Do strong SSRIs raise ischemic risk?
Strong selective serotonin reuptake inhibitor (SSRI) antidepressants did not raise the risk of myocardial infarction (MI) more than weak inhibitors and potentially lowered the risk of ischemic stroke, a population-based case-control study showed.
Compared with weak inhibitors of serotonin reuptake, strong inhibitors were associated with a 12% lower rate of ischemic stroke and transient ischemic attack (TIA), but the effect size was smaller in some sensitivity analyses, reported Christel Renoux, MD, PhD, of McGill University in Montreal, and co-authors in Neurology.
The rate of MI was similar between strong and weak serotonin reuptake inhibitors, they added.
"We focused primarily on the degree of inhibition of serotonin reuptake of antidepressants when assessing the cardiovascular effects of these drugs," she told MedPage Today. "Overall, we found no effect of antidepressants that are strong inhibitors of serotonin reuptake on the risk of myocardial infarction compared with weak inhibitors and a potential small decreased risk of ischemic stroke."
Renoux explained that as SSRIs are among the most commonly prescribed drugs, they are frequently prescribed to patients at increased cardiovascular risk.
"Assessing whether antidepressants are associated with the risk of cardio and cerebrovascular events is important," she said. "Although several previous studies addressed this question, they have produced conflicting results and mostly compared different classes of antidepressants."
The results contradict two other studies that showed an increased risk of ischemic stroke tied to strong SSRIs.
This contradiction may be a function of study design: one study used a "so-called case-crossover design, which was initially developed to assess the risks of transient exposures such as vaccines or antibiotics," which may not be appropriate for drugs taken regularly like antidepressants, Renoux and colleagues wrote. "The other study did not adjust for important confounders such as cardiovascular comorbid conditions or co-medications, including oral anticoagulants, making the interpretation of the results challenging."
Other research, including an analysis of epidemiological studies, has linked SSRIs to a small but significant risk of intracranial and intracerebral hemorrhage.
For this study, Renoux and co-authors looked at new adult users of SSRIs or third-generation antidepressants from 1995 to 2014 in the U.K. Clinical Practice Research Datalink, following them until their first ischemic stroke/TIA or MI occurred. For each case, up to 30 matched controls were selected.
The researchers classified antidepressants, regardless of their class, by their degree of serotonin reuptake inhibition as follows:
- Strong inhibitors: duloxetine (Cymbalta), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft)
- Intermediate inhibitors: citalopram (Celexa), escitalopram (Lexapro), fluvoxamine, and venlafaxine (Effexor)
- Weak inhibitors: mianserin, mirtazapine (Remeron), nefazodone, reboxetine, agomelatine, and viloxazine
The cohort consisted of 868,755 new SSRI users and 69,633 third-generation antidepressant users; most (64%) were female and the average follow-up period was 5.7 years. During follow-up, the researchers identified 15,860 ischemic stroke/TIA and 8,626 MI cases, which they matched to 473,712 and 258,022 controls, respectively.
Current use of strong SSRIs was tied to a decreased rate of ischemic stroke/TIA (RR 0.88, 95% CI 0.80-0.97) compared with current use of weak inhibitors. The effect was more apparent in people who used the drugs from 61 to 180 days (RR 0.84, 95% CI 0.72-0.97). Sex, chronic kidney disease, or history of cardiovascular disease did not modify the association.
Ischemic stroke/TIA results were consistent in most of the five sensitivity analyses the researchers conducted, but in one that involved trimming the cohorts using a high-dimensional propensity score approach, the effect estimate did not reach statistical significance (RR 0.92, 95% CI 0.81-1.04). A similar result occurred with propensity score matching in post hoc analysis.
MI rates were similar between current users of both strong and weak serotonin reuptake inhibitors (RR 1.00, 95% CI 0.87-1.15) and followed the same trend for long-term users. Sex, chronic kidney disease, or history of cardiovascular disease did not modify the association and the results remained consistent in sensitivity and post hoc analyses.
"This is a strong study design because it eliminated much residual confounding by comparing strong SSRIs with weak SSRIs, rather than SSRIs versus no SSRIs," said Daniel Gidon Hackam, MD, PhD, of the University of Western Ontario Robarts Research Institute in London, Ontario, Canada, who was not involved with the study.
But "because these results stem from an observational study, they still need to be confirmed in a randomized trial," Hackam told MedPage Today.
The study has several limitations, Renoux and co-authors noted. Despite adjusting all models for numerous potential confounders, residual confounding may still exist. Prescriptions in the Clinical Practice Research Datalink are written by general practitioners -- who prescribe most antidepressants -- and specialist prescriptions are excluded. The potential that the outcome was misclassified also is possible, they added.
The study was supported by the Canadian Institutes of Health Research.
The authors reported no disclosures relevant to the manuscript.
Source Reference: Douros A, et al "Degree of serotonin reuptake inhibition of antidepressants and ischemic risk: A cohort study" Neurology 2019; DOI:10.1212/WNL.0000000000008060.
Read the original article on Medpage Today: Stroke, MI, and Antidepressants