Lisinopril May Cut Risk of Conduction-System Disease Development, Says ALLHAT Analysis

Deborah Brauser

June 30, 2016

SAN FRANCISCO, CA — Treatment with the ACE inhibitorlisinopril may lower the development of conduction-system disease in patients with hypertension and at least one cardiac risk factor, new research suggests[1].

In a secondary analysis of more than 21,000 participants from the landmark ALLHAT trial, investigators examined three treatment arms: up to 40 mg/day of lisinopril, up to 25 mg/day of chlorthalidone, and up to 10 mg/day of amlodipine besylate. They found that those randomized to lisonopril had a 19% reduction in conduction-system defects up to 5 years later, as shown with 12-lead ECG, vs those randomized to chlorthalidone (P=0.01).

Although there was also a reduction in the lisonopril vs amlodipine groups, this wasn't statistically significant. And there was no significant difference between chlorthalidone and amlodipine.

Further analysis showed significant multvariable risk predictors for incident conduction-system disease, included having left ventricular (LV) hypertrophy or being male or older (all P<0.001) or having diabetes (P=0.003).

Corresponding author Dr Gregory M Marcus (University of California, San Francisco) told heartwire from Medscape that it was interesting to see that lisonopril reduced conduction disease over chlorthalidone "despite chlorthalidone reducing blood pressure. So this demonstrates that this effect, if there is a causal relationship, is not simply related to blood-pressure reduction—but has something to do with the mechanism of the drug itself."

Still, Marcus cautioned that the findings need to be replicated "before we can strongly suggest that this represents the absolute truth. But I think it is compelling."

The results were published online June 27, 2016 in JAMA Internal Medicine.

In an accompanying editorial[2], Drs Sanjiv M Narayan, Tina Baykaner, and David J Maron (Stanford University, CA) write that "to our knowledge, this is the first report that incident conduction-system disease may be prevented by drug therapy."

Maron added to heartwire that although the disease is relatively common, "we really haven't had much information about how to prevent it. So this an exciting new avenue."

Disease Complacency

"Conduction disease and how to prevent it in the first place has really been ignored," said Marcus, adding that the disease is the main reason individuals need pacemakers.

He noted that because pacemaker implantation is still relatively straightforward and effective, "we've become complacent. And the incentive to figure out how to prevent the need for a pacemaker hasn't really been there."

However, "pacemakers aren't perfect," and there can be procedure complications, he said. "And even in those without pacemakers, we now recognize that people with conduction disease, especially those with left bundle branch block, are likely at risk for heart failure."

Marcus explained that the investigators wanted to assess whether lisinopril could reduce conduction disease, "given previous evidence that inhibiting the renin-angiotensin-aldosterone system appears to be an antifibrotic strategy."

To test this hypothesis in a large population who underwent "the gold standard of ECG," they turned to the publicly accessible ALLHAT trial and examined data on 21,004 of the participants >55 years (56% men; mean age 66.5 years), who were enrolled at 623 centers in North America.

Of these, 5542 were randomly assigned to lisinopril, 9726 to chlorthalidone, and 5736 to amlodipine besylate. In addition, the participants with elevated fasting LDL-C levels were randomized to either pravastatin sodium (up to 40 mg/day) or usual treatment.

All participants underwent ECGs at baseline and at 2-year follow-ups (mean follow-up total 5 years).

Conduction Abnormalities

Among the 1114 conduction abnormalities that developed during the study, 570 were right bundle branch blocks, 389 were left bundle branch blocks, and 155 were intraventricular conduction delays. "The overall incidence was 13.0 (95% CI 12.2–13.7) per 1000 person-years for any conduction abnormality," report the investigators.

The hazard ratio [HR] for conduction-disease development in the lisinopril group was only 0.81 vs the chlorthalidone group (95% CI 0.69–0.95). Neither amlodipine nor pravastatin had significantly reduced adjusted risks for the condition.

The HRs for the significant risk factors for conduction disease were:

  • 3.20 for LV hypertrophy (95% CI 2.61–3.94).

  • 1.47 for older age, per 10-year increase (95% CI 1.34–1.63).

  • 1.23 for diabetes (95% CI 1.07–1.42).

  • 1.81 for male sex (95% CI 1.54–2.11).

However, being black was associated with a significant reduction in adjusted risk for the disease vs being white (HR 0.59, 95% CI 0.5–0.7; P<0.001).

Overall, "further studies are warranted to determine whether pharmacologic treatment affects conduction-abnormality outcomes, including pacemaker implantation," write the investigators.

"I don't want to be prematurely jumping the gun," agreed Marcus. "On the one hand, it's exciting because it's a new finding. But on the other hand, it's the first study to look at something like this. So yes, it definitely needs to be replicated," he said.

"In general, I'd say that it's important for both clinicians and researchers to shift our mind-set to how we can prevent arrhythmias like conduction disease instead of considering the disease and a need for a pacemaker an inevitable conclusion," he added.

Added Bonus?

"At present, no paradigm to treat ECG conduction abnormalities in patients without cardiomyopathy or heart block exists," write the editorialists.

But they note that the new findings line up with past research showing that "angiotensin-converting enzyme inhibition has salutary effects on inflammation, hypertrophy, and fibrosis.

"If confirmed in other populations, the ability to prevent conduction-system disease could have substantial clinical and research implications," they write, adding that this is "indeed an exciting prospect."

Maron explained further to heartwire that "until now, we haven't thought of pharmacologic therapy as a method to prevent conduction-system disease. But this study suggests that that is a possibility. We need to confirm that, and there may be other agents that are equally or more effective," he noted.

Still, if an individual meets the inclusion criteria for ALLHAT and needs pharmacologic therapy to treat hypertension, "why not select an ACE inhibitor as opposed to a calcium-channel blocker or a diuretic if it has the added benefit of potentially preventing conduction disease?" asked Maron.

"That would be a practical take-home from this study. All things being equal, why not use, in this case lisinopril, for the prevention of hypertension when there could be an added bonus?"

The study was funded by a grant from the American Heart Association and by the Joseph Drown Foundation; the National Heart Lung, and Blood Institute; the US Department of Health and Human Services from the National Institutes of Health (NIH); and by Pfizer. The current study authors report no relevant financial relationships. ALLHAT's investigators acknowledged study medications were supplied by AstraZeneca and Bristol-Myers Squibb and study medications and financial support was provided by Pfizer. Narayan reports receiving research grants from the NIH; being coinventor of "intellectual property" licensed to Topera, in which he held equity; and receiving consulting fees from the American College of Cardiology and Uptodate and speaking fees from St Jude Medical and Medtronic. Maron and Baykaner report no relevant financial relationships.

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