A Cohort Study Osler Journal Club September 8,2010

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1 Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated with Rosiglitazone or Pioglitazone A Cohort Study Osler Journal Club September 8,2010 Faculty advisor: J Hunter Young, MD MHS Rupa Krishnaswamy, MD

2 Background Use of rosiglitazone may be associated with increased risk of serious CV events when compared with pioglitazone 2007 Meta-analysis of 42 RCTs with rosiglitazone: 1.4 fold increase in AMI (compared with non-thiazolidinediones) Meta-analysis of 19 RCTs with pioglitazone: reduction in composite outcome of non-fatal AMI, stroke, and all-cause mortality

3 Study Outline OBJECTIVE: If risk of serious CV harm is increased with rosiglitazone compared with pioglitazone DESIGN: Observational, retrospective cohort study of Medicare beneficiaries ENDPOINTS: AMI, stroke, heart failure, death

4 Cohort Study Cohort assembled based on particular exposure Followed over time for development of outcome

5 Pros VS Cons PROS Time based study allows speculation of causality Observational nature allows study of toxic exposures Can study multiple outcomes of a specific exposure CONS Time consuming Not randomized Not good for rare diseases or outcomes with a long natural hx Attrition

6 Participants Medicare beneficiaries Age > 65 (mean age = 74.4yrs) Began treatment with thiazolidinedione between July 2006 June 2009 Follow-up for up to 3yrs after initiation of treatment (median: 105 days, range ) Similar background characteristics, including medical conditions and medications

7 Design New-user inception cohort design At least 6 months continuous Part D enrollment and at least 12 months continuous Parts A&B enrollement prior to first thiazolidinedione prescription Data collected on medical history and use of medications prior to initiating thiazolidinedione CV, cerebrovascular, DM-related complications, chronic medical conditions Medications for CV disease, DM, hyperlipidemia

8 Baseline Characteristics of Cohort Members at Initiation of Thiazolidinedione Therapy Graham, D. J. et al. JAMA 2010;304:

9 Core Cardiovascular Medical Conditions and Medications Used Among Cohort Members During the 12-Month (Medical Conditions) or 6-Month (Medications) Period Preceding Initiation of Thiazolidinedione Therapy Graham, D. J. et al. JAMA 2010;304:

10 Additional Medical Conditions and Medications Used Among Cohort Members During the 12-Month (Medical Conditions) and 6-Month (Medications) Period Preceding Initiation of Thiazolidinedione Therapy Graham, D. J. et al. JAMA 2010;304:

11 Study End Points Time to event evaluated for the following events: Acute myocardial infarction Stroke Heart failure All-cause mortality (death) *CV disease accounts for ~70% of deaths in patients with DM. All-cause mortality may be an indicator of CV mortality.

12 Follow-up Patient follow-up from time of cohort entry to: First end-point occurrence Gap in treatment > 7days Switching to different thiazolidinedione Hospitalization End of study period

13 Statistics Baseline characteristics compared using standardized mean differences NOT influenced by sample size Useful for comparing cohorts in large observational studies Value of 0.1 SD or less: negligible difference in means between compared groups

14 Statistics Kaplan-Meier cumulative incidence plots show time to event for each end point Hazard ratios with 95% confidence intervals calculated with Cox proportional hazard models HR: effect of an explanatory variable on the risk of an event Number needed to harm estimated using attributable risk Attributable risk: the difference in rate of a condition between an exposed population and an unexposed population

15 Kaplan-Meier Cumulative Incidence of Time to Event for Acute Myocardial Infarction, Stroke, Heart Failure, and All-Cause Mortality in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone Graham, D. J. et al. JAMA 2010;304:

16 Kaplan-Meier Cumulative Incidence of Time to Event for the Composite of Acute Myocardial Infarction, Stroke, Heart Failure, and All-Cause Mortality in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone Graham, D. J. et al. JAMA 2010;304:

17 Results 1746 AMIs (21.7% fatal) 1052 Strokes (7.3% fatal) 3307 Heart failure hospitalizations (2.6% fatal) 2562 Deaths from all causes

18 Results: Rosiglitazone vs Pioglitazone For composite of all end-points, attributable risk is 1.68 (95% CI ) per 100 personyears of rosiglitazone compared with pioglitazone Number needed to harm is 60 (95% CI 48-79) persons treated for 1 year to generate 1 excess event

19 Results: Rosiglitazone vs Pioglitazone Kaplan-Meier plots show no differences in risk for AMI between rosiglitazone and pioglitazone Increased risk of stroke, heart failure, and death with rosiglitazone compared with pioglitazone

20 Results Hazard Ratios Adjusted HRs for stroke, heart failure, and death increased with rosiglitazone Adjusted HRs for composite of AMI, stroke, heart failure, or death increased with rosiglitazone Adjusted HR for AMI NOT significantly increased

21 Incidence Rates, Attributable Risks (Rate Differences), and Numbers Needed to Harm for AMI, Stroke, Heart Failure, All-Cause Mortality, and a Composite Individual End Point in Elderly Medicare Patients Treated With Rosiglitazone vs Pioglitazone Graham, D. J. et al. JAMA 2010;304:

22 Post Hoc Analyses Proportional hazards assumption met for AMI, stroke, heart failure Proportional hazards assumption: that covariates multiply hazard Assumption NOT met for death or composite of all end-points Investigate importance of nonproportionality

23 Post Hoc Analyses Cohort patients (prior to May 21, 2007) Importance of date: Publication of rosiglitazone meta-analysis by Nissen and Wolski that showed increased risk of AMI with rosiglitazone Proportional hazards assumption now met for death Analysis of patients who entered after May 2007 showed similar results

24 Post Hoc Analyses HRs for death and the composite increased with rosiglitazone compared with pioglitazone Analyzed in time intervals: 0-2mon, 2-4mon, >4mon Proportional hazards assumption met for death HRs for rosiglitazone compared with pioglitazone were statistically significantly increased during the third interval Death: HR 1.21 (95% CI, ) Composite: HR 1.23 (95% CI, )

25 Post Hoc Analyses Compare effects of the two thiazolidinediones on end points within subpopulations Based on use or nonuse of: Insulin, sulfonylureas, metformin, nitrates, and statins HRs for each end point similar in patients with and without baseline use

26 Conlusions Rosiglitazone associated with increased risk of stroke, heart failure, death, and composite of AMI, stroke, heart failure, or death compared with pioglitazone When compared with pioglitazo, rosiglitazone associated with: 1.25-fold (95% CI, ) increase in risk of heart failure 1.27-fold (95% CI, ) increase in risk of stroke 1.14-fold (95% CI, ) increase in risk of death

27 Conclusions Risk of AMI not different among the two thiazolidinediones in elderly Medicare patients Studies that have revealed this risk conducted in younger patients Assumption: Patients survive to hospitalization to be counted Incidence of sudden cardiac death increases 6-fold between 6 th and 8 th decades of life

28 Conclusions Incidence rates of AMI, stroke, heart failure, and death for pioglitazone cohort similar to PROactive trial CV trial comparing pioglitazone with other DM therapies Mean age 61.1, but patients with established macrovascular disease

29 Strengths and Weaknesses Strengths Long duration of follow-up Temporal association of exposure with outcome Increased generalizability Wide array of variables among study cohort 2 groups indistinguishable Limitations Not an RCT Misclassification of end-points

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