Evidence supports the clinical equivalence of generic and brand-name cardiovascular drugs, according to a meta-analysis published in the Journal of the American Medical Association. Despite this evidence, more than half of the editorials discussing the issue of generic interchangeability that were assessed in this analysis do not support generic substitution for brand-name cardiovascular drugs.

Using Medline, EMBASE, and International Pharmaceutical Abstracts, the investigators performed a systematic search of articles on the treatment of cardiovascular (CV) disease published between January 1984 and August 2008. Studies were included if they compared 1 brand-name drug with at least 1 generic version and if the evaluation included measurement of at least 1 clinical efficacy or safety outcome (ie, vital sign, clinical laboratory study, patient morbidity or mortality, or health-system utilization). Both randomized controlled trials and observational studies were included. Included studies were subdivided on the basis of whether the drugs had a wide therapeutic index (WTI) or a narrow therapeutic index (NTI). Investigators also used Medline and EMBASE searches to identify editorials published during the same time frame about the appropriateness of generic drug substitution in treating patients with CV disease.

A total of 8,556 records were identified during the initial literature search; after application of exclusion criteria, 47 articles were included in the final analysis. These articles evaluated 9 subclasses of CV drugs. Out of the 47 studies, 38 (81%) were randomized controlled trials.

WTI drugs that were assessed in 34 trials included beta-blockers, diuretics, calcium-channel blockers, antiplatelet agents, angiotensin-converting enzyme (ACE) inhibitors, statins, and alpha-blockers. In 9 articles that assessed beta-blockers, no significant differences were observed between brand-name and generic drugs on primary outcomes such as blood pressure and heart rate; 1 study demonstrated a significant increase in adverse events among patients taking the generic version of the drug. In 11 articles that assessed diuretics, only 1 study demonstrated a significant difference between brand-name and generic drugs on the primary outcome of 6-hour urine output; the other studies demonstrated nonsignificant differences in primary outcomes such as urine electrolytes and urine volume. In 7 studies that assessed calcium-channel blockers, no significant differences were demonstrated between brand-name and generic drugs on primary outcomes such as blood pressure and heart rate, although 2 studies did demonstrate slight but significant differences in PR interval. In the remaining 7 studies of antiplatelet agents, ACE inhibitors, statins, and alpha-blockers, only nonsignificant differences between brand-name and generic drugs were observed.

NTI drugs assessed in 13 articles included class I antiarrhythmic drugs and warfarin. Of 2 studies of antiarrhythmic drugs, investigators observed a slight but significant reduction in total emergency department (ED) discharges and ED visits for chest pain with the generic drug compared with the brand-name drug in 1 study and no significant differences between the brand-name and generic drug in the second study. In the studies of warfarin, clinical outcomes were similar between the brand-name and generic drug on clinical outcomes in 9 of the studies. Of the remaining 2 studies, one demonstrated a small but significant decrease in INR in patients who received generic warfarin, and another demonstrated increased healthcare system use in patients treated with the generic drug.

In their review of editorials discussing generic substitution, the investigators observed that, of 43 commentaries included in the analysis, 23 (53%) expressed a negative view of generic interchangeability, 12 (28%) expressed a positive view, and 8 (19%) did not reach a conclusion. The investigators suggested that these commentaries “may be more likely to highlights physicians’ concerns based on anecdotal experience or other nonclinical trial settings.”

The study authors discussed several limitations of their study, including the small populations of many of the included trials, a disproportionate number of young and healthy participants in the trials, and the small number of studies in classes other than beta-blockers, calcium-channel blockers, diuretics, and warfarin. In spite of these limitations, the authors stated that “it is reasonable for physicians and patients to rely on FDA bioequivalence rating as a proxy for clinical equivalence among a number of important cardiovascular drugs, even in high-risk contexts such as the NTI drug warfarin.”

Source
Kesselheim AS, Misono AS, Lee JL, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: A systematic review and meta-analysis. JAMA. 2008;300:2514–2526.