Beta Blocker Fails to Shorten Time to First COPD Exacerbation

By Gene Emery

October 23, 2019

(Reuters Health) - A new randomized placebo-controlled trial that was halted early for safety reasons has failed to confirm observational studies suggesting that beta-blockers reduce exacerbations in moderate or severe chronic obstructive pulmonary disease (COPD).

The beta-blocker tested was extended-release metoprolol.

None of the 532 volunteers was taking a beta-blocker or had an established reason for taking one. The median time to first exacerbation was 202 days with the drug and 222 days with placebo (P=0.66).

"There had been a lot of enthusiasm for the idea that there might be a role for beta-blockers in exacerbation prevention, and clearly we didn't demonstrate that," chief author Dr. Mark Dransfield, a professor of medicine at the University of Alabama told Reuters Health in a telephone interview.

In fact, the drug increased the odds of an exacerbation leading to hospitalization, nearly doubling the risk.

"Our hope was to demonstrate that the drugs were well tolerated, and therefore make people feel more comfortable using them in settings where they are absolutely indicated" such as after a heart attack or with significant heart failure, said Dr. Dransfield. "Unfortunately, we didn't demonstrate that degree of safety."

The findings from the BLOCK COPD trial were released at the American College of Chest Physicians annual meeting in New Orleans and online by the New England Journal of Medicine.

The results come at a time when doctors are looking for better treatments for preventing exacerbations in a disease that is the third leading cause of death worldwide.

A 2012 meta-analysis of nine studies had suggested a 31% lower risk of COPD-related death with beta-blockers, and a 2014 analysis of 15 studies had found a 28% lower rate of death from any cause with the drugs.

The limitation of such observational studies is why the BLOCK COPD trial was undertaken.

It now appears that the ability of beta-blockers to reduce mortality in patients who have not had a heart attack or do not suffer from heart failure don't extend to COPD patients.

In a Journal editorial, Dr. William MacNee of the University of Edinburgh Medical School cautioned that "the results of this trial should not deter the use of beta-blockers in patients with COPD who have cardiovascular indications, with the caveat that the risk-benefit ratio should be considered carefully in patients with very severe COPD at high risk for severe exacerbation."

"Just as there were observational data to suggest that beta-blockers might reduce exacerbation risk -- which we went on to show that was not the case -- the data would suggest that COPD patients derive the same benefits from beta blockers as do non-COPD patients when they do have absolute indications to receive the drug. But this is all based on observational data as well. So some of those same concerns exist," Dr. Dransfield said. "We propose we might need prospective trials to test that."

In the new study, conducted at 26 U.S. medical centers, the volunteers were treated for up to 336 days, with some receiving less treatment because the trial was halted in March. None had absolute indications for beta-blockers such as a recent heart attack or very severe heart failure, but 15% had self-reported coronary disease and 45% had hypertension.

While the adjusted rate of any degree of first exacerbation was 12% higher in the metoprolol group, it was 46% higher when exacerbations of moderate severity or greater were assessed and 108% higher for severe or very severe exacerbations.

Eleven people taking metoprolol died versus five in the placebo group. Seven deaths in the metoprolol group were due to COPD compared with just one in the placebo group.

The beta-blocker did not seem to worsen lung function, "However, metoprolol was associated with worsening of dyspnea and the overall burden of COPD symptoms," the researchers reported. Because there were more discontinuations in the metoprolol group, there may be "adverse respiratory effects not captured by spirometry."

The rate of hospitalization was 0.66 people per year with metoprolol and 0.42 with placebo.

If beta blockers didn't worsen lung function, why were recipients going to the hospital or having exacerbations?

Dr. Dransfield theorized that "patients rely on the capacity to increase their heart rate in episodes where they get sick. If we block their ability to do that by giving them a beta-blocker, they become less able to compensate for that insult and can deteriorate. But that's pretty speculative."


N Engl J Med 2019.


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