Outline

1. Outline • General endpoint considerations • Surrogate endpoints • Composite endpoints • Safety outcomes (adverse events)

2. 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

3. Examples of Combined Endpoints Study Endpoint 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 * Non-fatal events treated hierarchically

4. 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

5. Composite Examples for Heart Failure (HF) Studies:Time to Event Analysis • Time to the 1st 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 (more sensitive to treatment differences particularly among patients with less severe heart failure)

6. Composite Example: CVD Death or HF Hospitalization Patient X 1 HF Hosp. X 2 CVD Death 0 3 Non-CVD Death X X X X 4 HF Hosp. HF Hosp. HF Hosp. CVD Death 0 Follow-up Time t

7. 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

8. Clinical Relevance? Patient 1 2 3 0 X Candidiasis End of Study X Death X 0 X X End of Study Candidiasis MAI PCP 0 Follow-up Time t

9. 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.

10. Composite Endpoint Cautions Loss of power if: • Treatment has little or no effect on some components • Early events are less likely to represent “treatment failures” compared to later events (Yusuf and Negassa referred to this as “masking” of events) Unclear interpretation if: • Components show a different pattern for treatments • Less serious or more subjectively assessed events are accounting for treatment difference • “Mixing apples and oranges” Neaton JD et al, Stat Med 1994 and Yusuf S and Negassa A, Amer Heart J 2002.

11. Adding a Component to a CompositeDoes Not Always Have a Favorable Effect on Sample Size • 10% versus 5% event rate – 1,170 patients total • Add a new component • 30% versus 15% event rate – 330 patients • 30% versus 22.5% event rate – 1,450 patients Alpha = 0.05 (2-sided) and power = 0.90

12. Neaton J et al, J Cardiac Failure 2005

13. Informative Censoring - 1 Patient X 1 HF Hosp. X 2 CVD Death 0 3 Non-CVD Death X X X X 4 HF Hosp. HF Hosp. HF Hosp. CVD Death 0 Follow-up Time t

14. Informative Censoring - 2 • If a patient dying from a non-CVD cause would have had a different risk of HF hospitalization (had they survived) than survivors, the censoring is “informative”. • Bias could result if risk of non-CVD death varied by treatment group.

15. PICO HF Trial: Ranked Clinical Outcome at 24 Weeks Assigned Treatment Pimobendan(N=209) Placebo(N=108) Testsame/higher than baseline132 (63%) 64 (59%) Testlower duration than baseline 48 (23%) 34 (31%) Too sick to undergo exercise test 5 (2%) 4 (4%) Died before 24 weeks 24 (12%) 6 (6%) P=0.5 for 63% versus 59%; P < 0.05 for difference in exercise duration.

16. Women’s Angiographic Vitamin and Estrogen Trial (WAVE) • Objective:to determine whether HRT or antioxidant vitamin supplements influenced the progression of coronary artery disease as measured by serial angiograms (2x2 factorial study). • Target population: women with 15-75% coronary stenosis at entry. • Primary endpoint: change in lumen diameter; deaths and MIs assigned worst rank. JAMA 2002; 288: 2432-2440.

17. Freemantle Guidelines for Reporting • Components of composite outcomes should always be defined as secondary outcomes and reported alongside the results of the primary analysis, preferably in a table. • Ensure that the reporting of composite outcomes is clear and avoids the suggestion that individual components of the composite have been demonstrated to be effective. • Systematic overviews and quantitative meta-analysis should be used to identify the effects of treatments on rare but important endpoints that may be included as part of composite outcomes in individual trials. Freemantle N, et al. JAMA 2003.

18. Guide to Interpreting Composite End Points • Are the component end points of similar importance to patients? • Did the more and less important end points occur with similar frequency? • Is the underlying biology of the component end points similar? • Are the point estimates of the relative risk reduction similar and the confidence intervals sufficiently narrow? Montori VM et al, BMJ 2005.

19. Recommendations on Reporting of Composite Outcomes • How often did each component contribute to composite outcome (descriptive)? • What is the relative hazard for each component of the composite - the separate number of events and rate for each component (“Consumer Reports approach”)?

20. Multiple Outcomes are a Necessity,So No Matter What You Do… • Collect data on all components of the combined endpoint for trial duration • Report not only the combined endpoint, but also: • how often each component contributed to it • the separate number of events and rate for each component (“Consumer Reports approach”) • See NuCOMBO (N Eng J Med 1996) and EPHESUS (N Eng J Med 2003) trials for good examples of composite outcome reporting.

21. Example: NuCOMBO AIDS Trial How often did each component occur as 1st event? Death 75 54 PCP 32 51 Esophageal 30 22 Candidiasis MAC 23 30 CMV 20 28 Other AIDS 27 29 infections Malignancies 9 13 Other conditions 10 17 AIDS/Death 226 244 AZT(N=372) AZT+ddI(N=363) Hazard ratio: 0.86 (0.71 to 1.03)

22. Example: NuCOMBO AIDS Trial What is the separate incidence of each component of the combined endpoint “Consumer Reports approach”? Death 176 191 0.88 PCP 42 60 0.65 Esophageal 43 42 0.97 Candidiasis MAC 42 58 0.66 CMV 49 49 0.96 Other AIDS 37 38 0.94 infections Malignancies 19 27 0.64 Other conditions 17 26 0.60 AIDS/Death 226 244 0.86 HazardRatio AZT(N=372) AZT+ddI(N=363)

23. Pitfalls of Usual Approach • Usual analysis of composites focuses on 1st event • Components of composite usually vary in severity and in impact on quality of life • Many patients experience multiple events Approaches for considering multiple events of varying severity need to be studied.

24. Weighting the Components of Composite Outcomes • Risk of death associated with different components • Rank-ordering of outcomes in terms of severity and quality of life by clinicians and patients • Rating the entire event profile

25. General Approaches for Accounting for Severity of Events and Event Histories • Ranking of entire event histories (Follmann et. al., Stat Med 1992) • Marginal models with ranking of events according to risk of death or subjective ranking by clinicians and/or patients (Neaton et.al., Stat Med 1994) • Rule based ranking (Bjorling and Hodges, Stat Med, 1997) • - Severity, timing, number • Weights determined by clinical investigators for trials of thrombolytic therapy (Armstrong P et al, Am Heart J, 2011) [death 1.0, shock 0.5, CHF 0.3, recurrent MI 0.2]

26. Considerations in Analysis of All Events • Events are not independent – SE’s have to be adjusted • 2nd, 3rd … events may not add much to signal from 1st event • A loss of power could result if treatment was modified after 1st event

27. Alternatives to Compositeor Combined Endpoints • Single outcome • Quality of life • Death • Co-primary endpoints (requires an adjustment to Type I error if success is defined as “significant” on any) • Global index (may not be easily interpretable) • Hierarchical scoring/ranking of multiple outcomes • Primary + supportive outcome (SMART)

28. Multiple Primary Endpoints • Different than a single combined endpoint • Type I error adjustment may be required (usually is) • Strategy for controlling type I error depends on research question

29. Early HIV (High CD4+) Treatment Trial: Co-Primary Endpoints or Single Composite? • Serious AIDS • Any fatal AIDS event • Non-fatal AIDS events except herpes simplex, esophageal candidiasis and pulmonary tuberculosis • Serious non-AIDS • Non-AIDS deaths • CV disease • Liver disease • Renal disease • Non-AIDS malignancies (excluding skin cancer)

30. What is the question? Four possible alternative hypotheses? • HA: Treatment effect in at least one of K endpoints • HA: Treatment effect in all K endpoints (no type I error adjustment needed) • HA: Treatment effect in M of K endpoints • HA: Treatment effect in weighted average of K endpoints Capizzi T, Zhang J. Drug Info J, 30:949-956, 1996.

31. Strategies for  (type I error) Adjustment for 1st Hypothesis:Treatment effect in at least 1 of K endpoints Bonferroni adjustment most common -- conservative Suppose there are 2 co-primary endpoints. Prob [no type 1 error for trial (T)] = 1- T = (1- 1)(1- 2) and T = 1 - (1- 1)(1- 2) is the  level for trial For case of 1=2 = 0.05, T =0.098 (unacceptably high) For T =0.05, each  = 1- (1- T)1/2 = 0.0253 or more generally 1- (1- T)1/n This is approximately equal to T/n or 0.05/2=0.025 for this case Example: EPHESUS heart failure study of eplerenone (Cardio Drugs and Therapy,15:79-87, 2001) -- 2 primary endpoints – total mortality (0.04) and CV mortality or morbidity (0.01); overall study type 1 error of 0.05.

32. Other Strategies • Global tests, e.g., MANOVA and Hotelling’s T2 (good approach if endpoints are not correlated) or O’Brien’s rank test (best when all outcomes are expected to go in the same direction). Problem – not specific enough. • Sequential testing procedures, e.g., Holm’s step-down procedure or Hochberg’s step-up procedure (both less conservative than Bonferroni) – marginal testing with control of overall error rate

33. Example • 4 endpoints (ordered by p-values): p=0.081; p=0.024; p=0.020; p=0.005 • Bonferroni: judge each against 0.05/4=0.0125; only 4th endpoint is significant • Holm step-down: reject 4th endpoint since p=0.005<0.0125; p-value for 3rd endpoint = 0.020 > 0.05/3=0.017, therefore stop and accept H0 for other 3 endpoints • Hochbergstep-up: accept H0 for 1st endpoint since 0.081 > 0.05; reject H0 for 2nd endpoint and all remaining endpoints since 0.024< 0.05/2=0.025. Sankoh et al Stat Med 16:2529-2542, 1997

34. O’Brien’s Rank Sum Procedure • Rank the responses of patients for each of the K endpoints, e.g., Wilcoxon’s rank sum test • Sum the ranks for each patients • Carry out an analysis of variance (ANOVA) on the sum of the ranks O’Brien P. Biometrics 40:1079-1087, 1984. See TOMHS report in JAMA for application

35. Advantages and Disadvantages of Different Approaches to Defining Primary Endpoint

36. Summary • In study planning, focus on methods for defining, ascertaining, and measuring major endpoints. • Composite outcomes can be difficult to interpret if the components do not go in the same direction – choose components carefully. • A “Consumer Reports” analysis should be kept in mind for reporting – full disclosure of all relevant outcomes.