Cardiology

The signature electrocardiographic sign indicating ST-segment-elevation MI may be a less-consistent indicator of actual STEMI at a time when patients with COVID-19 have come to overwhelm many hospital ICUs.

Many of the 18 such patients identified at six New York City hospitals who showed ST-segment elevation on their 12-lead ECG in the city’s first month of fighting the pandemic turned out to be free of either obstructive coronary artery disease by angiography or of regional wall-motion abnormalities (RWMA) by ECG, according to a letter published in the New England Journal of Medicine.

Those 10 patients in the 18-case series were said to have noncoronary myocardial injury, perhaps from myocarditis – a prevalent feature of severe COVID-19 – and the remaining 8 patients with obstructive coronary artery disease, RWMA, or both were diagnosed with STEMI. Of the latter patients, six went to the cath lab and five of those underwent percutaneous coronary intervention, Sripal Bangalore, MD, MHA, of New York University, and colleagues reported.

In an interview, Dr. Bangalore framed the case-series report as a caution against substituting fibrinolytic therapy for primary percutaneous coronary intervention in patients with STE while hospitals are unusually burdened by the COVID-19 pandemic and invasive procedures intensify the threat of SARS-CoV-2 exposure to clinicians.

The strategy was recently advanced as an option for highly selected patients in a statement from the American College of Cardiology and Society for Cardiovascular Angiography and Interventions (SCAI).

“During the COVID-19 pandemic, one of the main reasons fibrinolytic therapy has been pushed is to reduce the exposure to the cath-lab staff,” Dr. Bangalore observed. “But if you pursue that route, it’s problematic because more than half may not have obstructive disease and fibrinolytic therapy may not help. And if you give them fibrinolytics, you’re potentially increasing their risk of bleeding complications.

“The take-home from these 18 patients is that it’s very difficult to guess who is going to have obstructive disease and who is going to have nonobstructive disease,” Dr. Bangalore said. “Maybe we should assess these patients with not just an ECG but with a quick echo, then make a decision. Our practice so far has been to take these patients to the cath lab.”

The ACC/SCAI statement proposed that “fibrinolysis can be considered an option for the relatively stable STEMI patient with active COVID-19” after careful consideration of possible patient benefit versus the risks of cath-lab personnel exposure to the virus.

Only six patients in the current series, including five in the STEMI group, are reported to have had chest pain at about the time of STE, observed Michael J. Blaha, MD, MPH, of Johns Hopkins Hospital, Baltimore.

So, he said in an interview, “one of their points is that you have to take ST elevations with a grain of salt in this [COVID-19] era, because there are a lot of people presenting with ST elevations in the absence of chest pain.”

That, and the high prevalence of nonobstructive disease in the series, indeed argues against the use of fibrinolytic therapy in such patients, Dr. Blaha said.

Normally, when there is STE, “the pretest probability of STEMI is so high, and if you can’t make it to the cath lab for some reason, sure, it makes sense to give lytics.” However, he said, “COVID-19 is changing the clinical landscape. Now, with a variety of virus-mediated myocardial injury presentations, including myocarditis, the pretest probability of MI is lower.”

The current report “confirms that, in the COVID era, ST elevations are not diagnostic for MI and must be considered within the totality of clinical evidence, and a conservative approach to going to the cath lab is probably warranted,” Dr. Blaha said in an interview.

However, with the reduced pretest probability of STE for STEMI, he agreed, “I almost don’t see any scenario where I’d be comfortable, based on ECG changes alone, giving lytics at this time.”

Dr. Bangalore pointed out that all of the 18 patients in the series had elevated levels of the fibrin degradation product D-dimer, a biomarker that reflects ongoing hemostatic activation. Levels were higher in the 8 patients who ultimately received a STEMI diagnosis than in the remaining 10 patients.

But COVID-19 patients in general may have elevated D-dimer and “a lot of microthrombi,” he said. “So the question is, are those microthrombi also causal for any of the ECG changes we are also seeing?”

Aside from microthrombi, global hypoxia and myocarditis could be other potential causes of STE in COVID-19 patients in the absence of STEMI, Dr. Bangalore proposed. “At this point we just generally don’t know.”

Dr. Bangalore reported no conflicts; disclosures for the other authors are available at nejm.org. Dr. Blaha disclosed receiving grants from Amgen and serving on advisory boards for Amgen and other pharmaceutical companies.

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

The signature electrocardiographic sign indicating ST-segment-elevation MI may be a less-consistent indicator of actual STEMI at a time when patients with COVID-19 have come to overwhelm many hospital ICUs.

Many of the 18 such patients identified at six New York City hospitals who showed ST-segment elevation on their 12-lead ECG in the city’s first month of fighting the pandemic turned out to be free of either obstructive coronary artery disease by angiography or of regional wall-motion abnormalities (RWMA) by ECG, according to a letter published in the New England Journal of Medicine.

Those 10 patients in the 18-case series were said to have noncoronary myocardial injury, perhaps from myocarditis – a prevalent feature of severe COVID-19 – and the remaining 8 patients with obstructive coronary artery disease, RWMA, or both were diagnosed with STEMI. Of the latter patients, six went to the cath lab and five of those underwent percutaneous coronary intervention, Sripal Bangalore, MD, MHA, of New York University, and colleagues reported.

In an interview, Dr. Bangalore framed the case-series report as a caution against substituting fibrinolytic therapy for primary percutaneous coronary intervention in patients with STE while hospitals are unusually burdened by the COVID-19 pandemic and invasive procedures intensify the threat of SARS-CoV-2 exposure to clinicians.

The strategy was recently advanced as an option for highly selected patients in a statement from the American College of Cardiology and Society for Cardiovascular Angiography and Interventions (SCAI).

“During the COVID-19 pandemic, one of the main reasons fibrinolytic therapy has been pushed is to reduce the exposure to the cath-lab staff,” Dr. Bangalore observed. “But if you pursue that route, it’s problematic because more than half may not have obstructive disease and fibrinolytic therapy may not help. And if you give them fibrinolytics, you’re potentially increasing their risk of bleeding complications.

“The take-home from these 18 patients is that it’s very difficult to guess who is going to have obstructive disease and who is going to have nonobstructive disease,” Dr. Bangalore said. “Maybe we should assess these patients with not just an ECG but with a quick echo, then make a decision. Our practice so far has been to take these patients to the cath lab.”

The ACC/SCAI statement proposed that “fibrinolysis can be considered an option for the relatively stable STEMI patient with active COVID-19” after careful consideration of possible patient benefit versus the risks of cath-lab personnel exposure to the virus.

Only six patients in the current series, including five in the STEMI group, are reported to have had chest pain at about the time of STE, observed Michael J. Blaha, MD, MPH, of Johns Hopkins Hospital, Baltimore.

So, he said in an interview, “one of their points is that you have to take ST elevations with a grain of salt in this [COVID-19] era, because there are a lot of people presenting with ST elevations in the absence of chest pain.”

That, and the high prevalence of nonobstructive disease in the series, indeed argues against the use of fibrinolytic therapy in such patients, Dr. Blaha said.

Normally, when there is STE, “the pretest probability of STEMI is so high, and if you can’t make it to the cath lab for some reason, sure, it makes sense to give lytics.” However, he said, “COVID-19 is changing the clinical landscape. Now, with a variety of virus-mediated myocardial injury presentations, including myocarditis, the pretest probability of MI is lower.”

The current report “confirms that, in the COVID era, ST elevations are not diagnostic for MI and must be considered within the totality of clinical evidence, and a conservative approach to going to the cath lab is probably warranted,” Dr. Blaha said in an interview.

However, with the reduced pretest probability of STE for STEMI, he agreed, “I almost don’t see any scenario where I’d be comfortable, based on ECG changes alone, giving lytics at this time.”

Dr. Bangalore pointed out that all of the 18 patients in the series had elevated levels of the fibrin degradation product D-dimer, a biomarker that reflects ongoing hemostatic activation. Levels were higher in the 8 patients who ultimately received a STEMI diagnosis than in the remaining 10 patients.

But COVID-19 patients in general may have elevated D-dimer and “a lot of microthrombi,” he said. “So the question is, are those microthrombi also causal for any of the ECG changes we are also seeing?”

Aside from microthrombi, global hypoxia and myocarditis could be other potential causes of STE in COVID-19 patients in the absence of STEMI, Dr. Bangalore proposed. “At this point we just generally don’t know.”

Dr. Bangalore reported no conflicts; disclosures for the other authors are available at nejm.org. Dr. Blaha disclosed receiving grants from Amgen and serving on advisory boards for Amgen and other pharmaceutical companies.

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

The signature electrocardiographic sign indicating ST-segment-elevation MI may be a less-consistent indicator of actual STEMI at a time when patients with COVID-19 have come to overwhelm many hospital ICUs.

Many of the 18 such patients identified at six New York City hospitals who showed ST-segment elevation on their 12-lead ECG in the city’s first month of fighting the pandemic turned out to be free of either obstructive coronary artery disease by angiography or of regional wall-motion abnormalities (RWMA) by ECG, according to a letter published in the New England Journal of Medicine.

Those 10 patients in the 18-case series were said to have noncoronary myocardial injury, perhaps from myocarditis – a prevalent feature of severe COVID-19 – and the remaining 8 patients with obstructive coronary artery disease, RWMA, or both were diagnosed with STEMI. Of the latter patients, six went to the cath lab and five of those underwent percutaneous coronary intervention, Sripal Bangalore, MD, MHA, of New York University, and colleagues reported.

In an interview, Dr. Bangalore framed the case-series report as a caution against substituting fibrinolytic therapy for primary percutaneous coronary intervention in patients with STE while hospitals are unusually burdened by the COVID-19 pandemic and invasive procedures intensify the threat of SARS-CoV-2 exposure to clinicians.

The strategy was recently advanced as an option for highly selected patients in a statement from the American College of Cardiology and Society for Cardiovascular Angiography and Interventions (SCAI).

“During the COVID-19 pandemic, one of the main reasons fibrinolytic therapy has been pushed is to reduce the exposure to the cath-lab staff,” Dr. Bangalore observed. “But if you pursue that route, it’s problematic because more than half may not have obstructive disease and fibrinolytic therapy may not help. And if you give them fibrinolytics, you’re potentially increasing their risk of bleeding complications.

“The take-home from these 18 patients is that it’s very difficult to guess who is going to have obstructive disease and who is going to have nonobstructive disease,” Dr. Bangalore said. “Maybe we should assess these patients with not just an ECG but with a quick echo, then make a decision. Our practice so far has been to take these patients to the cath lab.”

The ACC/SCAI statement proposed that “fibrinolysis can be considered an option for the relatively stable STEMI patient with active COVID-19” after careful consideration of possible patient benefit versus the risks of cath-lab personnel exposure to the virus.

Only six patients in the current series, including five in the STEMI group, are reported to have had chest pain at about the time of STE, observed Michael J. Blaha, MD, MPH, of Johns Hopkins Hospital, Baltimore.

So, he said in an interview, “one of their points is that you have to take ST elevations with a grain of salt in this [COVID-19] era, because there are a lot of people presenting with ST elevations in the absence of chest pain.”

That, and the high prevalence of nonobstructive disease in the series, indeed argues against the use of fibrinolytic therapy in such patients, Dr. Blaha said.

Normally, when there is STE, “the pretest probability of STEMI is so high, and if you can’t make it to the cath lab for some reason, sure, it makes sense to give lytics.” However, he said, “COVID-19 is changing the clinical landscape. Now, with a variety of virus-mediated myocardial injury presentations, including myocarditis, the pretest probability of MI is lower.”

The current report “confirms that, in the COVID era, ST elevations are not diagnostic for MI and must be considered within the totality of clinical evidence, and a conservative approach to going to the cath lab is probably warranted,” Dr. Blaha said in an interview.

However, with the reduced pretest probability of STE for STEMI, he agreed, “I almost don’t see any scenario where I’d be comfortable, based on ECG changes alone, giving lytics at this time.”

Dr. Bangalore pointed out that all of the 18 patients in the series had elevated levels of the fibrin degradation product D-dimer, a biomarker that reflects ongoing hemostatic activation. Levels were higher in the 8 patients who ultimately received a STEMI diagnosis than in the remaining 10 patients.

But COVID-19 patients in general may have elevated D-dimer and “a lot of microthrombi,” he said. “So the question is, are those microthrombi also causal for any of the ECG changes we are also seeing?”

Aside from microthrombi, global hypoxia and myocarditis could be other potential causes of STE in COVID-19 patients in the absence of STEMI, Dr. Bangalore proposed. “At this point we just generally don’t know.”

Dr. Bangalore reported no conflicts; disclosures for the other authors are available at nejm.org. Dr. Blaha disclosed receiving grants from Amgen and serving on advisory boards for Amgen and other pharmaceutical companies.

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

Hospitalized COVID-19 patients with hypertension and on treatment with an renin-angiotensin system inhibiting drug had significantly better survival, compared with similar hypertensive patients not on these drugs, in observational, propensity score–matched analyses that drew from a pool of more than 3,430 patients hospitalized at any of nine Chinese hospitals during December 2019–February 2020.

Courtesy CDC

“Among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI [ACE inhibitor]/ARB [angiotensin receptor blocker] was associated with lower risk of all-cause mortality, compared with ACEI/ARB nonusers, during 28 days of follow-up. While study interpretation needs to consider the potential for residual confounders, it is unlikely that inpatient ACEI/ARB would be associated with an increased risk of mortality,” wrote Peng Zhang, MD, a cardiology researcher at Renmin Hospital of Wuhan University, China, and coauthors in Circulations Research, buttressing recent recommendations from several medical societies to maintain COVID-19 patients on these drugs.

“Our findings in this paper provide evidence supporting continuous use of ACEI/ARB for patients with hypertension infected with SARS-COV-2,” wrote the authors, backing up recent recommendations from cardiology societies that called for not stopping ACEI/ARB prescriptions in patients at risk for contracting or already have COVID-19 infection, including a statement from the American College of Cardiology, American Heart Association, and Heart Failure Society of America, and also guidance from the European Society of Cardiology.

The study included 1,128 patients with a history of hypertension, including 188 (17%) who received an ACEI/ARB drug during hospitalization. During 28-day follow-up, 99 died (9%), including 7 deaths among the 188 patients (4%) on an ACEI/ARB drug and 92 deaths among the 940 other hypertensive patients (10%).

The authors ran several analyses to try to adjust for the influence of possible confounders. A mixed-effect Cox model with four adjusted variables showed that treatment with an ACEI/ARB drug was tied to a statistically significant 58% lower death rate, compared with patients not receiving these drugs.

The researchers also ran several propensity score–adjusted analyses. One matched 174 of the patients who received an ACEI/ARB drug with 522 who did not, and comparing these two matched arms showed that ACEI/ARB use was linked with a statistically significant 63% cut in mortality, compared with patients not getting these drugs. A second propensity score–matched analysis first excluded the 383 patients who were hypertensive but received no antihypertensive medication during hospitalization. From the remaining 745 patients who received at least one antihypertensive medication, the authors identified 181 patients who received an ACEI/ARB and propensity-score matched them with 181 hypertensive patients on a different medication class, finding that ACEI/ARB use linked with a statistically significant 71% lower rate of all-cause mortality.

Additional analyses also showed that patients with hypertension had a statistically significant, 41% increased rate of all-cause death, compared with patients without hypertension, and another propensity score–matched analysis showed that among hypertensives treatment with an ACEI/ARB drug was linked with a statistically significant 68% reduced rate of septic shock.

Although this report was received with caution and some skepticism, it was also acknowledged as a step forward in the creation of an evidence base addressing ACEI/ARB treatment during COVID-19 infection.

“These drugs are lifesaving and should not be discontinued” for patients with hypertension, heart failure, and other cardiovascular disease, commented Gian Paolo Rossi, MD, professor and chair of medicine and director of the high blood pressure unit at the University of Padua (Italy). The analysis by Zhang and associates included the largest number of hospitalized COVID-19 patients with hypertension yet reported to assess the impact of treatment with ACEI/ARB drugs, and adds important evidence in favor of continuing these drugs in patients who develop COVID-19 infection, Dr. Rossi said in an interview. He recently coauthored a review that argued against ACEI/ARB discontinuation in COVID-19 patients based on previously reported evidence (Elife. 2020 Apr 6. doi: 10.7554/eLife.57278).

But other researchers take a wary view of the potential impact of ACEI/ARB agents. “If ACEI/ARB therapy increases ACE2 and the virus down-regulates it, and because ACE2 is the viral entry port into cells, why would ACE2-mediated down-regulation of the renin-angiotensin-aldosterone system lead to amelioration of [COVID-19] disease?” asked Laurence W. Busse, MD, a critical care physician at Emory University, Atlanta. “A number of issues could potentially confound the results, including the definition of COVID-19 and imbalance of antiviral therapy,” added Dr. Busse, who recently coauthored an editorial that posited using angiotensin II (Giapreza), an approved vasopressor drug, as an alternative renin-angiotensin system intervention for COVID-19 patients including both those in shock as well as potentially those not in shock (Crit Care. 2020 Apr 7. doi: 10.1186/s13054-020-02862-1). Despite these caveats, the new Chinese findings reported by Dr. Zhang and associates “are hypothesis generating and worth further exploration.”

The authors of an editorial that accompanied the Zhang study in Circulation Research made similar points. “While the investigators used standard techniques to attempt to reduce bias in this observational study via propensity matching, it is not a randomized study and the residual confounding inherent to this approach renders the conclusions hypothesis generating at best,” wrote Ravi V. Shah, MD, and two coauthors in the editorial (Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317174). They also agreed with the several society statements that have supported continued use of ACEI/ARB drugs in COVID-19 patients. “Withdrawal of these medications in the context of those conditions in which they have proven benefit (e.g., heart failure with reduced left ventricular ejection fraction) may actually inflict more harm than good,” they warned. “In the end we must rely on randomized clinical science,” and while this level of evidence is currently lacking, “the study by Zhang and colleagues is a direct step toward that goal.”

Dr. Zhang and coauthors had no commercial disclosures. Dr. Rossi and Dr. Busse had no disclosures. The authors of the Circulation Research editorial reported several disclosures.

mzoler@mdedge.com

SOURCE: Zhang P et al. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.

Hospitalized COVID-19 patients with hypertension and on treatment with an renin-angiotensin system inhibiting drug had significantly better survival, compared with similar hypertensive patients not on these drugs, in observational, propensity score–matched analyses that drew from a pool of more than 3,430 patients hospitalized at any of nine Chinese hospitals during December 2019–February 2020.

Courtesy CDC

“Among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI [ACE inhibitor]/ARB [angiotensin receptor blocker] was associated with lower risk of all-cause mortality, compared with ACEI/ARB nonusers, during 28 days of follow-up. While study interpretation needs to consider the potential for residual confounders, it is unlikely that inpatient ACEI/ARB would be associated with an increased risk of mortality,” wrote Peng Zhang, MD, a cardiology researcher at Renmin Hospital of Wuhan University, China, and coauthors in Circulations Research, buttressing recent recommendations from several medical societies to maintain COVID-19 patients on these drugs.

“Our findings in this paper provide evidence supporting continuous use of ACEI/ARB for patients with hypertension infected with SARS-COV-2,” wrote the authors, backing up recent recommendations from cardiology societies that called for not stopping ACEI/ARB prescriptions in patients at risk for contracting or already have COVID-19 infection, including a statement from the American College of Cardiology, American Heart Association, and Heart Failure Society of America, and also guidance from the European Society of Cardiology.

The study included 1,128 patients with a history of hypertension, including 188 (17%) who received an ACEI/ARB drug during hospitalization. During 28-day follow-up, 99 died (9%), including 7 deaths among the 188 patients (4%) on an ACEI/ARB drug and 92 deaths among the 940 other hypertensive patients (10%).

The authors ran several analyses to try to adjust for the influence of possible confounders. A mixed-effect Cox model with four adjusted variables showed that treatment with an ACEI/ARB drug was tied to a statistically significant 58% lower death rate, compared with patients not receiving these drugs.

The researchers also ran several propensity score–adjusted analyses. One matched 174 of the patients who received an ACEI/ARB drug with 522 who did not, and comparing these two matched arms showed that ACEI/ARB use was linked with a statistically significant 63% cut in mortality, compared with patients not getting these drugs. A second propensity score–matched analysis first excluded the 383 patients who were hypertensive but received no antihypertensive medication during hospitalization. From the remaining 745 patients who received at least one antihypertensive medication, the authors identified 181 patients who received an ACEI/ARB and propensity-score matched them with 181 hypertensive patients on a different medication class, finding that ACEI/ARB use linked with a statistically significant 71% lower rate of all-cause mortality.

Additional analyses also showed that patients with hypertension had a statistically significant, 41% increased rate of all-cause death, compared with patients without hypertension, and another propensity score–matched analysis showed that among hypertensives treatment with an ACEI/ARB drug was linked with a statistically significant 68% reduced rate of septic shock.

Although this report was received with caution and some skepticism, it was also acknowledged as a step forward in the creation of an evidence base addressing ACEI/ARB treatment during COVID-19 infection.

“These drugs are lifesaving and should not be discontinued” for patients with hypertension, heart failure, and other cardiovascular disease, commented Gian Paolo Rossi, MD, professor and chair of medicine and director of the high blood pressure unit at the University of Padua (Italy). The analysis by Zhang and associates included the largest number of hospitalized COVID-19 patients with hypertension yet reported to assess the impact of treatment with ACEI/ARB drugs, and adds important evidence in favor of continuing these drugs in patients who develop COVID-19 infection, Dr. Rossi said in an interview. He recently coauthored a review that argued against ACEI/ARB discontinuation in COVID-19 patients based on previously reported evidence (Elife. 2020 Apr 6. doi: 10.7554/eLife.57278).

But other researchers take a wary view of the potential impact of ACEI/ARB agents. “If ACEI/ARB therapy increases ACE2 and the virus down-regulates it, and because ACE2 is the viral entry port into cells, why would ACE2-mediated down-regulation of the renin-angiotensin-aldosterone system lead to amelioration of [COVID-19] disease?” asked Laurence W. Busse, MD, a critical care physician at Emory University, Atlanta. “A number of issues could potentially confound the results, including the definition of COVID-19 and imbalance of antiviral therapy,” added Dr. Busse, who recently coauthored an editorial that posited using angiotensin II (Giapreza), an approved vasopressor drug, as an alternative renin-angiotensin system intervention for COVID-19 patients including both those in shock as well as potentially those not in shock (Crit Care. 2020 Apr 7. doi: 10.1186/s13054-020-02862-1). Despite these caveats, the new Chinese findings reported by Dr. Zhang and associates “are hypothesis generating and worth further exploration.”

The authors of an editorial that accompanied the Zhang study in Circulation Research made similar points. “While the investigators used standard techniques to attempt to reduce bias in this observational study via propensity matching, it is not a randomized study and the residual confounding inherent to this approach renders the conclusions hypothesis generating at best,” wrote Ravi V. Shah, MD, and two coauthors in the editorial (Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317174). They also agreed with the several society statements that have supported continued use of ACEI/ARB drugs in COVID-19 patients. “Withdrawal of these medications in the context of those conditions in which they have proven benefit (e.g., heart failure with reduced left ventricular ejection fraction) may actually inflict more harm than good,” they warned. “In the end we must rely on randomized clinical science,” and while this level of evidence is currently lacking, “the study by Zhang and colleagues is a direct step toward that goal.”

Dr. Zhang and coauthors had no commercial disclosures. Dr. Rossi and Dr. Busse had no disclosures. The authors of the Circulation Research editorial reported several disclosures.

mzoler@mdedge.com

SOURCE: Zhang P et al. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.

Hospitalized COVID-19 patients with hypertension and on treatment with an renin-angiotensin system inhibiting drug had significantly better survival, compared with similar hypertensive patients not on these drugs, in observational, propensity score–matched analyses that drew from a pool of more than 3,430 patients hospitalized at any of nine Chinese hospitals during December 2019–February 2020.

Courtesy CDC

“Among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI [ACE inhibitor]/ARB [angiotensin receptor blocker] was associated with lower risk of all-cause mortality, compared with ACEI/ARB nonusers, during 28 days of follow-up. While study interpretation needs to consider the potential for residual confounders, it is unlikely that inpatient ACEI/ARB would be associated with an increased risk of mortality,” wrote Peng Zhang, MD, a cardiology researcher at Renmin Hospital of Wuhan University, China, and coauthors in Circulations Research, buttressing recent recommendations from several medical societies to maintain COVID-19 patients on these drugs.

“Our findings in this paper provide evidence supporting continuous use of ACEI/ARB for patients with hypertension infected with SARS-COV-2,” wrote the authors, backing up recent recommendations from cardiology societies that called for not stopping ACEI/ARB prescriptions in patients at risk for contracting or already have COVID-19 infection, including a statement from the American College of Cardiology, American Heart Association, and Heart Failure Society of America, and also guidance from the European Society of Cardiology.

The study included 1,128 patients with a history of hypertension, including 188 (17%) who received an ACEI/ARB drug during hospitalization. During 28-day follow-up, 99 died (9%), including 7 deaths among the 188 patients (4%) on an ACEI/ARB drug and 92 deaths among the 940 other hypertensive patients (10%).

The authors ran several analyses to try to adjust for the influence of possible confounders. A mixed-effect Cox model with four adjusted variables showed that treatment with an ACEI/ARB drug was tied to a statistically significant 58% lower death rate, compared with patients not receiving these drugs.

The researchers also ran several propensity score–adjusted analyses. One matched 174 of the patients who received an ACEI/ARB drug with 522 who did not, and comparing these two matched arms showed that ACEI/ARB use was linked with a statistically significant 63% cut in mortality, compared with patients not getting these drugs. A second propensity score–matched analysis first excluded the 383 patients who were hypertensive but received no antihypertensive medication during hospitalization. From the remaining 745 patients who received at least one antihypertensive medication, the authors identified 181 patients who received an ACEI/ARB and propensity-score matched them with 181 hypertensive patients on a different medication class, finding that ACEI/ARB use linked with a statistically significant 71% lower rate of all-cause mortality.

Additional analyses also showed that patients with hypertension had a statistically significant, 41% increased rate of all-cause death, compared with patients without hypertension, and another propensity score–matched analysis showed that among hypertensives treatment with an ACEI/ARB drug was linked with a statistically significant 68% reduced rate of septic shock.

Although this report was received with caution and some skepticism, it was also acknowledged as a step forward in the creation of an evidence base addressing ACEI/ARB treatment during COVID-19 infection.

“These drugs are lifesaving and should not be discontinued” for patients with hypertension, heart failure, and other cardiovascular disease, commented Gian Paolo Rossi, MD, professor and chair of medicine and director of the high blood pressure unit at the University of Padua (Italy). The analysis by Zhang and associates included the largest number of hospitalized COVID-19 patients with hypertension yet reported to assess the impact of treatment with ACEI/ARB drugs, and adds important evidence in favor of continuing these drugs in patients who develop COVID-19 infection, Dr. Rossi said in an interview. He recently coauthored a review that argued against ACEI/ARB discontinuation in COVID-19 patients based on previously reported evidence (Elife. 2020 Apr 6. doi: 10.7554/eLife.57278).

But other researchers take a wary view of the potential impact of ACEI/ARB agents. “If ACEI/ARB therapy increases ACE2 and the virus down-regulates it, and because ACE2 is the viral entry port into cells, why would ACE2-mediated down-regulation of the renin-angiotensin-aldosterone system lead to amelioration of [COVID-19] disease?” asked Laurence W. Busse, MD, a critical care physician at Emory University, Atlanta. “A number of issues could potentially confound the results, including the definition of COVID-19 and imbalance of antiviral therapy,” added Dr. Busse, who recently coauthored an editorial that posited using angiotensin II (Giapreza), an approved vasopressor drug, as an alternative renin-angiotensin system intervention for COVID-19 patients including both those in shock as well as potentially those not in shock (Crit Care. 2020 Apr 7. doi: 10.1186/s13054-020-02862-1). Despite these caveats, the new Chinese findings reported by Dr. Zhang and associates “are hypothesis generating and worth further exploration.”

The authors of an editorial that accompanied the Zhang study in Circulation Research made similar points. “While the investigators used standard techniques to attempt to reduce bias in this observational study via propensity matching, it is not a randomized study and the residual confounding inherent to this approach renders the conclusions hypothesis generating at best,” wrote Ravi V. Shah, MD, and two coauthors in the editorial (Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317174). They also agreed with the several society statements that have supported continued use of ACEI/ARB drugs in COVID-19 patients. “Withdrawal of these medications in the context of those conditions in which they have proven benefit (e.g., heart failure with reduced left ventricular ejection fraction) may actually inflict more harm than good,” they warned. “In the end we must rely on randomized clinical science,” and while this level of evidence is currently lacking, “the study by Zhang and colleagues is a direct step toward that goal.”

Dr. Zhang and coauthors had no commercial disclosures. Dr. Rossi and Dr. Busse had no disclosures. The authors of the Circulation Research editorial reported several disclosures.

mzoler@mdedge.com

SOURCE: Zhang P et al. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.

International Laboratories has initiated a voluntary recall to the consumer level in the United States of a single lot of the antiplatelet clopidogrel because it is mislabeled and may contain simvastatin, a cholesterol-lowering drug, instead of clopidogrel.

The recalled product ― lot number 117099A of clopidogrel tablets (USP 75 mg) packaged in bottles of 30 tablets ― may contain clopidogrel 75 mg tablets or it could contain simvastatin tablets (USP 10 mg), according to a company announcement posted on the US Food and Drug Administration (FDA) website.

“Missed doses of clopidogrel increases the risk of heart attack and stroke which can be life threatening. Additionally, unintentional consumption of simvastatin could include the common side effects associated with its use and may cause fetal harm when administered to a pregnant woman,” the company cautions.

To date, the company has not received any reports of harm arising from the problem that prompted the recall.

The recalled product was distributed nationwide and was delivered to distribution centers in Arkansas, Georgia, Indiana, California, and Maryland and to retail stores in all US states.

International Laboratories is notifying distributors and customers by letter and is arranging for the return of all recalled products.

For questions regarding this recall, contact Inmar by phone 855-258-7280 (weekdays between 9:00 AM and 5:00 PM EST) or by email at internationallabs@inmar.com.

Adverse reactions or quality problems experienced with the use of this product should be reported to the FDA’s MedWatch adverse event reporting program.
 

This article first appeared on Medscape.com.

International Laboratories has initiated a voluntary recall to the consumer level in the United States of a single lot of the antiplatelet clopidogrel because it is mislabeled and may contain simvastatin, a cholesterol-lowering drug, instead of clopidogrel.

The recalled product ― lot number 117099A of clopidogrel tablets (USP 75 mg) packaged in bottles of 30 tablets ― may contain clopidogrel 75 mg tablets or it could contain simvastatin tablets (USP 10 mg), according to a company announcement posted on the US Food and Drug Administration (FDA) website.

“Missed doses of clopidogrel increases the risk of heart attack and stroke which can be life threatening. Additionally, unintentional consumption of simvastatin could include the common side effects associated with its use and may cause fetal harm when administered to a pregnant woman,” the company cautions.

To date, the company has not received any reports of harm arising from the problem that prompted the recall.

The recalled product was distributed nationwide and was delivered to distribution centers in Arkansas, Georgia, Indiana, California, and Maryland and to retail stores in all US states.

International Laboratories is notifying distributors and customers by letter and is arranging for the return of all recalled products.

For questions regarding this recall, contact Inmar by phone 855-258-7280 (weekdays between 9:00 AM and 5:00 PM EST) or by email at internationallabs@inmar.com.

Adverse reactions or quality problems experienced with the use of this product should be reported to the FDA’s MedWatch adverse event reporting program.
 

This article first appeared on Medscape.com.

International Laboratories has initiated a voluntary recall to the consumer level in the United States of a single lot of the antiplatelet clopidogrel because it is mislabeled and may contain simvastatin, a cholesterol-lowering drug, instead of clopidogrel.

The recalled product ― lot number 117099A of clopidogrel tablets (USP 75 mg) packaged in bottles of 30 tablets ― may contain clopidogrel 75 mg tablets or it could contain simvastatin tablets (USP 10 mg), according to a company announcement posted on the US Food and Drug Administration (FDA) website.

“Missed doses of clopidogrel increases the risk of heart attack and stroke which can be life threatening. Additionally, unintentional consumption of simvastatin could include the common side effects associated with its use and may cause fetal harm when administered to a pregnant woman,” the company cautions.

To date, the company has not received any reports of harm arising from the problem that prompted the recall.

The recalled product was distributed nationwide and was delivered to distribution centers in Arkansas, Georgia, Indiana, California, and Maryland and to retail stores in all US states.

International Laboratories is notifying distributors and customers by letter and is arranging for the return of all recalled products.

For questions regarding this recall, contact Inmar by phone 855-258-7280 (weekdays between 9:00 AM and 5:00 PM EST) or by email at internationallabs@inmar.com.

Adverse reactions or quality problems experienced with the use of this product should be reported to the FDA’s MedWatch adverse event reporting program.
 

This article first appeared on Medscape.com.

The American Society of Echocardiography (ASE) has issued a statement on protecting patients and echocardiography service providers during the COVID-19 pandemic.

Given the risk for cardiovascular complications associated with COVID-19, echocardiographic services will likely be needed for patients with suspected or confirmed COVID-19, meaning echo providers will be exposed to SARS-CoV-2, write the statement authors, led by James N. Kirkpatrick, MD, director of the echocardiography laboratory at University of Washington Medical Center in Seattle.

The statement was published online April 6 in the Journal of the American College of Cardiology.

The authors say the statement is intended to help guide the practice of echocardiography in this “challenging time.” It was developed with input from a variety of echocardiography providers and institutions who have experience with the COVID-19, or have been “actively and thoughtfully preparing for it.”

Who, When, Where, and How

The statement covers triaging and decision pathways for handling requests for echocardiography, as well as indications and recommended procedures, in cases of suspected or confirmed COVID-19.

Among the recommendations:

• Only perform transthoracic echocardiograms (TTE), stress echocardiograms, and transesophageal echocardiograms (TEE) if they are expected to provide clinical benefit. Appropriate-use criteria represent the first decision point as to whether an echocardiographic test should be performed.
• Determine which studies are “elective” and reschedule them, performing all others. Identify “nonelective” (urgent/emergent) indications and defer all others.
• Determine the clinical benefit of echocardiography for symptomatic patients whose SARS-CoV-2 status is unknown.
• Cautiously consider the benefit of a TEE examination weighed against the risk for exposure of healthcare personnel to aerosolization in a patient with suspected or confirmed COVID-19.
• Postpone or cancel TEEs if an alternative imaging modality can provide the necessary information.
• Note that treadmill or bicycle stress echo tests in patients with COVID-19 may lead to exposure because of deep breathing and/or coughing during exercise. These tests should generally be deferred or converted to a pharmacologic stress echo.
   

   

The ASE statement also provides advice on safe imaging protocol and adequate personal protection measures.

“In addition to limiting the number of echocardiography practitioners involved in scanning, consideration should be given to limiting the exposure of staff who may be particularly susceptible to severe complications of COVID-19,” the ASE advises.

Staff who are older than 60 years, who have chronic conditions, are immunocompromised or are pregnant may wish to avoid contact with patients suspected or confirmed to have COVID-19.

It’s also important to realize the risk for transmission in reading rooms. “Keyboards, monitors, mice, chairs, phones, desktops, and door knobs should be frequently cleaned, and ventilation provided wherever possible,” the ASE advises. When the echo lab reading room is located in a high-traffic area, remote review of images or via webinar might be advisable, they suggest.

Summing up, Kirkland and colleagues say providing echocardiographic service “remains crucial in this difficult time of the SARS-CoV-2 outbreak. Working together, we can continue to provide high-quality care while minimizing risk to ourselves, our patients, and the public at large. Carefully considering ‘Whom to Image’, ‘Where to Image’ and ‘How to Image’ has the potential to reduce the risks of transmission.”

The authors note that the statements and recommendations are primarily based on expert opinion rather than on scientifically verified data and are subject to change as the COVID-19 outbreak continues to evolve and new data emerges.
 

This article first appeared on Medscape.com.

The American Society of Echocardiography (ASE) has issued a statement on protecting patients and echocardiography service providers during the COVID-19 pandemic.

Given the risk for cardiovascular complications associated with COVID-19, echocardiographic services will likely be needed for patients with suspected or confirmed COVID-19, meaning echo providers will be exposed to SARS-CoV-2, write the statement authors, led by James N. Kirkpatrick, MD, director of the echocardiography laboratory at University of Washington Medical Center in Seattle.

The statement was published online April 6 in the Journal of the American College of Cardiology.

The authors say the statement is intended to help guide the practice of echocardiography in this “challenging time.” It was developed with input from a variety of echocardiography providers and institutions who have experience with the COVID-19, or have been “actively and thoughtfully preparing for it.”

Who, When, Where, and How

The statement covers triaging and decision pathways for handling requests for echocardiography, as well as indications and recommended procedures, in cases of suspected or confirmed COVID-19.

Among the recommendations:

• Only perform transthoracic echocardiograms (TTE), stress echocardiograms, and transesophageal echocardiograms (TEE) if they are expected to provide clinical benefit. Appropriate-use criteria represent the first decision point as to whether an echocardiographic test should be performed.
• Determine which studies are “elective” and reschedule them, performing all others. Identify “nonelective” (urgent/emergent) indications and defer all others.
• Determine the clinical benefit of echocardiography for symptomatic patients whose SARS-CoV-2 status is unknown.
• Cautiously consider the benefit of a TEE examination weighed against the risk for exposure of healthcare personnel to aerosolization in a patient with suspected or confirmed COVID-19.
• Postpone or cancel TEEs if an alternative imaging modality can provide the necessary information.
• Note that treadmill or bicycle stress echo tests in patients with COVID-19 may lead to exposure because of deep breathing and/or coughing during exercise. These tests should generally be deferred or converted to a pharmacologic stress echo.
   

   

The ASE statement also provides advice on safe imaging protocol and adequate personal protection measures.

“In addition to limiting the number of echocardiography practitioners involved in scanning, consideration should be given to limiting the exposure of staff who may be particularly susceptible to severe complications of COVID-19,” the ASE advises.

Staff who are older than 60 years, who have chronic conditions, are immunocompromised or are pregnant may wish to avoid contact with patients suspected or confirmed to have COVID-19.

It’s also important to realize the risk for transmission in reading rooms. “Keyboards, monitors, mice, chairs, phones, desktops, and door knobs should be frequently cleaned, and ventilation provided wherever possible,” the ASE advises. When the echo lab reading room is located in a high-traffic area, remote review of images or via webinar might be advisable, they suggest.

Summing up, Kirkland and colleagues say providing echocardiographic service “remains crucial in this difficult time of the SARS-CoV-2 outbreak. Working together, we can continue to provide high-quality care while minimizing risk to ourselves, our patients, and the public at large. Carefully considering ‘Whom to Image’, ‘Where to Image’ and ‘How to Image’ has the potential to reduce the risks of transmission.”

The authors note that the statements and recommendations are primarily based on expert opinion rather than on scientifically verified data and are subject to change as the COVID-19 outbreak continues to evolve and new data emerges.
 

This article first appeared on Medscape.com.

The American Society of Echocardiography (ASE) has issued a statement on protecting patients and echocardiography service providers during the COVID-19 pandemic.

Given the risk for cardiovascular complications associated with COVID-19, echocardiographic services will likely be needed for patients with suspected or confirmed COVID-19, meaning echo providers will be exposed to SARS-CoV-2, write the statement authors, led by James N. Kirkpatrick, MD, director of the echocardiography laboratory at University of Washington Medical Center in Seattle.

The statement was published online April 6 in the Journal of the American College of Cardiology.

The authors say the statement is intended to help guide the practice of echocardiography in this “challenging time.” It was developed with input from a variety of echocardiography providers and institutions who have experience with the COVID-19, or have been “actively and thoughtfully preparing for it.”

Who, When, Where, and How

The statement covers triaging and decision pathways for handling requests for echocardiography, as well as indications and recommended procedures, in cases of suspected or confirmed COVID-19.

Among the recommendations:

• Only perform transthoracic echocardiograms (TTE), stress echocardiograms, and transesophageal echocardiograms (TEE) if they are expected to provide clinical benefit. Appropriate-use criteria represent the first decision point as to whether an echocardiographic test should be performed.
• Determine which studies are “elective” and reschedule them, performing all others. Identify “nonelective” (urgent/emergent) indications and defer all others.
• Determine the clinical benefit of echocardiography for symptomatic patients whose SARS-CoV-2 status is unknown.
• Cautiously consider the benefit of a TEE examination weighed against the risk for exposure of healthcare personnel to aerosolization in a patient with suspected or confirmed COVID-19.
• Postpone or cancel TEEs if an alternative imaging modality can provide the necessary information.
• Note that treadmill or bicycle stress echo tests in patients with COVID-19 may lead to exposure because of deep breathing and/or coughing during exercise. These tests should generally be deferred or converted to a pharmacologic stress echo.
   

   

The ASE statement also provides advice on safe imaging protocol and adequate personal protection measures.

“In addition to limiting the number of echocardiography practitioners involved in scanning, consideration should be given to limiting the exposure of staff who may be particularly susceptible to severe complications of COVID-19,” the ASE advises.

Staff who are older than 60 years, who have chronic conditions, are immunocompromised or are pregnant may wish to avoid contact with patients suspected or confirmed to have COVID-19.

It’s also important to realize the risk for transmission in reading rooms. “Keyboards, monitors, mice, chairs, phones, desktops, and door knobs should be frequently cleaned, and ventilation provided wherever possible,” the ASE advises. When the echo lab reading room is located in a high-traffic area, remote review of images or via webinar might be advisable, they suggest.

Summing up, Kirkland and colleagues say providing echocardiographic service “remains crucial in this difficult time of the SARS-CoV-2 outbreak. Working together, we can continue to provide high-quality care while minimizing risk to ourselves, our patients, and the public at large. Carefully considering ‘Whom to Image’, ‘Where to Image’ and ‘How to Image’ has the potential to reduce the risks of transmission.”

The authors note that the statements and recommendations are primarily based on expert opinion rather than on scientifically verified data and are subject to change as the COVID-19 outbreak continues to evolve and new data emerges.
 

This article first appeared on Medscape.com.

Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.

The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.

One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.

The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).

The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.

In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).

The aortic stenosis connection

A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.

During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.

Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.

The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
 

What it could mean

These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.

Bruce Jancin/MDedge News

“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.

“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”

“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.

“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.

“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
 

How it might work

A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).

Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”

Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.

The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”

Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
 

The future of Lp(a) lowering

This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).

“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”

“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.

Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”

FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.

mzoler@mdedge.com

Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.

The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.

One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.

The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).

The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.

In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).

The aortic stenosis connection

A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.

During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.

Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.

The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
 

What it could mean

These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.

Bruce Jancin/MDedge News

“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.

“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”

“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.

“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.

“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
 

How it might work

A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).

Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”

Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.

The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”

Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
 

The future of Lp(a) lowering

This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).

“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”

“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.

Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”

FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.

mzoler@mdedge.com

Post hoc analyses of recent large, clinical outcomes studies of PCSK9 inhibitors have revealed two tantalizing and unexpected potential benefits from these drugs: an ability to substantially reduce the incidence or severity of venous thromboembolism and aortic stenosis.

The evidence also suggests that these effects are linked to the ability of these drugs to reduce blood levels of Lp(a) lipoprotein by roughly a quarter, currently the biggest known effect on Lp(a) levels of any approved medication.

One study ran post hoc analyses of venous thromboembolism (VTE) events in the FOURIER pivotal trial of evolocumab (Repatha), with more than 27,500 randomized patients (N Engl J Med. 2017 May 4; 376[18]:1713-22), and in the ODYSSEY OUTCOMES pivotal trial of alirocumab (Praluent), with nearly 19,000 randomized patients (N Engl J Med. 2018 Nov 29;379[22]:2097-2107). The analyses showed that, with evolocumab treatment, the incidence of VTE events fell by a statistically significant 29%, compared with patients on placebo, while in ODYSSEY OUTCOMES patients treated with alirocumab had a 33% cut in VTE events, compared with placebo-treated patients, a difference that just missed statistical significance (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046524) in analyses that were not prespecified before these trials started, Nicholas A. Marston, MD, said in a presentation of his research during the joint scientific sessions of the American College of Cardiology and the World Heart Federation, which was presented online this year. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

A combined analysis of 46,488 patients from both studies showed a 31% cut in VTE events with PCSK9 inhibitor treatment, a highly significant finding using VTE endpoints that were not specifically tallied nor adjudicated but collected as part of the serious adverse event reporting in the two pivotal trials, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. This is the first report of a statistically significant link between treatment with PCSK9-inhibiting agents and a reduction in VTE, he added. Researchers from the ODYSSEY OUTCOMES trial had reported a VTE analysis in 2019, and while data from that trial on its own showed a nominal 33% lower VTE rate with alirocumab treatment, it just missed statistical significance.

The VTE effect took about a year on treatment to start to manifest. During the first 12 months of FOURIER, the rate of VTE events among patients in the two treatment arms was virtually identical. But starting during months 13-18 on treatment, the event curves in the two arms began to increasingly diverge, and overall during the period from month 13 to the end of the study treatment with evolocumab was linked with a statistically significant 46% reduction in VTE events, compared with patients who received placebo. The results Dr. Marston reported were also published online (Circulation. 2020 Mar 29. doi: 10.1161/CIRCULATIONAHA.120.046397).

The suggestion that this association may be linked to the impact of PCSK9 inhibitors on Lp(a) came from an additional analysis that Dr. Marston presented, which looked at the link between evolocumab use and a change in VTE event rates, compared with placebo, depending on baseline lipoprotein levels. Evolocumab treatment was associated with a roughly similar, modest, and not statistically significant reduction in VTE events, compared with placebo regardless of whether patients had baseline levels of LDL cholesterol below the median or at or above the median. In contrast, when a similar analysis divided patients based on whether their Lp(a) level at baseline was below, or at or above, the median the results showed no discernible effect of evolocumab treatment, compared with on VTE events in patients with lower baseline Lp(a), but in those with higher levels treatment with evolocumab linked with a 48% cut in VTE events, compared with placebo, a statistically significant difference.

In FOURIER, treatment with evolocumab lowered baseline Lp(a) levels by a median of 27%, compared with placebo, among the 25,096 enrolled patients who had their baseline levels measured. As previously reported, prespecified analysis of FOURIER data also showed that the impact of evolocumab, compared with placebo, on the combined rate of coronary heart disease death, MI, or need for urgent coronary revascularization was enhanced among patients with elevated baseline Lp(a) and moderated in those who entered with lower levels. Among patients who entered FOURIER with Lp(a) levels at or below the median treatment with evolocumab cut the primary endpoint by 7%, compared with placebo, a difference that was not statistically significant. Among patients who began the study with Lp(a) levels above the median, evolocumab treatment cut the primary endpoint by 23%, compared with placebo, a statistically significant effect (Circulation. 2019 Mar 19;139[12]:1483-92).

The aortic stenosis connection

A second study reported in the online scientific sessions (Abstract 914-08) used only FOURIER data, and showed that patients treated with evolocumab had a roughly similar response pattern in their incidence of aortic stenosis (AS) events as they did for VTE events.

During the first year of the study, the incidence of AS events was virtually identical among patients treated with evolocumab and those who received placebo. But after the first 12 months and through the study’s end, patients on evolocumab showed a statistically significant 52% relative reduction in AS events, compared with control patients, said Brian A. Bergmark, MD. For the entire study duration, treatment with evolocumab linked with a 34% relative reduction in AS events, compared with placebo, a difference that did not reach statistical significance, added Dr. Bergmark, an interventional cardiologist also at Brigham and Women’s Hospital. The observed halving in total AS events that linked with evolocumab treatment after the first year of the study included a similar-magnitude reduction specifically in the incidence of aortic valve replacement procedures in the evolocumab-treated patients.

Further analysis of both total AS events and aortic valve replacements in FOURIER patients showed that they occurred at a significantly elevated rate in patients who entered the study with higher baseline Lp(a) levels in a multivariate analysis, but a similar analysis showed no significant association between the incidence of these AS-related events and baseline levels of LDL cholesterol, he said.

The AS analysis carried the same important limitations as the VTE analysis: It ran on a post hoc basis and focused on events that were relatively uncommon and not adjudicated, Dr. Bergmark cautioned. Nonetheless, other investigators saw important potential implications from both the VTE and AS observations, with the huge caveat that they need replication in prospective studies designed to specifically address the validity of these findings.
 

What it could mean

These observed associations between PCSK9 inhibitor treatment and apparent reductions in the rate of both VTE and AS events “represent a tremendous clinical breakthrough,” commented Michelle L. O’Donoghue, MD, a cardiologist at Brigham and Women’s Hospital who is a FOURIER coinvestigator and has led some of the Lp(a) analyses run from that study.

Bruce Jancin/MDedge News

“To date, we have not identified any therapies that slow progression of AS. Other classes of lipid-lowering therapies, such as statins, have been tested and not demonstrated a significant effect,” Dr. O’Donoghue said in an interview.

“For AS, the results are very intriguing. If confirmed, it could be groundbreaking. AS is the most common valve disease in the developed world, and no medical therapy exists. The potential is immense,” commented George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University, Montreal. “Having a medical treatment that could slow AS progression would completely change the disease. It’s conceivable to slow the disease enough that patients may never require valve replacement.” But an interview he cautioned that, “although the results are exciting, the analysis has many limitations. What we need is a dedicated, randomized trial for AS. I hope this stimulates that.”

“For VTE, it’s an interesting finding, but I don’t think it will have clinical utility because we have good treatment for VTE,” added Dr. Thanassoulis, but others saw more opportunity from what could be a new way to reduce VTE risk.

“Given that many patients have difficulty with the bleeding risk from anticoagulants, this option [a PCSK9 inhibitor] may be quite welcome for preventing VTE,” commented Gregory Piazza, MD, a cardiologist and VTE specialist at Brigham and Women’s Hospital who was not involved in any of the PCSK9 inhibitor studies.

“At this time we would not suggest that PCSK9 inhibitors replace an anticoagulant for patients with an established clot or at high risk for a recurrent clot, but if patients have an indication for a PCSK9 inhibitor, the further reduction in venous clot can be viewed as an additional benefit of this therapy,” said Dr. O’Donoghue.
 

How it might work

A possible mechanism underlying a VTE effect is unclear. Results from the JUPITER trial more than a decade ago had shown a significant association between treatment with 20 mg/day of rosuvastatin and a cut in VTE episodes, compared with placebo, in a prespecified, secondary analysis of the trial with nearly 18,000 patients selected for having a relatively high level of high-sensitivity C-reactive protein (N Engl J Med. 2009 Apr 30;360[18]:1851-61). But a meta-analysis of 29 controlled statin trials that used a variety of statin types and dosages (and included the JUPITER results) failed to confirm a statistically significant change in VTE rates from statins, though they produced a small, nominal reduction (PLoS Med. 2012 Sep 18. doi: 10.1371/journal.pmed.1001310).

Lp(a) “has long been linked to thrombosis, in particular arterial thrombosis,” so the link observed in the PCSK9 inhibitor trials “is not surprising,” said Dr. Piazza. Dr. O’Donoghue agreed that prior evidence had “suggested a prothrombotic role for Lp(a).”

Dr. Thanassoulis was more skeptical of a Lp(a) connection to VTE. “There has always been controversy regarding the prothrombotic effects of Lp(a) and whether it’s clinically relevant,” he said. “The genetic data, from Mendelian randomization studies, is not consistent” with a Lp(a) and VTE link.

The association of AS and Lp(a) may be stronger. “Our team showed that people with genetic variants that predispose to high Lp(a) have a much higher incidence of AS,” Dr. Thanassoulis noted. “We and others have also demonstrated that both Lp(a) and LDL are likely causal mediators of aortic valve calcification and stenosis.”

Dr. O’Donoghue also cited observational genetic data that linked elevated Lp(a) with AS. “Mendelian randomization studies have demonstrated that Lp(a) is a causal contributer to AS, and evolocumab reduced Lp(a) by 25%-30%, raising the possibility that Lp(a) lowering with these drugs may be the mechanism,” she said.
 

The future of Lp(a) lowering

This last point from Dr. O’Donoghue, that PCSK9 inhibitors cut Lp(a) levels by about 25%-30%, means that they are the most potent Lp(a)-lowering agents currently available, but it also leaves lots of room for other agents to do even better in cutting Lp(a).

“There are now drugs in development that block production of the Lp(a) protein and dramatically reduce its concentration, by about 80%,” Dr. O’Donoghue noted. “It will be of interest to study whether these novel therapies, now in phase 2 and phase 3 studies, have any effect on the risk for VTE and AS.”

“Several drugs in development, including antisense RNA and RNA-interfering molecules, are much more potent and lower Lp(a) by 80%-90%. Because of this potency they can completely normalize Lp(a) in most patients. For Lp(a) lowering, the future is in these new molecules. Randomized trials have started, and we will hopefully have some results in about 5 years,” said Dr. Thanassoulis.

Until then, the prospect of possibly soon documenting benefits from PCSK9 inhibitors beyond their impact on cutting LDL cholesterol raises some hope to get more bang for the considerable buck these drugs cost. But Dr. Thanassoulis was skeptical it would move the cost-benefit ratio much. “VTE and AS are relatively rare, compared with atherosclerotic cardiovascular events, and therefore the added value at the population level would be small,” he predicted. But if treatment with a drug could help patients avoid surgical or percutaneous valve interventions “that could be really interesting from a cost-benefit perspective.”

FOURIER was funded by Amgen, the company that markets evolocumab (Repatha). ODYSSEY OUTCOMES was funded by Sanofi and Regeneron, the companies that developed and market alirocumab (Praluent). Dr. Marston had no disclosures. Dr. Bergmark has been a consultant to Daiichi Sankyo, Janssen, Quark, and Servier and has received research funding from Abbott Vascular, AstraZeneca, and MedImmune. Dr. O’Donoghue has been a consultant to and has received research funding from Amgen; has been a consultant to Janssen and Novartis; and has received research funding from AstraZeneca, Eisai, GlaxoSmithKline, Janssen, Medimmune, Merck, and The Medicines Company. Dr. Thanassoulis has been an adviser to and speaker for Amgen; an adviser to Ionis and Sanofi/Regeneron; a speaker on behalf of Boehringer Ingelheim, Sanofi, and Servier; and has received research funding from Ionis and Servier. Dr. Piazza has been a consultant to Optum, Pfizer, and Thrombolex and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola.

mzoler@mdedge.com

The American Heart Association (AHA) and seven other medical societies have issued interim guidance to inform treatment of victims of cardiac arrest with suspected or confirmed COVID-19, focusing on reducing provider exposure, and prioritizing oxygenation and ventilation strategies, goals of care, and appropriateness of resuscitation.

“We were very specific in calling this ‘interim guidance’ based on expert opinion because things are evolving so quickly and we are learning more and more every day as more and more patients with COVID-19 are taken care of,” corresponding author Comilla Sasson, MD, PhD, vice president, Emergency Cardiovascular Care (ECC) Science and Innovation, American Heart Association, told theheart.org | Medscape Cardiology.

“We wanted this to be a starting point for providing the clinical guidance that everyone is looking for and, as we collect more data, the guidance will change, as it has for CDC [Centers for Disease Control and Prevention] and WHO [World Health Organization],” she said.

“The guidance sought to balance the provision of timely, high-quality resuscitation to patients while simultaneously protecting rescuers,” she added.

The guidance was published online April 9 in Circulation. The AHA produced the guidelines in collaboration with the American Academy of Pediatrics, American Association for Respiratory Care, American College of Emergency Physicians, the Society of Critical Care Anesthesiologists, and the American Society of Anesthesiologists, with support from the American Association of Critical Care Nurses and National EMS Physicians.
 

Respiratory Etiologies

“We think of cardiac arrest in adults, especially as related to cardiac etiologies, but we are now thinking of it in COVID-19 more as hypoxemia or respiratory failure, which can predispose patients to cardiac arrest,” Sasson explained.

Healthcare workers are the “highest-risk profession” for contracting the COVID-19, with resuscitations carrying “added risk” for several reasons, the authors note.

Administering CPR involves performing numerous aerosol-generating procedures that can cause viral particles to remain suspended in the air and be inhaled by those nearby, with a half-life of approximately 1 hour, they point out.

Moreover, resuscitation efforts “require numerous providers to work in close proximity to one another and the patient,” and the high-stress emergent nature of these events may result in lapses in infection-control procedures.

The guidance is designed “to protect not only the patient but also the provider and involves strategies regarding oxygenation and ventilation that differ from what we’ve done in the past since we have a strong feeling that this is a different disease process that may require different approaches than what we’ve dealt with in the past,” Sasson commented.

Reducing Provider Exposure

Providers should don PPE to protect both themselves and their colleagues from unnecessary exposure, the authors advise, noting that recommendations for PPE standards may “vary considerably,” so health or emergency medical services (EMS) standards should be taken into account.

Moreover, it is important to allow only the most essential providers into the room or on the scene. In keeping with reducing the number of rescuers, the authors recommend replacing manual chest compressions with mechanical CPR devices for patients who meet height and weight criteria in settings with “protocols and expertise in place for their use.”

COVID-19 status should be communicated to any new providers prior to their arrival on the scene, the authors stress.
 

Oxygenation and Ventilation Strategies

“Reducing risk of aerosolization during the process of intubation is key,” Sasson emphasized.

For this reason, a high-efficiency particulate air HEPA filter (if available) should be attached to any manual or mechanical ventilation device, specifically in the path of exhaled gas, before any breaths are administered.

Moreover, it is important to intubate early with a cuffed tube and connect to a mechanical ventilator, if possible. The intubator should be engaged with the “highest chance of first-pass success,” and chest compression should be paused to intubate.

To further increase the chance of a successful first intubation, use of video laryngoscopy (if available) is helpful.

Additional guidance includes:

• Using a bag-mask device (or T-piece in neonates) with a HEPA filter and a tight seal prior to intubation
• Considering passive oxygenation with non-rebreathing face mask as an alternative to bag-mask device for short duration (in adults)
• Considering supraglottic airway if intubation is delayed
• Minimizing closed circuit disconnections.

Resuscitation Considerations

“One big take-home point of the guidance is to consider resuscitation appropriateness, starting with goals of care when the patient comes to us, and continuing or stopping resuscitation when needed, based on the discussion with the family as well as local protocol,” Sasson said.

A variety of factors need to be taken into account, including age, comorbidities, and illness severity to determine the appropriateness of resuscitation, and “the likelihood of success” must be balanced “against the risk to rescuers and patients from whom resources are being diverted,” the authors state.

An Array of Scenarios

“We divided bystander CPR into adults vs pediatrics and into those who are living with a person who is in cardiac arrest – because they have already been exposed [to COVID-19] – vs those who are not living with the patient,” Sasson reported. “We also addressed the role of lay bystanders.”

For lay rescuers:

• Household members should perform at least hands-only CPR, if willing and able to do so
• Use of a face mark or cloth covering of the mouth and nose of the rescuer and/or patient may reduce the risk of transmission to a nonhousehold member
• In children, lay rescuers should perform chest compressions and “consider mouth-to-mouth resuscitation,” especially if they are household members.
• If available, an automated external defibrillator should be used to assess and treat victims of out-of-hospital cardiac arrest (OHCA).

The authors offer additional guidance for in-hospital cardiac arrest (IHCA), including addressing advanced care directives, closing the door when possible to prevent airborne contamination of adjacent space, and considering leaving the patient on a mechanical ventilator with HEPA filter.

They additionally address the special needs of neonates, recommending the presence of a “skilled attendant prepared to resuscitate, irrespective of COVID-19 status,” and stressing the importance of PPE since the mother may be a “potential source of aerosolization for the neonatal team.” Additional measures include avoidance of routine airway suctioning and the use of endotracheal medications.

Critically ill pregnant women with COVID-19 are more vulnerable to acute decompensation because of the cardiopulmonary physiological changes associated with pregnancy, the authors note. Preparation for a potential perimortem delivery should take place after 4 minutes of resuscitation and be initiated early in the resuscitation algorithm so as to allow specialized obstetrical and neonatal teams with PPE to convene.

“We will be continually updating this guidance and we are encouraging people to ask questions,” Sasson summarized.

She noted that a hospital-based COVID-19 registry is being formed to collect “clinically relevant data” that will inform and update the current guidance.

Sasson reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.
 

This article first appeared on Medscape.com.

The American Heart Association (AHA) and seven other medical societies have issued interim guidance to inform treatment of victims of cardiac arrest with suspected or confirmed COVID-19, focusing on reducing provider exposure, and prioritizing oxygenation and ventilation strategies, goals of care, and appropriateness of resuscitation.

“We were very specific in calling this ‘interim guidance’ based on expert opinion because things are evolving so quickly and we are learning more and more every day as more and more patients with COVID-19 are taken care of,” corresponding author Comilla Sasson, MD, PhD, vice president, Emergency Cardiovascular Care (ECC) Science and Innovation, American Heart Association, told theheart.org | Medscape Cardiology.

“We wanted this to be a starting point for providing the clinical guidance that everyone is looking for and, as we collect more data, the guidance will change, as it has for CDC [Centers for Disease Control and Prevention] and WHO [World Health Organization],” she said.

“The guidance sought to balance the provision of timely, high-quality resuscitation to patients while simultaneously protecting rescuers,” she added.

The guidance was published online April 9 in Circulation. The AHA produced the guidelines in collaboration with the American Academy of Pediatrics, American Association for Respiratory Care, American College of Emergency Physicians, the Society of Critical Care Anesthesiologists, and the American Society of Anesthesiologists, with support from the American Association of Critical Care Nurses and National EMS Physicians.
 

Respiratory Etiologies

“We think of cardiac arrest in adults, especially as related to cardiac etiologies, but we are now thinking of it in COVID-19 more as hypoxemia or respiratory failure, which can predispose patients to cardiac arrest,” Sasson explained.

Healthcare workers are the “highest-risk profession” for contracting the COVID-19, with resuscitations carrying “added risk” for several reasons, the authors note.

Administering CPR involves performing numerous aerosol-generating procedures that can cause viral particles to remain suspended in the air and be inhaled by those nearby, with a half-life of approximately 1 hour, they point out.

Moreover, resuscitation efforts “require numerous providers to work in close proximity to one another and the patient,” and the high-stress emergent nature of these events may result in lapses in infection-control procedures.

The guidance is designed “to protect not only the patient but also the provider and involves strategies regarding oxygenation and ventilation that differ from what we’ve done in the past since we have a strong feeling that this is a different disease process that may require different approaches than what we’ve dealt with in the past,” Sasson commented.

Reducing Provider Exposure

Providers should don PPE to protect both themselves and their colleagues from unnecessary exposure, the authors advise, noting that recommendations for PPE standards may “vary considerably,” so health or emergency medical services (EMS) standards should be taken into account.

Moreover, it is important to allow only the most essential providers into the room or on the scene. In keeping with reducing the number of rescuers, the authors recommend replacing manual chest compressions with mechanical CPR devices for patients who meet height and weight criteria in settings with “protocols and expertise in place for their use.”

COVID-19 status should be communicated to any new providers prior to their arrival on the scene, the authors stress.
 

Oxygenation and Ventilation Strategies

“Reducing risk of aerosolization during the process of intubation is key,” Sasson emphasized.

For this reason, a high-efficiency particulate air HEPA filter (if available) should be attached to any manual or mechanical ventilation device, specifically in the path of exhaled gas, before any breaths are administered.

Moreover, it is important to intubate early with a cuffed tube and connect to a mechanical ventilator, if possible. The intubator should be engaged with the “highest chance of first-pass success,” and chest compression should be paused to intubate.

To further increase the chance of a successful first intubation, use of video laryngoscopy (if available) is helpful.

Additional guidance includes:

• Using a bag-mask device (or T-piece in neonates) with a HEPA filter and a tight seal prior to intubation
• Considering passive oxygenation with non-rebreathing face mask as an alternative to bag-mask device for short duration (in adults)
• Considering supraglottic airway if intubation is delayed
• Minimizing closed circuit disconnections.

Resuscitation Considerations

“One big take-home point of the guidance is to consider resuscitation appropriateness, starting with goals of care when the patient comes to us, and continuing or stopping resuscitation when needed, based on the discussion with the family as well as local protocol,” Sasson said.

A variety of factors need to be taken into account, including age, comorbidities, and illness severity to determine the appropriateness of resuscitation, and “the likelihood of success” must be balanced “against the risk to rescuers and patients from whom resources are being diverted,” the authors state.

An Array of Scenarios

“We divided bystander CPR into adults vs pediatrics and into those who are living with a person who is in cardiac arrest – because they have already been exposed [to COVID-19] – vs those who are not living with the patient,” Sasson reported. “We also addressed the role of lay bystanders.”

For lay rescuers:

• Household members should perform at least hands-only CPR, if willing and able to do so
• Use of a face mark or cloth covering of the mouth and nose of the rescuer and/or patient may reduce the risk of transmission to a nonhousehold member
• In children, lay rescuers should perform chest compressions and “consider mouth-to-mouth resuscitation,” especially if they are household members.
• If available, an automated external defibrillator should be used to assess and treat victims of out-of-hospital cardiac arrest (OHCA).

The authors offer additional guidance for in-hospital cardiac arrest (IHCA), including addressing advanced care directives, closing the door when possible to prevent airborne contamination of adjacent space, and considering leaving the patient on a mechanical ventilator with HEPA filter.

They additionally address the special needs of neonates, recommending the presence of a “skilled attendant prepared to resuscitate, irrespective of COVID-19 status,” and stressing the importance of PPE since the mother may be a “potential source of aerosolization for the neonatal team.” Additional measures include avoidance of routine airway suctioning and the use of endotracheal medications.

Critically ill pregnant women with COVID-19 are more vulnerable to acute decompensation because of the cardiopulmonary physiological changes associated with pregnancy, the authors note. Preparation for a potential perimortem delivery should take place after 4 minutes of resuscitation and be initiated early in the resuscitation algorithm so as to allow specialized obstetrical and neonatal teams with PPE to convene.

“We will be continually updating this guidance and we are encouraging people to ask questions,” Sasson summarized.

She noted that a hospital-based COVID-19 registry is being formed to collect “clinically relevant data” that will inform and update the current guidance.

Sasson reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.
 

This article first appeared on Medscape.com.

The American Heart Association (AHA) and seven other medical societies have issued interim guidance to inform treatment of victims of cardiac arrest with suspected or confirmed COVID-19, focusing on reducing provider exposure, and prioritizing oxygenation and ventilation strategies, goals of care, and appropriateness of resuscitation.

“We were very specific in calling this ‘interim guidance’ based on expert opinion because things are evolving so quickly and we are learning more and more every day as more and more patients with COVID-19 are taken care of,” corresponding author Comilla Sasson, MD, PhD, vice president, Emergency Cardiovascular Care (ECC) Science and Innovation, American Heart Association, told theheart.org | Medscape Cardiology.

“We wanted this to be a starting point for providing the clinical guidance that everyone is looking for and, as we collect more data, the guidance will change, as it has for CDC [Centers for Disease Control and Prevention] and WHO [World Health Organization],” she said.

“The guidance sought to balance the provision of timely, high-quality resuscitation to patients while simultaneously protecting rescuers,” she added.

The guidance was published online April 9 in Circulation. The AHA produced the guidelines in collaboration with the American Academy of Pediatrics, American Association for Respiratory Care, American College of Emergency Physicians, the Society of Critical Care Anesthesiologists, and the American Society of Anesthesiologists, with support from the American Association of Critical Care Nurses and National EMS Physicians.
 

Respiratory Etiologies

“We think of cardiac arrest in adults, especially as related to cardiac etiologies, but we are now thinking of it in COVID-19 more as hypoxemia or respiratory failure, which can predispose patients to cardiac arrest,” Sasson explained.

Healthcare workers are the “highest-risk profession” for contracting the COVID-19, with resuscitations carrying “added risk” for several reasons, the authors note.

Administering CPR involves performing numerous aerosol-generating procedures that can cause viral particles to remain suspended in the air and be inhaled by those nearby, with a half-life of approximately 1 hour, they point out.

Moreover, resuscitation efforts “require numerous providers to work in close proximity to one another and the patient,” and the high-stress emergent nature of these events may result in lapses in infection-control procedures.

The guidance is designed “to protect not only the patient but also the provider and involves strategies regarding oxygenation and ventilation that differ from what we’ve done in the past since we have a strong feeling that this is a different disease process that may require different approaches than what we’ve dealt with in the past,” Sasson commented.

Reducing Provider Exposure

Providers should don PPE to protect both themselves and their colleagues from unnecessary exposure, the authors advise, noting that recommendations for PPE standards may “vary considerably,” so health or emergency medical services (EMS) standards should be taken into account.

Moreover, it is important to allow only the most essential providers into the room or on the scene. In keeping with reducing the number of rescuers, the authors recommend replacing manual chest compressions with mechanical CPR devices for patients who meet height and weight criteria in settings with “protocols and expertise in place for their use.”

COVID-19 status should be communicated to any new providers prior to their arrival on the scene, the authors stress.
 

Oxygenation and Ventilation Strategies

“Reducing risk of aerosolization during the process of intubation is key,” Sasson emphasized.

For this reason, a high-efficiency particulate air HEPA filter (if available) should be attached to any manual or mechanical ventilation device, specifically in the path of exhaled gas, before any breaths are administered.

Moreover, it is important to intubate early with a cuffed tube and connect to a mechanical ventilator, if possible. The intubator should be engaged with the “highest chance of first-pass success,” and chest compression should be paused to intubate.

To further increase the chance of a successful first intubation, use of video laryngoscopy (if available) is helpful.

Additional guidance includes:

• Using a bag-mask device (or T-piece in neonates) with a HEPA filter and a tight seal prior to intubation
• Considering passive oxygenation with non-rebreathing face mask as an alternative to bag-mask device for short duration (in adults)
• Considering supraglottic airway if intubation is delayed
• Minimizing closed circuit disconnections.

Resuscitation Considerations

“One big take-home point of the guidance is to consider resuscitation appropriateness, starting with goals of care when the patient comes to us, and continuing or stopping resuscitation when needed, based on the discussion with the family as well as local protocol,” Sasson said.

A variety of factors need to be taken into account, including age, comorbidities, and illness severity to determine the appropriateness of resuscitation, and “the likelihood of success” must be balanced “against the risk to rescuers and patients from whom resources are being diverted,” the authors state.

An Array of Scenarios

“We divided bystander CPR into adults vs pediatrics and into those who are living with a person who is in cardiac arrest – because they have already been exposed [to COVID-19] – vs those who are not living with the patient,” Sasson reported. “We also addressed the role of lay bystanders.”

For lay rescuers:

• Household members should perform at least hands-only CPR, if willing and able to do so
• Use of a face mark or cloth covering of the mouth and nose of the rescuer and/or patient may reduce the risk of transmission to a nonhousehold member
• In children, lay rescuers should perform chest compressions and “consider mouth-to-mouth resuscitation,” especially if they are household members.
• If available, an automated external defibrillator should be used to assess and treat victims of out-of-hospital cardiac arrest (OHCA).

The authors offer additional guidance for in-hospital cardiac arrest (IHCA), including addressing advanced care directives, closing the door when possible to prevent airborne contamination of adjacent space, and considering leaving the patient on a mechanical ventilator with HEPA filter.

They additionally address the special needs of neonates, recommending the presence of a “skilled attendant prepared to resuscitate, irrespective of COVID-19 status,” and stressing the importance of PPE since the mother may be a “potential source of aerosolization for the neonatal team.” Additional measures include avoidance of routine airway suctioning and the use of endotracheal medications.

Critically ill pregnant women with COVID-19 are more vulnerable to acute decompensation because of the cardiopulmonary physiological changes associated with pregnancy, the authors note. Preparation for a potential perimortem delivery should take place after 4 minutes of resuscitation and be initiated early in the resuscitation algorithm so as to allow specialized obstetrical and neonatal teams with PPE to convene.

“We will be continually updating this guidance and we are encouraging people to ask questions,” Sasson summarized.

She noted that a hospital-based COVID-19 registry is being formed to collect “clinically relevant data” that will inform and update the current guidance.

Sasson reports no relevant financial relationships. The other authors’ disclosures are listed on the original paper.
 

This article first appeared on Medscape.com.

Because of their place at the interface between critical care and cardiovascular medicine, critical care cardiologists are in a good position to come up with novel approaches to adapting critical care systems to the current crisis. Health care and clinical resources have been severely strained in some places, and increasing evidence suggests that SARS-CoV-2 can cause injury to most organ systems. More than a quarter of hospitalized patients have cardiac injury, which can be a key reason for clinical deterioration.

An international group of critical care cardiologists led by Jason Katz, MD, of Duke University, Durham, N.C., offered suggestions for scalable models for critical care delivery in the context of COVID-19 in the Journal of the American College of Cardiology.

Critical care cardiology developed in response to changes in patient populations and their clinical needs. Respiratory insufficiency, heart failure, structural heart disease, and multisystem organ dysfunction became more common than patients with complicated acute MI, leading cardiologists in critical care cardiology to become more proficient in general critical care medicine, and to become leaders in forming collaborative multidisciplinary teams. The authors argued that COVID-19 is precipitating a similar need to adapt to the changing needs of patients.

“This pandemic should serve as a clarion call to our health care systems that we should continue to develop a nimble workforce that can adapt to change quickly during a crisis. We believe critical care cardiologists are well positioned to help serve society in this capacity,” the authors wrote.
 

Surge staging

They proposed four surge stages based in part on an American College of Chest Physicians–endorsed model (Chest 2014 Oct;146:e61S-74S), which regards a 25% capacity surge as minor. At the other end of the spectrum, a 200% surge is defined as a “disaster.” In minor surges (less than 25% increase), the traditional cardiac ICU (CICU) model can continue to be applied. During moderate (25%-100% increases) or major (100%-200%) surges, the critical care cardiologist should collaborate or consult within multiple health care teams. Physicians not trained in critical care can assist with care of intubated and critically ill patients under the supervision of a critical care cardiologist or under the supervision of a partnership between a non–cardiac critical care medicine provider and a cardiologist. The number of patients cared for by each team should increase in step with the size of the surge.

In disaster situations (more than 200% surge), there should be adaptive and dynamic staffing reorganization. The report included an illustration of a range of steps that can be taken, including alterations to staffing, regional care systems, resource management, and triage practices. Scoring systems such as Sequential Organ Failure Assessment may be useful for triaging, but the authors also suggest employment of validated cardiac disease–specific scores, because traditional ICU measures don’t always apply well to CICU populations.

At the hospital level, deferrals should be made for elective cardiac procedures that require CICU or postanesthesia care unit recovery periods. Semielective procedures should be considered after risk-benefit considerations when delays could lead to morbidity or mortality. Even some traditional emergency procedures may need to be reevaluated in the COVID-19 context: For example, some low-risk ST-segment elevation MI (STEMI) patients don’t require ICU care but are manageable in cardiac intermediate care beds instead. Historical triage practices should be reexamined to predict which STEMI patients will require ICU care.
 

Resource allocation

The CICU work flow will be affected as some of its beds are opened up to COVID-19 patients. Standard philosophies of concentrating intense resources will have to give way to a utilitarian approach that evaluates operations based on efficiency, equity, and justice. Physician-patient contact should be minimized using technological links when possible, and rounds might be reorganized to first examine patients without COVID-19, in order to minimize between-patient spread.

Military medicine, which is used to ramping up operations during times of crisis, has potential lessons for the current pandemic. In the face of mass casualties, military physicians often turn to the North Atlantic Treaty Organization triage system, which separates patients into four categories: immediate, requiring lifesaving intervention; delayed, requiring intervention within hours to days; minimal, where the patient is injured but ambulatory; and expectant patients who are deceased or too injured to save. Impersonal though this system may be, it may be required in the most severe scenarios when resources are scarce or absent.

The authors reported no relevant financial disclosures.

SOURCE: Katz J et al. J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.annonc.2020.02.01.

Because of their place at the interface between critical care and cardiovascular medicine, critical care cardiologists are in a good position to come up with novel approaches to adapting critical care systems to the current crisis. Health care and clinical resources have been severely strained in some places, and increasing evidence suggests that SARS-CoV-2 can cause injury to most organ systems. More than a quarter of hospitalized patients have cardiac injury, which can be a key reason for clinical deterioration.

An international group of critical care cardiologists led by Jason Katz, MD, of Duke University, Durham, N.C., offered suggestions for scalable models for critical care delivery in the context of COVID-19 in the Journal of the American College of Cardiology.

Critical care cardiology developed in response to changes in patient populations and their clinical needs. Respiratory insufficiency, heart failure, structural heart disease, and multisystem organ dysfunction became more common than patients with complicated acute MI, leading cardiologists in critical care cardiology to become more proficient in general critical care medicine, and to become leaders in forming collaborative multidisciplinary teams. The authors argued that COVID-19 is precipitating a similar need to adapt to the changing needs of patients.

“This pandemic should serve as a clarion call to our health care systems that we should continue to develop a nimble workforce that can adapt to change quickly during a crisis. We believe critical care cardiologists are well positioned to help serve society in this capacity,” the authors wrote.
 

Surge staging

They proposed four surge stages based in part on an American College of Chest Physicians–endorsed model (Chest 2014 Oct;146:e61S-74S), which regards a 25% capacity surge as minor. At the other end of the spectrum, a 200% surge is defined as a “disaster.” In minor surges (less than 25% increase), the traditional cardiac ICU (CICU) model can continue to be applied. During moderate (25%-100% increases) or major (100%-200%) surges, the critical care cardiologist should collaborate or consult within multiple health care teams. Physicians not trained in critical care can assist with care of intubated and critically ill patients under the supervision of a critical care cardiologist or under the supervision of a partnership between a non–cardiac critical care medicine provider and a cardiologist. The number of patients cared for by each team should increase in step with the size of the surge.

In disaster situations (more than 200% surge), there should be adaptive and dynamic staffing reorganization. The report included an illustration of a range of steps that can be taken, including alterations to staffing, regional care systems, resource management, and triage practices. Scoring systems such as Sequential Organ Failure Assessment may be useful for triaging, but the authors also suggest employment of validated cardiac disease–specific scores, because traditional ICU measures don’t always apply well to CICU populations.

At the hospital level, deferrals should be made for elective cardiac procedures that require CICU or postanesthesia care unit recovery periods. Semielective procedures should be considered after risk-benefit considerations when delays could lead to morbidity or mortality. Even some traditional emergency procedures may need to be reevaluated in the COVID-19 context: For example, some low-risk ST-segment elevation MI (STEMI) patients don’t require ICU care but are manageable in cardiac intermediate care beds instead. Historical triage practices should be reexamined to predict which STEMI patients will require ICU care.
 

Resource allocation

The CICU work flow will be affected as some of its beds are opened up to COVID-19 patients. Standard philosophies of concentrating intense resources will have to give way to a utilitarian approach that evaluates operations based on efficiency, equity, and justice. Physician-patient contact should be minimized using technological links when possible, and rounds might be reorganized to first examine patients without COVID-19, in order to minimize between-patient spread.

Military medicine, which is used to ramping up operations during times of crisis, has potential lessons for the current pandemic. In the face of mass casualties, military physicians often turn to the North Atlantic Treaty Organization triage system, which separates patients into four categories: immediate, requiring lifesaving intervention; delayed, requiring intervention within hours to days; minimal, where the patient is injured but ambulatory; and expectant patients who are deceased or too injured to save. Impersonal though this system may be, it may be required in the most severe scenarios when resources are scarce or absent.

The authors reported no relevant financial disclosures.

SOURCE: Katz J et al. J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.annonc.2020.02.01.

Because of their place at the interface between critical care and cardiovascular medicine, critical care cardiologists are in a good position to come up with novel approaches to adapting critical care systems to the current crisis. Health care and clinical resources have been severely strained in some places, and increasing evidence suggests that SARS-CoV-2 can cause injury to most organ systems. More than a quarter of hospitalized patients have cardiac injury, which can be a key reason for clinical deterioration.

An international group of critical care cardiologists led by Jason Katz, MD, of Duke University, Durham, N.C., offered suggestions for scalable models for critical care delivery in the context of COVID-19 in the Journal of the American College of Cardiology.

Critical care cardiology developed in response to changes in patient populations and their clinical needs. Respiratory insufficiency, heart failure, structural heart disease, and multisystem organ dysfunction became more common than patients with complicated acute MI, leading cardiologists in critical care cardiology to become more proficient in general critical care medicine, and to become leaders in forming collaborative multidisciplinary teams. The authors argued that COVID-19 is precipitating a similar need to adapt to the changing needs of patients.

“This pandemic should serve as a clarion call to our health care systems that we should continue to develop a nimble workforce that can adapt to change quickly during a crisis. We believe critical care cardiologists are well positioned to help serve society in this capacity,” the authors wrote.
 

Surge staging

They proposed four surge stages based in part on an American College of Chest Physicians–endorsed model (Chest 2014 Oct;146:e61S-74S), which regards a 25% capacity surge as minor. At the other end of the spectrum, a 200% surge is defined as a “disaster.” In minor surges (less than 25% increase), the traditional cardiac ICU (CICU) model can continue to be applied. During moderate (25%-100% increases) or major (100%-200%) surges, the critical care cardiologist should collaborate or consult within multiple health care teams. Physicians not trained in critical care can assist with care of intubated and critically ill patients under the supervision of a critical care cardiologist or under the supervision of a partnership between a non–cardiac critical care medicine provider and a cardiologist. The number of patients cared for by each team should increase in step with the size of the surge.

In disaster situations (more than 200% surge), there should be adaptive and dynamic staffing reorganization. The report included an illustration of a range of steps that can be taken, including alterations to staffing, regional care systems, resource management, and triage practices. Scoring systems such as Sequential Organ Failure Assessment may be useful for triaging, but the authors also suggest employment of validated cardiac disease–specific scores, because traditional ICU measures don’t always apply well to CICU populations.

At the hospital level, deferrals should be made for elective cardiac procedures that require CICU or postanesthesia care unit recovery periods. Semielective procedures should be considered after risk-benefit considerations when delays could lead to morbidity or mortality. Even some traditional emergency procedures may need to be reevaluated in the COVID-19 context: For example, some low-risk ST-segment elevation MI (STEMI) patients don’t require ICU care but are manageable in cardiac intermediate care beds instead. Historical triage practices should be reexamined to predict which STEMI patients will require ICU care.
 

Resource allocation

The CICU work flow will be affected as some of its beds are opened up to COVID-19 patients. Standard philosophies of concentrating intense resources will have to give way to a utilitarian approach that evaluates operations based on efficiency, equity, and justice. Physician-patient contact should be minimized using technological links when possible, and rounds might be reorganized to first examine patients without COVID-19, in order to minimize between-patient spread.

Military medicine, which is used to ramping up operations during times of crisis, has potential lessons for the current pandemic. In the face of mass casualties, military physicians often turn to the North Atlantic Treaty Organization triage system, which separates patients into four categories: immediate, requiring lifesaving intervention; delayed, requiring intervention within hours to days; minimal, where the patient is injured but ambulatory; and expectant patients who are deceased or too injured to save. Impersonal though this system may be, it may be required in the most severe scenarios when resources are scarce or absent.

The authors reported no relevant financial disclosures.

SOURCE: Katz J et al. J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.annonc.2020.02.01.

The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.

“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.

The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).

In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.

Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.

Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.

Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.

The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.

Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.

“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.

Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.

Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.

bjancin@mdedge.com

SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.

The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.

“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.

The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).

In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.

Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.

Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.

Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.

The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.

Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.

“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.

Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.

Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.

bjancin@mdedge.com

SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.

The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.

“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.

The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).

In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.

Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.

Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.

Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.

The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.

Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.

“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.

Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.

Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.

bjancin@mdedge.com

SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.

The take-home message from a growing number of recent COVID-19 case reports is that the infection might be far more than a respiratory disease.

Although a cause-and-effect relationship is unknown, people with the virus have presented with or developed heart disease, acute liver injury, ongoing GI issues, skin manifestations, neurologic damage, and other problems, especially among sicker people.

For example, French physicians described an association with encephalopathy, agitation, confusion, and corticospinal tract signs among 58 people hospitalized with acute respiratory distress (N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597).

In particular, Yale New Haven (Conn.) Hospital is dealing with unexpected complications up close. Almost half of the beds there are occupied by COVID-19 patients. Over 100 people are in the ICU, and almost 70 intubated. Of the more than 750 COVID admissions so far, only about 350 have been discharged. “Even in a bad flu season, you never see something like this; it’s just unheard of,” said Harlan Krumholz, MD, a Yale cardiologist and professor of medicine helping lead the efforts there.
 

Kidney injuries prominent

“When they get to the ICU, we are seeing lots of people with acute kidney injuries; lots of people developing endocrine problems; people having blood sugar control issues, coagulation issues, blood clots. We are just waking up to the wide range of ways this virus can affect people. Our ignorance is profound,” Dr. Krumholz said, but physicians “recognize that this thing has the capability of attacking almost every single organ system, and it may or may not present with respiratory symptoms.”

It’s a similar story at Mt. Sinai South Nassau, a hospital in Oceanside, N.Y. “We’ve seen a lot of renal injury in people having complications, a lot of acute dialysis,” but it’s unclear how much is caused by the virus and how much is simply because people are so sick, said Aaron Glatt, MD, infectious disease professor and chair of medicine at the hospital. However, he said things are looking brighter than at Yale.

“We are not seeing the same level of increase in cases that we had previously, and we are starting to see extubations and discharges. We’ve treated a number of patients with plasma therapy, and hopefully that will be of benefit. We’ve seen some response to” the immunosuppressive “tocilizumab [Actemra], and a lot of response to very good respiratory therapy. I think we are starting to flatten the curve,” Dr. Glatt said.
 

“Look for tricky symptoms”

The growing awareness of COVID’s protean manifestations is evident in Medscape’s Consult forum, an online community where physicians and medical students share information and seek advice; there’s been over 200 COVID-19 cases and questions since January.

Early on, traffic was mostly about typical pulmonary presentations, but lately it’s shifted to nonrespiratory involvement. Physicians want to know if what they are seeing is related to the virus, and if other people are seeing the same things.

There’s a case on Consult of a 37-year-old man with stomach pain, vomiting, and diarrhea, but no respiratory symptoms and a positive COVID test. A chest CT incidental to his abdominal scan revealed significant bilateral lung involvement.

A 69-year-old woman with a history of laparotomy and new onset intestinal subocclusion had only adhesions on a subsequent exploratory laparotomy, and was doing okay otherwise. She suddenly went into respiratory failure with progressive bradycardia and died 3 days later. Aspiration pneumonia, pulmonary embolism, and MI had been ruled out. “The pattern of cardiovascular failure was in favor of myocarditis, but we don’t have any other clue,” the physician said after describing a second similar case.

Another doctor on the forum reported elevated cardiac enzymes without coronary artery obstruction in a positive patient who went into shock, with an ejection fraction of 40% and markedly increased heart wall thickness, but no lung involvement. There are also two cases of idiopathic thrombocytopenia without fever of hypoxia.

An Italian gastroenterologist said: “Look for tricky symptoms.” Expand “patient history, asking about the sudden occurrence of dysgeusia and/or anosmia. These symptoms have become my guiding diagnostic light” in Verona. “Most patients become nauseated, [and] the taste of any food is unbearable. When I find these symptoms by history, the patient is COVID positive 100%.”
 

‘Make sure that they didn’t die in vain’

There was interest in those and other reports on Consult, and comments from physicians who have theories, but no certain answers about what is, and is not, caused by the virus.

Direct viral attack is likely a part of it, said Stanley Perlman, MD, PhD, a professor of microbiology and immunology at the University of Iowa, Iowa City.

The ACE2 receptor the virus uses to enter cells is common in many organs, plus there were extrapulmonary manifestations with severe acute respiratory syndrome (SARS), another pandemic caused by a zoonotic coronavirus almost 20 years ago. At least with SARS, “many organs were infected when examined at autopsy,” he said.

The body’s inflammatory response is almost certainly also in play. Progressive derangements in inflammatory markers – C-reactive protein, D-dimer, ferritin – correlate with worse prognosis, and “the cytokine storm that occurs in these patients can lead to a degree of encephalopathy, myocarditis, liver impairment, and kidney impairment; multiorgan dysfunction, in other words,” said William Shaffner, MD, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center, Nashville, Tenn.

But in some cases, the virus might simply be a bystander to an unrelated disease process; in others, the experimental treatments being used might cause problems. Indeed, cardiology groups recently warned of torsade de pointes – a dangerously abnormal heart rhythm – with hydroxychloroquine and azithromycin.

“We think it’s some combination,” but don’t really know, Dr. Krumholz said. In the meantime, “we are forced to treat patients by instinct and first principles,” and long-term sequelae are unknown. “We don’t want to be in this position for long.”

To that end, he said, “this is the time for us all to hold hands and be together because we need to learn rapidly from each other. Our job is both to care for the people in front of us and make sure that they didn’t die in vain, that the experience they had is funneled into a larger set of data to make sure the next person is better off.”

aotto@mdedge.com

The take-home message from a growing number of recent COVID-19 case reports is that the infection might be far more than a respiratory disease.

Although a cause-and-effect relationship is unknown, people with the virus have presented with or developed heart disease, acute liver injury, ongoing GI issues, skin manifestations, neurologic damage, and other problems, especially among sicker people.

For example, French physicians described an association with encephalopathy, agitation, confusion, and corticospinal tract signs among 58 people hospitalized with acute respiratory distress (N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597).

In particular, Yale New Haven (Conn.) Hospital is dealing with unexpected complications up close. Almost half of the beds there are occupied by COVID-19 patients. Over 100 people are in the ICU, and almost 70 intubated. Of the more than 750 COVID admissions so far, only about 350 have been discharged. “Even in a bad flu season, you never see something like this; it’s just unheard of,” said Harlan Krumholz, MD, a Yale cardiologist and professor of medicine helping lead the efforts there.
 

Kidney injuries prominent

“When they get to the ICU, we are seeing lots of people with acute kidney injuries; lots of people developing endocrine problems; people having blood sugar control issues, coagulation issues, blood clots. We are just waking up to the wide range of ways this virus can affect people. Our ignorance is profound,” Dr. Krumholz said, but physicians “recognize that this thing has the capability of attacking almost every single organ system, and it may or may not present with respiratory symptoms.”

It’s a similar story at Mt. Sinai South Nassau, a hospital in Oceanside, N.Y. “We’ve seen a lot of renal injury in people having complications, a lot of acute dialysis,” but it’s unclear how much is caused by the virus and how much is simply because people are so sick, said Aaron Glatt, MD, infectious disease professor and chair of medicine at the hospital. However, he said things are looking brighter than at Yale.

“We are not seeing the same level of increase in cases that we had previously, and we are starting to see extubations and discharges. We’ve treated a number of patients with plasma therapy, and hopefully that will be of benefit. We’ve seen some response to” the immunosuppressive “tocilizumab [Actemra], and a lot of response to very good respiratory therapy. I think we are starting to flatten the curve,” Dr. Glatt said.
 

“Look for tricky symptoms”

The growing awareness of COVID’s protean manifestations is evident in Medscape’s Consult forum, an online community where physicians and medical students share information and seek advice; there’s been over 200 COVID-19 cases and questions since January.

Early on, traffic was mostly about typical pulmonary presentations, but lately it’s shifted to nonrespiratory involvement. Physicians want to know if what they are seeing is related to the virus, and if other people are seeing the same things.

There’s a case on Consult of a 37-year-old man with stomach pain, vomiting, and diarrhea, but no respiratory symptoms and a positive COVID test. A chest CT incidental to his abdominal scan revealed significant bilateral lung involvement.

A 69-year-old woman with a history of laparotomy and new onset intestinal subocclusion had only adhesions on a subsequent exploratory laparotomy, and was doing okay otherwise. She suddenly went into respiratory failure with progressive bradycardia and died 3 days later. Aspiration pneumonia, pulmonary embolism, and MI had been ruled out. “The pattern of cardiovascular failure was in favor of myocarditis, but we don’t have any other clue,” the physician said after describing a second similar case.

Another doctor on the forum reported elevated cardiac enzymes without coronary artery obstruction in a positive patient who went into shock, with an ejection fraction of 40% and markedly increased heart wall thickness, but no lung involvement. There are also two cases of idiopathic thrombocytopenia without fever of hypoxia.

An Italian gastroenterologist said: “Look for tricky symptoms.” Expand “patient history, asking about the sudden occurrence of dysgeusia and/or anosmia. These symptoms have become my guiding diagnostic light” in Verona. “Most patients become nauseated, [and] the taste of any food is unbearable. When I find these symptoms by history, the patient is COVID positive 100%.”
 

‘Make sure that they didn’t die in vain’

There was interest in those and other reports on Consult, and comments from physicians who have theories, but no certain answers about what is, and is not, caused by the virus.

Direct viral attack is likely a part of it, said Stanley Perlman, MD, PhD, a professor of microbiology and immunology at the University of Iowa, Iowa City.

The ACE2 receptor the virus uses to enter cells is common in many organs, plus there were extrapulmonary manifestations with severe acute respiratory syndrome (SARS), another pandemic caused by a zoonotic coronavirus almost 20 years ago. At least with SARS, “many organs were infected when examined at autopsy,” he said.

The body’s inflammatory response is almost certainly also in play. Progressive derangements in inflammatory markers – C-reactive protein, D-dimer, ferritin – correlate with worse prognosis, and “the cytokine storm that occurs in these patients can lead to a degree of encephalopathy, myocarditis, liver impairment, and kidney impairment; multiorgan dysfunction, in other words,” said William Shaffner, MD, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center, Nashville, Tenn.

But in some cases, the virus might simply be a bystander to an unrelated disease process; in others, the experimental treatments being used might cause problems. Indeed, cardiology groups recently warned of torsade de pointes – a dangerously abnormal heart rhythm – with hydroxychloroquine and azithromycin.

“We think it’s some combination,” but don’t really know, Dr. Krumholz said. In the meantime, “we are forced to treat patients by instinct and first principles,” and long-term sequelae are unknown. “We don’t want to be in this position for long.”

To that end, he said, “this is the time for us all to hold hands and be together because we need to learn rapidly from each other. Our job is both to care for the people in front of us and make sure that they didn’t die in vain, that the experience they had is funneled into a larger set of data to make sure the next person is better off.”

aotto@mdedge.com

The take-home message from a growing number of recent COVID-19 case reports is that the infection might be far more than a respiratory disease.

Although a cause-and-effect relationship is unknown, people with the virus have presented with or developed heart disease, acute liver injury, ongoing GI issues, skin manifestations, neurologic damage, and other problems, especially among sicker people.

For example, French physicians described an association with encephalopathy, agitation, confusion, and corticospinal tract signs among 58 people hospitalized with acute respiratory distress (N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597).

In particular, Yale New Haven (Conn.) Hospital is dealing with unexpected complications up close. Almost half of the beds there are occupied by COVID-19 patients. Over 100 people are in the ICU, and almost 70 intubated. Of the more than 750 COVID admissions so far, only about 350 have been discharged. “Even in a bad flu season, you never see something like this; it’s just unheard of,” said Harlan Krumholz, MD, a Yale cardiologist and professor of medicine helping lead the efforts there.
 

Kidney injuries prominent

“When they get to the ICU, we are seeing lots of people with acute kidney injuries; lots of people developing endocrine problems; people having blood sugar control issues, coagulation issues, blood clots. We are just waking up to the wide range of ways this virus can affect people. Our ignorance is profound,” Dr. Krumholz said, but physicians “recognize that this thing has the capability of attacking almost every single organ system, and it may or may not present with respiratory symptoms.”

It’s a similar story at Mt. Sinai South Nassau, a hospital in Oceanside, N.Y. “We’ve seen a lot of renal injury in people having complications, a lot of acute dialysis,” but it’s unclear how much is caused by the virus and how much is simply because people are so sick, said Aaron Glatt, MD, infectious disease professor and chair of medicine at the hospital. However, he said things are looking brighter than at Yale.

“We are not seeing the same level of increase in cases that we had previously, and we are starting to see extubations and discharges. We’ve treated a number of patients with plasma therapy, and hopefully that will be of benefit. We’ve seen some response to” the immunosuppressive “tocilizumab [Actemra], and a lot of response to very good respiratory therapy. I think we are starting to flatten the curve,” Dr. Glatt said.
 

“Look for tricky symptoms”

The growing awareness of COVID’s protean manifestations is evident in Medscape’s Consult forum, an online community where physicians and medical students share information and seek advice; there’s been over 200 COVID-19 cases and questions since January.

Early on, traffic was mostly about typical pulmonary presentations, but lately it’s shifted to nonrespiratory involvement. Physicians want to know if what they are seeing is related to the virus, and if other people are seeing the same things.

There’s a case on Consult of a 37-year-old man with stomach pain, vomiting, and diarrhea, but no respiratory symptoms and a positive COVID test. A chest CT incidental to his abdominal scan revealed significant bilateral lung involvement.

A 69-year-old woman with a history of laparotomy and new onset intestinal subocclusion had only adhesions on a subsequent exploratory laparotomy, and was doing okay otherwise. She suddenly went into respiratory failure with progressive bradycardia and died 3 days later. Aspiration pneumonia, pulmonary embolism, and MI had been ruled out. “The pattern of cardiovascular failure was in favor of myocarditis, but we don’t have any other clue,” the physician said after describing a second similar case.

Another doctor on the forum reported elevated cardiac enzymes without coronary artery obstruction in a positive patient who went into shock, with an ejection fraction of 40% and markedly increased heart wall thickness, but no lung involvement. There are also two cases of idiopathic thrombocytopenia without fever of hypoxia.

An Italian gastroenterologist said: “Look for tricky symptoms.” Expand “patient history, asking about the sudden occurrence of dysgeusia and/or anosmia. These symptoms have become my guiding diagnostic light” in Verona. “Most patients become nauseated, [and] the taste of any food is unbearable. When I find these symptoms by history, the patient is COVID positive 100%.”
 

‘Make sure that they didn’t die in vain’

There was interest in those and other reports on Consult, and comments from physicians who have theories, but no certain answers about what is, and is not, caused by the virus.

Direct viral attack is likely a part of it, said Stanley Perlman, MD, PhD, a professor of microbiology and immunology at the University of Iowa, Iowa City.

The ACE2 receptor the virus uses to enter cells is common in many organs, plus there were extrapulmonary manifestations with severe acute respiratory syndrome (SARS), another pandemic caused by a zoonotic coronavirus almost 20 years ago. At least with SARS, “many organs were infected when examined at autopsy,” he said.

The body’s inflammatory response is almost certainly also in play. Progressive derangements in inflammatory markers – C-reactive protein, D-dimer, ferritin – correlate with worse prognosis, and “the cytokine storm that occurs in these patients can lead to a degree of encephalopathy, myocarditis, liver impairment, and kidney impairment; multiorgan dysfunction, in other words,” said William Shaffner, MD, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center, Nashville, Tenn.

But in some cases, the virus might simply be a bystander to an unrelated disease process; in others, the experimental treatments being used might cause problems. Indeed, cardiology groups recently warned of torsade de pointes – a dangerously abnormal heart rhythm – with hydroxychloroquine and azithromycin.

“We think it’s some combination,” but don’t really know, Dr. Krumholz said. In the meantime, “we are forced to treat patients by instinct and first principles,” and long-term sequelae are unknown. “We don’t want to be in this position for long.”

To that end, he said, “this is the time for us all to hold hands and be together because we need to learn rapidly from each other. Our job is both to care for the people in front of us and make sure that they didn’t die in vain, that the experience they had is funneled into a larger set of data to make sure the next person is better off.”

aotto@mdedge.com

Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.

“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).

“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.

The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.

Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).

In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.

Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.

None of the authors had any disclosures.

mzoler@mdedge.com

Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.

“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).

“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.

The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.

Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).

In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.

Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.

None of the authors had any disclosures.

mzoler@mdedge.com

Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.

“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).

“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.

The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.

Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).

In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.

Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.

None of the authors had any disclosures.

mzoler@mdedge.com