COMMENTARY

The 'Just-Because' Use of Beta-blockers Comes Into Question at ESC 2014

John Mandrola

Disclosures

September 04, 2014

On clinic days, I sometimes keep a running tally of how many drugs I prescribe and how many I stop. It's usually more than five to one—in favor of stopping. When I do prescribe medication, it is often beta-blockers. If a doctor could have a favorite class of drugs, mine would be beta-blockers. I like their wide therapeutic window; I like their proven safety record; and this: my patients here in suburban America are more often than not overserved on catecholamines.

But the European Society of Cardiology (ESC) 2014 Congress sessions were hard on these chemicals. Two abstracts in particular challenged conventional thinking. Interestingly, and this is a point I will revisit at the end of the piece, both studies questioned the use of drugs in stable patients for prevention purposes. Hmm.

Beta-Blockers in Patients With Heart Failure and AF

In the first of two beta-blocker abstracts, Dr Dipak Kotecha (University of Birmingham, UK) presented a meta-analysis of 10 major randomized controlled trials (RCTs) of beta-blockers in heart failure. (This paper was also published in the Lancet.[1]) Kotecha and colleagues were interested in how patients with atrial fibrillation (AF) and systolic heart failure fared with beta-blockers.

Kotecha reminded the standing-room-only audience the evidence base for beta-blocker benefit comes predominantly from studies that enrolled white middle-aged men. Women, the elderly, and those with AF were underrepresented in these trials. Current guidelines extend the benefit of beta-blockers to patients with AF. Should this be so?

To answer this question, the BB-Meta-HF collaborative group extracted individual patient-level data from the 10 RCTs. Study discussant Dr Lars Rydén (Karolinska Institute, Stockholm, Sweden) heaped praise onto the researchers, noting that their study represents "the highest-level standard of meta-analysis. Few [meta-analyses] live up to these standards," he said.

The study group included 18 254 patients, of which 13 946 (76.4%) were in sinus rhythm (SR) and 3066 (16.8%) in AF at baseline. Over 1.5 years of follow-up, 2237 of 13 946 (16%) patients with SR died vs 633 of 3064 (21%) patients with AF. In patients with SR, beta-blocker therapy conferred a statistically significant 27% reduction in mortality. In patients with AF, there was no difference (hazard ratio 0.97).

It's important to note the baseline patient characteristics from this study, particularly the observation that SR and AF patients had similar average heart rates. In the RCTs, beta-blocker therapy was used to prevent mortality, not just for rate control. That's an important point to consider when thinking about the authors' provocative conclusion:

"Beta-blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation."

Going further, the authors join the long list of people with disputes over guidelines:

"We dispute the preferential use of beta-blockers compared with other rate-control medications and emphasize the need for further trials in this common and increasingly important group of patients."
Beta-blocker Use Long After MI

Cardiologists are often asked whether patients who have had an MI and maintain a normal ejection fraction should continue taking beta-blocker years after the index event. It's a good question, because most trials of beta-blocker use in post-MI patients were performed in a different era. It's hardly controversial to say cardiovascular care today is different from the 1990s. European and North American guidelines differ on this question. In Europe, the recommendation for routine use of beta-blockers in this group has been downgraded to class IIa; in North America it remains a class Ia.

It is in this context that Dr Etienne Puymirat (European Hospital of Georges Pompidou, Paris France) presented the five-year follow-up of the FAST-MI trial.[2] The aim of this nationwide registry study was to evaluate the "real-world" management of patients with acute MI. Patients (n=3670) were enrolled from 223 centers in France.

Shelley Wood has detailed coverage of this abstract and its discussion here on theheart.org. In short, the investigators selected a subgroup of 1630 patients who had an ejection fraction >40%. This group was chosen because their beta-blocker prescription status was known one year after the acute MI. Researchers then matched patients in this group based on similar clinical features. The final analysis included 142 patients off beta-blockers and 280 patients on beta-blockers. Survival was reported for one- and five-year outcomes.

After one year, survival was 95.3% for patients on beta-blockers and 87.8% in those off the drug. The numerical advantage did not reach statistical significance. The story at five years was the opposite. More patients in the off-beta-blocker group were alive, but the difference did not reach statistical significance.

The FAST-MI investigators concluded "early beta-blocker treatment might be beneficial, but stopping the drugs after the first year was not associated with increased mortality." And once again, there was dispute over current North American guidelines. The final statement on their final slide read: "These results support changes adopted in the most recent ESC guidelines."

Thoughts

Let's first consider the use of beta-blockers in patients with systolic heart failure and AF. The BB-Meta-HF data are compelling. How does one argue with an analysis of individual patient-level data and something as simple to count as survival?

Yes, beta-blockers have a clear role in certain patients with AF and LV dysfunction—for control of ventricular rate, symptoms, or blood pressure, for instance. But not simply as an add-on to reduce mortality. Indeed, the specifics of that message are important. We don't want to overtreat patients. (To be clear, there was no signal of harm from beta-blockers.)

But please, I urge you to see the bigger issue with this study, the one about "evidence-based medicine." RCTs are surely an excellent way to test treatments. It is our interpretation of these tests that needs work. Individual people are not study populations. The act of decreeing benefit to all patients because benefit was observed within the cocoon of carefully controlled clinical trials performed in select groups of patients needs to be rethought. We should be smarter than that. Women, the elderly, and African Americans are common groups of people underrepresented in clinical trials. Does benefit extend to these groups? Maybe it does, maybe it does not.

Now let's address the "just-because" use of beta-blockers in post-MI patients with normal LV function. I could almost stop right there. Well, almost.

Hot-line trial discussant Dr Christopher Granger (Duke University, Durham, NC) was right when he said in the discussion following the presentation, "The FAST-MI trial was confounded." Agreed. It was a nonrandomized registry study that used a select subgroup.

I would argue, though, these findings make perfect sense. Think back to what emeritus professor Dr Arnold Katz (University of Connecticut, Farmington, CT) taught us at the dawn of the beta-blocker era decades ago: Adrenergic blockade is beneficial in diseased hearts because it promotes favorable neurohormonal energy balance, especially in the setting of post-MI healing. But . . . if patients have no LV dysfunction and are years out from myocardial injury, what neurohormonal imbalance is there? None.

Finally, I will close with a prescription for treating the collective misthink of using chemicals in stable nonsymptomatic patients in the name of prevention. Perhaps it is time for a change in our baseline thinking. After we prescribe good food, good movement, and good sleep, I say we prescribe a little more skepticism rather than drugs.

JMM

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