Quantifying the Role of Adverse Events in the Mortality Difference between First and Second-Generation Antipsychotics in Older Adults: Systematic Review and Meta-Synthesis

Abstract

BackgroundObservational studies have reported higher mortality among older adults treated with first-generation antipsychotics (FGAs) versus second-generation antipsychotics (SGAs). A few studies examined risk for medical events, including stroke, ventricular arrhythmia, venous thromboembolism, myocardial infarction, pneumonia, and hip fracture.Objectives1) Review robust epidemiologic evidence comparing mortality and medical event risk between FGAs and SGAs in older adults; 2) Quantify how much these medical events explain the observed mortality difference between FGAs and SGAs.Data sourcesPubmed and Science Citation Index.Study eligibility criteria, participants, and interventionsStudies of antipsychotic users that: 1) evaluated mortality or medical events specified above; 2) restricted to populations with a mean age of 65 years or older 3) compared FGAs to SGAs, or both to a non-user group; (4) employed a “new user” design; (5) adjusted for confounders assessed prior to antipsychotic initiation; (6) and did not require survival after antipsychotic initiation. A separate search was performed for mortality estimates associated with the specified medical events.Study appraisal and synthesis methodsFor each medical event, we used a non-parametric model to estimate lower and upper bounds for the proportion of the mortality difference—comparing FGAs to SGAs—mediated by their difference in risk for the medical event.ResultsWe provide a brief, updated summary of the included studies and the biological plausibility of these mechanisms. Of the 1122 unique citations retrieved, we reviewed 20 observational cohort studies that reported 28 associations. We identified hip fracture, stroke, myocardial infarction, and ventricular arrhythmias as potential intermediaries on the causal pathway from antipsychotic type to death. However, these events did not appear to explain the entire mortality difference.ConclusionsThe current literature suggests that hip fracture, stroke, myocardial infarction, and ventricular arrhythmias partially explain the mortality difference between SGAs and FGAs.

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

“…Comparative data providing information about different SGAs are sparse, and in particular, the cardiovascular safety of newer SGAs, such as ILO, LUR, BRE, and CAR, is missing. In the elderly, higher mortality with FGAs than SGAs seems to be partially explained by a greater risk for stroke and AMI (in addition to ventricular arrhythmias and hip fracture) 121. Broadly, in SMI, HAL, CPZ, OLA, RIS, and QUE have shown the strongest association with cardiovascular events 69,122–126.…”

Myocardial infarction risk and antipsychotics use revisited: a meta-analysis of 10 observational studies

“…CIs: 1.16-1.23] compared to atypical AP users (Jackson et al, 2014);however, this only identified two cohort studies. Another meta-analysis found a 1.88-fold higher likelihood [odds ratio (OR) = 1.88, 95% CIs: 1.39-2.54) of MI in AP users vs. non-users (Yu et al, 2016).…”

Mediators of First- Versus Second-generation Antipsychotic-related Mortality in Older Adults

“…First-generation antipsychotics have shown even higher mortality (1.4 fold) early after starting therapy, as when compared to second-generation antipsychotics in observational post-marketing studies. 3 These findings led the FDA to issue Black Box warnings. 4 …”

“…9 A systematic review of observational post-marketing studies using mostly administrative claims data compared risk of first- and second-generation antipsychotics for these medical events and concluded that stroke, hip fracture, myocardial infarction, and ventricular arrhythmia combined could explain between 17% and 42% of the mortality difference. 3 But this study was limited by its reliance on study-level data and published mortality rates.…”