investigator of the sham-controlled SPYRAL HTN-ON MED trial.

So far, the data, despite some inconsistencies, have supported “clinically meaningful” BP reductions and acceptable safety regardless of the device used, according to Dr. Kandzari. Although he also agrees with the basic premise that more long-term data are needed to better determine how renal denervation should be applied in management of hypertension, he does think it will eventually find a role that is “complimentary to, rather than a replacement for, drugs.”

“The effect is modest, but keep in mind that the effect size is similar to that of a single oral medication, and there are some features, such as an always-on 24-hour effect that could be useful,” he said.

“We have enough of a signal to start thinking of how this will be enveloped into routine care,” he said.

But it is not ready yet. This was the point made by Dr. Ahmad, and it was seconded by Dr. Kandzari. One of the senior authors of the meta-analysis, Deepak Bhatt, MD, executive director of interventional cardiovascular programs, Brigham and Women’s Health, Boston, was also asked to weigh on when it will be ready for prime time.

“At a minimum, I would recommend completion of ongoing sham-controlled randomized trials before considering clinical use of renal denervation. Longer term safety and durability data, as well as data on cost-effectiveness, are all still needed – preferably from randomized trials as opposed to registries,” he said.

“Ideally, larger sham-controlled trials with longer follow-up and clinical endpoints, as opposed to only blood pressure measurements, would be performed, although I am not aware of any plans at present,” he added.

Dr. Ahmad reported no financial relationships relevant to this research. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, including those developing products relevant to hypertension and renal denervation. Dr. Kandzari reported financial relationships with Ablative Solutions and Medtronic.

According to the latest meta-analysis of sham-controlled randomized trials, catheter-based renal sympathetic denervation produces clinically meaningful reductions in blood pressure with acceptable safety, but the strategy is not yet regarded as ready for prime time, according to a summary of the results to be presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

This meta-analysis was based on seven blinded trials, all of which associated denervation with a reduction in systolic ambulatory BP, according to Yousif Ahmad, BMBS, PhD, an interventional cardiologist at Yale University, New Haven, Conn.

Although the BP-lowering advantage in two of these studies did not reach statistical significance, the other five did, and all the data moved in the same direction.

For ambulatory diastolic pressure, the effect was more modest. One of the studies showed essentially a neutral effect. The reductions were statistically significant in only two, but, again, the data moved in the same direction in six of the studies, and a random-effects analysis suggested that the reductions, although modest, were potentially meaningful, according to Dr. Ahmad.

Overall, at a mean follow-up of 4.5 months, the reductions in ambulatory systolic and diastolic BPs were 3.61 and 1.85 mm Hg, respectively. The benefit was about the same whether renal denervation was or was not performed on the background of antihypertensive drugs, which was permitted in five of the seven trials. In the other two, all patients were off hypertensive medication.
 

Office-based systolic reduction: 6 mm Hg

When the same analysis was performed for office-based BP reductions, which were available for five of the seven trials, the overall reductions based on the meta-analysis were 5.86 and 3.63 mm Hg for the systolic and diastolic pressures, respectively. Again, background antihypertensive therapy was not a factor.

Of the seven trials, three randomized fewer than 100 patients. The largest, SYMPLICITY HTN-3, randomized 491 patients in 2:1 ratio to denervation or sham.

Three of the studies in the meta-analysis were trials of the Symplicity flex device. Another two evaluated the Symplicity Spyral catheter. Both deliver radiofrequency energy to for denervation. The Paradise device, the focus of the remaining two trials, employs energy in the form of ultrasound.

According to Dr. Ahmad, adverse events regardless of device were rare and not more common among those in the active treatment arm than in those treated with a sham procedure. Although one of these trials, RADIANCE-HTN SOLO associated denervation with efficacy and safety out to 12 months , Dr. Ahmad concluded that the mean follow-up of 4.5 months is not sufficient to consider long-term effects.

More than 20 meta-analyses published so far

By one count, there have been more than 20 meta-analyses of renal denervation published previously yet this intervention is still considered “controversial,” according to Dr. Ahmad. Relative to the previous meta-analyses, this included the RADIANCE-HTN TRIO trial, which is the latest such sham-controlled study and added 136 patients to the dataset of high-quality trials.

Basically, the results led Dr. Ahmad to conclude that, although the treatment effect is modest, it could be valuable in specific groups of patients, such as those reluctant or unable to take multiple medications or any medications at all. In addition to generating more data on efficacy and safety, he said longer follow-up is also needed for calculations of cost-effectiveness. Larger-scale observational studies might be one way of collecting these data, he reported.

The results of this study were published online in JACC Cardiovascular Interventions with an accompanying editorial by David E. Kandzari, MD, director of interventional cardiology, Piedmont Hart Institute, Atlanta.

Commenting on the large pile of meta-analyses, sometimes published months apart, Dr. Kandzari explained that their “short half-life” is a product of the continuous updating of data with new trials. For a procedure that remains controversial, he said these constant relooks are inevitable.

“My point is that, with more studies, we can expect to see more meta-analyses. It is just the way this is going to work,” Dr. Kandzari said in an interview.
 

Individual study data also relevant

Even as the authors of these analyses attempt to cull the best data from the most rigorously performed trials, “we are also going to have to look at the individual studies, because of the differences in the trial designs, particularly the devices used,” according to Dr. Kandzari, who was the principle investigator of the sham-controlled SPYRAL HTN-ON MED trial.

So far, the data, despite some inconsistencies, have supported “clinically meaningful” BP reductions and acceptable safety regardless of the device used, according to Dr. Kandzari. Although he also agrees with the basic premise that more long-term data are needed to better determine how renal denervation should be applied in management of hypertension, he does think it will eventually find a role that is “complimentary to, rather than a replacement for, drugs.”

“The effect is modest, but keep in mind that the effect size is similar to that of a single oral medication, and there are some features, such as an always-on 24-hour effect that could be useful,” he said.

“We have enough of a signal to start thinking of how this will be enveloped into routine care,” he said.

But it is not ready yet. This was the point made by Dr. Ahmad, and it was seconded by Dr. Kandzari. One of the senior authors of the meta-analysis, Deepak Bhatt, MD, executive director of interventional cardiovascular programs, Brigham and Women’s Health, Boston, was also asked to weigh on when it will be ready for prime time.

“At a minimum, I would recommend completion of ongoing sham-controlled randomized trials before considering clinical use of renal denervation. Longer term safety and durability data, as well as data on cost-effectiveness, are all still needed – preferably from randomized trials as opposed to registries,” he said.

“Ideally, larger sham-controlled trials with longer follow-up and clinical endpoints, as opposed to only blood pressure measurements, would be performed, although I am not aware of any plans at present,” he added.

Dr. Ahmad reported no financial relationships relevant to this research. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, including those developing products relevant to hypertension and renal denervation. Dr. Kandzari reported financial relationships with Ablative Solutions and Medtronic.