Meta-analysis of Placebo-Controlled Randomized Controlled Trials on the Prevalence of Statin Intolerance

Abstract

The prevalence of intolerance varies widely. Stopping statin therapy is associated with worse outcomes in patients with cardiovascular disease. Despite extensive studies, the benefits and risks of statins continue to be debated by clinicians and the lay public. We searched the PubMed, Medline, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for all randomized controlled trials of statins compared with placebo. Studies were included if they had ≥1,000 participants, had patients who were followed up for ≥1 year, and reported rates of drug discontinuation. Studies were pooled as per the random effects model. A total of 22 studies (statins = 66,024, placebo = 63,656) met the inclusion criteria. The pooled analysis showed that, over a mean follow-up of 4.1 years, the rates of discontinuation were 13.3% (8,872 patients) for statin-treated patients and 13.9% (8,898 patients) for placebo-treated patients. The random effects model showed no significant difference between the placebo and statin arms (odds ratio Statin intolerance is a common phenomenon and is reported in 5% to 20% of patients, often resulting in drug discontinuation.[1 Stopping statin therapy has been associated with worsened outcomes in patients with cardiovascular diseases (CVDs).2 With acceptance of the latest American College of Cardiology guidelines, the number of patients who require treatment with statins has increased even further.3 A number of mechanisms have been proposed to explain the phenomenon of statin intolerance. However, despite extensive studies, statin intolerance remains an elusive phenomenon.Most of our knowledge of the incidence of statin intolerance stems from observational studies and post hoc analyses. Assessing statin intolerance is important, as it can have widespread implications on public health. A number of patients on statins report muscle-related symptoms. There is little consensus among clinicians on whether to attribute muscle symptoms to statins; and in the absence of confirming laboratory parameters, judgment frequently remains subjective. Given this backdrop, we conducted a rigorous meta-analysis of historical randomized controlled trials (RCTs) to compare the rates of drug discontinuation for patients treated with statins and for patients treated with placebo. MethodsA PubMed and Medline literature search was conducted using the keywords "statin" and "clinical trials" (phase 1, phase 2, phase 3, and phase 4) as a filter. We also searched for "metaanalysis" as the article type and hand searched the reference lists of the selected systematic reviews to identify further studies. We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) database to expand the literature search using the keywords "statin AND placebo." No language restrictions were applied and the databases were searched from the inception of these databases until October 2016.

Introducing the ‘Drucebo’ effect in statin therapy: a systematic review of studies comparing reported rates of statin‐associated muscle symptoms, under blinded and open‐label conditions

“…The authors of the meta‐analysis raised the possibility of the ‘nocebo effect’ being responsible for the high rate of reporting of muscle symptoms in non‐blinded trials . These findings were confirmed in a more recent meta‐analysis …”

“…22 These findings were confirmed in a more recent meta-analysis. 23 Evidence relating to the role of the nocebo effect in statin intolerance was recently extensively reviewed by Tobert and Newman. 2 Since then, Gupta et al, in a retrospective analysis of the Anglo-Scandinavian Cardiac Outcomes Trial, found no difference between the incidence of muscle symptoms in patients taking atorvastatin 10 mg compared with placebo [hazard ratio 1.03, 95% confidence interval (CI) 0.88-1.21] in the initial double-blind phase of the trial, whereas in a later-open-label extension, significantly more muscle symptoms were reported in the statin-treated group 1.41 (1.10-1.79).…”

Atorvastatin for prevention of disease progression and hospitalisation in liver cirrhosis: protocol for a randomised, double-blind, placebo-controlled trial

“…The tolerability of statins has been evaluated in numerous trials in different patient populations 12 14 46. Possible side effects are rare or very rare, and include abdominal pain, mild hepatitis, pancreatitis, anaemia, myopathies or peripheral neuropathies or allergic reactions.…”

“…Possible side effects are rare or very rare, and include abdominal pain, mild hepatitis, pancreatitis, anaemia, myopathies or peripheral neuropathies or allergic reactions. Meta-analyses have found that statins are equally safe as control treatment regarding adverse and serious adverse events, and that rates of discontinuation and the most frequent side effect myopathy were equal between simvastatin and placebo in clinical trials 14 46. Safety of statins in chronic liver disease has been assessed in only a few clinical trials, but reviews of observational studies report high safety and low risk of adverse events 10 47 48…”

Statinassoziierte Muskelsymptome und Statinmyopathie

“…Im Gegensatz dazu liegt die Inzidenz von Muskelbeschwerden unter Statintherapie in randomisierten Studien nur bei 3-5 % [9,10] und damit im Bereich des Placeboarms. Zudem zeigt eine kürzlich publizierte Metaanalyse von 22 Studien auch keinen signifikanten Unterschied zu Placebo bezüglich Therapieabbruch und Auftreten von Myopathie [11]. Interessanterweise entsprach das mittlere Erkrankungsalter in der Subgruppe der HMGCR-positiven Patienten ohne Statinexposition mit ca.…”