Validation of Heart Failure Events in ALLHAT Participants Assigned to Doxazosin and Chlorthalidone

1. Validation of Heart Failure Events in ALLHAT Participants Assigned to Doxazosin and Chlorthalidone L.B.Piller, B.R.Davis, J.A.Cutler, W.C.Cushman, J.T. Wright, J.D.Williamson, F.H.Leenen, O.Randall, J.S.Golden The University of Texas School of Public Health Houston, Texas

2. At Issue

3. Objectives To describe the process by which the clinical reports of heart failure events were validated To describe the statistical analyses which led to the cessation of the doxazosin arm

5. Relative Risks and 95% CICongestive Heart Failure Doxazosin/Chlorthalidone

6. Methods Comparison of baseline characteristics of CHF and non-CHF participants Comparison of pre and post-event medical management Endpoints Subcommittee evaluation of a sample of hospitalized and fatal heart failure cases using study criteria Determination and comparison of frequency and severity of systolic dysfunction through ascertainment of ejection fractions (EF) Comparison of case-fatality rates and causes of death Evaluate more stringent CHF-defined outcome

7. Baseline Characteristics Do baseline characteristics differ in expected ways between participants with and without CHF, and are these differences generally similar in the doxazosin and chlorthalidone arms?

8. Baseline Characteristics:CHF vs. Non-CHF Participants

9. Baseline Characteristics:CHF vs. Non-CHF Participants

10. Eligibility Criteria: CHF vs. Non-CHF Participants

11. Pre and Post-Event Treatment of Heart Failure Participants Was pre-heart failure event step 1 treatment compliance equivalent in the chlorthalidone and doxazosin groups? Were the heart failure participants in the chlorthalidone and doxazosin groups managed similarly following the heart failure events?

12. Pre-Event Treatment ofHospitalized CHF Participants

13. Pre-Event Treatment of Non-Hospitalized but Treated CHF Participants

14. Post-Event Treatment ofHospitalized CHF Participants

15. Post-Event Treatment of Non-Hospitalized but Treated CHF Participants

16. Heart Failure Event Reporting Did the reports of hospitalized or fatal heart failure adhere to the study criteria?

17. ALLHAT Study Events Documentation required: Discharge summaries for all hospitalizations Death certificates for all deaths Additional QC documentation for random 10% sample of MI�s, strokes and fatal CHD Routinely reviewed for accuracy and appropriateness Queries sent to the sites for clarification of discrepancies A random 10% of MI�s, strokes and fatal CHD reports reevaluated by the Endpoints Subcommittee for quality control

18. Endpoint SubcommitteeEvaluation of CHF Events 50 cases of reported hospitalized and/or fatal CHF Each case reviewed by two Subcommittee members Criteria for confirmation of CHF as described in the Manual of Operations

19. Criteria for CHFEvaluation*

20. New York Heart Association Functional Classification of Congestive Heart Failure*

21. Framingham Criteria for the Diagnosis of Congestive Heart Failure*

22. Endpoints Subcommittee Evaluation of CHF Sample (n=50)

23. Severity of Heart Failure What is the frequency of systolic dysfunction in doxazosin and chlorthalidone participants with heart failure? Is the systolic dysfunction equally severe in the chlorthalidone and doxazosin participants with heart failure?

24. Assessment of the Severityof Hospitalized and Fatal Heart Failure Half of hospitalized or fatal heart failure events reviewed for ejection fractions (EF) If EF documented, further information sought How was it obtained? Was the EF equally severe across drug groups? Given possible differences between VA and non-VA sites in levels of diagnostic testing, was there a difference between the two groups in EF data?

25. CHF Ejection Fraction Data

26. CHF Ejection Fraction Data:Hospitalized or Fatal CHF

27. CHF Ejection Fraction Data: Hospitalized or Fatal CHF (VA Clinics)

28. CHF Ejection Fraction Data: Hospitalized or Fatal CHF (Non-VA Clinics)

29. Fatality Rates and Cause of Death Is all-cause mortality similar for the chlorthalidone and doxazosin participants? Are case-fatality rates similar and as high as expected for chlorthalidone and doxazosin participants hospitalized for heart failure? Are causes of deaths for chlorthalidone and doxazosin participants previously hospitalized for heart failure similarly distributed?

32. Causes of Death of Participants Hospitalized for CHF

33. Fatal and Hospitalized CHF: Increased Risk?

35. Relative Risks and 95% CIHospitalized or Fatal Congestive Heart Failure Doxazosin/Chlorthalidone

36. Conclusions (1) The risk for the more stringent outcome of hospitalized or fatal heart failure was significantly higher in the doxazosin treatment group compared to the chlorthalidone treatment group (RR, 1.83; 95% CI, 1.58-2.13). Case-fatality rates for participants with heart failure were high (20% in 2 years) and similar in both groups. Hospital discharge data for heart failure was largely consistent with the ALLHAT definition of heart failure. In both groups, two thirds of the hospitalized or fatal heart failure events with ejection fraction measurements had ejection fractions of 40% or less.

37. Conclusions (2) The treatment following the heart failure events in both groups was consistent with recommended treatment of heart failure in the community. Similar percentages of participants in both treatment groups were on step 1 medication prior to the heart failure event. Participants who developed heart failure had a greater history of coronary heart disease than participants who did not develop heart failure.