John Mandrola, MD


August 23, 2021

For the second year in a row the European Society of Cardiology (ESC) meeting will happen online instead of in Europe. Here are some of the big studies I am looking forward to:

SGLT2i for HFpEF

The headliner for this year's virtual ESC meeting will be the EMPEROR-Preserved trial, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) to placebo in approximately 6000 patients who have heart failure with preserved ejection fraction (HFpEF). This trial may be the biggest of 2021.

We know from a press release that the trial met its primary endpoint of cardiovascular death or hospital admission for HF.

The third bullet point at the top of the Boehringer Ingelheim press release says that empagliflozin "would become the first and only clinically proven therapy to improve outcomes for the full spectrum of heart failure regardless of ejection fraction."

The company is technically correct, but the question to be answered from the presented data is whether statistical significance (which can be inferred from the press release) translates to value and clinical significance.

Clinical significance will turn on critical appraisal of the trial. How robust was the reduction in outcomes? We should always shun arbitrary P value cutoffs, but a P value of .001 is more robust than one of .04.

More important than the P value, though, is the effect size of the benefit. I want to see the absolute risk reduction and whether the primary endpoint was driven by cardiovascular death or the softer endpoint of HF hospitalization. The diagnosis of HFpEF includes a wide variety of patients, which raises the likelihood of heterogenous treatment effects. The subgroup analysis may reveal groups of patients who stand to benefit more from the drug.

When considering value, I propose two extreme examples: a low-value case would be if the drug efficacy barely reaches statistical significance and  the primary endpoint is driven by modest absolute reductions in HF hospitalizations, not cardiovascular death, with no overall mortality benefit. A high-value case for empagliflozin would require a robust statistical result, reductions in both cardiovascular death and HF hospitalizations, and lower overall mortality.

On the internal validity front, I will wonder about blinding. SGLT2i can cause a brisk diuresis, which patients may recognize: "Hey, I am on the study drug, perhaps I should be more compliant with diet and exercise." Female patients who develop genitourinary fungal infections will surely suspect they are in the active arm.

Overall, I am impressed with this class of drugs, but I am also concerned about the cost and value of medical care. It is exciting to have a "positive" result in HFpEF, but we mustn't let this enthusiasm bias our critical appraisal.

During the same session, Milton Packer, MD, will present results from "EMPEROR-Pooled: effect of empagliflozin on serious adverse renal outcomes in chronic heart failure – a prospective alpha-protected, Individual patient-level pooled analysis." Does a pooled analysis slated to follow the main trial give us any clues? I am asking.

AF Screening

Thus far, digital health devices have delivered a lot of information but haven't increased our medical knowledge.

We can now easily detect minutes to hours of asymptomatic atrial fibrillation (AF). But then what? I have this exchange often: "My 70-year-old patient has 1 hour of AF; should I start an anticoagulant? And for how long? For life? Really, for 1 hour of AF?"  

The LOOP study randomly assigned about 6000 Danish patients older than 70 years who have one stroke risk factor to AF screening with an implantable cardiac monitor or usual care. The randomization is 3:1, with 4500 patients in the monitor arm and 1500 in the control arm.

This trial excites me because the primary outcome is time to first stroke or systemic embolism. This differs from the many previous AF screening trials, which consistently show that AF screening (of any type) leads to more detection of AF and more use of anticoagulation.

The finding we want to know is the net benefit of treating these episodes. Starting anticoagulants for short-duration AF is considered a good thing. But we don't actually know if it will deliver more benefit (stroke reduction) than harm (bleeding).

The first step in showing net benefit is to show that all the added anticoagulation from AF screening significantly reduces stroke.

The active arm of the LOOP protocol calls for anticoagulation for any detected AF lasting more than 6 minutes. That is a very low bar. Many more patients in the active arm will be receiving anticoagulation.

If LOOP shows a reduction in stroke, the next question will be at what cost. In the trial protocol, major bleeding is listed as an "other outcome," but I see it as a key outcome.

The Saddest Trial: ACST-2

Although the U.S. Preventive Services Task Force recommends against carotid vascular screening, low-cost screening programs continue in earnest. The ubiquity of ultrasound machines has transformed many asymptomatic persons into patients with vascular disease.

How to treat asymptomatic carotid artery disease has therefore become a common question for cardiologists and vascular surgeons.

Carotid endarterectomy has long been the standard, but carotid stenting has grown in popularity. The ACST-2 trial, which started in 2008, randomly assigned approximately 3600 patients to stenting or surgery. The primary outcome is both safety and long-term (5 to 10 years) prevention of stroke.

Why would such a big trial with legitimate endpoints make me sad? Because there was no medical treatment arm.

Carotid revascularization was established decades ago, at a time when there were either no statin drugs or only low-potency agents. A 2015 report on more than 3600 patients with asymptomatic carotid disease found that the risk for progression to carotid occlusion is well below the risk of carotid stenting or endarterectomy and has decreased markedly with more intensive medical therapy. Only 3 patients (0.9%) had a stroke on the same side of the lesion.

A more recent comparative effectiveness study of more than 5000 patients with asymptomatic carotid disease found that the absolute reduction in the risk for fatal and nonfatal strokes associated with early carotid endarterectomy was less than half the risk difference in trials from 20 years ago and no longer reached statistical significance after adjustment.

The phenomenon of declining event rates in many cardiovascular fields has made it more difficult to show incremental benefits from procedural interventions. We could have learned so much with a medical arm.

Targeting Fibrosis in AF Ablation

Electrophysiology meetings almost always have roundtable sessions on techniques for ablation of persistent AF. If there are 3 experts on the panel, there are usually 3 different approaches; with 4 experts, there are 4 different approaches. Translation: No one has a clue how best to ablate persistent AF.

Academic electrophysiologist Nassir Marrouche, MD, has a theory that left atrial fibrosis is not only an important predictor for AF and stroke but also a good target for ablation.

At ESC, he will present results of the DECAAF II trial, which randomly assigned patients with persistent AF to standard pulmonary vein isolation or pulmonary vein isolation plus fibrosis-guided ablation. The fibrosis will be defined by late gadolinium enhancement on MRI at baseline.

This is an important area of research not only because it may lead to better ablation but because it may give clues to the underlying causes of AF, which remain undiscovered.

Nassir Marrouche is one of the kindest and warmest people in electrophysiology. Everyone wants Nassir to succeed, but persistent AF is a mighty foe. And if DECAAF II turns positive, he's going to have to show us all how to do this brand of MRI.

Invasive Monitoring for HF

When I began training in medicine, experts used the pulmonary artery catheter to guide management of patients in the ICU. The idea was that surely more information was better. Well, you all know how that turned out. Swan-Ganz catheter use did not reduce heart failure hospitalizations or improve heart failure when tested in a randomized trial.

The advent of a better way to monitor hemodynamics has reinvigorated the more-information-is-better camp. The CardioMEMS HF System (Abbott Cardiovascular) consists of a wireless sensor implanted within the pulmonary artery and powered by an external interrogation device that provides real-time transmission of pulmonary arterial pressure data from ambulatory patients outside the HF clinic to a secure website; this allows provider review to guide decision making regarding HF management.

Indeed, the CHAMPION trial found that use of the device reduced HF hospitalizations in patients with New York Heart Association (NYHA) class III HF symptoms due to reduced ejection fraction.

But uptake of the device has been slow. It's invasive and expensive, and it requires expertise and energy to monitor the data. Clinicians want to know whether this extra cost and work will improve mortality and whether the device can be used in broader types of HF.

The GUIDE-HF trial will address these questions. The trial has a nice design. First, it includes a broad population of patients with NYHA class II to IV (regardless of left ventricular ejection fraction) who have elevated natriuretic peptide levels and/or a prior HF hospitalization. Second, the randomized portion of the trial includes 2  groups who receive the device: one group uses the data and the other does not.

The primary endpoint is a composite of cumulative HF events and all-cause mortality at 12 months. Secondary end points include quality-of-life and functional assessments.

Critical appraisal here will have to consider external validity and costs. Even if GUIDE-HF is "positive," will this approach be feasible in cost-contained health systems? This will depend on the effect size and the robustness of the results.

These are just five of the many studies from the world's largest cardiology meeting. There will surely be many other surprises.

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John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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