Beta-blockers in HF Get Bum Rap for Most 'Side Effects,' Says Study

July 12, 2013

WATFORD, UK — By a wide margin, most adverse side effects attributed to beta-blockers in randomized, controlled heart-failure trials weren't significantly more common with the drugs than they were with placebo, conclude researchers based on a meta-analysis[1].

"The majority of adverse effects reported with beta-blockers in heart failure are not caused by the beta-blockers per se but arise either from the disease itself, another coincident problem, or from the power of suggestion--the nocebo phenomenon," write the authors, led by Dr Anthony J Barron (St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK).

Yet, the researchers observe, physicians most places are obligated to caution their HF patients starting on beta-blockers that the drugs may indeed cause those side effects. And that, they say, is potentially disastrous for those who later stop taking beta-blockers after blaming them for ills the drugs aren't actually causing.

If they were so overwhelmed by the side effects that they had to stop, it was more likely from taking a placebo.

The analysis covered 13 randomized beta-blocker trials in heart failure that attributed side effects to the drugs. They included six trials withcarvedilol and up to two studies each with bucindolol, metoprolol, bisoprolol, and nebivolol (Bystolic, Forest Pharmaceuticals).

Of 33 signs or symptoms labeled a side effect in at least one of the 13 trials, only five were significantly more common with the beta-blocker than with placebo. "In the other 28 of 33 side effects, there is no evidence that the drug makes them more common," according to the group.

Remarkably, they include some that are routinely attributed to beta-blockers, such as fatigue. They also include some that make little sense as beta-blocker effects, such as tachycardia, and indeed were significantly less common on the drugs.

Overall, more "side effects" were experienced by placebo recipients than those given beta-blockers in the trials, and "if they were so overwhelmed by the side effects that they had to stop, it was more likely from taking a placebo," senior author Dr Darrel P Francis (St Mary's Hospital) told heartwire . His group's analysis was published online June 24, 2013 in the International Journal of Cardiology.

"Worse Than Useless"

For any drug, side effects noted in the labeling tend to include "anything that was ever experienced by anyone on the drug," according to Francis. Initially it's a short list, and then "it gets longer and longer, since there's no way of removing things from it." He sees the beta-blocker side-effect list as "totally useless to anyone, and it's worse than useless because it becomes the first point of call for a patient when they don't have their doctor with them and they feel peculiar at any stage after taking the drug," he said.

"If I give you a tablet and say it may cause fatigue, it will, particularly if it's a disease that has fatigue at its very core. And that’s a perfectly good reason to stop taking the drug--if you become convinced that it's causing fatigue." And as there's no substitute for beta-blockers in heart failure, he noted, without them the patients die earlier.

One of the reasons beta-blockers are underutilized is because of the fear and the perception of significant side effects.

"How did we get in this situation, where we feel obliged to say things to people that almost certainly are causing death?" Francis said. "I call this a lethal asymmetry. We are very cautious in ascribing any benefits to drugs . . . but it's unbelievable that we are so careless in ascribing harm. And the net result of this is that patients are walking around miserable for no reason at all, when in fact [they could have] been made better by the drugs."

According to Dr Prakash Deedwania (University of California San Francisco, Fresno), who isn't connected to the analysis, "it's absolutely an issue, because beta-blockers are the best cardioprotective agent in both MI and in heart-failure patients, and yet they are underutilized." And, he said to heartwire , "one of the reasons beta-blockers are underutilized is because of the fear and the perception of significant side effects."

Deedwania said he isn't skeptical about the analysis. "I believe these data." Still, he was "amazed" to see that fatigue was no more common on the drugs than on placebo--it's often the first potential side effect to be named in the physician-patient discussion.

It's true that initially after the start of beta-blocker therapy, patients may feel the drugs' negative inotropic effects, but that abates as cardiac output improves with positive myocardial remodeling, Deedwania observed. "So there should be less fatigue."

"They Think I'm Insane . . . "

The 21 so-called side effects that were about as common with placebo as with beta-blockers, other than fatigue, included impotence, weight gain, headache, postural hypotension, syncope, and hypotension.

The five alleged side effects that were significantly more common on beta-blockers than placebo in the 13 trials, according to Barron et al, were hyperglycemia, diarrhea, dizziness, claudication, and bradycardia. But "even for these five side effects, in many patients it is not the drug that is the cause." Of 100 patients developing dizziness on beta-blockers, for example, 81 would have developed it on placebo, their calculations indicate. Indeed, they suggest that about 70% to 80% of cases of dizziness, diarrhea, and hyperglycemia would not have been due to the beta-blocker itself.

You could say to patients that beta blockers might prevent depression, because our analysis suggests it cuts depression by a third..

Only for bradycardia (33 cases on placebo per 100 on beta blockers) and intermittent claudication (41 per 100 cases, respectively) would side effects have been predominantly due to beta-blockers, the group notes.

The five supposed side effects that were significantly less common with beta-blockers compared with placebo, other than tachycardia, included palpitations, depression, insomnia, cardiac failure, and chest pain (p<0.01 in each case).

Tachycardia would seem an unlikely consequence of beta-blocker therapy, Francis observed, "and yet it's listed as a side effect--which I think trashes the credibility of the rest of that list. It's something that people would guess would be not true and in fact is absolutely backward when you look at the research."

As for depression, "I have said to my colleagues, and they think I'm insane, that you could say [to patients] that beta-blockers might prevent depression, because [our analysis suggests] it cuts depression by a third," Francis said. "And of course that's because it makes heart failure better; it's not a direct effect on depression."

But would it be unethical to say beta-blockers can lower the rate of depression by one third, or perhaps unethical not to say it? Francis wondered.

You Can't Change The List, but . . .

"We are faced, on one hand, by regulatory requirement to tell them these [labeled side effects], and on the other hand with the fact that just as much of it is backward as it is the right way around and that much of it is unsubstantiated by any science," he said.

In their report, Francis and his colleagues propose alternative ways to discuss possible beta-blocker side effects with patients. For example, they write, "physicians might focus the patient's attention on a much smaller core of reliable information, together with information on the proportion of side effects that are nonpharmacological. Thus, adverse effects, when later experienced, are not automatically assumed to be caused by the drug."

I personally advise patients not to take any notice of the side-effect list, because most of it is not true.

The physician might tell the patient that according to the studies, 19% of patients on beta-blockers experienced dizziness while it occurred in 15.3% of those not taking the drugs or that 16.1% on beta blockers and 13.4% of those on placebo developed hyperglycemia.

"Currently, I personally [advise patients] not to take any notice of the side-effect list, because most of it is not true," Francis said. "I then tell them that [the beta-blocker] may make your heart rate go slower, and it may increase the blood circulation by opening up your blood vessels--which is why the pressure is lower. But that's not bad, it means less work for your heart. So I tend not to emphasize side effects, [which would be] giving people reasons to have a bad opinion of the drugs, and that could cost them their life."

Even if physicians can't change the FDA-mandated side-effect list when speaking to patients, "you can tell patients which ones were not more common than on placebo in the trials," Deedwania agreed. "For full disclosure, [physicians] can say yes, there's a chance, but also emphasize that they will do much better on the drug, because it is life-saving."

Barron and Francis disclose support from the British Heart Foundation. The coauthors have no disclosures. Deedwania said he has no relevant conflicts of interest.

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