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

1. ALLHAT 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. ALLHAT At Issue The doxazosin group showed a doubling of risk of CHF compared to the chlorthalidone group (RR, 2.04; 95% CI, 1.79-2.32).

3. ALLHAT 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

4. Rel Risk 2.04 95% CL 1.79-2.32 ALLHAT p < 0.001 Congestive Heart Failure 0.10 0.08 0.06 Cumulative Event Rate doxazosin chlorthalidone 0.04 0.02 9,541 5,457 9,541 5,457 9,541 5,457 5,531 3,089 2,427 1,351 13,644 7,845 0 0 1 2 3 4 C: 15,256 D: 9,061 Years of Follow-up

5. ALLHAT Relative Risks and 95% CICongestive Heart Failure Doxazosin/Chlorthalidone 4.50 4.00 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00 Age Age BNH WNH Hisp BNH WNH Hisp Nondi Total Diab <65 65+ Men Men Men W W W a 2.32 2.53 2.41 2.81 2.40 4.14 3.21 2.62 3.97 2.59 2.37 High 1.79 1.51 1.78 1.47 1.58 1.11 1.67 1.49 0.85 1.76 1.67 Low 2.04 1.96 2.07 2.04 1.94 2.15 2.32 1.98 1.84 2.14 1.98 RR

6. ALLHAT 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. ALLHAT 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. ALLHAT Baseline Characteristics:CHF vs. Non-CHF Participants

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

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

11. ALLHAT 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. ALLHAT Pre-Event Treatment ofHospitalized CHF Participants

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

14. ALLHAT Post-Event Treatment ofHospitalized CHF Participants

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

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

17. 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 ALLHAT ALLHAT Study Events Documentation Management

18. ALLHAT 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. ALLHAT Criteria for CHFEvaluation* *ALLHAT Manual of Operations, 5.3.4

20. New York Heart Association Functional Classification of Congestive Heart Failure* I No limitations of activity; ordinary activity does not cause undue fatigue, palpitations, dyspnea or anginal pain II Slight limitations of activity; asymptomatic at rest; ordinary activity results in fatigue, palpitations, dyspnea or anginal pain III Marked limitations of activity; usually asymptomatic at rest; less than ordinary activity causes fatigue, palpitations, dyspnea or anginal pain IV Inability to carry on any physical activity without discomfort; symptoms at rest; increased discomfort with any physical activity * Criteria Committee, New York Heart Association. Diseases of the heart and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. 1964:114.

21. Framingham Criteria for the Diagnosis of Congestive Heart Failure* • Major Criteria • Paroxysmal nocturnal dyspnea (A) • Neck vein distention (B) • Rales (B) • Cardiomegaly (B) • Acute pulmonary edema (B) • S3 gallop (B) • venous pressure (B) + hepatojugular reflux Minor Criteria Extremity edema (B) Night cough (A) Dyspnea on exertion (A) Hepatomegaly Pleural effusion (B) Vital capacity  by 1/3 of nml Tachycardia >120 bpm (B) Major or Minor Weight loss >4.5 kg over 5 days’ treatment At least two major or one major and two minor criteria are required for the diagnosis of CHF. *KKL Ho et al, Circulation 88:107, 1993.

22. ALLHAT Endpoints Subcommittee Evaluation of CHF Sample (n=50) Cases with insufficient data: 11/50 Remaining cases with CHF: 33/39 (85%) Remaining chlorthalidone cases with CHF: 9/10 (90%) Remaining doxazosin cases with CHF: 9/10 (90%)

23. ALLHAT 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. ALLHAT 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. ALLHAT CHF Ejection Fraction Data

26. ALLHAT CHF Ejection Fraction Data:Hospitalized or Fatal CHF

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

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

29. ALLHAT 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?

30. Rel Risk 1.03 95% CL 0.90-1.15 ALLHAT p = 0.56 All-Cause Mortality Cumulative Event Rate doxazosin chlorthalidone 10,513 6,118 5,702 3,287 2,530 1,481 13,739 8,054 C: 15,268 D: 9,067 Years of Follow-up

31. ALLHAT Cumulative Mortality for Hospitalized CHF Cases .5 .4 .3 Cumulative Mortality Rate chlorthalidone .2 doxazosin .1 0 0 1 2 3 4 Years Hospitalized CHF to Death

32. ALLHAT Causes of Death of Participants Hospitalized for CHF

33. ALLHAT Fatal and Hospitalized CHF: Increased Risk? Does the more stringent CHF outcome, fatal and hospitalized CHF, show a similarly increased CHF risk in the doxazosin group compared to the chlorthalidone group?

34. ALLHAT Hospitalized or Fatal CHF .06 Rel Risk 95% CI 1.83 1.58-2.13 p < 0.001 doxazosin Cumulative Event Rate .04 chlorthalidone .02 0 0 0 0 1 2 3 4 Years of Follow-up

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

36. ALLHAT 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. ALLHAT 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 1medication 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.