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) ALLHAT

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

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

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

ALLHAT provides a double-blind comparison of 4 drug classes in preventing transition from hypertension to overt heart failure 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: ) In BP Lowering Treatment Trialists’ Collaboration, there were differences among drug classes in occurrence of HF. (Lancet 2003, 362: )

Hypertension Trial ALLHAT 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

ALLHAT HF Criteria Must have one from each category: Category “A”Category “B” Paroxysmal nocturnal dyspneaRales Orthopnea2+ ankle edema NYHA Classification IIITachycardia >= 120/min Dyspnea at restCardiomegaly by CXR CXR characteristic of CHF S 3 gallop Jugular venous distention ALLHAT Manual of Operations, JAMA.1997;278: 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 ALLHAT

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

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 ALLHAT

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

2962 hospital records for 2045 patients received 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. ALLHAT HF Validation Study

Framingham HF Criteria Two major or one major plus two minor criteria: Major Paroxysmal nocturnal dyspnea Jugular venous distention Rales Cardiomegaly on CXR Acute pulmonary edema S 3 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 ALLHAT

Updated Framingham Criteria Require 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 S 3 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 ALLHAT

Updated Framingham Criteria Require 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 mm Hg LVEF 36 – 44% Cardiac Index 2.0 – 2.4 Evidence of moderate valvular disease ALLHAT

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. ALLHAT ALLHAT Framingham1 Framingham 2 Reviewers % agreement

Percent Agreement with investigator-assigned diagnosis ALLHAT ChlorAmlodLisinTOTAL N (patients with event reviewed) ALLHAT 169%73%72%71% ALLHAT 269%72%71%70% ALLHAT 366%69%70%68% ALLHAT 456%58%56%57% Framingham 179%81%79%80% Framingham272%73%71%72% Reviewers agree HF82%86%84%

Percent Agreement with investigator-assigned diagnosis ALLHAT ChlorDoxTOTAL N (patients with event reviewed) ALLHAT 167%69%68% ALLHAT 266%68%67% ALLHAT 364%67%65% ALLHAT 453% Framingham 177%76%77% Framingham269% Reviewers agree HF80%83%82%

HF Validation Study Verification 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. ALLHAT

HF*1.19 ( ) Hosp/fatal HF1.10 ( ) ALLHAT ( ) ALLHAT ( ) ALLHAT ( ) ALLHAT ( ) Framingham ( ) Framingham ( ) Reviewer agree1.15 ( ) Favors Lisinopril Favors Chlorthalidone Definition, Relative Risk and 95% Confidence Intervals Validation Study ACEI versus diuretic ALLHAT RR estimates calculated from 2-by-2 table Pre-specified endpoint of treated in hospital or as outpatient or fatal

HF*1.37 ( ) Hosp/fatal HF1.35 ( ) ALLHAT ( ) ALLHAT ( ) ALLHAT ( ) ALLHAT ( ) Framingham ( ) Framingham ( ) Reviewer agree1.45 ( ) Definition, Relative Risk and 95% Confidence Intervals Validation Study CCB versus diuretic Favors Amlodipine Favors Chlorthalidone ALLHAT Pre-specified endpoint of treated in hospital or as outpatient or fatal RR estimates calculated from 2-by-2 table

HF*1.77 ( ) Hosp/fatal HF1.60 ( ) ALLHAT ( ) ALLHAT ( ) ALLHAT ( ) ALLHAT ( ) Framingham ( ) Framingham ( ) Reviewer agree1.72 ( ) Validation Study α-blocker versus diuretic Definition, Relative Risk and 95% Confidence Intervals Favors Doxazosin Favors Chlorthalidone Pre-specified endpoint of treated in hospital or as outpatient or fatal RR estimates calculated from 2-by-2 table 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. 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 ALLHAT