Barron AJ, Zaman N, Cole GD, et al.
Int J Cardiol. 2013 Jun 21. doi: 10.1016/j.ijcard.2013.05.068

Background

Beta-blockers greatly improve survival in patients with chronic heart failure [1,2]. However, uptake is poor [3]. Perception of side-effects among patients and physicians might be at play. Patient experience of side-effects does not necessarily reflect the true pharmacological induction of side-effects by the drug. A well-intentioned warning by clinicians about a potential side-effect may condition patients to believe that any new symptom is a side-effect of the drug.
It would be helpful to have a delineation of reliable evidence on which side-effects can be induced by beta-blockers in patients with heart failure. Quantitative information on the probability of a reported side-effect to be a genuine consequence of the drug, would also be useful.
This systematic review therefore examined 13 double-blind randomised controlled trials (RCTs), in which patients and clinicians did not know whether the patient was taking the drug (n=7836) or placebo (n=7547).

Main results

• For 21 out of 33 listed side-effects, there was no significant difference between the beta-blocker and placebo-arm, including impotence, weight gain, postural hypotension and headache.
• 6 side-effects were more frequently reported in the placebo-arm, to wit depression, insomnia, worsening heart failure, palpitations, chest pain and tachycardia.
• Only 5 side-effects were significantly more common in the beta-blocker arm than in the placebo arm. These were examined in more detail. A ‘proportion of symptoms non-pharmacological’ was calculated to describe how many of the beta-blocker takers who reported a side-effect would have had that symptom on placebo.
  Out of 100 patients developing dizziness, 81 (95%CI: 73-89, P<0.01) would have experienced that on placebo as well, thus beta-blockers are only causative of dizziness in 19 out of every 100 patients. For diarrhea this proportion was 82 from 100 patients (95% CI 70–95, P< 0.01). For hyperglycemia this proportion was 83 (CI 68–98, P< 0.01), for intermittent claudication 41 (CI 2–81, P<  0.01), and for bradycardia 33 (CI 21–44, P<  0.01).
• People in the beta-blocker arm did not withdraw from the studies more often than people in the placebo arm, in fact they withdrew 20% less.
• Serious adverse events occurred in 22.1% of patients receiving beta-blocker, as compared to 25.6% receiving placebo. Being allocated to the beta-blocker arm therefore decreased the risk by 16% (95%CI: 4-27%, P=0.01).

Conclusion

RCTs in medicine are a means to reliably establish whether a treatment works. A similar recognition should also be applied to information about side-effects given to patients. This study demonstrated that the majority of adverse effects reported with beta-blockers in the treatment of heart failure are not caused by the beta-blocker per se. For only 2 out of 33 listed side-effects, bradycardia and intermittens claudication, the majority of sufferers had this truly as a result of the drug. In 3 side-effects, the drug was genuinely responsible in less than 1 of 4 sufferers. For the remaining 28 side-effects, there is no evidence that the drug makes them more common than placebo, thus this meta-analysis does not support their listing for heart failure patients. The current convention of providing incorrect information may be impeding uptake of drugs and achieving the target dose, thus impeding the therapeutic benefits.
This paper comes with a downloadable spreadsheet with which the physician can easily calculate, from one or more RCTs, the proportion of those who suffered a symptom who would have suffered it even without the medication.

References

1. CIBIS II Study Group. The cardiac insufficiency bisoprolol study II (CIBIS II): a randomized trial. Lancet 1999;353:9–13.
2. PackerM, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002;106(17):2194–9.
3. Cleland JG, McDonagh T, Rigby AS et al. National Heart Failure Audit Team for England and Wales. The national heart failure audit for England and Wales 2008–2009. Heart Jun 2011;97(11):876–86.

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