Mandrola’s Top 10 Cardiology Stories of 2022

1. REVIVED-BCIS2: Stable CAD Is Very Stable

At our hospital and probably yours too, patients with an undiagnosed cardiomyopathy are sent for coronary angiography. The purpose is to diagnose coronary artery disease (CAD), presumably because revascularizing it would improve ventricular function and outcomes.

The results of the REVIVED-BCIS2 trial upends the logic of this common practice. British investigators gave percutaneous coronary intervention (PCI) a near-perfect opportunity to shine. They randomly assigned 700 patients with ischemic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤ 35%) and anatomy amenable to PCI and substantial myocardial viability to either PCI or optimal medical therapy.

During 3.5 years, there was no difference in the primary outcome of death or hospitalization for heart failure (37.2% vs 38.0%). There were also no significant differences in LVEF or quality-of-life score. Pause here and imagine an angiogram with multivessel severe CAD and amenable lesions—and a cardiologist choosing medicines over stents.

Cardiac surgeons might argue that surgery would have fared better. In 5-year follow-up of STICH, a relatively similar group of patients sustained a near-significant 14% lower rate of death or hospitalization for cardiac causes with surgery vs medical therapy. And at 10-year follow-up, the 16% reduction in the primary endpoint with surgery did meet the threshold for significance. The rebuttal, however, is that medical therapy has improved greatly over the past decade, and surgery carries significant upfront risk.

This trial is not only a practice changer; it’s a thinking changer: stable CAD is very stable and medical therapy is darn good. No trial shows this more strongly than REVIVED-BCIS2.

2. Patient Selection for Percutaneous Left Atrial Appendage Occlusion

In 2022, doctors increasingly embraced percutaneous left atrial appendage occlusion or closure (LAAO). Regular readers know my skepticism of this procedure, which remains unchanged. That is not the story this year.

This year’s story was a series of studies suggesting dubious patient selection. The goal of LAAO is to eliminate the left atrial appendage as a source of cardiac emboli. The benefits should accrue—over time—through reduced stroke and reduced bleeding because anatomic plugging allows for reducing antithrombotic burden.

This requires two key factors: selection of patients with minimal competing causes of stroke and a lifespan long enough for net benefits to accrue. In January, Watchman investigators suggested that net benefit of the device over the Watchman device (Boston Scientific, Marlborough, Massachusetts) began at about 3 years. Series published this year from Spain, Israel, and the United States all found that clinicians are choosing older patients with frailty, significant comorbidities, and limited lifespan. A study comparing patients who received the device in trials vs registries found that mortality rates were more than twofold greater in the real world than in trials.

No matter your view of percutaneous closure, the increasing use of this device in patients least likely to benefit is a worrisome trend.

3. The 2022 Spin Award: GUIDE-HF

A decade before the CardioMEMS HF System (Abbott, Abbott Park, Illinois), the paperclip-sized pulmonary artery (PA) device,  was developed, another PA catheter, called the Swan-Ganz catheter, was found to be ineffective in three randomized controlled trials. The wireless CardioMEMS HF System is PA monitoring 2.0 for outpatients.

The device had been U.S. Food and Drug Administration (FDA) approved for a highly selected group of patients with heart failure. The GUIDE-HF trial investigators randomly assigned a broader group of 1000 patients to CardioMEMS-based management vs standard care. The stakes were high: if the $20,000 device passed muster, it stood to be expanded to over a million more patients. You do the math.

The GUIDE-HF investigators reported a nonsignificant 12% reduction in the primary endpoint of death, urgent heart failure visit, or hospitalization for heart failure (HR, 0.88; 95% CI, 0.75 - 1.05; P = .16). Because that is far from our accepted threshold of significance, you would have thought the FDA would have declined labeling for the broader indication.

But that is not what happened. Instead, the authors, in consultation with the FDA, reported a pre-COVID analysis. Slightly more than two thirds of patients in the trial finished their follow-up before the lockdowns. In an analysis of this subgroup, the hazard reduction was now 19% and the P value eked by at .05. Voila, the FDA approved the device on the basis of  this analysis.

The problems are many. The most worrisome is that in the 28% of patients followed during the pandemic, the wireless device, which should cut down on in-person visits, underperformed. During this time there were no differences in any component of the endpoints.

I wrote about these issues in March, making the case that underperformance of the device during a time when the pandemic raised the bar for hospitalizations suggests that pre-COVID reductions in heart failure hospitalizations were likely due to performance bias.

As I write this review, CardioMEMS advertisements adorn our breakrooms, interventional cardiologists implant the device, heart failure clinicians embrace the data, and payers pay. Meanwhile, disparities in healthcare outcomes for the under- and uninsured worsen.

4. Exemplary Science

I gave a lecture this year on critical appraisal tips and tricks. The intro slides ask a reader to first consider whether a trial is for science or marketing.

I use the CHAP trial on treating mild hypertension during pregnancy as an example of a trial seeking to answer an important scientific question. Hypertension affects about 2% of all pregnancies; it results in substantial risks to both child and mom. And it disproportionately affects Black women.

Funded by the National Institutes of Health, the CHAP trialists randomly assigned more than 2400 pregnant women with mild chronic hypertension to a medical regimen to reduce their blood pressure to  140/90 mm Hg or less vs a control arm of no medicines unless the blood pressure was 160/90 mm Hg or greater. They found a statistically significant 18% reduction in the primary endpoint of pre-eclampsia with severe features, preterm birth, placental abruption, or fetal or neonatal death. The nearly 5–percentage point absolute risk reduction was also clinically meaningful.

These findings strongly support a strategy of using medications to target a lower blood pressure rather than reserving therapy for higher blood pressures. Before this trial there was uncertainty. CHAP makes the top 10 list because it was an exemplary use of taxpayer resources to answer an important scientific question.

5. Big Electrophysiology Innovations

There were three (potentially) big developments in my field of electrophysiology in 2022.

One is a new way to ablate cardiac myocytes called pulsed field ablation (PFA). PFA uses short electrical pulses to disrupt cell membranes. The novelty is that it is cardioselective and does not affect adjacent structures, such as the phrenic nerve or esophagus. Many European centers have adopted PFA. It may not improve ablation efficacy, but avoiding esophageal injury would be a huge advance.

Patients with severe vasovagal syncope can be difficult to treat. These are often young people, who may face a lifetime with a pacemaker. Cardioneural ablation is a technique in which standard radiofrequency ablation can be used to target ganglionated plexi, which are close to where we ablate during atrial fibrillation ablation. Early reports are promising, but essentially all therapies for vasovagal conditions have failed in sham-controlled studies.

Pacing-induced cardiomyopathy used to be the price for implanting pacemakers for bradycardia. His-bundle pacing showed us that we could pace the heart without creating dyssynchrony, but it had downsides. In 2022, electrophysiologists increasingly adopted left bundle-branch area pacing, which is much easier to do and is associated with better pacing parameters. A small randomized trial showed early evidence that it may be as good as or better than standard biventricular pacing. This year we learned that the U.S. government will fund a large trial comparing left bundle-branch pacing to standard cardiac resynchronization therapy.

6. Screening for Disease

It is really hard to show survival benefits from screening for disease. Even if a screening test led to a reduction in death from one disease, there are thousands of competing causes of death.

The DANCAVAS trial showed us that an invitation to a comprehensive but efficient cardiovascular screening program might actually improve survival—if you are able to suspend binary thinking about P value thresholds.

The 40-minute screening program included a questionnaire; ankle-brachial index; CT of the chest and abdomen, which assessed only for calcium in the coronaries or aorta; a rhythm strip during CT;  and blood draw for lipids and glucose levels.

After more than 5 years of follow-up, there was a 5% lower rate of death in the invited-to-screening group. The CIs for this hazard ratio ranged from 0.90 to 1.00. The conclusion in the New England Journal of Medicine report noted that the screening program did not significantly reduce mortality, but the bulk of the CI was below 1.00. For a survival benefit.

This was an impressive effort, a surprising result, a humble presentation, and the DANCAVAS authors were clear that the only way to assess the results was in the invited-to-screen group, not the group that actually got the tests.

7. Sodium Restriction Dogma Felled

The question regarding advice for sodium restriction in patients with heart failure is a matter of degree.

No one tells these patients to feel free to have ham soup and potato chips on a regular basis. The question is how strong our sodium recommendations should be. The greater the restriction, the more educational capital we use—an important issue in heart failure therapeutics because patients have much to adhere to.

The international SODIUM-HF trial compared a modest sodium restriction of less than 1500 mg/day against standard care. Standard care included standard sodium-intake restrictions.

The pragmatic trial found no significant differences in the primary outcome of cardiac-related hospitalizations or emergency department visits or death.

Criticism of the trial centered on the fact that the control group consumed only 2000 mg of sodium per day vs 1600 mg/day in the active arm. The average U.S. diet usually includes more than 3000 mg/day. So, the thinking goes, if the SODIUM-HF intervention were compared to a U.S. diet, it would have been positive.

Maybe that is true. My rebuttal is that trials are what they are, not what you think they should be. We interpret the evidence as it is gathered.

What I take from this trial is that we don’t have to spend extra capital on severe restrictions. Give standard recommendations on sodium and move on to the many other important heart failure therapeutics.

8. More Beats Less in Heart Failure With Reduced Ejection Fraction

In recent years, heart failure experts have pushed for simultaneous initiation and rapid titration of guideline-directed medications. Observational data show sluggish uptake of full therapy in multiple health systems. And this inertia is associated with worse outcomes.

The results of the STRONG-HF trial gave the speed movement a boost. The trial enrolled about 1600 patients with acute heart failure in 14 countries. Patients were randomly assigned to a high-intensity arm that included aggressive uptitration of heart failure medications during four visits (with cardiologists) in the 6 weeks after admission vs a standard care arm.

Patients in the high-intensity arm had a statistically significant 34% reduction in the primary endpoint of readmission for heart failure or death. Notably, both all-cause death and cardiovascular death were reduced by 16% and 26%, respectively.

I felt strongly about STRONG-HF. The trial showed that if you are (very) serious about the intensity of follow-up and use of medications, outcomes are better. Of course, implementing such a program will require a commitment from health systems.

But there were criticisms of STRONG-HF. Danish cardiologist Søren Lund Kristensen argued that the trial had a weak control arm, and it "basically shows that close follow-up and treatment with HF meds work and [it] can't tell us much about what titration strategy is best."

9. The Dilemma of SGLT2 Inhibitors

In DELIVER, dapagliflozin vs placebo significantly reduced a primary endpoint of worsening heart failure or cardiovascular death in patients with heart failure with either a mildly reduced or preserved ejection fraction (HFpEF; mean LVEF of 54%). These results were largely consistent with those of the 2021 EMPEROR-Preserved trial.

The 18% reduction in the composite primary endpoint was driven mostly by fewer heart failure hospitalizations. There were no significant differences in cardiovascular death or all-cause death. The DELIVER investigators did not publish data on total hospitalizations, but in EMPEROR-Preserved, heart failure hospitalizations were a small fraction of total hospitalizations, which were not significantly different.

That is the dilemma of sodium-glucose cotransporter 2 (SGLT2) inhibitor use in patients with HFpEF: the drugs primarily reduce a small fraction of one type of hospital admission. Experts have countered this criticism by meta-analyzing the trials and concluding that SGLT2 inhibitors improve outcomes in a "broad range of patients with heart failure." I argue that the benefits depend on their indication.

The SGLT2 inhibitor data in patients with chronic kidney disease (CKD) support my take on indication-specific benefits.

In EMPA-KIDNEY, empagliflozin vs placebo reduced a primary endpoint of renal outcomes or cardiovascular death in patients with chronic kidney disease who had urinary albuminuria. The results were largely consistent with those of the 2020 DAPA-CKD trial. In patients with CKD, SGLT2 inhibitors reduce the progression of kidney disease, and in EMPA-KIDNEY, empagliflozin reduced total hospitalizations. Prevention of progressive kidney disease is a hugely important outcome.

When I visited Scotland this year, multiple doctors told me that SGLT2 inhibitor use was common because cost was not an issue. In the United States, cost is one of the core reasons doctors have to be parsimonious in the use of these largely beneficial drugs. This means adhering closely to trial data when prescribing.

10. Two Messages From the 2022 Diuretic Trials

The first message was that two trials finally gave us direct comparisons between commonly used diuretic drugs. The second message was that pragmatic trials have downsides.

The Diuretic Comparison Project (DCP)  studied the treatment of hypertension in primary care clinics. More than 13,000 patients were randomly assigned to chlorthalidone or hydrochlorothiazide. After 2.4 years, there were no significant differences in the composite outcome of major adverse cardiac events. Hypokalemia was higher in the chlorthalidone group (6.0% vs 4.4%). I was drawn to the fact that whereas experts had favored chlorthalidone, practicing doctors wrote nine times more prescriptions for hydrochlorothiazide, so DCP looked like a win for the collective wisdom of working-stiff doctors.

The TRANSFORM-HF trial randomly assigned nearly 3000 patients who were hospitalized for heart failure (of any type) to furosemide or torsemide. The primary outcome of death was not different over 1.5 years of follow-up. There were also no significant differences in total hospitalizations.

Both DCP and TRANSFORM-HF had major limitations due to their pragmatic nature.

In DCP, the enrolled patients were already taking hydrochlorothiazide and were assigned to stay on the drug or switch to chlorthalidone. The other issue was differing doses of the drugs—lower with chlorthalidone.

In TRANSFORM-HF, there were frequent crossovers, dosing was left to the discretion of clinicians, and all-cause mortality was surely an overly ambitious endpoint—the last heart failure trial that was able to show a mortality reduction was RALES, in 1999.

These two trials, plus SODIUM-HF, left me wondering about the pros and cons of pragmatic vs standard trials.

See you next year.

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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