Threefold Increased Stroke Risk Tied to Certain Antipsychotics

Batya Swift Yasgur, MA, LSW

November 13, 2017

Older adults taking atypical antipsychotics that induce rapid metabolic changes such as weight gain and that alter lipid profiles are much more likely to suffer from major cardiovascular events, particularly stroke, new research shows.

Investigators at the University of Buenos Aires, in Argentina, found that patients taking second-generation antipsychotics who experienced a high level or an intermediate level of metabolic changes had an almost threefold increased risk of experiencing a cardiovascular event ― especially stroke ― compared to their counterparts taking medications that were associated with a lower risk for metabolic changes.

"Older adult patients under antipsychotic regimens with high or intermediate risk of metabolic side effects may face a higher incidence of major cardiovascular events than those under a low-risk regimen during long-term follow-up," the researchers, with first author Alejandro G. Szmulewicz, MD, write.

The study was published online in the September/October issue of Journal of Clinical Psychiatry.

Stratifying Risk

The prevalence of obesity, type 2 diabetes mellitus (T2DM), hyperlipidemia, and metabolic syndrome is increased in patients with schizophrenia, bipolar disorder, and unipolar depression, a fact that "may largely explain the increased rate of cardiovascular disease [CVD] and mortality seen in this population, as compared to the general public," the authors note.

Antipsychotics often have significant side effects that may contribute to or intensify these comorbid conditions. In particular, second-generation antipsychotics are associated with weight gain and metabolic abnormalities, but there are differences in metabolic profiles between the various medications.

For this reason, "a better understanding of the severity and clinical impact of the metabolic side effect profiles is paramount," the authors note.

Previous studies comparing the risk for cardiovascular events or mortality in patients taking first- and second-generation antipsychotics have "yielded mixed results," the authors report. Previous studies have not compared antipsychotics "on the basis of their proneness to develop metabolic abnormalities," they add.

The study was designed to stratify the antipsychotics on the basis of their risk profile and to examine the impact of each category on cardiovascular events.

The researchers utilized a database of a tertiary teaching hospital in Buenos Aires. Data included drug prescriptions and their characteristics, dose, duration of treatment, and inpatient and outpatient information regarding baseline comorbidities, clinical outcomes, and laboratory measures. The registry also contained information on vital status and new cardiovascular events that occurred during follow-up.

The study included 1008 consecutive patients who received antipsychotic medication for the first time from January 2002 to December 2007. For inclusion, patients were required to be aged 30 years or older on index date. In addition, continuous information had to have been available for at least 1 year prior to the index date, and patients had to have been enrolled in a health plan for longer than 6 months and to have had two or more pharmacy claims during the first 6 months of treatment.

Patients who received antipsychotic medication during hospitalization and did not continue drug treatment after hospital discharge were excluded, as were patients older than 90 years at index date and those who had been discharged with a diagnosis of acute myocardial infarction (MI) or stroke during the 60 days preceding initiation of antipsychotic therapy.

The "primary exposure of interest" was antipsychotic therapy, which the researchers defined as therapy with any antipsychotic drug that was received by the patient for the first time in his or her life.

The researchers categorized antipsychotic medications on the basis of side effect profiles vis-a-vis developing metabolic abnormalities associated with CVD. Low-risk agents included haloperidol, aripiprazole, ziprasidone, trifluoperazine, and levomepromazine. Quetiapine and risperidone were regarded as intermediate-risk agents, and thioridazine, olanzapine, and clozapine were considered to be high risk.

Patients at high risk included those taking a combination of two or more antipsychotics concomitantly.

Patients were followed either from the index date to disenrollment from the health plan, the end of the study period, development of a cardiovascular event, or death.

The primary outcome measure was time to the composite of acute MI, acute coronary syndrome, ischemic stroke, peripheral artery disease, or a new revascularization procedure.

The composite secondary outcome was time to the composite primary outcome plus all-cause mortality, as well as onset of T2DM.

Dementia as Driver

Of all study patients (n = 1008), 223 received low-risk antipsychotic medications, 465 received intermediate-risk medications, and 320 received high-risk. Among those in the high-risk group, only 31 were treated with combination therapy.

Mean (SD) age of the patients was 68.7 (15.7), 75.1 (13.8), and 71.0 (14.6) years for the low-, intermediate- and high-risk groups, respectively. For the full cohort, the median follow-up time was 36.5 months. The most frequent diagnoses were dementia (63.4%), schizophrenia (9.6%), major depression (12.4%), and bipolar disorder (11.6%).

Although cardiovascular comorbidity at baseline was higher for patients receiving low-risk antipsychotics (more previous MI and T2DM), significantly more patients in the high-risk group (14.8%) developed obesity with antipsychotic therapy, compared to the low-risk group (2.4%).

Similarly, 15.9% of the high-risk and 6.7% of the low-risk groups developed T2DM, vs 5.8% of the low-risk group.

From the total cohort population, 19.6% experienced major cardiovascular events, although patients in the low-risk group had fewer events when compared to either intermediate- or high-risk groups.

The adjusted hazard ratios (HRs) in the intermediate- and high-risk groups were 2.57 (95% confidence interval [CI], 1.43 - 4.63) and 2.82 (95% CI, 1.57 - 5.05) times the HR of the low-risk group during the follow-up period.

At the 2- and 5- year follow-up, the effects of the antipsychotic medications in the intermediate- and high-risk groups were similar. However, of the patients who experienced a primary outcome, 91.2% were current users of antipsychotic medications.

There were no apparent differences in time between the groups in all-cause mortality. However, regarding the composite secondary outcome, the HR for the high-risk group compared to the low-risk group was 1.31 (95% CI, 0.95 - 1.80); for the intermediate-risk group, it was 1.46 (95% CI, 1.06 - 2.00).

Only patients undergoing treatment with high-risk agents presented with significantly more incident T2DM compared to the low-risk group.

On the basis of the crude cumulative incidence of outcome measures, stroke was the cardiovascular event most associated with risk level in the antipsychotics: 10.5% and 17.2% in the intermediate- and high-risk groups, respectively, vs 9.0% in the low risk group (P < .01).

Compared to the low-risk group, high- and intermediate-risk agents also were associated with diabetes (5.8% vs 6.7% and 15.9% respectively [P < .01]), weight gain (2.4% vs 4.9% and 14.8% respectively [P < .01]), MI (1.8% vs 3.01% and 5.0%, respectively [ P = .11]), and all-cause mortality (21.5% vs 25.6% and 26.3%, respectively [P = .41]).

The authors state that the higher risk for major cardiovascular events among those taking intermediate- or high-risk agents "appears to be mostly driven by the enhanced risk of stroke among our population, something that might be due to the high prevalence of patients with dementia or related to potential direct or indirect effects of antipsychotics."

Moreover, the great majority of patients who experienced cardiovascular events remained current users of these agents, suggesting "that isolated past exposure to these drugs had no relevant impact on the results reported."

Start Low

Commenting on the study for Medscape Medical News, Christoph U. Correll, MD, professor of psychiatry and molecular medicine, Hofstra Northwell School of Medicine, Hempstead, New York, and investigator, Center for Psychiatric Research and Neuroscience, Feinstein Institute for Medical Manhasset, New York, said that the study's statistical analyses were "quite well done."

"In the elderly, even with a short follow-up period of 36 months, you can actually see these cardiovascular effects, and they have to be taken seriously," he cautioned.

He expressed some surprise that the study included adult patients at age 30 years, although the mean age of the patients was in the high 70s.

"These agents are not typically used in older adults unless they have dementia. Since a relatively low percentage of participants had schizophrenia, most study participants were elderly patients with dementia," he said.

He pointed out that the cardiovascular effects of these medications in younger patients "are less obvious because there is a long lead time for the cardiovascular endpoints to emerge and develop."

Additionally, "antipsychotics are typically associated with fewer suicides and are associated with better health behaviors, such as healthy lifestyle behavior or being compliant with medical medications to treat diabetes, hypertension, and dyslipidemia."

For these reasons, "although they may enhance the risk of cardiovascular illness, being on antipsychotic treatment is actually better than not."

On the other hand, factors to take into the "overall equation" include weight gain, which can shorten life and can be related to quality of life. Patients with diabetes also experience lower quality of life.

"Start with lower-risk medications first as much as possible and allow responders to reap as much benefit as possible. Only graduate to medium- or higher-risk agents when necessary if lower-risk agents are not sufficiently effective," he said.

The authors encourage "differential follow-up strategies and assessment, even in the absence of weight gain or metabolic syndrome," in patients receiving long-term treatment with antipsychotics of intermediate or high risk.

"The adequate control of major cardiovascular risk factors remains paramount," they conclude

The study received no funding. The authors and Dr Correll have disclosed no relevant financial relationships .

J Clin Psychiatry. 2017;78:e905-e912. Abstract


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