U.S. Department of Health and Human Services

1. ALLHAT U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute Review of Heart Failure Events in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial:ALLHAT Heart Failure Validation Study Paula Einhorn, Barry Davis, Henry Black, William Cushman, John Kostis, Daniel Levy, Barry Massie, Barbara deLeon, Linda Piller, Lara Simpson, Chuke Nwachuku for The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) www.allhat.org

2. ALLHAT Heart Failure Validation Study Aimed to centrally review all hospitalized HF events in 42,418 ALLHAT participants.

3. Randomized Design of ALLHAT BP Trial ALLHAT 42,418 High-risk hypertensive patients Consent / Randomize Amlodipine Chlorthalidone Doxazosin Lisinopril Follow until death or end of study (4-8 years, mean 4.9 years) JAMA. 2002;288:2981-2997

4. Participants Hypertensive men and women Age 55 and older (mean 67) At least one additional CVD risk factor [old (>6 months) MI or stroke, LVH, h/o type 2 diabetes, current smoker, HDL<35, or documented other ASCVD] Excluded: h/o symptomatic HF and/or known LVEF <35% ALLHAT

5. ALLHAT provides a double-blind comparison of 4 drug classes in preventing transition from hypertension to overt heart failure ALLHAT

6. ALLHAT Hypertension and Heart Failure • In Framingham Heart Study, hypertension was the most common risk factor for HF, antedating it in 91% of cases. (JAMA. 1996;275:1557-1562) • In BP Lowering Treatment Trialists’ Collaboration, there were differences among drug classes in occurrence of HF. (Lancet 2003, 362:1527-35)

7. ALLHAT Hypertension Trial • Randomized, double-blind • Large, simple, practice-based trial • No protocol-mandated central review of HF events • Diagnoses assigned by clinic investigators guided by protocol-defined diagnostic criteria

8. ALLHAT ALLHAT HF Criteria ALLHAT Manual of Operations, 5.3.4 JAMA.1997;278:212-216

9. ALLHAT Origin of the HF Validation Study • HF endpoint defined as treated in hospital or as outpatient, or fatal • A component of combined CVD (CHD, stroke, HF, PAD) • Systematic review of hospitalized HF events was initiated in 2001, on advice of the DSMB

10. ALLHAT HF Validation Study Objectives • Evaluate ALLHAT investigator-assigned diagnoses • Compare treatment effects to those previously reported (JAMA. 2002;288:2981-2997)

11. ALLHAT HF Validation Study • Relevant hospital records requested for 2952 hospitalizations in 2047 patients with a diagnosis of HF on admission or during hospital course • Summary: face sheet, discharge /death summary, admitting H&P, ER notes • Imaging reports: chest X-ray, cardiac catheterization, echocardiography, radionuclide imaging • Other reports: pulmonary function tests, cardiology or pulmonary consultation, autopsy

12. ALLHAT HF Validation Study Definitions • ALLHAT/SHEP • Traditional Framingham Criteria • Updated Framingham Criteria • Reviewers’ global clinical judgment

13. HF Validation Study ALLHAT • 2962 hospital records for 2045 patients received. • 2811 records of 1951 patients suitable for review. • Abstracted by cardiology fellows blinded to treatment assignment. • Each record independently reviewed by two reviewers. • For algorithmic criteria (ALLHAT and Framingham), diagnoses were assigned by computer. • Reviewers’ clinical judgment entered as yes, no, don’t know.

14. ALLHAT Framingham HF CriteriaTwo major or one major plus two minor criteria: • Major • Paroxysmal nocturnal dyspnea • Jugular venous distention • Rales • Cardiomegaly on CXR • Acute pulmonary edema • S3 gallop • Central venous pressure Circ. time >25 seconds Hepatojugular reflux Autopsy findings: pulmonary edema, congestion, or cardiomegaly • Minor • Bilateral ankle edema • Nocturnal cough • Dyspnea on exertion • Hepatomegaly • Pleural effusion • Vital capacity 1/3 from max. Tachycardia > 120/min. Major or minor Weight loss > 4.5 kg in 5 days in response to treatment of HF KKL Ho et al, Circulation 88:107, 1993

15. ALLHAT Updated Framingham CriteriaRequire 2 major or 1 major plus 2 minor criteria; one has to be diagnostic and one clinical Part 1: Clinical Findings Major PND or orthopnea Jugular Venous Distention Pulmonary rales S3 gallop Hepatojugular reflux Diuresis of 10 lbs or 5 kg in response to diuretic treatment with clinical improvement in congestive symptoms Minor Bilateral ankle edema Nocturnal cough Dyspnea on exertion Hepatomegaly

16. ALLHAT Updated Framingham CriteriaRequire 2 major or 1 major plus 2 minor criteria; one has to be diagnostic and one clinical Part 2: Diagnostic Findings Major Acute pulmonary edema on CXR PCWP>= 20 mm Hg LVEF =< 35% Cardiac Index < 2.0 Evidence of severe valvular disease Pulmonary edema, congestion, or cardiomegaly on autopsy Minor Pleural effusion or vascular engorgement or redistribution on CXR PCWP 16-19 mm Hg LVEF 36 – 44% Cardiac Index 2.0 – 2.4 Evidence of moderate valvular disease

17. ALLHAT 100 90 80 70 60 % agreement 50 40 30 20 10 0 ALLHAT Reviewers Framingham1 Framingham 2 Percent agreement with investigator-assigned diagnosis Data refer to percentage of participants with at least one event of hospitalized or fatal heart failure that meet the criteria by at least one of the reviewers.

18. ALLHAT Percent Agreement with investigator-assigned diagnosis

19. ALLHAT Percent Agreement with investigator-assigned diagnosis

20. ALLHAT HF Validation StudyVerification of Treatment Effects For the various Validation Study definitions of HF, relative risks and 95% CIs were calculated using first events confirmed by a given definition.

21. Validation Study ACEI versus diuretic ALLHAT Definition, Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Lisinopril Favors Chlorthalidone • RR estimates calculated from 2-by-2 table • Pre-specified endpointof treated in hospital or as outpatient or fatal

22. Validation Study CCB versus diuretic ALLHAT 0.50 1 2 Definition, Relative Risk and 95% Confidence Intervals Favors Amlodipine Favors Chlorthalidone • Pre-specified endpointof treated in hospital or as outpatient or fatal • RR estimates calculated from 2-by-2 table

23. Validation Study α-blocker versus diuretic ALLHAT Definition, Relative Risk and 95% Confidence Intervals 0.50 1 2 3 Favors Doxazosin Favors Chlorthalidone • Pre-specified endpointof treated in hospital or as outpatient or fatal • RR estimates calculated from 2-by-2 table

24. ALLHAT Summary • An independent review of hospital records showed a high degree of agreement with the diagnoses assigned by ALLHAT investigators (71 – 84% agreement) • Relative risks calculated for several stringent definitions of HF confirm superiority of a thiazide-type diuretic over a CCB, an ACE-I and an alpha-blocker in preventing the onset of symptomatic HF in hypertensive patients with at least one additional risk factor.

25. ALLHAT Implications • HF is a costly and deadly complication of hypertension • Thiazide-type diuretics have greater efficacy for HF prevention and should be considered first-step therapy for prevention of HF in high risk patients with hypertension