Risk of Stroke and Death In Elderly Demented Patients Treated With Atypical Antipsychotics Rajesh R. Tampi, MD, MS, FAPA Associate Clinical Professor of Psychiatry Yale University School of Medicine, rajesh.tampi@yale.edu

Disclosures I have no financial relationships to disclose. All of the medications discussed today are “off-label”, as no agents have been approved by the FDA for the treatment of dementia-related psychosis or for the treatment of behavioral and psychological symptoms of dementia (BPSD).

Timeline of Events 2002: Health regulatory authorities in Canada and Switzerland were the first to raise concerns about the association of risperidone with CVAEs in clinical trials of elderly dementia patients. Spring of 2003: FDA followed suit and published similar warnings for risperidone. January of 2004: FDA added a warning of increased CVAEs with olanzapine.

2004: Eli Lilly releases similar warnings and made changes to prescribing information for olanzapine. March 2004: UK’s Committee on Safety of Medicines (CSM) advised prescribers that risperidone and olanzapine should not be used for the treatment of BPSD, because of “clear evidence of an increased risk of stroke”. February 2005: FDA added a warning of increased CVAEs with aripiprazole.

April 2005: FDA Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances

The Food and Drug Administration has determined that the treatment of behavioral disorders in elderly patients with dementia with atypical (second generation) antipsychotic medications is associated with increased mortality. 17 placebo controlled trials in elderly demented patients with behavioral disturbance, involving olanzapine, aripiprazole, risperidone, or quetiapine, enrolling a total of 5106 patients, were reviewed. 15 showed numerical increase in mortality (1.6-1.7 fold) in the drug-treated group compared to the placebo-treated patients. Examination of the specific causes of these deaths revealed that most were either due to heart related events (e.g., heart failure, sudden death) or infections (mostly pneumonia). The warning also extended to other atypical antipsychotic medications including clozapine, ziprasidone and combination olanzapine, fluoxetine. The FDA also added a similar warning to older antipsychotic medications because the limited data available suggested a similar increase in mortality for these drugs.

The New York Times April 11, 2005

Risk of cerebrovascular adverse events and death in elderly patients with dementia when treated with antipsychotic medications: a literature review of evidence. Mittal V, Kurup L, Williamson D, Muralee S, Tampi RR. Am J Alzheimers Dis Other Demen. 2011 Feb;26(1):10-28

The following search terms were used ‘stroke’, ‘cerebrovascular events’, ‘cerebrovascular accidents’, ‘death’, ‘dementia’, ‘behavioral symptoms’, ‘behavioral disturbance’, ‘BPSD’, ‘antipsychotics’ and ‘psychotropics’. The terms were searched within the following databases - Cochrane Library, Medline, EMBASE, and PsycINFO for English articles in humans from January 1, 1990- August 31, 2010. Of all the articles identified from the search, articles were selected that commented on CVAE and death with the use of antipsychotic treatment in dementia patients. These articles consisted of randomized controlled trials, pooled analysis, meta-analyses, systematic reviews, population based studies, prospective studies, retrospective studies, reviews and case reports. In addition, a manual search of bibliographies and the FDA website was done. The results are described for CVAEs followed by death. We organized the studies in the results section into subsections from the highest to the lowest level of evidence. Placebo controlled trials were given first priority followed by pooled analysis, meta-analysis and systematic reviews. Population based studies, retrospective analyses and other studies were considered lower on the level of evidence. We further arranged the studies in each of the subsections based on the date of publication to maintain a chronological order.

Results (CVAEs) In our review of the literature, we found 22 studies that evaluated the risk of CVAEs. Of these 22 studies, only two were prospective studies. The majority of the studies (14) were population based studies, retrospective analysis or other studies. The available data indicates that the risk of CVAEs is higher in the drug treated group (1.3-2.0 times). Although preliminary, existing data for atypical versus typical antipsychotics indicate that the risk of CVAEs is similar in both groups. No one drug has been found to be safer than the other in terms of the CVAEs. A higher than median doses of a drug, older age, a diagnosis of dementia especially vascular dementia and comorbid atrial fibrillation have been noted as risk factors for CVAEs. It appears that the time frame for which the risk of CVAEs remains elevated is about 20 months.

Results (Death) For the risk of death of death, we found a total of 14 studies which addressed this risk. Of these 14 studies, only three were placebo controlled trials. Preliminary data indicates that risk of death with atypical and typical antipsychotics is greater than when compared to the placebo group or the group that did not use these medications. The risk is about 1.2-1.6 times higher in the drug treated group. Existing data for atypical versus typical antipsychotics indicate that the risk of death is similar in both groups. No one drug has been found to be safer than the other in terms of the death. Older age, male gender, severe dementia and functional impairment are associated with a higher risk of death. The risk remains elevated from 30 days to 2 years.

Mechanisms: The development of orthostatic hypotension, most likely as a result of antagonism at alpha-adrenergic receptors. In an individual with cerebrovascular insufficiency or atherosclerosis, they might experience a CVAE as a consequence of hypotension aggravating the deficit in cerebral perfusion. Also, tachycardia induced by alpha-adrenergic antagonism might cause a decrease in cerebral perfusion as a result of a rate-induced decrease in diastolic filling and cardiac output or tachycardia might dislodge a thrombus in the patient with atrial fibrillation. Antipsychotics have a variable degree of effect on prolactin levels by their actions on dopamine transmission involved in the tuberoinfundibular tract. Theoretically, hyperprolactinemia can accelerate atherosclerosis and increase the risk of TIAs and strokes. It is possible that sedation or obtundation might cause antipsychotic treated patient to develop dehydration and hemoconcentration, leading on to the development of a thrombus. Antipsychotic medications have also been associated with an increased risk of venous thromboembolism. These thrombi could be potentially dislodged into the arterial circulation, causing TIAs and strokes especially in patients with atrial fibrillation.

The mechanisms by which antipsychotic medications may contribute to death remains to be established. Most deaths are thought to be due to cardiovascular events (mostly arrhythmias) and infections (pneumonia for the great majority). Antipsychotic use has been associated with a lengthening of QTc interval on electrocardiograms. Recently, atypical medications, such as ziprasidone, quetiapine, risperidone, and olanzapine, have been linked to QTc prolongation, although the highest estimate of risk has been documented for thioridazine. An increased risk of ischemic cerebrovascular events has been also linked to the use of atypical antipsychotics in patients with dementia. It must also be kept in mind that older patients with dementia are at higher risk for cerebrovascular events and death per say and their comorbidities along with the use of these medications only adds to this risk.

Do atypical antipsychotics cause stroke. Herrmann N, Lanctôt KL Do atypical antipsychotics cause stroke? Herrmann N, Lanctôt KL. CNS Drugs. 2005;19(2):91-103. 11 studies 48 out of 2187 (2.2%) drug-treated subjects experienced CVAEs vs. 10 out of 1190 (0.8%) placebo treated. The combined relative risk was 2.7 (95% CI, 1.4 to 5.3). Numerically more risperidone-treated patients (33 of 1009 [3.3%]) experienced CVAEs compared with olanzapine-treated patients (15 of 1178 [1.3%]). The weighted relative risk was statistically significant for risperidone (3.2, 95% CI, 1.4 to 7.2), but not for olanzapine (1.8, 95% CI, 0.5 to 6.3).

In 3 placebo-controlled trials of aripiprazole in elderly AD patients. European Agency for the evaluation of Medicinal Products http://www.emea.eu.int/humandocs/PDFs/EPAR/abilify/089304en 6.pdf In 3 placebo-controlled trials of aripiprazole in elderly AD patients. Mean age: 84 years, range: 78-88 years. 1.3% of aripiprazole-treated patients reported CVAEs vs. 0.6% of placebo-treated patients. This difference was reported not to be statistically significant. In a fixed-dose trial, there was a significant dose response relationship for CVAEs in patients treated with aripiprazole.

Schneider LS, Dagerman K, and Insel PS. Efficacy and Adverse Effects of Atypical Antipsychotics for Dementia: Meta-analysis of Randomized, Placebo-Controlled Trials. Schneider LS, Dagerman K, and Insel PS. Am J Geriatr Psychiatry. 2006 March;14:3; 191-210.

Results Cerebrovascular Adverse Events (CVAEs): There were 63/3327 (1.9%) events in the medication group versus 16/1728 (0.9%) in placebo group. The OR by meta-analysis was 2.13, with CI of 1.20-3.75 and p=0.009. Of note, significantly increased risk was found with risperidone with OR=3.43 (3.1 vs. 1.0% pooled).

Schneider LS, Dagerman KS, Insel P. JAMA. 2005 Oct 19;294(15):1934-43. Risk of Death with Atypical Antipsychotic Drug Treatment for Dementia: Meta-Analysis of Randomized Placebo-Controlled Trials. Schneider LS, Dagerman KS, Insel P. JAMA. 2005 Oct 19;294(15):1934-43.

Objective Assess the evidence for increased all-cause mortality from atypical antipsychotic drug treatment for patients with dementia.

Results 15 trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of AAPs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). 11 trials were performed in nursing homes and 4 with outpatients.

Results 3 with aripiprazole, 603 patients 2 in nursing homes and 1 with outpatients (10-week duration) 5 with olanzapine, 1184 patients 2 in nursing homes, 3 with outpatients, and 1 with a risperidone comparison (6- to 26-week durations) 5 with risperidone , 1175 patients including the outpatient trial above with an olanzapine comparison, 4 in nursing homes, 1 with a haloperidol comparison (8- to 12-week durations) 3 with quetiapine, 391 patients all nursing home trials, 1 with a haloperidol comparison and another with rivastigmine (10- to 26-week durations)

Results A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. All but one of the trials were sponsored and conducted by drug manufacturers. 87% had Alzheimer disease Mean age 81.2 (7.8) years old 70% were women Mean MMSE was 11.3

Results Medication No of events in the treatment group No of events in the placebo group Odds Ratio (95% chance) Aripiprazole 21/603 6/348 1.73 (0.70-4.30) Olanzapine 31/1184 6/478 1.91 (0.79-4.59) Quetiapine 21/391 7/246 1.67 (0.70-4.03) Risperidone 45/1175 22/779 1.30 (0.76-2.23) Overall 118/3353 (3.5%) 41/1851 (2.3%) 1.54 (1.06-2.23) p=0.02

Results Incidence in exposed: 118/3353=3.5% Incidence in non-exposed: 41/1851=2.3% Relative Risk: (Incidence in exposed)/(Incidence in non-exposed): 3.5/2.3=1.52 Absolute Risk Increase: 3.5% -2.3%=1.2% (upper limits on CI of 4% to 5%) Number Needed to Harm: 1/ARI = 1/0.012 = 83 with a 95% CI ranging from 53 to 1000. Thus, implying that there may be 1 death due to atypical drug use for every 83 patients treated over 10 to 12 weeks Numbers Needed to Treat (NNT): 4 to 12 in meta-analyses

Results Likelihood of Harm versus Help (LHHH): NNH/NNT: 83/4 (21) to 83/12 (7) Thus, for every 7 to 21 persons helped in these trials, there possibly will be 1 death. If NNH is 1000, then for every 83 to 250 persons helped, there will be 1 death. If NNH is 53, then for every 4 to 13 persons helped, there will be 1 death. Limitations: Old-old population with mean age >81. Also, authors did not comment on or appear to control for pre-existing cardiovascular conditions or risk factors.

Results Attributable Risk Percent (ARP): ARI/(risk of death in the exposed group) X 100%. (3.5%-2.3%)/3.5% x 100 = 34%. Therefore, almost 34% of the total risk of death in elderly patients with dementia who are exposed to AAPs is due to AAPs.

Take Home Points Death occurred more often over the first 8 to 12 weeks of treatment among patients randomized to an atypical antipsychotic than to placebo, 118 [3.5%] vs 40 [2.3%] The OR by meta-analysis was 1.54 with a 95% CI of 1.06 to 2.23, p = 0.02 The RR by a random-effects model was 1.65 with a 95% CI of 1.19 to 2.29 Likelihood of Harm versus Help (LHHH) indicates that for every 7 to 21 persons helped, there will possibly be 1 death Excess mortality was not due to any particular atypical antipsychotic but could only be appreciated when this class of medications were examined as a whole Subgroup analysis did not reveal differences between patients of lower cognitive function, psychosis of AD, or inpatients versus outpatients

Risk of Death in Elderly Users of Conventional vs Risk of Death in Elderly Users of Conventional vs. Atypical Antipsychotic Medications. Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, Brookhart MA. N Engl J Med. 2005 Dec 1;353(22):2335-41.

Methodology Retrospective cohort study involving 22,890 patients 65 years of age or older who had drug insurance benefits in Pennsylvania and who began receiving a conventional or atypical antipsychotic medication, for the first time, between 1994 and 2003 Analyses of mortality rates and Cox proportional-hazards models were used to compare the risk of death within 180 days, less than 40 days, 40 to 79 days, and 80 to 180 days after the initiation of therapy with an antipsychotic medication. The data was controlled for potential confounding variables.

In the first 180 days of use: Results In the first 180 days of use: 17.9% of patients receiving conventional antipsychotics died 14.6% of patients receiving atypical antipsychotics died This difference was statistically significant, with p<0.001 Only cancer, congestive heart failure, and HIV conferred greater adjusted risks of death

Results Relative Risk of Death within 180 Days After Beginning Therapy with Conventional as Compared with Atypical Antipsychotic Medications Time Period Relative Risk (RR) 95% Confidence Interval <40 days 1.56 1.37 to 1.78 40-79 days 1.37 1.19 to 1.59 80-180 days 1.27 1.14 to 1.41 >180 days 1.27 to 1.49

Results

Results Conventional antipsychotic medications were associated with a significantly higher adjusted risk of death than were atypical antipsychotic medications at all time intervals studied and in all subgroups defined, according to the presence or absence of dementia or nursing home residency. On average for every 100 patients treated with a conventional agent instead of an atypical drug there would be 7 additional deaths.

Results The greatest increase in the adjusted risk of death for conventional antipsychotics as compared with atypical antipsychotics occurred with higher doses of conventional agents and during the first 40 days after initiation of therapy.

Take Home Points Conventional antipsychotics are more likely than atypical agents to increase the risk of death among elderly persons, RR = 1.37. On average for every 100 patients treated with a conventional agent instead of an atypical drug there could be 7 additional deaths. The risk of death with conventional antipsychotics is greatest within the first 40 days of use and with higher doses.

Antipsychotic Drug Use and Mortality in Older Adults with Dementia. Gill SS, Bronskill SE, Normand SLT, et al. Ann Intern Med. 2007; 146:775-786.

Methodology Population-based, retrospective cohort study Ontario, Canada from April 1997 to March 2003 New use of antipsychotics Risk for all-cause mortality was determined at 30, 60, 120, and 180 days. Comparisons: atypical antipsychotics versus no antipsychotic use, conventional versus atypical antipsychotic use Groups were also divided by place of residence: community, long-term care facility

27,259 matched pairs were identified Results 27,259 matched pairs were identified Mean age was > 80 for all groups In both the community and long-term care cohorts: 75.2% of atypical antipsychotic users started risperidone 60.2% of conventional antipsychotic started haloperidol

Results

Results

Final Thoughts Older adults with dementia who are exposed to atypical antipsychotics have a small but significant increase in cerebrovascular adverse events and mortality. Use of conventional antipsychotics seems to confer an equal risk for CVAEs and death as with atypical antipsychotic use. Therefore, caution must be used when treating these patients with this class of medications. Rabins and Lyketsos (2005) suggest an approach that limits the use of these drugs to situations in which “there is an identifiable risk of harm to the patient or others, when the distress caused by symptoms is significant, or when alternate therapies have failed and symptom relief would be beneficial”.

Cardiovascular and cerebrovascular risks should be carefully considered and documented before initiating treatment with an atypical antipsychotic in a patient with a previous history of stroke, transient ischemic attack, or myocardial infarction. Consideration should also be given to other potential etiologies of the problem behavior such as delirium, under treated or over treated medical illness, environmental triggers, etc. Prescribe medications at the lowest effective dosages. If there is no response to the medication within 4-6 weeks, consider discontinuation of the drug. If the patient does respond to the medication, continued treatment should be contingent on close monitoring for side-effects and control of risk factors. Treaters must reevaluate benefits and risks frequently and consider discontinuation of treatment when appropriate.

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