LECTURE 09 2011

LECTURE 09 2011 - Outline General endpoint considerations...

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Outline General endpoint considerations Surrogate endpoints Composite endpoints Safety outcomes (adverse events)
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Composite Event (def.) “An event that is considered to have occurred if any one of several different events or outcomes are observed.” Meinert CL. Clinical Trials Dictionary , 1996. Combined Endpoint = Composite Event
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Examples of Combined Endpoints Multiple Risk Factor CHD death (MI, sudden death) Intervention Trial (MRFIT) Systolic Hypertension in the Fatal or non-fatal stroke Elderly Trial (SHEP) CPCRA TOXO Study Toxoplasmic encephalitis or death Physician’s Health Study Fatal/non-fatal myocardial infarction Fatal/non-fatal stroke GISSI-2* Death Late congestive heart failure EF < 35% 45% or more injured myocardial segments QRS score < 10 Study Endpoint * Non-fatal events treated hierarchically
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Survey of Cardiovascular Trials Composite outcomes in CVD trials are frequent (37% of 1,231 published trials) Typically comprise 3-4 individual components More components were used in the composite outcome in smaller in trials The components vary in their clinical significance; death was the most common component included Ann Intern Med 2008;149:612-617
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Composite Examples for Heart Failure (HF) Studies: Time to Event Analysis Time to the 1 st occurrence of any of the outcomes that are part of the combined endpoint Examples: Time to death or hospitalization Time to death or CVD hospitalization Time to CVD death or or CVD hospitalization Time to CVD death or hospitalization for HF
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Composite Example: CVD Death or HF Hospitalization Patient 0 Follow-up Time t HF Hosp. 1 X CVD Death 2 HF Hosp. X X HF Hosp. X HF Hosp. X CVD Death 4 0 Non-CVD Death 3 X
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Progression to AIDS Endpoint (A Composite with Many Components) Cryptosporidiosis Isosporiasis Toxoplasmosis Mycobacterium avium , other non-tuberculous mycobacterial infections Mycobacterium tuberculosis , extrapulmonary or pulmonary Cryptococcosis Histoplasmosis Cytomegalovirus disease Lymphoma Kaposi’s sarcoma (visceral) HIV encephalopathy or AIDS dementia complex, Stage 2 or higher Progressive multifocal leukoencephalopathy HIV wasting syndrome Pneumocystis carinii , pulmonary or extrapulmonary Candidiasis, esophageal or pulmonary Herpes simplex bronchitis, pneumonitis, esophagitis Herpes zoster, disseminated Non-typhoidal Salmonella septicemia
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Clinical Relevance? Candidiasis Candidiasis Patient 1 2 3 0 X 0 0 X Death X PCP X MAI X End of Study End of Study Follow-up Time t
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Composites or Combined Endpoints Rationale More events = greater power (or smaller sample size or shorter trial duration) (maybe) Inclusion of some components may reduce/eliminate bias due to informative censoring (but may result in a loss of power) A solution to handling disagreement over which outcome should be primary (not always the best solution) Freemantle N et al, JAMA 2003.
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LECTURE 09 2011 - Outline General endpoint considerations...

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