Reopening the Book on Treating PVCs: More Evidence for PVC-HF Link

July 13, 2015

WASHINGTON, DC — A higher percentage of premature ventricular contractions (PVCs) predicted a dropoff in LV ejection fraction and a greater risk of incident heart failure and mortality in a long-term follow-up of >1100 participants in a community-based study[1]. All persons in the analysis had been older than 65 and free of heart failure with a normal LVEF at baseline when they underwent 24-hour Holter monitoring for PVC assessment.

Although links between frequent PVCs and ongoing heart failure have been observed, the current analysis, based on a cohort from the Cardiovascular Health Study (CHS), provides "the first evidence that PVC percentage predicts new systolic dysfunction, as well as clinically diagnosed CHF and overall mortality," say the authors in their report, published in the July 14, 2015 issue of the Journal of the American College of Cardiology. It also raises the issue of whether PVCs might sometimes be an appropriate target for treatments aimed at preventing heart failure.

The risk of heart failure that could be attributed to PVCs reached 8.1% compared with the general population, an increase in the same league as such recognized HF risk factors as increased body-mass index, hypertension, advanced age, and coronary artery disease. The risk of decreased LVEF over 5 years tripled in the highest PVC-frequency quartile vs the first quartile; mortality risk over a median of >13 years went up 31%.

The observational study can't demonstrate causality, note the authors, led by Dr Jonathan W Dukes (University of California, San Francisco). But overall, the findings "suggest that PVCs might be an important cause of occult or 'idiopathic' cardiomyopathy and might be an important determinant of incident CHF among those with other established CHF risk factors."

Ablate PVCs in HF, LVEF Can Improve

"There's this general notion that PVCs are very benign, which is certainly what I was taught, even in my general cardiology fellowship, before the more recent data that came out of the electrophysiology labs," senior author Dr Gregory M Marcus (UCSF) said in an interview with heartwire from Medscape.

In recent years, he said, it's been appreciated that ablation of PVCs in patients with lots of them can improve quality of life by alleviating symptoms such as syncope. And there are series of patients with PVCs and primarily nonischemic cardiomyopathy in the EP literature suggesting that "if you ablate those PVCs, their heart failure improves and often their reduced ejection fraction normalizes," according to Marcus. "Many of us have seen that and witnessed it firsthand in many of our own patients."

Those experiences aren't necessarily well known in all corners of cardiology, he observed. Probably more broadly known are the findings published in 1989 from a prospective randomized trial that has turned out to be one of the most influential in medicine[2].

CASTing a New Light on Treatment of PVCs

The Cardiac Arrhythmia Suppression Trial (CAST), Marcus noted, "taught us a lot of important lessons. More generally, it was a great example of the need to look at hard outcomes rather than secondary or surrogate outcomes."

As cardiology textbooks have since noted, CAST randomized about 2300 patients who had asymptomatic or only mildly symptomatic PVCs after acute MI to receive one of three antiarrhythmic agents or placebo. The drugs, which included the class Ic agents encainide and flecainide, were mostly effective at suppressing PVCs. But over a mean 10 months of follow-up, patients who had received those drugs showed steep rise in rate of arrhythmic death (the primary end point) as well as nonfatal cardiac arrest, almost certainly due to proarrhythmic effects.

The widely learned lesson: post-MI suppression of PVCs, a surrogate for the pathology behind sudden cardiac death in ischemic heart disease, doesn't lower its risk; in fact, treatment of surrogate markers can make things a lot worse. (Importantly, CAST was conducted in the early days of arrhythmia ablation and implantable defibrillators, which were not options for its patients.)

As a result, according to Marcus, class Ic agents are generally avoided in patients with structural heart disease. "I think that while the proarrhythmic effects of those drugs were known, they weren't fully appreciated, and CAST taught us to be wary of them."

Some other lessons may have been misguided. "I think that the CAST trial's reach probably extends further than it should in many circumstances and kind of closes the mind to considering other alternatives and ways that PVCs may yet be a therapeutic target," Marcus said.

An editorial accompanying the new analysis agrees[3]. The trial, it says, "led to a misleading and absolutely held conclusion: [PVC] suppression should not be considered as a therapeutic target to reduce the risk of adverse cardiovascular events. This errant conviction still holds among many investigators, who continue to provide significant intellectual resistance to studies confirming the significant cardiovascular risk associated with [PVCs], as well as to studies suggesting a benefit of PVC suppression when it can be achieved without the use of toxic antiarrhythmic medications, such as with successful catheter ablation procedures."

Adjusted Hazard Ratios for Baseline PVC-Percentage Quartile 4 vs Quartile 1 in CHS Cohort, n=1139

End points HR (95% CI)a P
LVEF reductionb 3.10 (1.42–6.77) 0.005
Incident HF 1.48 (1.08–2.04) 0.02
Mortality 1.31 (1.06–1.63) 0.01
a. Adjusted for age, sex, race, body-mass index, beta-blocker use, Holter-based atrial fibrillation, number of Holter-based ventricular-tachycardia episodes, and history of hypertension, diabetes, and coronary artery disease
b. Change in LVEF category (normal, borderline, or abnormal) by echocardiography at 5 years vs baseline

Compelling, But With Caveats

The findings of the current analysis, continue Drs Pasquale Santangeli and Francis E Marchlinski (University of Pennsylvania, Philadelphia) in their editorial, "are compelling and offer additional evidence supporting the relevance of [PVCs] as a therapeutic target to potentially modify the longitudinal risk of heart failure and death."

On the other hand, as Marcus points out, there are important distinctions between the CAST population and that of the current study, and among the PVC-suppressing therapies relevant to each. Whereas CAST patients all had a history of MI and a low LVEF and received daily drug therapy for their PVCs, the CHS cohort consisted of people in the community with normal LVEF, as defined by echocardiography, and no heart failure, who had been randomly selected for 24-hour Holter monitoring. The PVC-suppression treatment that would be considered for them today, catheter ablation, is usually a one-time procedure that targets a highly localized part of the heart.

"PVC-induced cardiomyopathy has been described, but it usually occurs with much higher PVC burden," compared with patients in the current study, "so I am not sure that treating PVCs with medications or ablation would prevent EF deterioration and HF in patients like theirs," Dr Sana M Al-Khatib (Duke University Medical Center, Durham, NC) told heartwire in an email. "This deserves investigation."

Patients in the current analysis had a median PVC prevalence of 0.011%; the highest quartile was 0.123% to 17.7%.

Also, she said, the report doesn't say much about distribution of PVC morphologies. "If most patients had several different PVC morphologies, ablation may not be effective."

Marcus said one of the next steps in this line of research could be to identify any predictors that would help identify patients most prone to heart failure from a high PVC burden, including, possibly, PVC morphology.

Al-Khatib raised cautions about the study's observational nature, which prevents any conclusion that greater PVC prevalence was related to incident heart failure and reductions in LVEF. She points out that the patients with greater PVC burden also had "more prevalent coronary artery disease and a thicker ventricle at baseline. Both of these conditions predispose people to future HF."

Although the analysis tried to control for such factors, she said, the question remains "whether PVCs are causing deterioration in EF and HF or if they are simply a marker of underlying disease. If the former is true, then treating PVCs would help. But if the latter is true, then treating PVCs may not make a difference."

Marcus acknowledges that PVCs may be simply a risk marker in people with sick hearts. "But even if that's the case, I think it's potentially a very useful marker." He said he hopes the report will help "motivate future research in potentially two different directions. One, might ablation be an effective therapy to prevent heart failure in the right patients? Alternatively, could this be used to help predict heart failure and implement other strategies, such as beta-blockers, to prevent heart failure in those patients?"

The CHS is sponsored by the National Heart, Lung, and Blood Institute. Dukes and Marcus report that they have no relevant financial relationships; disclosures for the other authors are in the report. Santangeli and Marchlinski report that they have no relevant financial relationships. Al-Khatib says she has no relevant financial relationships with industry.

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