This review included 44 studies that evaluated the risk of either death, cerebrovascular events, hip fracture or pneumonia associated with antipsychotic prescribing in the elderly. We found that observational evidence appears to support the findings from RCTs, where available, however the magnitude risk differed according to the methods used to control for confounding.
RCT evidence for atypical antipsychotics showed an absolute increase of 1 extra death per 100 people treated. Collectively, observational evidence showed that conventional antipsychotics were associated with a greater risk of death than the atypical antipsychotics, however, the estimates of absolute risk differed between studies. Risk estimates from covariate adjusted cohort studies ranged from 2 to 3 extra deaths per 100 patients treated with conventional compared to atypical antipsychotics over 6
months while instrumental variable analysis estimates ranged from 4 and 7 extra deaths per 100 patients over 6
months. These discrepancies suggest that unmeasured confounding may have contributed to an underestimate of risk in the traditional cohort studies. Many of the cohort studies also employed propensity score methods to adjust for confounding either by use of propensity score matching [22
] or numerical adjustment by propensity score quintiles [28
]. In these latter studies propensity score adjustment estimates were consistent with multivariate adjusted results while instrumental variable analyses were marginally different suggesting some residual unmeasured confounding in the propensity score and multivariate adjusted analyses. Additionally studies have undertaken sensitivity analyses to rule out potential bias from unmeasured confounding which revealed that only very strong unmeasured confounders would explain the observed increased mortality association with conventional antipsychotic use, if in fact, the observed difference was not true [22
RCT evidence of the risk of cerebrovascular events was limited to the atypical antipsychotics and demonstrated an increased risk of all cerebrovascular events[1
] but not serious strokes requiring hospitalization [4
]. Cerebrovascular events were the most studied and reported adverse event in observational studies of antipsychotics compared to non-use, however, the definition of this outcome was not consistent between studies. In general, cohort studies reported negative associations when investigating cerebrovascular hospitalisation events and positive associations when investigating outcomes defined as a diagnosis of all cerebrovascular events from general practitioners’ medical records which supports the findings from available RCTs. In contrast, case–control studies failed to find statistically significant results for either outcome definition. Case–control studies often employ techniques to minimise possible bias, such as matching or numerical adjustment for potential confounders, however, studies of this type may still be subject to unmeasured confounding [57
]. Self-controlled case-series studies found similar results to RCT evidence when similar definition of cerebrovascular events were used which suggests that this technique may be a reliable design for the investigation of adverse events not previously detected in RCTs. One of the advantages of the self-controlled case-series design is that it controls implicitly for patient-specific confounders that do not vary over time. This means that it is not necessary to adjust for variables such as sex, frailty or other risk factors that are constant over time. However, a limitation of this approach is that it is unable to adjust for changes in prescribing due to rapid changes in underlying disease severity [17
]. Observational cohort studies comparing the antipsychotic classes have used consistent definitions of outcome, specifically, hospitalisation for stroke, however, results vary according to the methods employed to adjust for differences between treatment groups. Of the 6 studies that used numerical covariate adjustment, three found no difference in risk [42
] between the classes, one found a reduced risk [39
], while two found an increased risk [33
] with conventional compared to atypical antispychotics. One study [45
], used an instrumental variable method to adjust for unmeasured confounding. This study found a 10% increased risk of stroke with conventional compared to atypical antipsychotics but only after 60
days treatment, however, the instrumental variable estimates were not presented and the prevalence of cerebrovascular disease at baseline in the studied population, described in a separate paper, was high [29
While no RCT data for the risk of hospitalisation for hip fracture could be located, a Cochrane review [1
] found that risperidone may be associated with an increased risk of falls in the elderly which suggests that an increased risk of hip fracture may also be likely. Observational studies reported an increased risk of hip fracture with both classes compared to non-use and this risk may increase with increasing duration of therapy. A study using a self-controlled case-series design [50
], found an increased risk of hospitalization for hip fracture for both conventional and atypical antipsychotics. It is unclear whether the risk of hip fracture differs between the classes. Only one cohort study [46
] investigated the comparative risk of hip fracture between the classes finding an increased risk with conventional antipsychotics.
] of randomized controlled trials found that one of the major causes of death associated with atypical antipsychotics was pneumonia. Few observational studies, however, have investigated the risk of pneumonia associated with antipsychotics in elderly patients, and most have used a case–control design. An increased risk of pneumonia was found with both classes [52
] compared to non-use or previous use [53
]. One case–control study identified that the risk appeared to be highest in the first week of treatment but returned to baseline after 90
]. A study using a self-controlled case-series design [50
] also found and increased risk of hospitalization for pneumonia for both conventional and atypical antipsychotics. The risk of pneumonia was similar between the classes [46
]. One study, which used an instrumental variable analysis, found no difference in the risk of pneumonia between conventional and atypical antipsychotics [45
As in any systematic review, publication bias is a potential limitation of this study. It is possible that only positive observational study findings may have been published. In particular, the majority of published studies investigating hip fracture and pneumonia associated with antipsychotics reported significantly increased risks with treatment compared to non-use. Additionally, our search criteria specified that only those study designs that resulted in standard effect estimates were included for comparison purposes. We therefore excluded case reports and studies that used designs such as the self-controlled cohort analysis [59
]. We only included outcomes that could be consistently defined to limit heterogeneity across studies. The endpoints for this study, cerebrovascular events, hip fracture and pneumonia, were chosen because we believed that patients were likely to present to hospital for these conditions, and therefore were outcomes that would most likely be available in observational studies using administrative claims databases. The application of methods such as the self controlled case-series and instrumental variable analyses have evolved mainly to address unmeasured confounding due to the lack of clinical information in claims databases. Antipsychotics have also been associated with other adverse events such as deep vein thrombosis, diabetes onset and heat stroke which were not included in this review.
The aim of this review was to explore the effects of study design on the results of observational studies of antipsychotics. To do this we simplified our comparisons to with-in class comparisons and we have not considered differences according to individual products, dose or effect modifiers. The majority of published observational studies have provided comparisons between classes, however, where available we have presented the results by individual products and by dose. Besides study design, many other factors may have contributed to the differences observed among observational studies. These include differences in populations studied, in terms of drug utilization patterns and health care settings, differences in the definition of outcome and variations in the number and type of confounders that may have been included in the analysis. We have attempted to limit the impact of these effects by considering the effects of antipsychotics in the elderly only and by limiting our events to serious adverse events potentially requiring hospitalization. In the case of cerebrovascular events we considered cerebrovascular events separately to hospitalizations for stroke as these were the two events most often considered in observational studies.
Where possible we compared available meta-analyses and randomised controlled trial evidence with the results of observational studies, however, experimental evidence was typically generated prior to when many of the observational studies were performed and may have included different patient populations. RCT evidence is generally considered of higher quality than observational studies,[18
] however, there are many examples where RCTs on the same clinical topic have produced conflicting results [60
]. High quality observational studies, whether cohort or case–control designs, have consistently found similar results to RCTs [60