Download Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death

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
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
Study Outline
• OBJECTIVE: If risk of serious CV harm is increased
with rosiglitazone compared with pioglitazone
• DESIGN: Observational, retrospective cohort
study of 227 571 Medicare beneficiaries
• ENDPOINTS: AMI, stroke, heart failure, death
Cohort Study
• Cohort assembled based on particular
exposure
• Followed over time for development of
outcome
Pros VS Cons
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PROS
Time based study allows speculation of causality
Observational nature allows study of toxic exposures
Can study multiple outcomes of a specific exposure
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CONS
Time consuming
Not randomized
Not good for rare diseases or outcomes with a long natural hx
Attrition
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 1-1093)
• Similar background characteristics, including
medical conditions and medications
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
Baseline Characteristics of Cohort Members at Initiation of Thiazolidinedione Therapy
Graham, D. J. et al. JAMA 2010;304:411-418.
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;304:411-418.
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;304:411-418.
Study End Points
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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.
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
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
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
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;304:411-418.
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;304:411-418.
Results
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1746 AMIs (21.7% fatal)
1052 Strokes (7.3% fatal)
3307 Heart failure hospitalizations (2.6% fatal)
2562 Deaths from all causes
Results:
Rosiglitazone vs Pioglitazone
• For composite of all end-points, attributable
risk is 1.68 (95% CI 1.27-2.08) 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
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
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
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;304:411-418.
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
Post Hoc Analyses
• Cohort 110 950 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 15 009 patients who entered after
May 2007 showed similar results
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, 1.05-1.39)
– Composite: HR 1.23 (95% CI, 1.14-1.34)
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
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, 1.16-1.34) increase in risk of heart
failure
– 1.27-fold (95% CI, 1.12-1.45) increase in risk of stroke
– 1.14-fold (95% CI, 1.05-1.24) increase in risk of death
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 6th and 8th decades of life
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
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