Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information

Abstract

Background: Patients trying life-preserving agents such as beta-blockers may be discouraged by listings of harmful effects provided in good faith by doctors, drug information sheets, and media. We systematically review the world experience of side-effect information in blinded, placebo-controlled beta-blockade in heart failure. We present information for a physician advising a patient experiencing an unwanted symptom and suspecting the drug.

Methods: We searched Medline for double-blinded randomized trials of beta-blocker versus placebo in heart failure reporting side-effects. We calculated, per 100 patients reporting the symptom on beta-blockade, how many would have experienced it on placebo: the "proportion of symptoms non-pharmacological".

Results: 28 of the 33 classically-described side-effects are not significantly more common on beta-blockers than placebo. Of the 100 patients developing dizziness on beta-blockers, 81 (95% CI 73-89) would have developed it on placebo. For diarrhoea this proportion is 82/100 (70-95), and hyperglycaemia 83/100 (68-98). For only two side-effects is this under half (i.e. predominantly due to beta-blocker): bradycardia (33/100, CI 21-44) and intermittent claudication (41/100, 2-81). At least 6 so-called side-effects are less common on beta-blocker than placebo, including depression (reduced by 35%, p<0.01) and insomnia (by 27%, p=0.01).

Conclusions: Clinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect, when randomized controlled trials show no significant increase, or indeed a significant reduction. A better informed consultation could, in patients taking beta-blockers, alleviate suffering. In patients who might otherwise not take the drug, it might prevent deaths.

Keywords: Beta-blockers; Heart failure; Side-effects.

Supplementary Fig. 1

Funnel plots for 10 commonly reported side-effects. The y axis for all plots is the log odds ratio of a treatment effect (i.e. beta-blocker causing symptom to the right, alleviating symptom to the left), with the dark line the overall log odds ratio. The x axis is the standard error as a measure of the sample size. For most of these side-effects there is spread of values to either side of the overall log odds ratio, with smaller studies (larger standard error) generally diverging furthest from the overall log odds ratio, which does not suggest publication bias.

Fig. 1

An example of how the proportion of symptoms non-pharmacological has been calculated for a single listed side-effect on beta-blocker therapy. The square chart represents 100 patients with heart failure. The open circles show how many would expect to experience the side effect without the drug. The filled circles show how many additional patients would experience the side effect if all 100 took the drug. From this the physician and the patient can visualise the proportion of side effects that are non-pharmacological: it is the proportion of circles that are open. The spreadsheet that calculates these proportions, and automatically displays the square chart, operates on the free and open-source LibreOffice (www.libreoffice.org) or the widely-available Microsoft Excel. It is downloadable as an Online Supplement of this article.

Fig. 2

PRISMA flow diagram of the studies.

Fig. 3

The proportions of patients where beta-blocker is causative (± confidence intervals) for 5 side-effects statistically more prevalent in the beta-blocker arm of RCTs.

Fig. 4

Forest Plot of 5 frequently discussed perceived side-effects of beta-blocker use — fatigue, hypotension, hyperglycaemia, dizziness and bradycardia.

Fig. 5

Forest Plot of drug withdrawal (A) and serious adverse events (B) amongst RCTs of double-blind beta-blocker versus placebo controlled trials. Overall there are more withdrawals and serious adverse events amongst participants in the placebo groups.

Fig. 6

A rational side-effect note to give patients regarding beta blockers for heart failure. When advising patients to disregard regulatory notes because they are incorrect, it would be useful to have a replacement note whose content is supported by the blinded placebo-controlled studies. This proposed note is designed to show the available information simply for use by patients with heart failure.