Assessing Residual Confounding of the Association between Antipsychotic Medications and Risk of Death using Survey Data

Division of Pharmacoepidemiology and Pharmacoeconomics, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA.
CNS Drugs (Impact Factor: 5.11). 02/2009; 23(2):171-80. DOI: 10.2165/00023210-200923020-00006
Source: PubMed


Nonrandomised studies on the causal effects of psychotropic medications may be biased by patient characteristics that are not fully adjusted.
Studies using linked claims databases found that typical antipsychotic medications were associated with increased short-term mortality compared with atypical antipsychotics. It has been suggested that such results may be due to residual confounding by factors that cannot be measured in claims databases. Using detailed survey data we identified the direction and magnitude of such residual confounding.
Cross-sectional survey data.
17 776 participants aged > or =65 years from the Medicare Current Beneficiary Survey (MCBS).
To determine the association between typical antipsychotic use and potential confounding factors we assessed five factors not measured in Medicare claims data but in the MCBS, i.e. body mass index, smoking, activities of daily living (ADL) score, cognitive impairment and Rosow-Breslau physical impairment scale. We estimated adjusted associations between these factors and antipsychotic use. Combined with literature estimates of the independent effect of confounders on death, we computed the extent of residual confounding caused by a failure to adjust for these factors.
Comparing typical antipsychotic users with atypical antipsychotic users, we found that not adjusting for impairments in the ADL score led to an underestimation of the association with death (-13%), as did a failure to adjust for cognitive impairment (-7%). The combination of all five unmeasured confounders resulted in a net confounding of -5% (range -19% to +2%). After correction, the reported association between typical antipsychotic use and death compared with atypical antipsychotic use was slightly increased from a relative risk (RR) of 1.37 to 1.44 (95% CI 1.33, 1.56). Comparing any antipsychotic use with non-users would result in overestimations of >50% if cognitive impairment remained unadjusted.
Claims data studies tend to underestimate the association of typical antipsychotics with death compared with atypical antipsychotics because of residual confounding by measures of frailty. Studies comparing antipsychotic use with non-users may substantially overestimate harmful effects of antipsychotics.

Full-text preview

Available from:
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RIASSUNTO. Introduzione. Lo scopo di questo studio è stato quello di valutare il rischio di morte tra pazienti ambulatoriali anziani (di età >65 anni) con diagnosi di demenza trattati con antipsicotici atipici. Metodi. Abbiamo condotto uno studio di coorte comprendente 696 pazienti trattati nell'Unità di Valutazione Alzheimer (UVA) della ASL di Teramo (Italia centrale) durante un periodo di 3 anni (gennaio 2007-dicembre 2009). Tra questi pazienti, 375 sono stati trattati con antipsicotici atipici (quetiapina, risperidone e olanzapina). I dati sono stati collezionati dalle schede di monitoraggio farmaci mandate al Servizio Farmaceutico della ASL. Risultati. I pazienti in trattamento con antipsicotici atipici hanno mostrato un aumento del tasso di mortalità rispetto ai pazienti non trattati con antipsicotici. Il rischio relativo di morte nei pazienti trattati con antipsicotici rispetto ai controlli è stato di 2.354 (IC 95% 1.704-3.279). Il più grande incremento del tasso di mortalità si è osservato in prossimità dell'ultima dose di antipsicotico usata; nei pazienti che hanno interrotto la terapia, il tasso di mortalità si è ridotto esponenzialmente con il passare del tempo dall'ultima dose di antipsicotico assunta. La quetiapina è stato il farmaco più prescritto e le dosi più alte del farmaco sono state associate ad un più alto tasso di mortalità. Conclusioni. Questi risultati sono in linea con l'informativa della Food and Drug Administration (FDA) dell'aprile 2005, che nei pazienti anziani con demenza il trattamento dei sintomi comportamentali con antipsicotici atipici è associato ad un più alto tasso di mortalità. Dato il potenziale rischio di mortalità con antipsicotici, e poiché solo pochi pazienti traggono beneficio dal trattamento con questi farmaci, sono chiaramente necessari nuovi approcci terapeutici per trattare i sintomi neuropsichiatrici nella demenza.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: When second-generation antipsychotics (SGAs), also called atypical antipsychotics, were introduced in the 1990s, early research suggested that these drugs offered better tolerability and adherence than first-generation antipsychotics (FGAs), or typical antipsychotics. This presumably would reduce the need for hospital services. However, health research to test this hypothesis has focused mostly on psychiatric readmissions. The objective of this study was to compare rates of all-cause hospitalization among patients receiving different classes of antipsychotics (SGAs, FGAs, both, or neither) in a large, all-ages sample of both institutionalized and noninstitutionalized Medicare beneficiaries. We examined the 2005 Medicare Current Beneficiary Survey Cost and Use file for 11,236 survey participants. Antipsychotic utilization was characterized in terms of class: FGA (ie, chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, thiothixene, thioridazine, or trifluoperazine) or SGA (ie, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, or ziprasidone). Hospitalization was defined in terms of whether a Medicare beneficiary was admitted to the hospital for any reason in 2005, and was measured in terms of the number of hospital visits. In our final model, we included the following confounding variables: disability status (> or =1 limitation in activities of daily living), Rosow-Breslau impairment score (difficulty with walking, stooping, crouching, kneeling, or doing heavy housework), cognitive impairment (diagnosis of Alzheimer's disease or memory loss that interfered with daily activity), and health behavior variables (body mass index and smoking status). A total of 3.5% of Medicare beneficiaries (1.3 million) filled > or =1 prescription for an antipsychotic medication in 2005. Controlling for demographic, socioeconomic, health, and disability variables, SGA-only users were more than twice as likely (odds ratio [OR] = 2.2 [95% CI, 1.7-2.9]) and combination users were more than 6 times as likely (OR = 6.3 [95% CI, 2.4-16.2]) as nonusers to be hospitalized. The odds of FGA users being hospitalized were not significantly different from nonusers (OR = 1.4 [95% CI, 0.7-2.8]). This analysis yielded provocative, but by no means conclusive, evidence that SGAs as a class are not necessarily superior to FGAs in mitigating patient's use of hospital services under real-world conditions. Systematic analysis of this relationship with a large, multiple-year sample of Medicare beneficiaries is warranted.
    Clinical Therapeutics 12/2009; 31(12):2931-9. DOI:10.1016/j.clinthera.2009.12.017 · 2.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Observational studies have investigated the comparative safety of antipsychotics with varying results. Instrumental variable analysis has been suggested as a possible alternative to conventional analyses when there is concern about the effect of unmeasured confounding in observational studies. Using the example of the risk of death with typical compared to atypical antipsychotics, we aimed to explore the performance of two different instruments. We used the doctor prescribing preference instrument, which has been used in previous studies, to investigate further the assumptions of this instrument in the Australian population. We also propose an alternative instrument, nursing home facility preference. With the Australian Department of Veterans' Affairs administrative claims database, we used an instrumental variable analysis to compare the risk of death after 12 months between the two antipsychotic classes. Using the doctor prescribing preference instrument we estimated that typical antipsychotics were associated with an extra 24 (95% Confidence Interval (CI) 18-30) deaths per 100 patients per year compared to atypical antipsychotics, and an extra 10 (95% CI 7-14) deaths per 100 patients per year among nursing home residents. Facility prescribing preference was a stronger instrument (OR=19.2 95% CI 17.1-21.6) and provided a better balance of covariates than doctor prescribing preference. Our study has shown that valid instruments in one population may not be directly applicable to other health care settings and testing of assumptions is crucial when performing IV analyses. Facility prescribing preference appears to be a potentially valid instrument for further work in this area.
    Pharmacoepidemiology and Drug Safety 07/2010; 19(7):699-707. DOI:10.1002/pds.1942 · 2.94 Impact Factor
Show more