Sep 4, 2020 This Week in Cardiology Podcast

John M. Mandrola, MD


September 04, 2020

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast.

In This Week’s Podcast

For the week ending September 4, 2020, John Mandrola, MD comments on the following news and features stories.

COVID Update: Vaccine Controversy

The big news in the United States is how the FDA will handle the coming vaccines. The worry is that a vaccine will be released without proper trial data. Politics is in the mix. Everyone has probably heard how FDA commissioner Stephen Hahn misrepresented the results of the observational trial on convalescent plasma use in COVID-19 patients.

He claimed that a 35% relative risk reduction was equivalent to saving 35 lives out of 100 patients treated, which is actually a 35% absolute risk reduction. That’s a big error for a medical student, never mind the head of the FDA.

People suggested this “error” may have been politically motivated. Hahn apologized publicly the next day. But Medscape editor-in-chief Eric Topol was not impressed. Topol has penned a remarkable letter to Dr. Hahn: “Dear Commissioner Hahn: Tell the Truth or Resign.” In an era when tone is heavily policed, Topol’s plain-speak is truly stunning. He lays out Hahn’s mistakes, and gives five reasons why Hahn’s apology was insufficient.

I lead the podcast with this because the main thrust of TWIC is the evaluation of clinical science. And now, as we get ready to adjudicate COVID vaccines, the matter of trust in scientists and regulators could not be more vital.

European Society of Cardiology Virtual Congress: Part 1

My colleagues at | Medscape Cardiology have great coverage of the ESC 2020 Congress. Read it. In 20 minutes, I can only hit the highlights.

SGLT2 Inhibitors

Two studies presented as hot-line trials at ESC strengthened the evidence for the sodium glucose cotransporter 2 (SGLT2) inhibitors. Recall that SGLT2 inhibitors reduce renal tubular glucose reabsorption, producing a reduction in blood glucose without stimulating insulin release. Other benefits include reducing blood pressure and weight.

EMPEROR-Reduced enrolled about 3700 patients with heart failure with reduced ejection fraction (HFrEF), about half of them with diabetes. Participants were randomly assigned to receive empagliflozin 10 mg daily or placebo. The primary endpoints were cardiovascular (CV) death and heart failure hospitalization (HFH). In sum, patients in the empagliflozin arm had a 31% reduction in HFH and an 8% reduction in CV death.

Empagliflozin had statistically significant effect on renal outcomes (not seen in DAPA-HF) and had beneficial effects on the primary endpoints in all subgroups, including the group taking angiotensin receptor neprilysin inhibitor (ARNi) drugs.

The big discussion point is that the primary endpoint was driven by the non-fatal outcome of HFH. The confidence interval for CV death was 0.75-1.12, so some might say non-significant. This contrasts with DAPA-HF where CV death was 18% lower and the CI did not include 1.

DAPA-CKD was primarily a renal outcomes trial, but there were interesting CV secondary outcomes as well. About 4300 patients with CKD and albuminuria were randomly assigned to receive dapagliflozin vs placebo. The primary endpoint was a composite of ≥ 50% decline in glomerular filtration rate, end stage kidney disease, renal death, or CV death.

There were 197 primary endpoint events in the dapagliflozin arm vs 312 in the placebo arm, for a 39% relative risk reduction and about 5% absolute risk reduction with dapagliflozin. This reduction was seen in diabetics and non-diabetics. Secondary endpoints of CV death and HFH, as well as all-cause mortality were also lower in dapagliflozin arm.

The effects of SGLT2 inhibitors are consistent across trials; the CV death reduction and overall death signals are favorable, renal preservation looks consistent, side effects are not awful, and the benefit is seen in non-diabetics and diabetics alike.

I think we have a new class of drugs in cardiology.


The surprise of ESC came with favorable results from a digoxin trial. Dipak Kotecha from the University of Birmingham, England, presented results of the Rate AF trial comparing digoxin vs bisoprolol in patients with permanent atrial fibrillation (AF). Kudos to the research team for studying permanent AF. Most of the research goes to paroxysmal AF and persistent AF, but probably half of the millions of patients with AF have permanent AF.

About 160 patients were randomly assigned to either digoxin or bisoprolol.

The primary endpoint included patient-reported quality of life measures. Secondary endpoints included BNP, ejection fraction, and clinical events.

Sit down for the results: Heart rate responses were identical. Physical function at 6 months—the primary endpoint —was not significantly different in either group. More than 50% of patients receiving digoxin compared with less than 10% on β-blockers improved more than two classes in the modified European Heart Rhythm Association (EHRA) symptom score (mEHRA for AF is similar to New York Heart Association [NYHA] for heart failure and ranges from I to IV).

Over 6 to 12 months, improvement in NYHA class and NTproBNP level was significantly greater in the digoxin arm. Left ventricular ejection fraction remained unchanged in both arms. While the trial was not powered for clinical events, there were fewer all-cause deaths (4 vs 7), cardiovascular deaths (3 vs 15), and adverse events (29 vs 142) in the digoxin arm.

While I love this trial, there are reasons for serious caution: This was an oral presentation. The details of the paper will be key. How did they use digoxin; did they do drug levels? Also, digoxin use has a narrow therapeutic window, clinicians have to consider drug-drug interactions and renal clearance and these things are easier to do in a trial than in a busy practice. Another reason for caution was the open-label nature of the trial. Beta bockers have strong nocebo effects and this may bias the self-assessment of physical functioning.

The authors wrote in their protocol paper that RATE-AF trial will also act as a feasibility study to plan a future, event-driven clinical trial exploring the impact of different rate control strategies on cardiovascular events and unplanned hospital admissions.

Besides the stunning results, another reason this trial excites me is the digoxin backstory: namely, that digoxin had been unfairly made into a toxic drug. I say unfairly because the studies that caused its fall from favor were nonrandomized observational studies. RATE-AF shows again the power of randomization. In addition to the specifics of AF care, it again humbles us regarding the temptation to make causal claims from nonrandomized observational data.

East AFNET 4

The EAST AFNET 4 trial, which henceforth I will refer simply as EAST, asked a highly relevant question: would an early-rhythm control approach to patients with AF improve “clinical” outcomes vs a conventional strategy of rate control. The background is that early rhythm control might prevent unfavorable atrial (and ventricular) remodeling and that could cause better CV outcomes.

On the other hand, rhythm control is complicated. AF ablation is inelegant and comes with a finite risk for complications. Antiarrhythmic drugs are super-inelegant and surely come with adverse effects. That is why you need an RCT. The highly pragmatic study overflows with lessons.

This was a multicenter trial that included a wide variety of non-permanent AF types. New AF, paroxysmal AF, persistent AF, and asymptomatic AF were all substantially represented. About 2800 patients were randomly assigned to early rhythm control vs usual care. Importantly the trial was open-label, though outcomes were adjudged in a blinded fashion. The authors chose co-primary efficacy endpoints: the first was a composite of cardiovascular (CV) death, stroke, hospital admission for heart failure or acute coronary syndrome, and the second was days spent in the hospital.

The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm control. The overlap of having stroke and death in both efficacy and safety outcomes is a problem. Stay tuned for that.

About 90% of both groups continued to receive oral anticoagulant therapy throughout the trial. And early rhythm control was indeed early—patients were randomized about a month after their diagnosis. EAST-AFNET 4 was stopped for efficacy after a median of 5 years.

A primary outcome event occurred in 249 patients in the early care arm vs 316 patients in the usual care arm.  The hazard ratio was 0.79, with a confidence interval of 0.66 to 0.94 (P=.005). The absolute risk reduction was 1.1% per 100 person-years and 3% over 5 years. Each component of the primary outcome was numerically lower in the early care arm. In a trial of almost 2800 patients, there were 27 fewer CV deaths in the early care group (1.0% vs 1.3% per 100 patient-years). The average days spent in hospital were similar in both groups. The overall primary safety outcome did not differ significantly between the two treatment arms.

Here is the problem—the components of the composite diverged. Serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care.

How could the overall outcome then be different? Stroke was lower in the early care arm. But the authors had already used this in the efficacy endpoint. Using it in the safety composite helps “dilute” the higher rate of serious advents in the early care group. Same story with death—though it is more complicated. CV death was lower in the early care group and this helped drive the primary efficacy endpoint. Overall death has CV death as a component. If you subtract the number of CV deaths in each group from the overall death, you find non-CV death was 71 and 70 respectively. Thus, by using overall death in the safety outcome you further dilute the serious adverse events in the rhythm-control arm.

There were other concerns: substantial missing data, and that HF and acute coronary syndrome admissions is a potentially biased endpoint in an open label trial. External validity is relevant because these were expert centers. In less expert centers, serious adverse events from antiarrhythmic drugs or ablation might be much higher.

In sum, early rhythm-control strategy may improve outcomes compared with a strategy of rate control. But these potential gains come with a risk for serious adverse events. EAST should not be oversimplified to mean "use more antiarrhythmic drugs" or "do more ablation." Instead, the nuance and tradeoffs in these findings strongly support a shared understanding between clinician and patient.


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