Bradycardia Linked to Adverse Outcomes, But Only in Conjunction With Heart Rate-Modifying Drugs

Asymptomatic bradycardia has no apparent influence on whether patients are likely to develop cardiovascular disease or die over a 10-year time span, unless they are concurrently taking heart rate-modifying medications. The findings, which raise the potential that such drugs could be doing more harm than good, arise from a retrospective analysis of the Multi-Ethnic Study of Atherosclerosis (MESA).

“We don’t really know if anything is causally linked at this point—whether the medications actually cause what we saw as an increased signal in mortality,” lead author Ajay Dharod, MD, of Wake Forest School of Medicine (Winston Salem, NC), told TCTMD. “However, the results are overall reassuring.”

In the past, high resting heart rate has been thought to be potentially linked with a higher incidence of cardiovascular disease. But the data has been unclear as to the effects of asymptomatic bradycardia—low resting heart rate—with some studies pointing to improved outcomes and longer lives in this population.

Of 6,733 patients initially free of cardiovascular disease who were enrolled in MESA and followed for 10 years, 86.6% were not taking any heart rate-modifying drugs. Mean resting heart rate for this subgroup was 63 bpm, with 5.3% classified as having bradycardia, defined as a heart rate less than 50 bpm.

Patients who were prescribed medications were generally older and higher risk—most received beta-blockers (71.1%) or calcium channel-blockers (27.8%). Bradycardia in this population was more likely in men, those on beta-blockers, and patients with lower BMI.

Findings were published online last week in JAMA Internal Medicine.

Medication Affects Outcomes

Over the study period, there were 633 occurrences of cardiovascular disease, the incidence of which was lowest in patients with heart rates of 50-59 bpm regardless of medication use and highest in those with heart rates of > 80 bpm. After adjusting for baseline differences, the slight excess of cardiovascular disease among those with bradycardia vs with those having heart rates of 50-59 bpm was not significant (P = .74).

Almost 700 patients died during the 10-year follow up, and 160 of the deaths were cardiac in nature. A U-shaped mortality curve was seen, with the highest death rates for patients with bradycardia and those with heart rates > 80 bpm who were on heart rate-modifying drugs. The lowest mortality was seen among patients with heart rates of 60-69 bpm. Among patients on these medications, those with bradycardia (adjusted HR 2.42; 95% CI 1.39-4.20) and heart rate > 80 bpm (adjusted HR 3.55; 95% CI 1.65-7.65) had a higher mortality risk than those with heart rates 60-69 bpm. For patients not on heart rate-modifying drugs, the mortality pattern appeared more linear, according to the authors.

Study Design Leaves Open Questions

The findings “clearly confirm” prior research showing a survival advantage in patients with low heart rates who are not on heart rate-modifying drugs, according to Carl J. Pepine, MD, of the University Of Florida College of Medicine (Gainesville, FL), who was the senior author of a similar study published in 2008. But he told TCTMD that he is disturbed by the implications for patients with bradycardia who are taking these medications.

He pointed out that 71% of the drugs used were beta-blockers, yet 97.5% of these patients seemed to have hypertension. “There’s [prior] evidence that beta-blockers are beneficial in many cardiovascular disorders,” Pepine said. “So if I’m interpreting the data correctly,… this is just suggesting that the beta-blockers were not adequately controlling blood pressure perhaps.”

The most important question, he continued, relates to understanding what is responsible for the increased risk of mortality among patients with heart rates under 60 bpm who are “principally taking beta-blockers.”

Dharod said that, given the design of the study, “I don’t think we can actually make any conclusions about [the efficacy of beta-blockers].”

A big limitation, the authors write in their paper, is “the potential for confounding by indication because we could not determine why individuals were taking [heart rate]-modifying drugs at baseline. It is possible that these individuals may have been using these drugs for arrhythmias, heart failure, or other [cardiovascular disease] not reported to MESA.”

Pepine said he would like to see this information recorded during a future trial, with Dharod adding that only a randomized controlled trial would be able to overcome the aforementioned confounding.

Source: 
Dharod A, Soliman EZ, Dawood F, et al. Association of asymptomatic bradycardia with incident cardiovascular disease and mortality: the Multi-Ethnic Study of Atherosclerosis (MESA). JAMA Intern Med. 2016;Epub ahead of print.

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