Cardiology

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

THE CASE

An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.

The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.

The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.

Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.

The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).

THE DIAGNOSIS

The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.

Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.¹ Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.¹ (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.¹) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.¹ Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.

Continue to: Within 5 days...

Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.

DISCUSSION

There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.²

What the evidence shows. The ­TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.³ Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.³ Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).⁴ The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.⁵ Torsemide has also been shown to improve quality of life compared to furosemide.⁶

Given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to his diuretic regimen.

Preliminary results from the TORNADO trial,⁷ a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.⁸ The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).⁸ A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.⁸

A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.⁹

Continue to: Our patient

Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.

On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.

The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.

THE TAKEAWAY

A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.

A growing body of literature^9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.

CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; ryan_paulus@med.unc.edu

THE CASE

An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.

The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.

The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.

Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.

The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).

THE DIAGNOSIS

The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.

Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.¹ Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.¹ (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.¹) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.¹ Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.

Continue to: Within 5 days...

Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.

DISCUSSION

There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.²

What the evidence shows. The ­TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.³ Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.³ Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).⁴ The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.⁵ Torsemide has also been shown to improve quality of life compared to furosemide.⁶

Given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to his diuretic regimen.

Preliminary results from the TORNADO trial,⁷ a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.⁸ The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).⁸ A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.⁸

A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.⁹

Continue to: Our patient

Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.

On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.

The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.

THE TAKEAWAY

A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.

A growing body of literature^9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.

CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; ryan_paulus@med.unc.edu

THE CASE

An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.

The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.

The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.

Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.

The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).

THE DIAGNOSIS

The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.

Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.¹ Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.¹ (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.¹) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.¹ Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.

Continue to: Within 5 days...

Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.

DISCUSSION

There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.²

What the evidence shows. The ­TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.³ Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.³ Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).⁴ The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.⁵ Torsemide has also been shown to improve quality of life compared to furosemide.⁶

Given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to his diuretic regimen.

Preliminary results from the TORNADO trial,⁷ a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.⁸ The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).⁸ A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.⁸

A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.⁹

Continue to: Our patient

Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.

On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.

The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.

THE TAKEAWAY

A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.

A growing body of literature^9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.

CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; ryan_paulus@med.unc.edu

ILLUSTRATIVE CASE

A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.

Should this patient continue taking a daily aspirin for primary prevention of CVD?

Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).² This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.³ (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.

STUDY SUMMARY

No reduction in risk, increased chance of bleeding

Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.¹ The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and ­nonfatal ischemic stroke.

Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence ­interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice.

Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I² = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.

WHAT’S NEW?

Study is emblematic of a shift away from daily aspirin

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.

Continue to: The USPSTF guidelines...

The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.²

The 2019 American College of ­Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of ­bleeding should not be started on a daily aspirin.⁴

CAVEATS

Jury is still out regarding very high-risk patients

While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to give up an accepted practice

Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.

Should this patient continue taking a daily aspirin for primary prevention of CVD?

Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).² This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.³ (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.

STUDY SUMMARY

No reduction in risk, increased chance of bleeding

Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.¹ The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and ­nonfatal ischemic stroke.

Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence ­interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice.

Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I² = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.

WHAT’S NEW?

Study is emblematic of a shift away from daily aspirin

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.

Continue to: The USPSTF guidelines...

The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.²

The 2019 American College of ­Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of ­bleeding should not be started on a daily aspirin.⁴

CAVEATS

Jury is still out regarding very high-risk patients

While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to give up an accepted practice

Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.

Should this patient continue taking a daily aspirin for primary prevention of CVD?

Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).² This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.³ (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.

STUDY SUMMARY

No reduction in risk, increased chance of bleeding

Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.¹ The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and ­nonfatal ischemic stroke.

Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence ­interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice.

Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I² = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.

WHAT’S NEW?

Study is emblematic of a shift away from daily aspirin

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.

Continue to: The USPSTF guidelines...

The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.²

The 2019 American College of ­Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of ­bleeding should not be started on a daily aspirin.⁴

CAVEATS

Jury is still out regarding very high-risk patients

While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to give up an accepted practice

Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Febuxostat (Uloric) emerged as noninferior to allopurinol regarding risk of cardiovascular death among people 60 years and older with gout and at least one additional cardiovascular risk factor, results of the Febuxostat versus Allopurinol Streamlined Trial (FAST) suggest.

This primary outcome of the FAST trial stands in contrast to results of the CARES trial in 2018. The CARES researchers previously reported a 4.3% increased risk of cardiovascular death associated with febuxostat, compared with a 3.2% rate with allopurinol, a statistically significant 34% increase in the relative risk.

“In contrast to previous studies, there was no evidence of increased mortality with febuxostat, and we believe the regulators should review febuxostat licensing restrictions,” senior author Thomas MacDonald, MD, of the University of Dundee (Scotland), said during a late-breaking abstract session at the virtual annual meeting of the American College of Rheumatology.

The results of the FAST trial were simultaneously published online in The Lancet.

Both febuxostat and allopurinol treat gout by lowering urate levels. Concerns about the cardiovascular safety of febuxostat led to two post-licensing studies: the Cardiovascular Safety of Febuxostat and Allopurinol in Participants with Gout and Cardiovascular Comorbidities (CARES) study, mandated by the U.S. Food and Drug Administration, and FAST, requested by the European Medicines Agency. In February 2019, the FDA added a warning about elevated cardiovascular death and death risk associated with febuxostat.

“When CARES was published, it was somewhat of a threat to our study,” Dr. MacDonald said. “After hearing from our data-monitoring committee, we were told we could continue the trial.”
 

Some switched from allopurinol to febuxostat

So Dr. MacDonald, lead author Isla Mackenzie, MBChB, and their colleagues enrolled 6,128 people with gout in the United Kingdom, Sweden, and Denmark between December 2011 and January 2018. They followed patients for a median of 4 years. Participants had a mean age of 71 years, 85% were men, and 33% had a history of cardiovascular disease. The investigators excluded anyone with a stroke or myocardial infarction in the previous 6 months.

All participants were being treated with allopurinol. The investigators titrated those not at target up to an ideal dose that achieved a serum urate concentration of less than 0.357 mmol/L (< 6 mg/dL). Next, they randomly assigned 3,065 people to continue allopurinol and another 3,063 to switch to 80-120 mg of febuxostat.

The primary outcome of the multicenter, prospective, randomized, open-label FAST trial was a composite of hospitalization for nonfatal MI or biomarker positive for acute coronary syndrome, nonfatal stroke, or cardiovascular death.
 

Key findings

“There was definitely a noninferior primary outcome,” Dr. MacDonald said. In the on-treatment analysis, 172 patients in the febuxostat group reached the composite endpoint versus 241 patients in the allopurinol group. There were 1.72 events per 100 patient-years in the febuxostat group versus 2.05 events in the allopurinol group (adjusted hazard ratio, 0.85; 95% confidence interval, 0.70-1.03). An intent-to-treat analysis also found that febuxostat was noninferior to allopurinol on this measure.

Urate levels were approximately 80 micromoles lower in the febuxostat group versus the allopurinol group each year of the study, Dr. MacDonald said.

At least one gout flare was experienced by 1,017 patients in the febuxostat group and by 1,044 participants in the allopurinol group. “However, there was no placebo group, so we don’t know the effectiveness of either of these agents at preventing flares” based on this research, he said.

Both the on-treatment and intention-to-treat (ITT) secondary analyses demonstrated the noninferiority of febuxostat, compared with allopurinol, for all-cause death, each individual component of the composite primary outcome – cardiovascular death, hospitalization for heart failure, and hospitalization for new, unstable, or worsening angina.

In contrast, the ITT analysis revealed a “nominally significant increase” in hospitalization for arrhythmia with no evidence of ischemia in the febuxostat group. The 0.583 events per 100 patient-years in this group versus 0.385 events in the allopurinol cohort generated an adjusted HR of 1.51 (95% CI, 1.05-2.17).

In terms of all-cause mortality, 222 participants (7.2%) in the febuxostat group died, compared with 263 people (8.6%) in the allopurinol group.

Adverse events and withdrawals

A total 1,720 participants (57.3%) in the febuxostat group experienced at least one serious adverse event, as did 1,812 participants (59.4%) in the allopurinol group. Less than 1% of serious adverse events in each group were considered treatment-related.

Dr. MacDonald said that 6.2% of the febuxostat patients and 5.5% of the allopurinol group withdrew from the study. “We had pretty good follow-up [94%],” Dr. MacDonald said. “I don’t want to criticize CARES, but 47% did drop out of that study, and they could not follow them anymore.”

Limitations of FAST include its open-label design and lack of a placebo group, although Dr. MacDonald pointed out that a placebo group would have been unethical. Strengths included its large randomized trial design and good external validity, he added. “This is what will happen in clinical practice if you switch people from allopurinol to febuxostat.”

When asked how he would treat people with gout now given the FAST findings, Dr. MacDonald said, “I’m not a rheumatologist, I’m a cardiovascular physician. But I would say from the evidence from the FAST trial, it appears to be safe to give patients febuxostat whether or not they have cardiovascular risk factors or prior cardiovascular disease.”

“The FAST study indicates that febuxostat is similar to allopurinol in terms of cardiovascular events during the treatment period. The strengths of this study are its large sample size, excellent follow-up rate, and the relatively long follow-up time,” session moderator Shervin Assassi, MD, said when asked for comment. Dr. Assassi, director of the division of rheumatology at the University of Texas Health Science Center at Houston, was not involved in the research.

Menarini, Ipsen, and Teijin Pharma funded the study. The University of Dundee receives research funds from Menarini. Dr. MacDonald disclosed that he received speaker or consultant fees from Menarini. Dr. Assassi had no relevant disclosures.

SOURCE: MacDonald T et al. Arthritis Rheumatol. 2020;72(suppl 10). ACR 2020, Abstract L08.

Febuxostat (Uloric) emerged as noninferior to allopurinol regarding risk of cardiovascular death among people 60 years and older with gout and at least one additional cardiovascular risk factor, results of the Febuxostat versus Allopurinol Streamlined Trial (FAST) suggest.

This primary outcome of the FAST trial stands in contrast to results of the CARES trial in 2018. The CARES researchers previously reported a 4.3% increased risk of cardiovascular death associated with febuxostat, compared with a 3.2% rate with allopurinol, a statistically significant 34% increase in the relative risk.

“In contrast to previous studies, there was no evidence of increased mortality with febuxostat, and we believe the regulators should review febuxostat licensing restrictions,” senior author Thomas MacDonald, MD, of the University of Dundee (Scotland), said during a late-breaking abstract session at the virtual annual meeting of the American College of Rheumatology.

The results of the FAST trial were simultaneously published online in The Lancet.

Both febuxostat and allopurinol treat gout by lowering urate levels. Concerns about the cardiovascular safety of febuxostat led to two post-licensing studies: the Cardiovascular Safety of Febuxostat and Allopurinol in Participants with Gout and Cardiovascular Comorbidities (CARES) study, mandated by the U.S. Food and Drug Administration, and FAST, requested by the European Medicines Agency. In February 2019, the FDA added a warning about elevated cardiovascular death and death risk associated with febuxostat.

“When CARES was published, it was somewhat of a threat to our study,” Dr. MacDonald said. “After hearing from our data-monitoring committee, we were told we could continue the trial.”
 

Some switched from allopurinol to febuxostat

So Dr. MacDonald, lead author Isla Mackenzie, MBChB, and their colleagues enrolled 6,128 people with gout in the United Kingdom, Sweden, and Denmark between December 2011 and January 2018. They followed patients for a median of 4 years. Participants had a mean age of 71 years, 85% were men, and 33% had a history of cardiovascular disease. The investigators excluded anyone with a stroke or myocardial infarction in the previous 6 months.

All participants were being treated with allopurinol. The investigators titrated those not at target up to an ideal dose that achieved a serum urate concentration of less than 0.357 mmol/L (< 6 mg/dL). Next, they randomly assigned 3,065 people to continue allopurinol and another 3,063 to switch to 80-120 mg of febuxostat.

The primary outcome of the multicenter, prospective, randomized, open-label FAST trial was a composite of hospitalization for nonfatal MI or biomarker positive for acute coronary syndrome, nonfatal stroke, or cardiovascular death.
 

Key findings

“There was definitely a noninferior primary outcome,” Dr. MacDonald said. In the on-treatment analysis, 172 patients in the febuxostat group reached the composite endpoint versus 241 patients in the allopurinol group. There were 1.72 events per 100 patient-years in the febuxostat group versus 2.05 events in the allopurinol group (adjusted hazard ratio, 0.85; 95% confidence interval, 0.70-1.03). An intent-to-treat analysis also found that febuxostat was noninferior to allopurinol on this measure.

Urate levels were approximately 80 micromoles lower in the febuxostat group versus the allopurinol group each year of the study, Dr. MacDonald said.

At least one gout flare was experienced by 1,017 patients in the febuxostat group and by 1,044 participants in the allopurinol group. “However, there was no placebo group, so we don’t know the effectiveness of either of these agents at preventing flares” based on this research, he said.

Both the on-treatment and intention-to-treat (ITT) secondary analyses demonstrated the noninferiority of febuxostat, compared with allopurinol, for all-cause death, each individual component of the composite primary outcome – cardiovascular death, hospitalization for heart failure, and hospitalization for new, unstable, or worsening angina.

In contrast, the ITT analysis revealed a “nominally significant increase” in hospitalization for arrhythmia with no evidence of ischemia in the febuxostat group. The 0.583 events per 100 patient-years in this group versus 0.385 events in the allopurinol cohort generated an adjusted HR of 1.51 (95% CI, 1.05-2.17).

In terms of all-cause mortality, 222 participants (7.2%) in the febuxostat group died, compared with 263 people (8.6%) in the allopurinol group.

Adverse events and withdrawals

A total 1,720 participants (57.3%) in the febuxostat group experienced at least one serious adverse event, as did 1,812 participants (59.4%) in the allopurinol group. Less than 1% of serious adverse events in each group were considered treatment-related.

Dr. MacDonald said that 6.2% of the febuxostat patients and 5.5% of the allopurinol group withdrew from the study. “We had pretty good follow-up [94%],” Dr. MacDonald said. “I don’t want to criticize CARES, but 47% did drop out of that study, and they could not follow them anymore.”

Limitations of FAST include its open-label design and lack of a placebo group, although Dr. MacDonald pointed out that a placebo group would have been unethical. Strengths included its large randomized trial design and good external validity, he added. “This is what will happen in clinical practice if you switch people from allopurinol to febuxostat.”

When asked how he would treat people with gout now given the FAST findings, Dr. MacDonald said, “I’m not a rheumatologist, I’m a cardiovascular physician. But I would say from the evidence from the FAST trial, it appears to be safe to give patients febuxostat whether or not they have cardiovascular risk factors or prior cardiovascular disease.”

“The FAST study indicates that febuxostat is similar to allopurinol in terms of cardiovascular events during the treatment period. The strengths of this study are its large sample size, excellent follow-up rate, and the relatively long follow-up time,” session moderator Shervin Assassi, MD, said when asked for comment. Dr. Assassi, director of the division of rheumatology at the University of Texas Health Science Center at Houston, was not involved in the research.

Menarini, Ipsen, and Teijin Pharma funded the study. The University of Dundee receives research funds from Menarini. Dr. MacDonald disclosed that he received speaker or consultant fees from Menarini. Dr. Assassi had no relevant disclosures.

SOURCE: MacDonald T et al. Arthritis Rheumatol. 2020;72(suppl 10). ACR 2020, Abstract L08.

Febuxostat (Uloric) emerged as noninferior to allopurinol regarding risk of cardiovascular death among people 60 years and older with gout and at least one additional cardiovascular risk factor, results of the Febuxostat versus Allopurinol Streamlined Trial (FAST) suggest.

This primary outcome of the FAST trial stands in contrast to results of the CARES trial in 2018. The CARES researchers previously reported a 4.3% increased risk of cardiovascular death associated with febuxostat, compared with a 3.2% rate with allopurinol, a statistically significant 34% increase in the relative risk.

“In contrast to previous studies, there was no evidence of increased mortality with febuxostat, and we believe the regulators should review febuxostat licensing restrictions,” senior author Thomas MacDonald, MD, of the University of Dundee (Scotland), said during a late-breaking abstract session at the virtual annual meeting of the American College of Rheumatology.

The results of the FAST trial were simultaneously published online in The Lancet.

Both febuxostat and allopurinol treat gout by lowering urate levels. Concerns about the cardiovascular safety of febuxostat led to two post-licensing studies: the Cardiovascular Safety of Febuxostat and Allopurinol in Participants with Gout and Cardiovascular Comorbidities (CARES) study, mandated by the U.S. Food and Drug Administration, and FAST, requested by the European Medicines Agency. In February 2019, the FDA added a warning about elevated cardiovascular death and death risk associated with febuxostat.

“When CARES was published, it was somewhat of a threat to our study,” Dr. MacDonald said. “After hearing from our data-monitoring committee, we were told we could continue the trial.”
 

Some switched from allopurinol to febuxostat

So Dr. MacDonald, lead author Isla Mackenzie, MBChB, and their colleagues enrolled 6,128 people with gout in the United Kingdom, Sweden, and Denmark between December 2011 and January 2018. They followed patients for a median of 4 years. Participants had a mean age of 71 years, 85% were men, and 33% had a history of cardiovascular disease. The investigators excluded anyone with a stroke or myocardial infarction in the previous 6 months.

All participants were being treated with allopurinol. The investigators titrated those not at target up to an ideal dose that achieved a serum urate concentration of less than 0.357 mmol/L (< 6 mg/dL). Next, they randomly assigned 3,065 people to continue allopurinol and another 3,063 to switch to 80-120 mg of febuxostat.

The primary outcome of the multicenter, prospective, randomized, open-label FAST trial was a composite of hospitalization for nonfatal MI or biomarker positive for acute coronary syndrome, nonfatal stroke, or cardiovascular death.
 

Key findings

“There was definitely a noninferior primary outcome,” Dr. MacDonald said. In the on-treatment analysis, 172 patients in the febuxostat group reached the composite endpoint versus 241 patients in the allopurinol group. There were 1.72 events per 100 patient-years in the febuxostat group versus 2.05 events in the allopurinol group (adjusted hazard ratio, 0.85; 95% confidence interval, 0.70-1.03). An intent-to-treat analysis also found that febuxostat was noninferior to allopurinol on this measure.

Urate levels were approximately 80 micromoles lower in the febuxostat group versus the allopurinol group each year of the study, Dr. MacDonald said.

At least one gout flare was experienced by 1,017 patients in the febuxostat group and by 1,044 participants in the allopurinol group. “However, there was no placebo group, so we don’t know the effectiveness of either of these agents at preventing flares” based on this research, he said.

Both the on-treatment and intention-to-treat (ITT) secondary analyses demonstrated the noninferiority of febuxostat, compared with allopurinol, for all-cause death, each individual component of the composite primary outcome – cardiovascular death, hospitalization for heart failure, and hospitalization for new, unstable, or worsening angina.

In contrast, the ITT analysis revealed a “nominally significant increase” in hospitalization for arrhythmia with no evidence of ischemia in the febuxostat group. The 0.583 events per 100 patient-years in this group versus 0.385 events in the allopurinol cohort generated an adjusted HR of 1.51 (95% CI, 1.05-2.17).

In terms of all-cause mortality, 222 participants (7.2%) in the febuxostat group died, compared with 263 people (8.6%) in the allopurinol group.

Adverse events and withdrawals

A total 1,720 participants (57.3%) in the febuxostat group experienced at least one serious adverse event, as did 1,812 participants (59.4%) in the allopurinol group. Less than 1% of serious adverse events in each group were considered treatment-related.

Dr. MacDonald said that 6.2% of the febuxostat patients and 5.5% of the allopurinol group withdrew from the study. “We had pretty good follow-up [94%],” Dr. MacDonald said. “I don’t want to criticize CARES, but 47% did drop out of that study, and they could not follow them anymore.”

Limitations of FAST include its open-label design and lack of a placebo group, although Dr. MacDonald pointed out that a placebo group would have been unethical. Strengths included its large randomized trial design and good external validity, he added. “This is what will happen in clinical practice if you switch people from allopurinol to febuxostat.”

When asked how he would treat people with gout now given the FAST findings, Dr. MacDonald said, “I’m not a rheumatologist, I’m a cardiovascular physician. But I would say from the evidence from the FAST trial, it appears to be safe to give patients febuxostat whether or not they have cardiovascular risk factors or prior cardiovascular disease.”

“The FAST study indicates that febuxostat is similar to allopurinol in terms of cardiovascular events during the treatment period. The strengths of this study are its large sample size, excellent follow-up rate, and the relatively long follow-up time,” session moderator Shervin Assassi, MD, said when asked for comment. Dr. Assassi, director of the division of rheumatology at the University of Texas Health Science Center at Houston, was not involved in the research.

Menarini, Ipsen, and Teijin Pharma funded the study. The University of Dundee receives research funds from Menarini. Dr. MacDonald disclosed that he received speaker or consultant fees from Menarini. Dr. Assassi had no relevant disclosures.

SOURCE: MacDonald T et al. Arthritis Rheumatol. 2020;72(suppl 10). ACR 2020, Abstract L08.

Dietary patterns with higher inflammatory potential were significantly associated with a higher incidence of cardiovascular disease (CVD) and stroke in a new pooled analysis of three prospective cohort studies.

The analysis included 210,145 U.S. women and men followed for up to 32 years in the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study.

After adjustment for use of anti-inflammatory medications and CVD risk factors, those whose dietary pattern ranked in the highest quintile of inflammatory potential had a 38% higher risk of CVD (hazard ratio comparing highest with lowest quintiles, 1.38), a 46% higher risk of coronary heart disease (HR, 1.46), and a 28% higher risk of stroke (HR, 1.28) (all P for trend < .001).

Jun Li, MD, PhD, and colleagues at Harvard School of Public Health and Harvard Medical School, Boston, published the findings of their study in the Nov. 10 issue of the Journal of the American College of Cardiology.

The inflammatory potential of a diet was assessed using a food-based, dietary index called the “empirical dietary inflammatory pattern” or EDIP.

In an interview, Dr. Li explained that the EDIP was developed 4 years ago by many of the same authors involved with this study, including nutrition heavyweights Walter C. Willett, MD, DrPH, and Frank B. Hu, MD, PhD, both from Harvard.

“We summarized all the foods people eat into 39 defined food groups and did a reduced-rank regression analysis that looked at these 39 food groups and three inflammatory markers – interleukin-6, C-reactive protein, and tumor necrosis factor–alpha receptor 2. We found 18 food groups that are most predictive of these biomarkers, and the EDIP was calculated as the weighted sum of these 18 food groups.”

Individuals who had higher intakes of green-leafy vegetables (kale, spinach, arugula), dark-yellow vegetables (pumpkin, yellow peppers, carrots), whole grains, fruits, tea, coffee and wine had lower long-term CVD risk than those with higher intakes of red meat, processed meat, organ meat, refined carbohydrates, and sweetened beverages. 

The associations were consistent across cohorts and between sexes and remained significant in multiple sensitivity analysis that adjusted for alcohol consumption, smoking pack-years, use of lipid-lowering and antihypertensive medications, sodium intake, and blood pressure.

In a secondary analysis, diets with higher inflammatory potential were also associated with significantly higher biomarker levels indicative of more systemic, vascular, and metabolic inflammation, as well as less favorable lipid profiles.

“We wanted to be able to provide guidance on dietary patterns and food combinations,” said Dr. Li. “If you tell people to eat more polyunsaturated fats instead of saturated fat or trans fat, most people don’t know what foods are higher and lower in those nutrients. Also, many foods have different nutrients – some of which are good and some of which are bad – so we wanted to help people find the foods with the higher proportion of healthy nutrients rather than point out specific nutrients to avoid.”

Researchers used prospectively gathered data from the Nurses’ Health Studies I and II starting from 1984 and from the Health Professionals Follow-up Study. After excluding participants with missing diet information or previously diagnosed heart disease, stroke or cancer, over 210,000 participants were included in the analysis. Participants completed a survey every 4 years to ascertain dietary intake. 
 

Prevention, not treatment

In an editorial comment, Ramon Estruch, MD, PhD, from the Hospital Clinic in Barcelona, and colleagues suggested that it might be time for better dietary guidelines.

“A better knowledge of health protection provided by different foods and dietary patterns, mainly their anti-inflammatory properties, should provide the basis for designing even healthier dietary patterns to protect against heart disease,” the editorialists wrote.

They added extra-virgin olive oil, fatty fish, and tomatoes to the list of foods with “established anti-inflammatory activity.”

In a comment, Dr. Estruch said the findings of this new study are confirmatory of the PREDIMED trial, which showed a reduction in risk of major CV events in individuals at high cardiovascular risk assigned to an anti-inflammatory Mediterranean diet pattern supplemented with extra-virgin olive oil or nuts as compared with those assigned to a reduced-fat diet. 

“The study of Jun Li et al. confirms that an anti-inflammatory diet is useful to prevent cardiovascular events and, more important, that healthy dietary patterns may be even healthier if subjects increase consumption of foods with the highest anti-inflammatory potential,” he said, adding that “mechanistic explanations add plausibility to the results of observational studies.”

Dr. Estruch was the principal investigator of PREDIMED. This trial was originally published in 2013 and then retracted and republished in 2018, with some required corrections, but the results had not materially changed.

Dr. Li is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Boston Nutrition Obesity Research Center. Dr. Estruch disclosed no financial relationships relevant to the contents of this article.  

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

Dietary patterns with higher inflammatory potential were significantly associated with a higher incidence of cardiovascular disease (CVD) and stroke in a new pooled analysis of three prospective cohort studies.

The analysis included 210,145 U.S. women and men followed for up to 32 years in the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study.

After adjustment for use of anti-inflammatory medications and CVD risk factors, those whose dietary pattern ranked in the highest quintile of inflammatory potential had a 38% higher risk of CVD (hazard ratio comparing highest with lowest quintiles, 1.38), a 46% higher risk of coronary heart disease (HR, 1.46), and a 28% higher risk of stroke (HR, 1.28) (all P for trend < .001).

Jun Li, MD, PhD, and colleagues at Harvard School of Public Health and Harvard Medical School, Boston, published the findings of their study in the Nov. 10 issue of the Journal of the American College of Cardiology.

The inflammatory potential of a diet was assessed using a food-based, dietary index called the “empirical dietary inflammatory pattern” or EDIP.

In an interview, Dr. Li explained that the EDIP was developed 4 years ago by many of the same authors involved with this study, including nutrition heavyweights Walter C. Willett, MD, DrPH, and Frank B. Hu, MD, PhD, both from Harvard.

“We summarized all the foods people eat into 39 defined food groups and did a reduced-rank regression analysis that looked at these 39 food groups and three inflammatory markers – interleukin-6, C-reactive protein, and tumor necrosis factor–alpha receptor 2. We found 18 food groups that are most predictive of these biomarkers, and the EDIP was calculated as the weighted sum of these 18 food groups.”

Individuals who had higher intakes of green-leafy vegetables (kale, spinach, arugula), dark-yellow vegetables (pumpkin, yellow peppers, carrots), whole grains, fruits, tea, coffee and wine had lower long-term CVD risk than those with higher intakes of red meat, processed meat, organ meat, refined carbohydrates, and sweetened beverages. 

The associations were consistent across cohorts and between sexes and remained significant in multiple sensitivity analysis that adjusted for alcohol consumption, smoking pack-years, use of lipid-lowering and antihypertensive medications, sodium intake, and blood pressure.

In a secondary analysis, diets with higher inflammatory potential were also associated with significantly higher biomarker levels indicative of more systemic, vascular, and metabolic inflammation, as well as less favorable lipid profiles.

“We wanted to be able to provide guidance on dietary patterns and food combinations,” said Dr. Li. “If you tell people to eat more polyunsaturated fats instead of saturated fat or trans fat, most people don’t know what foods are higher and lower in those nutrients. Also, many foods have different nutrients – some of which are good and some of which are bad – so we wanted to help people find the foods with the higher proportion of healthy nutrients rather than point out specific nutrients to avoid.”

Researchers used prospectively gathered data from the Nurses’ Health Studies I and II starting from 1984 and from the Health Professionals Follow-up Study. After excluding participants with missing diet information or previously diagnosed heart disease, stroke or cancer, over 210,000 participants were included in the analysis. Participants completed a survey every 4 years to ascertain dietary intake. 
 

Prevention, not treatment

In an editorial comment, Ramon Estruch, MD, PhD, from the Hospital Clinic in Barcelona, and colleagues suggested that it might be time for better dietary guidelines.

“A better knowledge of health protection provided by different foods and dietary patterns, mainly their anti-inflammatory properties, should provide the basis for designing even healthier dietary patterns to protect against heart disease,” the editorialists wrote.

They added extra-virgin olive oil, fatty fish, and tomatoes to the list of foods with “established anti-inflammatory activity.”

In a comment, Dr. Estruch said the findings of this new study are confirmatory of the PREDIMED trial, which showed a reduction in risk of major CV events in individuals at high cardiovascular risk assigned to an anti-inflammatory Mediterranean diet pattern supplemented with extra-virgin olive oil or nuts as compared with those assigned to a reduced-fat diet. 

“The study of Jun Li et al. confirms that an anti-inflammatory diet is useful to prevent cardiovascular events and, more important, that healthy dietary patterns may be even healthier if subjects increase consumption of foods with the highest anti-inflammatory potential,” he said, adding that “mechanistic explanations add plausibility to the results of observational studies.”

Dr. Estruch was the principal investigator of PREDIMED. This trial was originally published in 2013 and then retracted and republished in 2018, with some required corrections, but the results had not materially changed.

Dr. Li is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Boston Nutrition Obesity Research Center. Dr. Estruch disclosed no financial relationships relevant to the contents of this article.  

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

Dietary patterns with higher inflammatory potential were significantly associated with a higher incidence of cardiovascular disease (CVD) and stroke in a new pooled analysis of three prospective cohort studies.

The analysis included 210,145 U.S. women and men followed for up to 32 years in the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study.

After adjustment for use of anti-inflammatory medications and CVD risk factors, those whose dietary pattern ranked in the highest quintile of inflammatory potential had a 38% higher risk of CVD (hazard ratio comparing highest with lowest quintiles, 1.38), a 46% higher risk of coronary heart disease (HR, 1.46), and a 28% higher risk of stroke (HR, 1.28) (all P for trend < .001).

Jun Li, MD, PhD, and colleagues at Harvard School of Public Health and Harvard Medical School, Boston, published the findings of their study in the Nov. 10 issue of the Journal of the American College of Cardiology.

The inflammatory potential of a diet was assessed using a food-based, dietary index called the “empirical dietary inflammatory pattern” or EDIP.

In an interview, Dr. Li explained that the EDIP was developed 4 years ago by many of the same authors involved with this study, including nutrition heavyweights Walter C. Willett, MD, DrPH, and Frank B. Hu, MD, PhD, both from Harvard.

“We summarized all the foods people eat into 39 defined food groups and did a reduced-rank regression analysis that looked at these 39 food groups and three inflammatory markers – interleukin-6, C-reactive protein, and tumor necrosis factor–alpha receptor 2. We found 18 food groups that are most predictive of these biomarkers, and the EDIP was calculated as the weighted sum of these 18 food groups.”

Individuals who had higher intakes of green-leafy vegetables (kale, spinach, arugula), dark-yellow vegetables (pumpkin, yellow peppers, carrots), whole grains, fruits, tea, coffee and wine had lower long-term CVD risk than those with higher intakes of red meat, processed meat, organ meat, refined carbohydrates, and sweetened beverages. 

The associations were consistent across cohorts and between sexes and remained significant in multiple sensitivity analysis that adjusted for alcohol consumption, smoking pack-years, use of lipid-lowering and antihypertensive medications, sodium intake, and blood pressure.

In a secondary analysis, diets with higher inflammatory potential were also associated with significantly higher biomarker levels indicative of more systemic, vascular, and metabolic inflammation, as well as less favorable lipid profiles.

“We wanted to be able to provide guidance on dietary patterns and food combinations,” said Dr. Li. “If you tell people to eat more polyunsaturated fats instead of saturated fat or trans fat, most people don’t know what foods are higher and lower in those nutrients. Also, many foods have different nutrients – some of which are good and some of which are bad – so we wanted to help people find the foods with the higher proportion of healthy nutrients rather than point out specific nutrients to avoid.”

Researchers used prospectively gathered data from the Nurses’ Health Studies I and II starting from 1984 and from the Health Professionals Follow-up Study. After excluding participants with missing diet information or previously diagnosed heart disease, stroke or cancer, over 210,000 participants were included in the analysis. Participants completed a survey every 4 years to ascertain dietary intake. 
 

Prevention, not treatment

In an editorial comment, Ramon Estruch, MD, PhD, from the Hospital Clinic in Barcelona, and colleagues suggested that it might be time for better dietary guidelines.

“A better knowledge of health protection provided by different foods and dietary patterns, mainly their anti-inflammatory properties, should provide the basis for designing even healthier dietary patterns to protect against heart disease,” the editorialists wrote.

They added extra-virgin olive oil, fatty fish, and tomatoes to the list of foods with “established anti-inflammatory activity.”

In a comment, Dr. Estruch said the findings of this new study are confirmatory of the PREDIMED trial, which showed a reduction in risk of major CV events in individuals at high cardiovascular risk assigned to an anti-inflammatory Mediterranean diet pattern supplemented with extra-virgin olive oil or nuts as compared with those assigned to a reduced-fat diet. 

“The study of Jun Li et al. confirms that an anti-inflammatory diet is useful to prevent cardiovascular events and, more important, that healthy dietary patterns may be even healthier if subjects increase consumption of foods with the highest anti-inflammatory potential,” he said, adding that “mechanistic explanations add plausibility to the results of observational studies.”

Dr. Estruch was the principal investigator of PREDIMED. This trial was originally published in 2013 and then retracted and republished in 2018, with some required corrections, but the results had not materially changed.

Dr. Li is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Boston Nutrition Obesity Research Center. Dr. Estruch disclosed no financial relationships relevant to the contents of this article.  

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

Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

Thyroid dysfunction had virtually no independent impact on survival in a retrospective study of nearly 5,000 English patients with chronic heart failure, adding to evidence that subclinical thyroid disorders in these patients requires no special management beyond ongoing monitoring.

Sebastian Kaulitzki/Fotolia

“Although thyroid dysfunction is related to outcome in patients with chronic heart failure, the association disappears when adjustment is made for established prognostic variables, such as age, NT-proBNP [N-terminal of the prohormone brain natriuretic peptide], and [New York Heart Association] class,” wrote Nathan A. Samuel, MBChB, and coauthors in the American Journal of Cardiology.

Results from several earlier studies had shown evidence for reduced survival in heart failure patients with thyroid dysfunction, but in analyses that did not adjust for heart failure severity, such as a 2013 report that used data from the Sudden Cardiac Death in Heart Failure Trial SCD-HeFT. Other studies that adjusted for heart failure severity based on serum level of natriuretic peptides did not show significant associations between thyroid function and mortality, and when those results couple with the new report they together minimize the immediate risk from subclinical thyroid dysfunction faced by heart failure patients, wrote the authors of the new report.

Don’t treat subclinical thyroid dysfunction

“Our results suggest that subclinical thyroid disease has little impact on outcomes, and that we should not treat subclinical hypothyroidism in the expectation of improving outlook,” said Andrew L. Clark, MD, senior author on the new report and professor and head of the department of academic cardiology at Hull (England) York Medical School.

“Both hyper-and hypothyroidism can cause heart failure, so thyroid function should always be checked in patients when they present with heart failure. A small proportion of patients have heart failure that is potentially reversible” with thyroid-directed treatment, Dr. Clark said in an interview.

But “subclinical disease should probably not be treated, although we have not conducted a clinical trial that proves this assertion. We speculate, based on our findings, that such a trial is unlikely to be positive.”

Patients with subclinical thyroid disorders, particularly subclinical hypothyroidism, “need to be followed and treated should they develop clinical disease,” he maintained. “Except in extreme circumstances, such as the handful of patients who might have gross myxedema and may be near coma, thyroid replacement therapy for those [with heart failure] who have clinical hypothyroidism should follow standard lines.”

It is important to monitor thyroid function,” agreed Dr. Samuel, a researcher in the department of academic cardiology at Hull York Medical School. “We found that thyroxine use was most common among patients with hyperthyroidism, suggesting that they were previously hypothyroid and had received inappropriate treatment.”

Confounder adjustment mitigates the thyroid link

The new analysis used data collected from 6,782 consecutive heart failure patients enrolled during 2000-2018 at a community heart failure clinic that serves patients in the region of Hull, England. The researchers identified 4,992 of these patients with confirmed heart failure and adequate data for their analyses, including 2,997 (60%) with heart failure with reduced ejection fraction (HFrEF) and 1,995 (40%) with heart failure with normal ejection fraction (HFnEF, the term used by the authors but often called heart failure with preserved ejection fraction).

Thyroid hormone levels showed that 90% of these patients were euthyroid, 6% were hyperthyroid, and 4% were hypothyroid, rates consistent with prior reports for both the general population and heart failure patients. Only 12 patients (0.2%) had overt hypothyroidism, and fewer that 1% (about 45 patients) had overt hyperthyroidism. Patients averaged about 73 years of age, and during a median 4.6 years of follow-up 58% died.

Both the hypo- and hyperthyroid patients showed significantly higher mortality rates than euthyroid patients in a univariate analysis. But the patients with thyroid dysfunction also had more comorbidities, more severe heart failure symptoms measured by NYHA functional class, and more severe heart failure measured as higher serum levels of NT-proBNP.

In a multivariate analysis that adjusted for these factors, the significant differences disappeared among the entire group of heart failure patients for the outcomes of all-cause mortality, and mortality or hospitalization with heart failure. The multivariate analysis also showed no significant association between higher levels of thyroid-stimulating hormone (TSH) and all-cause death or death plus heart failure hospitalization among the patients with HFrEF.

Among patients with HFnEF, the multivariate adjusted analysis showed a small increase in both mortality and mortality plus hospitalization for heart failure, a 2% rise for each of these two endpoints for each 1 mIU/L increase in TSH, the authors reported. Although the P value for each of these two significant differences among patients with HFnEF was .02, the 95% confidence interval included 1.00 and ranged from 1.00 to 1.04.

The multivariate analysis identified three variables with the strongest associations with all-cause mortality: older age, higher levels of NT-proBNP, and higher NYHA class indicating greater functional impairment.

The results support the hypothesis that “worsening heart failure can lead to down-regulation of thyroid hormone signaling,” the authors suggested. Their study is also “the first to examine the prognostic significance of thyroid dysfunction in a large population of patients with HFnEF.” This analysis showed a “weak but significant association between increasing TSH and both mortality and the composite endpoint in patients with HFnEF.”

“HFnEF is a heterogeneous group of conditions that are difficult to diagnose in many cases. Therefore, future studies are needed to provide further clarity on the effect of thyroid dysfunction in these patients,” Dr. Samuel said.

The study received no commercial funding. Dr. Samuel and Dr. Clark had no disclosures.

mzoler@mdedge.com

SOURCE: Samuel NA et al. Am J Cardiol. 2020 Oct 24. doi: 10.1016/j.amjcard.2020.10.034.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Five common therapies and practices related to children’s heart health may be unnecessary, and physicians and parents should be careful about using them, the American Academy of Pediatrics explained in guidance released Nov. 2.

The AAP Section on Cardiology and Cardiac Surgery developed the recommendations as part of the Choosing Wisely campaign after reviewing evidence pertaining to practices common during pediatric visits, such as routinely ordering an electrocardiogram (ECG) as part of a sports exam.

The guidance lets physicians know what is not necessary or not indicated, with noted exceptions, Christopher S. Snyder, MD, chair of the section, said in an interview.

In all cases, family history is key, said Dr. Snyder, who is also chief of the division of pediatric cardiology at University Hospitals Cleveland Medical Center. That means taking the time necessary to ask about aunts, uncles, and all first-degree relatives, not just asking the single question of whether a patient has a family history of cardiac problems.

The following are the targeted practices and the AAP’s guidance on each.
 

ECG for sports participation

A screening ECG should not be ordered as part of a routine sports entry examination in otherwise healthy patients who have no symptoms and no personal or family history of cardiac disease, the committee says.

Some medical societies argue that all children who participate in sports should have an ECG, but, Dr. Snyder said, “Currently there are no data that support that, especially in the United States.”

ECGs often yield false positive findings, he noted: “About 10% of them will say the child is a little abnormal.”

That can be a particular problem in places with few or no pediatric cardiologists because kids can become sidelined from sports without access to experts who could clear them.

“In the U.S.,” he said, “we believe that the preparticipation physical exam and screening, which is routine for all high school athletes for sure and most athletes who compete in sports, is currently good enough.”

However, he warned, patients with a family history of heart disease need to see a pediatric cardiologist and “those patients need an ECG.”

The test is not perfect, though, he noted: “You could get your screening, go home, get a fever, COVID, something like that, and come back and have myocarditis and drop dead.”
 

ECG before ADHD therapy

Similarly, a screening ECG is not routinely needed before initiating therapy for ADHD in asymptomatic, otherwise healthy children who have no personal or family history of cardiac disease, according to the new guidance.

Dr. Snyder said that it has become routine for children to undergo an ECG before ADHD therapy, but evidence doesn’t support the practice, and with the rise in the number of ADHD diagnoses, the tests have increasingly become a burden.

Twenty years ago, the prevalence of ADHD was 3%-4%, Dr. Snyder said. It is now almost threefold higher.

The AAP committee points out that, when ECG abnormalities are identified, they rarely lead to a change in ADHD therapy. Additionally, the typical stimulants used to treat ADHD “have never shown any major effect on the heart,” Dr. Snyder said.

“Black box warnings have been put on these medications, but nothing has been found in the very routine stimulants in normal, routine doses to warrant an ECG,” he said.
 

Echocardiogram for syncope

The committee says routine use of echocardiograms for children with syncope is unnecessary unless a child has a concerning history or ECG abnormalities.

Most patient who have true syncope or are passing out or fainting are diagnosed through thorough family history, Dr. Snyder said.

“The vast majority of those need an ECG to rule out one other cause that can do this and a physical exam. If those things are normal, there really is no indication to do an echocardiogram,” he said.

“If the patient passes out while they’re running, they pass out doing strenuous exercise, or they pass out for 10-15 minutes as opposed to 20 seconds – those are the ones that need a thorough cardiac workup. But routine passing out, waking up in seconds, those do not.”
 

Echocardiogram for chest pain

Children with chest pain do not need an echocardiogram unless an ECG is abnormal or the patient has a concerning history, according to the new recommendations.

Too often, Dr. Snyder said, providers treat kids as they would adults.

“Often it comes down to what you learn in medical school,” Dr. Snyder said. “In medical school, we have 6 weeks of cardiology and we had 1 hour of pediatric cardiology.”

That younger patients will clog their arteries with fatty foods and high lipids “is really exceptionally rare,” Dr. Snyder said.

Chest pain “rarely, if ever” means heart attack in younger children, he added.

A thorough history and complete physical exam are critical, “without jumping immediately to an echocardiogram, which 99.9% of the time is going to be normal,” he said.
 

Troponins for chest pain

In addition, a typical workup for pediatric chest pain need not include evaluating troponins unless there is a concerning history or ECG abnormalities.

Snyder notes that kids with chest pain are often brought to emergency departments that are not pediatric specific, and thus clinicians turn to the standard treatment for adults with chest pain: ECG and troponin.

“The reason we in pediatric cardiology don’t love this is that troponins tend not to be specific just for heart in kids,” Dr. Snyder said. “If someone has anginal chest pain – shortness of breath, chest pain doing anything and everything, [chest pain that] occurs when they’re exercising, feels like an elephant standing on their chest – then we do encourage troponins on those patients.”

The guidance discourages ordering troponins without careful consideration of the patient’s age and condition, he said.

This list was developed by faculty in Pediatric Cardiology at University Hospitals in Cleveland. It was revised and approved by the AAP Section on Cardiology and Cardiac Surgery and the AAP Executive Committee.
 

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

Five common therapies and practices related to children’s heart health may be unnecessary, and physicians and parents should be careful about using them, the American Academy of Pediatrics explained in guidance released Nov. 2.

The AAP Section on Cardiology and Cardiac Surgery developed the recommendations as part of the Choosing Wisely campaign after reviewing evidence pertaining to practices common during pediatric visits, such as routinely ordering an electrocardiogram (ECG) as part of a sports exam.

The guidance lets physicians know what is not necessary or not indicated, with noted exceptions, Christopher S. Snyder, MD, chair of the section, said in an interview.

In all cases, family history is key, said Dr. Snyder, who is also chief of the division of pediatric cardiology at University Hospitals Cleveland Medical Center. That means taking the time necessary to ask about aunts, uncles, and all first-degree relatives, not just asking the single question of whether a patient has a family history of cardiac problems.

The following are the targeted practices and the AAP’s guidance on each.
 

ECG for sports participation

A screening ECG should not be ordered as part of a routine sports entry examination in otherwise healthy patients who have no symptoms and no personal or family history of cardiac disease, the committee says.

Some medical societies argue that all children who participate in sports should have an ECG, but, Dr. Snyder said, “Currently there are no data that support that, especially in the United States.”

ECGs often yield false positive findings, he noted: “About 10% of them will say the child is a little abnormal.”

That can be a particular problem in places with few or no pediatric cardiologists because kids can become sidelined from sports without access to experts who could clear them.

“In the U.S.,” he said, “we believe that the preparticipation physical exam and screening, which is routine for all high school athletes for sure and most athletes who compete in sports, is currently good enough.”

However, he warned, patients with a family history of heart disease need to see a pediatric cardiologist and “those patients need an ECG.”

The test is not perfect, though, he noted: “You could get your screening, go home, get a fever, COVID, something like that, and come back and have myocarditis and drop dead.”
 

ECG before ADHD therapy

Similarly, a screening ECG is not routinely needed before initiating therapy for ADHD in asymptomatic, otherwise healthy children who have no personal or family history of cardiac disease, according to the new guidance.

Dr. Snyder said that it has become routine for children to undergo an ECG before ADHD therapy, but evidence doesn’t support the practice, and with the rise in the number of ADHD diagnoses, the tests have increasingly become a burden.

Twenty years ago, the prevalence of ADHD was 3%-4%, Dr. Snyder said. It is now almost threefold higher.

The AAP committee points out that, when ECG abnormalities are identified, they rarely lead to a change in ADHD therapy. Additionally, the typical stimulants used to treat ADHD “have never shown any major effect on the heart,” Dr. Snyder said.

“Black box warnings have been put on these medications, but nothing has been found in the very routine stimulants in normal, routine doses to warrant an ECG,” he said.
 

Echocardiogram for syncope

The committee says routine use of echocardiograms for children with syncope is unnecessary unless a child has a concerning history or ECG abnormalities.

Most patient who have true syncope or are passing out or fainting are diagnosed through thorough family history, Dr. Snyder said.

“The vast majority of those need an ECG to rule out one other cause that can do this and a physical exam. If those things are normal, there really is no indication to do an echocardiogram,” he said.

“If the patient passes out while they’re running, they pass out doing strenuous exercise, or they pass out for 10-15 minutes as opposed to 20 seconds – those are the ones that need a thorough cardiac workup. But routine passing out, waking up in seconds, those do not.”
 

Echocardiogram for chest pain

Children with chest pain do not need an echocardiogram unless an ECG is abnormal or the patient has a concerning history, according to the new recommendations.

Too often, Dr. Snyder said, providers treat kids as they would adults.

“Often it comes down to what you learn in medical school,” Dr. Snyder said. “In medical school, we have 6 weeks of cardiology and we had 1 hour of pediatric cardiology.”

That younger patients will clog their arteries with fatty foods and high lipids “is really exceptionally rare,” Dr. Snyder said.

Chest pain “rarely, if ever” means heart attack in younger children, he added.

A thorough history and complete physical exam are critical, “without jumping immediately to an echocardiogram, which 99.9% of the time is going to be normal,” he said.
 

Troponins for chest pain

In addition, a typical workup for pediatric chest pain need not include evaluating troponins unless there is a concerning history or ECG abnormalities.

Snyder notes that kids with chest pain are often brought to emergency departments that are not pediatric specific, and thus clinicians turn to the standard treatment for adults with chest pain: ECG and troponin.

“The reason we in pediatric cardiology don’t love this is that troponins tend not to be specific just for heart in kids,” Dr. Snyder said. “If someone has anginal chest pain – shortness of breath, chest pain doing anything and everything, [chest pain that] occurs when they’re exercising, feels like an elephant standing on their chest – then we do encourage troponins on those patients.”

The guidance discourages ordering troponins without careful consideration of the patient’s age and condition, he said.

This list was developed by faculty in Pediatric Cardiology at University Hospitals in Cleveland. It was revised and approved by the AAP Section on Cardiology and Cardiac Surgery and the AAP Executive Committee.
 

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

Five common therapies and practices related to children’s heart health may be unnecessary, and physicians and parents should be careful about using them, the American Academy of Pediatrics explained in guidance released Nov. 2.

The AAP Section on Cardiology and Cardiac Surgery developed the recommendations as part of the Choosing Wisely campaign after reviewing evidence pertaining to practices common during pediatric visits, such as routinely ordering an electrocardiogram (ECG) as part of a sports exam.

The guidance lets physicians know what is not necessary or not indicated, with noted exceptions, Christopher S. Snyder, MD, chair of the section, said in an interview.

In all cases, family history is key, said Dr. Snyder, who is also chief of the division of pediatric cardiology at University Hospitals Cleveland Medical Center. That means taking the time necessary to ask about aunts, uncles, and all first-degree relatives, not just asking the single question of whether a patient has a family history of cardiac problems.

The following are the targeted practices and the AAP’s guidance on each.
 

ECG for sports participation

A screening ECG should not be ordered as part of a routine sports entry examination in otherwise healthy patients who have no symptoms and no personal or family history of cardiac disease, the committee says.

Some medical societies argue that all children who participate in sports should have an ECG, but, Dr. Snyder said, “Currently there are no data that support that, especially in the United States.”

ECGs often yield false positive findings, he noted: “About 10% of them will say the child is a little abnormal.”

That can be a particular problem in places with few or no pediatric cardiologists because kids can become sidelined from sports without access to experts who could clear them.

“In the U.S.,” he said, “we believe that the preparticipation physical exam and screening, which is routine for all high school athletes for sure and most athletes who compete in sports, is currently good enough.”

However, he warned, patients with a family history of heart disease need to see a pediatric cardiologist and “those patients need an ECG.”

The test is not perfect, though, he noted: “You could get your screening, go home, get a fever, COVID, something like that, and come back and have myocarditis and drop dead.”
 

ECG before ADHD therapy

Similarly, a screening ECG is not routinely needed before initiating therapy for ADHD in asymptomatic, otherwise healthy children who have no personal or family history of cardiac disease, according to the new guidance.

Dr. Snyder said that it has become routine for children to undergo an ECG before ADHD therapy, but evidence doesn’t support the practice, and with the rise in the number of ADHD diagnoses, the tests have increasingly become a burden.

Twenty years ago, the prevalence of ADHD was 3%-4%, Dr. Snyder said. It is now almost threefold higher.

The AAP committee points out that, when ECG abnormalities are identified, they rarely lead to a change in ADHD therapy. Additionally, the typical stimulants used to treat ADHD “have never shown any major effect on the heart,” Dr. Snyder said.

“Black box warnings have been put on these medications, but nothing has been found in the very routine stimulants in normal, routine doses to warrant an ECG,” he said.
 

Echocardiogram for syncope

The committee says routine use of echocardiograms for children with syncope is unnecessary unless a child has a concerning history or ECG abnormalities.

Most patient who have true syncope or are passing out or fainting are diagnosed through thorough family history, Dr. Snyder said.

“The vast majority of those need an ECG to rule out one other cause that can do this and a physical exam. If those things are normal, there really is no indication to do an echocardiogram,” he said.

“If the patient passes out while they’re running, they pass out doing strenuous exercise, or they pass out for 10-15 minutes as opposed to 20 seconds – those are the ones that need a thorough cardiac workup. But routine passing out, waking up in seconds, those do not.”
 

Echocardiogram for chest pain

Children with chest pain do not need an echocardiogram unless an ECG is abnormal or the patient has a concerning history, according to the new recommendations.

Too often, Dr. Snyder said, providers treat kids as they would adults.

“Often it comes down to what you learn in medical school,” Dr. Snyder said. “In medical school, we have 6 weeks of cardiology and we had 1 hour of pediatric cardiology.”

That younger patients will clog their arteries with fatty foods and high lipids “is really exceptionally rare,” Dr. Snyder said.

Chest pain “rarely, if ever” means heart attack in younger children, he added.

A thorough history and complete physical exam are critical, “without jumping immediately to an echocardiogram, which 99.9% of the time is going to be normal,” he said.
 

Troponins for chest pain

In addition, a typical workup for pediatric chest pain need not include evaluating troponins unless there is a concerning history or ECG abnormalities.

Snyder notes that kids with chest pain are often brought to emergency departments that are not pediatric specific, and thus clinicians turn to the standard treatment for adults with chest pain: ECG and troponin.

“The reason we in pediatric cardiology don’t love this is that troponins tend not to be specific just for heart in kids,” Dr. Snyder said. “If someone has anginal chest pain – shortness of breath, chest pain doing anything and everything, [chest pain that] occurs when they’re exercising, feels like an elephant standing on their chest – then we do encourage troponins on those patients.”

The guidance discourages ordering troponins without careful consideration of the patient’s age and condition, he said.

This list was developed by faculty in Pediatric Cardiology at University Hospitals in Cleveland. It was revised and approved by the AAP Section on Cardiology and Cardiac Surgery and the AAP Executive Committee.
 

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

Survivors of Kawasaki disease remain at a higher long-term risk for cardiovascular events into young adulthood, including myocardial infarction, compared to people without the disease, new evidence reveals. The elevated risks emerged in survivors both with and without cardiovascular involvement at the time of initial diagnosis.

Overall risk of cardiovascular events was highest in the first year following Kawasaki disease diagnosis, and about 10 times greater than in healthy children, Cal Robinson, MD, said during a press conference at the virtual annual meeting of the American College of Rheumatology.

“The risk gradually decreased over time. However, even 10 years after diagnosis of their illness, they still had a 39% higher risk,” said study author Dr. Robinson, a PGY4 pediatric nephrology fellow at The Hospital for Sick Children in Toronto.

Dr. Robinson also put the numbers in perspective. “We fully acknowledged these are very rare events in children, especially healthy children, which is why we needed such a large cohort to study this. Interpret the numbers cautiously.”

In terms of patient and family counseling, “I would say children with Kawasaki disease have a higher risk of myocardial infarction, but the absolute risk is still low,” he added. For example, 16 Kawasaki disease survivors experienced a heart attack during follow-up, or 0.4% of the affected study population, compared to a rate of 0.1% among matched controls.

“These families are often very frightened after the initial Kawasaki disease diagnosis,” Dr. Robinson said. “We have to balance some discussion with what we know about Kawasaki disease without overly scaring or terrifying these families, who are already anxious.”

To quantify the incidence and timing of cardiovascular events and cardiac disease following diagnosis, Dr. Robinson and colleagues assessed large databases representing approximately 3 million children. They focused on children hospitalized with a Kawasaki disease diagnosis between 1995 and 2018. These children had a median length of stay of 3 days and 2.5% were admitted to critical care. The investigators matched his population 1:100 to unaffected children in Ontario.

Follow-up was up to 24 years (median, 11 years) in this retrospective, population-based cohort study.

Risks raised over a decade and beyond

Compared to matched controls, Kawasaki disease survivors had a higher risk for a cardiac event in the first year following diagnosis (adjusted hazard ratio, 11.65; 95% confidence interval, 10.34-13.13). The 1- to 5-year risk was lower (aHR, 3.35), a trend that continued between 5 and 10 years (aHR, 1.87) and as well as after more than 10 years (aHR, 1.39).

The risk of major adverse cardiac events (MACE, a composite of myocardial infarction, stroke, or cardiovascular death) was likewise highest in the first year after diagnosis (aHR, 3.27), followed by a 51% greater risk at 1-5 years, a 113% increased risk at 5-10 years, and a 17% elevated risk after 10 years.

The investigators compared the 144 Kawasaki disease survivors who experienced a coronary artery aneurysm (CAA) within 90 days of hospital admission to the 4,453 others who did not have a CAA. The risk for a composite cardiovascular event was elevated at each time point among those with a history of CAA, especially in the first year. The adjusted HR was 33.12 in the CAA group versus 10.44 in the non-CAA group.

“The most interesting finding of this study was that children with Kawasaki syndrome are at higher risk for composite cardiovascular events and major adverse cardiac events even if they were not diagnosed with coronary artery aneurysm,” session comoderator Shervin Assassi, MD, professor of medicine and director of division of rheumatology at the University of Texas Health Science Center at Houston, said when asked to comment.

Dr. Robinson and colleagues also looked at outcomes based on presence or absence of coronary involvement at the time of Kawasaki disease diagnosis. For example, among those with initial coronary involvement, 15% later experienced a cardiovascular event and 10% experienced a major cardiovascular event.

“However, we were specifically interested in looking at children without initial coronary involvement. In this group, we also found these children were at increased risk for cardiovascular events compared to children without Kawasaki disease,” Dr. Robinson said. He said the distinction is important because approximately 95% of children diagnosed with Kawasaki disease do not feature initial coronary involvement.

In terms of clinical care, “our data provides an early signal that Kawasaki disease survivors – including those without initial coronary involvement – may be at higher risk of cardiovascular events into early adulthood.”
 

A call for closer monitoring

“Based on our results, we find that Kawasaki disease survivors may benefit from additional follow-up and surveillance for cardiovascular disease risk factors, such as obesity, high blood pressure, and high cholesterol,” Dr. Robinson said. Early identification of heightened risk could allow physicians to more closely monitor this subgroup and emphasize potentially beneficial lifestyle modifications, including increasing physical activity, implementing a heart healthy diet, and avoiding smoking.

Mortality was not significantly different between groups. “Despite the risk of cardiac events we found, death was uncommon,” Dr. Robinson said. Among children with Kawasaki disease, 1 in 500 died during follow-up, so “the risk of death was actually lower than for children without Kawasaki disease.”

Similar findings of lower mortality have been reported in research out of Japan, he added during a plenary presentation at ACR 2020. Future research is warranted to evaluate this finding further, Dr. Robinson said.
 

Future plans

Going forward, the investigators plan to evaluate noncardiovascular outcomes in this patient population. They would also like to examine health care utilization following a diagnosis of Kawasaki disease “to better understand what kind of follow-up is happening now in Ontario,” Dr. Robinson said.

Another unanswered question is whether the cardiovascular events observed in the study stem from atherosclerotic disease or a different mechanism among survivors of Kawasaki disease.

The research was supported by a McMaster University Resident Research Grant, a Hamilton Health Sciences New Investigator Award, and Ontario’s Institute for Clinical Evaluative Sciences. Dr. Robinson had no relevant financial disclosures.

SOURCE: Robinson C et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0937.

Survivors of Kawasaki disease remain at a higher long-term risk for cardiovascular events into young adulthood, including myocardial infarction, compared to people without the disease, new evidence reveals. The elevated risks emerged in survivors both with and without cardiovascular involvement at the time of initial diagnosis.

Overall risk of cardiovascular events was highest in the first year following Kawasaki disease diagnosis, and about 10 times greater than in healthy children, Cal Robinson, MD, said during a press conference at the virtual annual meeting of the American College of Rheumatology.

“The risk gradually decreased over time. However, even 10 years after diagnosis of their illness, they still had a 39% higher risk,” said study author Dr. Robinson, a PGY4 pediatric nephrology fellow at The Hospital for Sick Children in Toronto.

Dr. Robinson also put the numbers in perspective. “We fully acknowledged these are very rare events in children, especially healthy children, which is why we needed such a large cohort to study this. Interpret the numbers cautiously.”

In terms of patient and family counseling, “I would say children with Kawasaki disease have a higher risk of myocardial infarction, but the absolute risk is still low,” he added. For example, 16 Kawasaki disease survivors experienced a heart attack during follow-up, or 0.4% of the affected study population, compared to a rate of 0.1% among matched controls.

“These families are often very frightened after the initial Kawasaki disease diagnosis,” Dr. Robinson said. “We have to balance some discussion with what we know about Kawasaki disease without overly scaring or terrifying these families, who are already anxious.”

To quantify the incidence and timing of cardiovascular events and cardiac disease following diagnosis, Dr. Robinson and colleagues assessed large databases representing approximately 3 million children. They focused on children hospitalized with a Kawasaki disease diagnosis between 1995 and 2018. These children had a median length of stay of 3 days and 2.5% were admitted to critical care. The investigators matched his population 1:100 to unaffected children in Ontario.

Follow-up was up to 24 years (median, 11 years) in this retrospective, population-based cohort study.

Risks raised over a decade and beyond

Compared to matched controls, Kawasaki disease survivors had a higher risk for a cardiac event in the first year following diagnosis (adjusted hazard ratio, 11.65; 95% confidence interval, 10.34-13.13). The 1- to 5-year risk was lower (aHR, 3.35), a trend that continued between 5 and 10 years (aHR, 1.87) and as well as after more than 10 years (aHR, 1.39).

The risk of major adverse cardiac events (MACE, a composite of myocardial infarction, stroke, or cardiovascular death) was likewise highest in the first year after diagnosis (aHR, 3.27), followed by a 51% greater risk at 1-5 years, a 113% increased risk at 5-10 years, and a 17% elevated risk after 10 years.

The investigators compared the 144 Kawasaki disease survivors who experienced a coronary artery aneurysm (CAA) within 90 days of hospital admission to the 4,453 others who did not have a CAA. The risk for a composite cardiovascular event was elevated at each time point among those with a history of CAA, especially in the first year. The adjusted HR was 33.12 in the CAA group versus 10.44 in the non-CAA group.

“The most interesting finding of this study was that children with Kawasaki syndrome are at higher risk for composite cardiovascular events and major adverse cardiac events even if they were not diagnosed with coronary artery aneurysm,” session comoderator Shervin Assassi, MD, professor of medicine and director of division of rheumatology at the University of Texas Health Science Center at Houston, said when asked to comment.

Dr. Robinson and colleagues also looked at outcomes based on presence or absence of coronary involvement at the time of Kawasaki disease diagnosis. For example, among those with initial coronary involvement, 15% later experienced a cardiovascular event and 10% experienced a major cardiovascular event.

“However, we were specifically interested in looking at children without initial coronary involvement. In this group, we also found these children were at increased risk for cardiovascular events compared to children without Kawasaki disease,” Dr. Robinson said. He said the distinction is important because approximately 95% of children diagnosed with Kawasaki disease do not feature initial coronary involvement.

In terms of clinical care, “our data provides an early signal that Kawasaki disease survivors – including those without initial coronary involvement – may be at higher risk of cardiovascular events into early adulthood.”
 

A call for closer monitoring

“Based on our results, we find that Kawasaki disease survivors may benefit from additional follow-up and surveillance for cardiovascular disease risk factors, such as obesity, high blood pressure, and high cholesterol,” Dr. Robinson said. Early identification of heightened risk could allow physicians to more closely monitor this subgroup and emphasize potentially beneficial lifestyle modifications, including increasing physical activity, implementing a heart healthy diet, and avoiding smoking.

Mortality was not significantly different between groups. “Despite the risk of cardiac events we found, death was uncommon,” Dr. Robinson said. Among children with Kawasaki disease, 1 in 500 died during follow-up, so “the risk of death was actually lower than for children without Kawasaki disease.”

Similar findings of lower mortality have been reported in research out of Japan, he added during a plenary presentation at ACR 2020. Future research is warranted to evaluate this finding further, Dr. Robinson said.
 

Future plans

Going forward, the investigators plan to evaluate noncardiovascular outcomes in this patient population. They would also like to examine health care utilization following a diagnosis of Kawasaki disease “to better understand what kind of follow-up is happening now in Ontario,” Dr. Robinson said.

Another unanswered question is whether the cardiovascular events observed in the study stem from atherosclerotic disease or a different mechanism among survivors of Kawasaki disease.

The research was supported by a McMaster University Resident Research Grant, a Hamilton Health Sciences New Investigator Award, and Ontario’s Institute for Clinical Evaluative Sciences. Dr. Robinson had no relevant financial disclosures.

SOURCE: Robinson C et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0937.

Survivors of Kawasaki disease remain at a higher long-term risk for cardiovascular events into young adulthood, including myocardial infarction, compared to people without the disease, new evidence reveals. The elevated risks emerged in survivors both with and without cardiovascular involvement at the time of initial diagnosis.

Overall risk of cardiovascular events was highest in the first year following Kawasaki disease diagnosis, and about 10 times greater than in healthy children, Cal Robinson, MD, said during a press conference at the virtual annual meeting of the American College of Rheumatology.

“The risk gradually decreased over time. However, even 10 years after diagnosis of their illness, they still had a 39% higher risk,” said study author Dr. Robinson, a PGY4 pediatric nephrology fellow at The Hospital for Sick Children in Toronto.

Dr. Robinson also put the numbers in perspective. “We fully acknowledged these are very rare events in children, especially healthy children, which is why we needed such a large cohort to study this. Interpret the numbers cautiously.”

In terms of patient and family counseling, “I would say children with Kawasaki disease have a higher risk of myocardial infarction, but the absolute risk is still low,” he added. For example, 16 Kawasaki disease survivors experienced a heart attack during follow-up, or 0.4% of the affected study population, compared to a rate of 0.1% among matched controls.

“These families are often very frightened after the initial Kawasaki disease diagnosis,” Dr. Robinson said. “We have to balance some discussion with what we know about Kawasaki disease without overly scaring or terrifying these families, who are already anxious.”

To quantify the incidence and timing of cardiovascular events and cardiac disease following diagnosis, Dr. Robinson and colleagues assessed large databases representing approximately 3 million children. They focused on children hospitalized with a Kawasaki disease diagnosis between 1995 and 2018. These children had a median length of stay of 3 days and 2.5% were admitted to critical care. The investigators matched his population 1:100 to unaffected children in Ontario.

Follow-up was up to 24 years (median, 11 years) in this retrospective, population-based cohort study.

Risks raised over a decade and beyond

Compared to matched controls, Kawasaki disease survivors had a higher risk for a cardiac event in the first year following diagnosis (adjusted hazard ratio, 11.65; 95% confidence interval, 10.34-13.13). The 1- to 5-year risk was lower (aHR, 3.35), a trend that continued between 5 and 10 years (aHR, 1.87) and as well as after more than 10 years (aHR, 1.39).

The risk of major adverse cardiac events (MACE, a composite of myocardial infarction, stroke, or cardiovascular death) was likewise highest in the first year after diagnosis (aHR, 3.27), followed by a 51% greater risk at 1-5 years, a 113% increased risk at 5-10 years, and a 17% elevated risk after 10 years.

The investigators compared the 144 Kawasaki disease survivors who experienced a coronary artery aneurysm (CAA) within 90 days of hospital admission to the 4,453 others who did not have a CAA. The risk for a composite cardiovascular event was elevated at each time point among those with a history of CAA, especially in the first year. The adjusted HR was 33.12 in the CAA group versus 10.44 in the non-CAA group.

“The most interesting finding of this study was that children with Kawasaki syndrome are at higher risk for composite cardiovascular events and major adverse cardiac events even if they were not diagnosed with coronary artery aneurysm,” session comoderator Shervin Assassi, MD, professor of medicine and director of division of rheumatology at the University of Texas Health Science Center at Houston, said when asked to comment.

Dr. Robinson and colleagues also looked at outcomes based on presence or absence of coronary involvement at the time of Kawasaki disease diagnosis. For example, among those with initial coronary involvement, 15% later experienced a cardiovascular event and 10% experienced a major cardiovascular event.

“However, we were specifically interested in looking at children without initial coronary involvement. In this group, we also found these children were at increased risk for cardiovascular events compared to children without Kawasaki disease,” Dr. Robinson said. He said the distinction is important because approximately 95% of children diagnosed with Kawasaki disease do not feature initial coronary involvement.

In terms of clinical care, “our data provides an early signal that Kawasaki disease survivors – including those without initial coronary involvement – may be at higher risk of cardiovascular events into early adulthood.”
 

A call for closer monitoring

“Based on our results, we find that Kawasaki disease survivors may benefit from additional follow-up and surveillance for cardiovascular disease risk factors, such as obesity, high blood pressure, and high cholesterol,” Dr. Robinson said. Early identification of heightened risk could allow physicians to more closely monitor this subgroup and emphasize potentially beneficial lifestyle modifications, including increasing physical activity, implementing a heart healthy diet, and avoiding smoking.

Mortality was not significantly different between groups. “Despite the risk of cardiac events we found, death was uncommon,” Dr. Robinson said. Among children with Kawasaki disease, 1 in 500 died during follow-up, so “the risk of death was actually lower than for children without Kawasaki disease.”

Similar findings of lower mortality have been reported in research out of Japan, he added during a plenary presentation at ACR 2020. Future research is warranted to evaluate this finding further, Dr. Robinson said.
 

Future plans

Going forward, the investigators plan to evaluate noncardiovascular outcomes in this patient population. They would also like to examine health care utilization following a diagnosis of Kawasaki disease “to better understand what kind of follow-up is happening now in Ontario,” Dr. Robinson said.

Another unanswered question is whether the cardiovascular events observed in the study stem from atherosclerotic disease or a different mechanism among survivors of Kawasaki disease.

The research was supported by a McMaster University Resident Research Grant, a Hamilton Health Sciences New Investigator Award, and Ontario’s Institute for Clinical Evaluative Sciences. Dr. Robinson had no relevant financial disclosures.

SOURCE: Robinson C et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0937.

Patients who take the vitamin K antagonist warfarin to prevent thromboembolic events are significantly more likely to require knee or hip replacement surgery – a surrogate endpoint for end-stage osteoarthritis – than are patients who take direct oral anticoagulants (DOACs), results of a U.K.-based study showed.

In a nested case-control study, warfarin use was associated with a 1.5-fold risk for knee and hip replacement, compared with use of DOACs.

The findings provide additional evidence for the role of vitamin K and vitamin K–dependent proteins for limiting osteoarthritis progression, said lead author Priyanka Ballal, MD, a rheumatology fellow at Boston University.

“Given the prevalence and impact of osteoarthritis, our data, along with the existing literature, support the need for a well-powered, randomized, controlled trial for evaluating vitamin K supplementation in osteoarthritis. Our study also raises the consideration of using DOACs over warfarin when indicated in people with or at risk of osteoarthritis,“ she said in a plenary session at the virtual annual meeting of the American College of Rheumatology.

Warfarin targets vitamin K for its role in coagulation, but vitamin K is also an essential co-factor for vitamin K-dependent proteins in bone and cartilage, Dr. Ballal said,

Inadequate vitamin K levels are associated with abnormal joint tissue mineralization, and with increased incidence and prevalence of osteoarthritis. In a randomized, controlled trial, vitamin K supplementation was associated with trends toward less osteoarthritis progression among patients with vitamin K deficiency, she said.

To see whether warfarin therapy has biologic effects similar to that seen in patients with vitamin K deficiency, Dr. Ballal and colleagues conducted a nested, case-control study using data from The Health Improvement Network (THIN), an electronic medical record database of patients enrolled with general practitioners in the United Kingdom.

The sample included adults aged 40-80 years with atrial fibrillation who had received one or more prescriptions for warfarin or a DOAC beginning in 2009, a year after DOACs were first marketed in the United Kingdom, and within 1 year of the index date (date of joint replacement surgery). The researchers excluded patients with knee or hip replacements before 2014, severe comorbidities that would limit joint replacement, or who had used either warfarin or a DOAC prior to study entry. Each case was matched by age, gender, and index date with up to four control patients (those who did not have surgery).

A total of 913 cases and 3,652 controls were included. The groups had similar characteristics (sex, age, cancer, renal disease, chronic lung disease, hypertension, and incidence of venous thromboembolism [VTE]), except for somewhat higher rates of diabetes and heart failure among controls, and a higher rate of obesity among cases.

The investigators first looked at warfarin use among all knee and/or hip replacement cases and controls and calculated an odds ratio of 1.57 (95% confidence interval [CI], 1.30-1.89) for knee and hip replacement with warfarin after adjustment for body mass index, factors influencing choice of anticoagulant, comorbidities, other medications, general practitioner visits, and hospitalizations.

The association between warfarin and joint replacement held up in an analysis restricted to knee replacement only, with an adjusted OR of 1.48 (95% CI, 1.16-1.89).

There was also a clear association between duration of warfarin use and risk of knee and hip replacement.

“This abstract suggests the role of adequate vitamin K may be important in decreasing progression of osteoarthritis, which would then favor patients with OA who are on warfarin to consider changing to a DOAC; however, further studies are needed to confirm this finding and consider its impact on VTE and wound healing postop,” said Minna Kohler, MD, director of the rheumatology musculoskeletal ultrasound program at Massachusetts General Hospital in Boston. Dr. Kohler, who was not involved in the study, replied to an email request for comment.

The study was supported by grants from the National Institutes of Health. Dr. Ballal and Dr. Kohler reported having no conflicts of interest to disclose.

SOURCE: Ballal P et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0934.

Patients who take the vitamin K antagonist warfarin to prevent thromboembolic events are significantly more likely to require knee or hip replacement surgery – a surrogate endpoint for end-stage osteoarthritis – than are patients who take direct oral anticoagulants (DOACs), results of a U.K.-based study showed.

In a nested case-control study, warfarin use was associated with a 1.5-fold risk for knee and hip replacement, compared with use of DOACs.

The findings provide additional evidence for the role of vitamin K and vitamin K–dependent proteins for limiting osteoarthritis progression, said lead author Priyanka Ballal, MD, a rheumatology fellow at Boston University.

“Given the prevalence and impact of osteoarthritis, our data, along with the existing literature, support the need for a well-powered, randomized, controlled trial for evaluating vitamin K supplementation in osteoarthritis. Our study also raises the consideration of using DOACs over warfarin when indicated in people with or at risk of osteoarthritis,“ she said in a plenary session at the virtual annual meeting of the American College of Rheumatology.

Warfarin targets vitamin K for its role in coagulation, but vitamin K is also an essential co-factor for vitamin K-dependent proteins in bone and cartilage, Dr. Ballal said,

Inadequate vitamin K levels are associated with abnormal joint tissue mineralization, and with increased incidence and prevalence of osteoarthritis. In a randomized, controlled trial, vitamin K supplementation was associated with trends toward less osteoarthritis progression among patients with vitamin K deficiency, she said.

To see whether warfarin therapy has biologic effects similar to that seen in patients with vitamin K deficiency, Dr. Ballal and colleagues conducted a nested, case-control study using data from The Health Improvement Network (THIN), an electronic medical record database of patients enrolled with general practitioners in the United Kingdom.

The sample included adults aged 40-80 years with atrial fibrillation who had received one or more prescriptions for warfarin or a DOAC beginning in 2009, a year after DOACs were first marketed in the United Kingdom, and within 1 year of the index date (date of joint replacement surgery). The researchers excluded patients with knee or hip replacements before 2014, severe comorbidities that would limit joint replacement, or who had used either warfarin or a DOAC prior to study entry. Each case was matched by age, gender, and index date with up to four control patients (those who did not have surgery).

A total of 913 cases and 3,652 controls were included. The groups had similar characteristics (sex, age, cancer, renal disease, chronic lung disease, hypertension, and incidence of venous thromboembolism [VTE]), except for somewhat higher rates of diabetes and heart failure among controls, and a higher rate of obesity among cases.

The investigators first looked at warfarin use among all knee and/or hip replacement cases and controls and calculated an odds ratio of 1.57 (95% confidence interval [CI], 1.30-1.89) for knee and hip replacement with warfarin after adjustment for body mass index, factors influencing choice of anticoagulant, comorbidities, other medications, general practitioner visits, and hospitalizations.

The association between warfarin and joint replacement held up in an analysis restricted to knee replacement only, with an adjusted OR of 1.48 (95% CI, 1.16-1.89).

There was also a clear association between duration of warfarin use and risk of knee and hip replacement.

“This abstract suggests the role of adequate vitamin K may be important in decreasing progression of osteoarthritis, which would then favor patients with OA who are on warfarin to consider changing to a DOAC; however, further studies are needed to confirm this finding and consider its impact on VTE and wound healing postop,” said Minna Kohler, MD, director of the rheumatology musculoskeletal ultrasound program at Massachusetts General Hospital in Boston. Dr. Kohler, who was not involved in the study, replied to an email request for comment.

The study was supported by grants from the National Institutes of Health. Dr. Ballal and Dr. Kohler reported having no conflicts of interest to disclose.

SOURCE: Ballal P et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0934.

Patients who take the vitamin K antagonist warfarin to prevent thromboembolic events are significantly more likely to require knee or hip replacement surgery – a surrogate endpoint for end-stage osteoarthritis – than are patients who take direct oral anticoagulants (DOACs), results of a U.K.-based study showed.

In a nested case-control study, warfarin use was associated with a 1.5-fold risk for knee and hip replacement, compared with use of DOACs.

The findings provide additional evidence for the role of vitamin K and vitamin K–dependent proteins for limiting osteoarthritis progression, said lead author Priyanka Ballal, MD, a rheumatology fellow at Boston University.

“Given the prevalence and impact of osteoarthritis, our data, along with the existing literature, support the need for a well-powered, randomized, controlled trial for evaluating vitamin K supplementation in osteoarthritis. Our study also raises the consideration of using DOACs over warfarin when indicated in people with or at risk of osteoarthritis,“ she said in a plenary session at the virtual annual meeting of the American College of Rheumatology.

Warfarin targets vitamin K for its role in coagulation, but vitamin K is also an essential co-factor for vitamin K-dependent proteins in bone and cartilage, Dr. Ballal said,

Inadequate vitamin K levels are associated with abnormal joint tissue mineralization, and with increased incidence and prevalence of osteoarthritis. In a randomized, controlled trial, vitamin K supplementation was associated with trends toward less osteoarthritis progression among patients with vitamin K deficiency, she said.

To see whether warfarin therapy has biologic effects similar to that seen in patients with vitamin K deficiency, Dr. Ballal and colleagues conducted a nested, case-control study using data from The Health Improvement Network (THIN), an electronic medical record database of patients enrolled with general practitioners in the United Kingdom.

The sample included adults aged 40-80 years with atrial fibrillation who had received one or more prescriptions for warfarin or a DOAC beginning in 2009, a year after DOACs were first marketed in the United Kingdom, and within 1 year of the index date (date of joint replacement surgery). The researchers excluded patients with knee or hip replacements before 2014, severe comorbidities that would limit joint replacement, or who had used either warfarin or a DOAC prior to study entry. Each case was matched by age, gender, and index date with up to four control patients (those who did not have surgery).

A total of 913 cases and 3,652 controls were included. The groups had similar characteristics (sex, age, cancer, renal disease, chronic lung disease, hypertension, and incidence of venous thromboembolism [VTE]), except for somewhat higher rates of diabetes and heart failure among controls, and a higher rate of obesity among cases.

The investigators first looked at warfarin use among all knee and/or hip replacement cases and controls and calculated an odds ratio of 1.57 (95% confidence interval [CI], 1.30-1.89) for knee and hip replacement with warfarin after adjustment for body mass index, factors influencing choice of anticoagulant, comorbidities, other medications, general practitioner visits, and hospitalizations.

The association between warfarin and joint replacement held up in an analysis restricted to knee replacement only, with an adjusted OR of 1.48 (95% CI, 1.16-1.89).

There was also a clear association between duration of warfarin use and risk of knee and hip replacement.

“This abstract suggests the role of adequate vitamin K may be important in decreasing progression of osteoarthritis, which would then favor patients with OA who are on warfarin to consider changing to a DOAC; however, further studies are needed to confirm this finding and consider its impact on VTE and wound healing postop,” said Minna Kohler, MD, director of the rheumatology musculoskeletal ultrasound program at Massachusetts General Hospital in Boston. Dr. Kohler, who was not involved in the study, replied to an email request for comment.

The study was supported by grants from the National Institutes of Health. Dr. Ballal and Dr. Kohler reported having no conflicts of interest to disclose.

SOURCE: Ballal P et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0934.