The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) heart failure Validation Study: Diagnosis and prognosis

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1 Prevention and Rehabilitation The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) heart failure Validation Study: Diagnosis and prognosis Paula T. Einhorn, MD, MS, a Barry R. Davis, MD, PhD, b Barry M. Massie, MD, c William C. Cushman, MD, d Linda B. Piller, MD, MPH, b Lara M. Simpson, PhD, b Daniel Levy, MD, e Chuke E. Nwachuku, DrPH, MA, MPH, a and Henry R. Black, MD, f for the ALLHAT Collaborative Research Group Bethesda, MD; Houston, TX; San Francisco, CA; Memphis, TN; Framingham, MA; and Chicago, IL Background ALLHAT, a randomized, double-blind, active-controlled hypertension treatment trial in patients, reported that a thiazide-type diuretic (chlorthalidone) was superior to a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an a 1 -blocker (doxazosin) in preventing the new onset of heart failure (HF). However, questions have been raised regarding the validity of the HF diagnosis. Methods The ALLHAT HF Validation Study was designed to validate and elucidate the significance of HF events in ALLHAT. Records for 2778 HF hospitalizations in 1935 patients were centrally reviewed using several prespecified algorithms (based on ALLHAT and Framingham criteria) and reviewers global clinical judgment. Percent agreement with diagnoses assigned by ALLHAT site physicians, relative risks across randomized comparisons, incidence rates, and mortality after HF hospitalization were evaluated for first events validated by each of the criteria sets. Results Percent agreements with site physician diagnoses were 71%, 80%, and 84% for ALLHAT, Framingham, and reviewers judgment, respectively. Using these 3 criteria, relative risks (95% CI) for new-onset HF compared with chlorthalidone were, respectively, 1.46 ( ), 1.42 ( ), and 1.45 ( ) for amlodipine; 1.18 ( ), 1.13 ( ), and 1.15 ( ) for lisinopril; and 1.79 ( ), 1.71 ( ), and 1.80 ( ) for doxazosin. Conclusions An independent review of source documentation showed a high degree of agreement with the HF diagnoses assigned by site physicians and confirmed the higher risk of HF associated with first-step therapy using amlodipine, lisinopril, or doxazosin compared with chlorthalidone. Thiazide-type diuretics should be the preferred first-step therapy for prevention of HF in high-risk patients with hypertension. (Am Heart J 2007;153:42253.) From the a National Heart, Lung, and Blood Institute, Bethesda, MD, b University of Texas Health Science Center School of Public Health, Houston, TX, c San Francisco Veterans Affairs Medical Center, San Francisco, CA, d Memphis Veterans Affairs Medical Center, Memphis, TN, e Framingham Heart Study/National Heart, Lung, and Blood Institute, Framingham, MA, and f Rush Presbyterian St. Luke s Medical Center, Chicago, IL. This study was supported by contract NO1-HC from the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer Inc (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin) and financial support provided by Pfizer Inc. The National Heart, Lung, and Blood Institute sponsored the study and was involved in all aspects other than direct operations of the study centers. This included collection, analysis, and interpretation of the data plus the decision to submit the manuscript for publication. Pfizer Inc, AstraZeneca, and Bristol-Myers Squibb had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation or approval of the manuscript. Disclosures. Dr Davis consulting: GlaxoSmithKline, Merck, Takeda. Dr Massie grant: Bristol-Myers Squibb; consulting: Abbott, Bristol-Myers Squibb, Sanofi-Synthelabo, GlaxoSmithKline, Novartis. Dr Cushman grant: Abbott Laboratories, AstraZeneca, Novartis; consulting: AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, Novartis, Pfizer, Sankyo, Sanofi-Synthelabo. Dr Nwachuku currently employed by AstraZeneca. Dr Black consulting: Biovail, Boehringer Ingleheim, Bristol-Myers Squibb, CV Therapeutics, Merck, Myogen, Novartis, Pfizer, Sanofi-Synthelabo; Data and Safety Monitoring Board chair, Novartis (ACCOMPLISH). Dr Einhorn, Dr Piller, Dr Simpson, and Dr Levy none. The ALLHAT HF Validation Study was designed by the ALLHAT Heart Failure Advisory Group: William Cushman (Chair), John Kostis, Daniel Levy, Barry Massie, Clinical Trial Coordinating Center (Barry Davis, Linda Piller, Sara Pressel, Lara Simpson), and The National Heart, Lung, and Blood Institute Project Office (Paula Einhorn, Jeffrey Cutler, Chuke Nwachuku, Michael Proschan). The ALLHAT Data and Safety Monitoring Board, under the chairmanship of Dr Robert Califf, has reviewed the concept and procedures of the HF validation study. A list of the ALLHAT Collaborative Research Group members has been published previously. 10 Submitted February 13, 2006; accepted October 9, Reprint requests: Paula T. Einhorn, MD, MS, National Heart, Lung, and Blood Institute, Division of Epidemiology and Clinical Applications, Two Rockledge Centre Room 8122, 6701 Rockledge Drive MSC 7936, Bethesda, MD (20817 for courier) /$ - see front matter n 2007, Published by Mosby, Inc. doi: /j.ahj

2 American Heart Journal Volume 153, Number 1 Einhorn et al 43 Figure 1 ALLHAT HF Validation Study population. Heart failure (HF) is an important public health problem. It is the most frequent cause of hospitalization among people z65 years, and these hospitalizations are central to the enormous cost of the disease. 1,2 Despite recently reported favorable trends in HF incidence and survival after the onset of HF, the postincident event mortality rates remain high (N20% at 1 year), emphasizing the importance of prevention. 3,4 Although several risk factors for HF have been identified, the Framingham Heart Study showed that hypertension was the most common modifiable risk factor for HF, antedating it in 91% of cases. 5 Clinical trials have documented that hypertension treatment can substantially reduce the incidence of HF, especially in older patients with systolic hypertension. 6-8 ALLHAT, a randomized, double-blind, practice-based hypertension treatment trial sponsored by the National Heart, Lung, and Blood Institute, was carried out in high-risk individuals with hypertension, but without symptomatic HF or known left ventricular ejection fraction (LVEF) b35%. 9 Heart failure was a prespecified component of the combined cardiovascular disease (CVD)

3 44 Einhorn et al American Heart Journal January 2007 Figure 2 ALLHAT and Framingham HF criteria. outcome, which was a major secondary end point of the trial. Compared with chlorthalidone-based treatment, newonset HF occurred more frequently in patients randomized to amlodipine-, lisinopril-, and doxazosin-based strategies (relative risks [RRs] 1.38, 1.19, and 1.80, respectively). 10,11 However, questions have been raised regarding the validity of the diagnosis of HF because it was not routinely adjudicated by the end point subcommittee and because nonspecific peripheral edema, either occurring spontaneously or as a side effect of amlodipine, might have prompted a misdiagnosis of HF We undertook a validation study to systematically evaluate all hospitalized HF events in a rigorous manner, blinded to treatment assignment in accordance with a recommendation of the ALLHAT Data and Safety Monitoring Board. Based on the subset of incident HF events with a hospitalization or followed by a HF hospitalization, this article (1) explores the agreement of HF diagnoses assigned by ALLHAT site physicians with 6 different algorithms for HF and with the opinion of a clinician-reviewer; (2) compares the relative risks of validated HF between randomized treatment groups with the relative risks previously reported in the trial s main results; and (3) evaluates incidence of validated HF and examines subsequent mortality rates as indicators of the clinical significance of this outcome. Methods ALLHAT design and participants ALLHAT was a large, randomized, double-blind, activecontrolled hypertension treatment trial. 9 Its overall purpose was to determine whether newer antihypertensive drug classes calcium-channel blockers (amlodipine), angiotensin-converting enzyme (ACE) inhibitors (lisinopril), or a 1 -blockers (doxazosin) are superior to an older class of thiazide-type diuretics (chlorthalidone) in preventing cardiovascular complications of hypertension when each drug is used as the primary antihypertensive treatment (with step-up drugs as needed). The

4 American Heart Journal Volume 153, Number 1 Einhorn et al 45 Table I. Baseline characteristics Baseline characteristics (n [%]) All HF* (n = 2772) Hospitalized HF (n = 2207) Validated HFy (n = 1789) Not validated HFz (n = 146) Age (y) (mean [SD]) 70.2 (8.1) 70.3 (8.2) 70.0 (8.0) 72.5 (9.5) (27.1) 579 (26.2) 483 (27.1) 34 (23.3) z (72.9) 1628 (73.8) 2021 (72.9) 112 (76.7) Black 959 (34.6) 780 (35.3) 631 (35.3) 44 (30.1) Women 1198 (43.2) 965 (43.7) 773 (43.2) 65 (44.5) Education (y) (mean [SD]) 10.9 (3.8) 10.7 (3.8) 10.8 (3.8) 10.8 (3.5) Treated (antihypertensive) 2590 (93.4) 2057 (93.2) 1675 (93.6) 134 (91.8) Eligibility risk factorst Current smoker 500 (18.0) 416 (18.9) 337 (18.8) 25 (17.1) ASCVDt 1788 (64.5) 1421 (64.5) 1150 (64.3) 96 (65.8) History of MI or stroke 997 (36.0) 795 (36.0) 654 (36.6) 48 (32.9) Type II diabetes 1308 (47.2) 1082 (49.0) 891 (49.8) 67 (45.9) LVH by ECG (reported) 518 (18.7) 416 (18.9) 338 (18.9) 27 (18.5) LVH by echo (reported) 141 (5.2) 116 (5.3) 96 (5.4) 9 (6.2) History of CHD 1058 (38.5) 825 (37.7) 668 (37.7) 55 (37.9) BMI (mean [SD]) 30.5 (6.9) 30.3 (6.9) 30.6 (7.0) 28.7 (6.3) Blood pressure mmhg SBP (mean [SD]) (16.3) (16.3) (16.3) (16.9) DBP (mean [SD]) 81.9 (10.7) 81.9 (10.7) 81.9 (10.7) 80.0 (10.0) Treated SBP (mean [SD]) (16.3) (16.3) (16.3) (16.7) DBP (mean [SD]) 81.5 (10.6) 81.6 (10.6) 81.5 (10.7) 79.6 (9.9) Untreated SBP (mean [SD]) (11.1) (11.1) (11.1) (13.9) DBP (mean [SD]) 86.9 (10.9) 86.3 (11.0) 86.8 (10.8) 83.7 (10.2) Fasting glucose (mean [SD]) (65.4) (67.3) (67.7) (70.7) GFR (mean [SD]) 71.8 (20.9) 71.6 (21.2) 71.7 (20.9) 71.7 (21.1) LDL (mg/dl) (mean [SD]) (38.9) (39.6) (39.5) (38.0) HDL (mg/dl) (mean [SD]) 44.8 (14.5) 44.7 (14.4) 44.3 (14.3) 47.5 (15.6) Triglyceride (mg/dl) (mean [SD]) (140.4) (137.2) (137.0) (159.5) ASCVD, atherosclerotic CVD; ECG, electrocardiogram; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; GFR, glomerular filtration rate; LDL, low-density lipoprotein. 4Original prespecified HF outcome (treated, hospitalized, or fatal HF). yvalidated by any criteria set. znot validated by any criteria set. P b.05. Not validated compared to all HF. tsee baseline characteristics in Ref. [10]. primary end point was a composite of nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD). Major secondary end points were all-cause mortality, stroke, combined CHD (primary end point, coronary revascularization, hospitalized angina), and combined CVD (combined CHD, stroke, nonhospitalized treated angina, peripheral arterial disease, and HF). ALLHAT enrolled men and women (47%), aged 55 years or older (mean 67), with at least 1 additional CVD risk factor: previous (N6 months) MI or stroke, left ventricular hypertrophy (LVH) by electrocardiogram or echocardiogram, history of type 2 diabetes, current cigarette smoking, high-density lipoprotein (HDL) b35 mg/dl, or other documented atherosclerotic CVD. By race/ethnicity, 35% were black and 19% were Hispanic. Individuals with a history of symptomatic HF and/or known LVEF b35% were excluded. The protocol did not include a study-measured LVEF. 10 Validation Study Population All ALLHAT participants with at least 1 reported hospitalization with a diagnosis of HF on admission or during their hospital course were included in the Validation Study (Figure 1). Diagnosis of HF in ALLHAT HF diagnoses in ALLHAT were assigned by site physicians, blinded to treatment assignment, guided by prespecified criteria previously used in the SHEP, which required at least 1 symptom and 1 sign of HF (Figure 2). 6,16 Investigators were advised to be conservative in diagnosing HF in patients with pulmonary disease. Heart failure events identified by site physicians were reported to the Clinical Trials Center (CTC) only if the patient was also hospitalized or treated out of hospital, or if the event was fatal. Because ALLHAT was a large simple trial, central committee review of all HF events was not mandated by the protocol. However, hospital discharges and death summaries related to all end points, including HF, were required and were reviewed by the CTC staff blinded to treatment assignments. When HF events described in the documentation were not reported as such by the site physician, or if the documentation did not agree with the diagnosis, the CTC physician contacted the site physician, who could then correct the report. To further minimize underreporting, administrative databases were searched regularly for potential events, which had to be verified by site physicians to be included as end points.

5 46 Einhorn et al American Heart Journal January 2007 Data collection for the Validation Study Between November 2001 and March 2002, the CTC requested source documentation for all HF hospitalizations that occurred between February 1, 1994, and March 31, 2002 (February 15, 2000, for the doxazosin/chlorthalidone comparison). 17 It included face sheets with diagnoses and procedure codes, emergency department notes, admission history and physical examination, and cardiology and pulmonary consultation reports. Chest x-ray (CXR), echocardiography, cardiac radionuclide study, magnetic resonance imaging, and cardiac catheterization procedure reports were also requested, as well as discharge summaries (if not previously received) and autopsy reports. Each site submitted all obtainable records and noted records that could not be obtained. Data collection for the HF Validation Study ended in June 2002, approximately 1 month before any unblinding of study coordinators as to treatment assignments in the lisinopril and amlodipine comparisons with chlorthalidone. Diagnosis of HF in the Validation Study Because of concerns about accessibility and quality of office records, it was decided a priori that only hospitalized events would be included as outcomes. Heart failure hospitalizations, whether for initial presentation or after outpatient treatment, constituted 78.9%, 78.6%, 74.5%, and 72.5% of all HF events in the chlorthalidone-, amlodipine-, lisinopril-, and doxazosinbased groups, respectively. An abstracting form was developed to provide documentation of the presence, absence, or uncertainty/lack of information with respect to HF signs and symptoms, past medical history, concurrent conditions, precipitating factors, cardiac function, and medications at discharge. Each individual event was independently abstracted by 2 blinded-to-treatment-assignment reviewers, randomly selected from a panel of 11 cardiology fellows from the Baylor College of Medicine. To fully explore the validity of HF diagnoses, the Validation Study used 6 different algorithms and a global judgment of the reviewers. Algorithms were based on ALLHAT and Framingham criteria. The ALLHAT (A1) criteria (Figure 2), required a presence of one sign and one symptom. Several more stringent ALLHATderived criteria sets were defined as follows: A2, excluded events with z2+ pedal edema as the only sign; A3, required CXR evidence of HF; A4, required intravenous treatment for HF (diuretics, vasodilators, or positive inotropic agents), in addition to meeting A1. The Framingham criteria (F1) require 2 major or 1 major and 2 minor criteria to make a diagnosis (Figure 2). 18 In the modified Framingham criteria (F2), the rule is the same, but at least one criterion has to be diagnostic (imaging, cardiac catheterization, or autopsy findings) and at least one criterion clinical (Figure 2). Algorithm-based diagnoses were assigned by computer. In addition, the reviewers were asked whether, in their clinical judgment, the patient had HF. The possible answers were byes,q bno,q or bdon t know.q An event was validated if confirmed by at least 1 reviewer, that is, considered to be HF by N2 of the 3 observers, including the ALLHAT site physician. Statistical methods For each definition of HF, percent confirmation of site physician assigned diagnoses was calculated using contingency tables to determine the proportion of patients with at least 1 documented HF hospitalization for which the disease was verified by at least 1 reviewer. To determine the degree of support for the treatment effects reported in the main result articles, 10,11 analyses were repeated for each Validation Study definition of HF to estimate RRs and 95% CIs. Relative risks were calculated from 2 2 tables because the Cox proportional hazards principle was violated. (The Cox proportional hazards regression model assumption was examined using log-log plots and testing a treatment-bytime interaction term.) 10 Heterogeneity of treatment effect across racial subgroups (black vs nonblack) was examined by stratification of the 2 2 tables using the Mantel-Haenszel test of homogeneity. Because there were no significant interactions ( P b.05), only overall RRs are reported. Life tables were used to calculate mortality rates after the first validated hospitalized event. Analyses were conducted separately for the comparisons of amlodipine or lisinopril versus chlorthalidone and doxazosin versus chlorthalidone because of different durations of follow-up. 10,11 Results g For 2031 patients fulfilling the validation study inclusion criteria, relevant hospital records were requested for 2917 hospitalizations with a diagnosis of HF on admission or during the hospital course. The CTC received 2850 records for 1987 patients (98%), of which 97% (2778 records for 1935 patients) were suitable for review (Figure 1). Discharge summaries were received for 93% of first events; admitting history and physical, and emergency department notes for 71% and 38%, respectively. At least 1 type of imaging report was available for 79% of first events (69%, 48%, 7%, 16%, respectively, for CXR, echocardiography, radionuclide imaging, and cardiac catheterization). For nonvalidated compared to validated events, as would be expected, lesser documentation was received for all validation criteria sets, especially emergency department notes, admitting history and physical, and imaging reports (43%, 79%, 76% [CXR], and 61% [other imaging] vs 30%, 55%, 56%, and 45%, respectively, for A1). Nursing notes and medication charts were not requested. Information on intravenous medications was missing for 27% of reviewed events, whereas absence of intravenous treatment was documented only in 3%. Verification of ALLHAT site physician-assigned diagnoses Percent agreements with site physician assigned diagnoses for the various Validation Study criteria for HF g Unless noted otherwise, results are presented for the chlorthalidone/amlodipine/lisinopril comparison and are similar to the chlorthalidone/doxazosin comparison.

6 American Heart Journal Volume 153, Number 1 Einhorn et al 47 Table II. Incident hospitalized HF outcomes by antihypertensive treatment group (amlodipine/lisinopril vs chlorthalidone) Chlorthalidone (n = 15255) Amlodipine (n = 9048) No. of events 6-y Rate per 100 persons (SE) Incidence rate/ 1000 patient-years (95% CI) No. of events 6-y Rate per 100 persons (SE) Incidence rate/ 1000 patient-years (95% CI) Site physician (0.26) 8.7 ( ) (0.40) 12.1 ( ) ALLHAT (A1) (0.23) 6.0 ( ) (0.35) 8.7 ( ) ALLHAT (A2) (0.23) 5.9 ( ) (0.34) 8.6 ( ) ALLHAT (A3) (0.23) 5.7 ( ) (0.34) 8.2 ( ) ALLHAT (A4) (0.21) 4.8 ( ) (0.31) 7.0 ( ) Framingham (F1) (0.24) 6.9 ( ) (0.35) 9.8 ( ) Framingham (F2) (0.24) 6.2 ( ) (0.34) 8.7 ( ) Reviewers (0.25) 7.1 ( ) (0.36) 10.4 ( ) were similar across randomized treatment groups (Figure 1). The highest (84%) was for reviewers judgment (Reviewers), followed by F1 (80%). The percent agreement for A2 was virtually the same as that for A1 because there were only 12 patients with z2+ ankle edema as the only prespecified sign of HF. All events validated by Reviewers met at least one other set of criteria. In 8% of patients, both reviewers concluded that they were uncertain about the diagnosis, and in another 8%, both reviewers agreed that documentation did not support the diagnosis of HF. Ninety-two percent of site physician assigned diagnoses met at least 1 set of the validation criteria, and two thirds met both A1 and F1 criteria. Patients whose diagnoses were confirmed by the Validation Study were similar to all patients who developed HF, whether hospitalized or treated without hospitalization (Table I). The 146 patients in whom HF was not confirmed were slightly older, had lower body mass index and diastolic blood pressure, and had higher HDL cholesterol at baseline. Of events validated by the algorithms, Reviewers agreed with 81.3%, 81.4%, 83.0%, 86.0%, 76.7%, and 81.3% of diagnoses for A1 to A4, F1, and F2, respectively. Verification of treatment effects As shown in Table II and Figure 3, RRs for developing HF, when verified by review using any criteria in the Validation Study, were all higher than those reported for hospitalized and fatal events in the main result articles, and for the amlodipine and doxazosin comparisons with chlorthalidone, they remained highly statistically significant ( P b.0001) despite lower event rates. 10,11 For the lisinopril/chlorthalidone comparison, the RRs ranged from 1.21 for the A3 criterion (requiring CXR evidence of HF) to 1.12 for F2. The lower limits of the 95% CIs were all close to unity, but for 4 criteria sets (A1, A2, A3, and Reviewers), the RRs were statistically significant. Incidence rates and mortality after validated hospitalized HF events Validated hospitalized HF incidence rates per 1000 patient-years ranged from 8.3 for Reviewers to 5.6 for A4 in the amlodipine/lisinopril/chlorthalidone comparison and from 9.3 for Reviewers to 6.1 for A4 in the doxazosin/chlorthalidone comparison. All-cause mortality rates after incident HF hospitalization were similar for validated compared to nonvalidated events (Figure 4). Percentage of fatal among first HF events validated by any of the criteria sets (8.7%) was considerably lower compared to first events not validated by any of the criteria sets (31.5%). (Validation rates for fatal events were only 47%, 62%, 48%, and 65% for A1, F1, F2, and Reviewers, respectively.) Discussion Principal findings and comparisons to prior reports The primary objective of this central review of HF events in ALLHAT was to evaluate the HF diagnoses assigned by ALLHAT site physicians by using independent reviewers and prespecified criteria to determine the degree of support for the trial s conclusions with regard to the HF outcome. Our major findings were as follows: (1) the site physicians diagnoses of HF were confirmed in most patients, according to 6 prespecified algorithms and reviewers judgment; (2) the previously reported treatment differences based on ALLHAT investigators reports were corroborated by RRs calculated when applying the 7 criteria sets; (3) 6-year incidence rates of validated hospitalized HF were comparable in magnitude to those of stroke (5.6%) and to about half of those of combined nonfatal MI and CHD deaths (11.4%), 10 demonstrating the clinical significance of this end point in the hypertensive population. The magnitude of the mortality rates subsequent to hospitalized HF (55% at 5 years) further underscores the importance of prevention.

7 48 Einhorn et al American Heart Journal January 2007 Table II. continued Lisinopril (n = 9054) Amlodipine vs chlorthalidone Lisinopril vs chlorthalidone No. of events 6-y Rate per 100 persons (SE) Incidence rate/ 1000 patient-years (95% CI) RR (95% CI) from 2 2 table P RR (95% CI) from 2 2 table P (0.35) 10.0 ( ) 1.39 ( ) b ( ) (0.30) 7.1 ( ) 1.46 ( ) b ( ) (0.30) 7.0 ( ) 1.46 ( ) b ( ) (0.29) 6.9 ( ) 1.45 ( ) b ( ) (0.26) 5.5 ( ) 1.45 ( ) b ( ) (0.31) 7.8 ( ) 1.42 ( ) b ( ) (0.30) 7.0 ( ) 1.41 ( ) b ( ) (0.31) 8.3 ( ) 1.45 ( ) b ( ).04 The high confirmation rates of the site physician diagnoses by independent reviewers and by Framingham criteria are similar to those reported by other studies. 19,20 Roger et al 4 reported that in Olmstead County, Minnesota, 82% of the cases coded by clinicians as ICD 428 met Framingham criteria for HF, a number similar to the 80% agreement found in this study. They also compared cases coded by Olmstead County clinicians as ICD 428 with their reviewers clinical judgment and found 90% confirmation rate. Again, this rate is similar to the 84% agreement with the reviewers judgment in ALLHAT. The comparisons of treatment effects for amlodipineand doxazosin-based strategies with a chlorthalidonebased strategy for the 7 criteria sets examined provide strong and conclusive evidence for the superiority of a chlorthalidone-based therapy in preventing transition from hypertension to overt HF. An excess of HF events was observed even when A2 criteria that exclude events with z2+ pedal edema as the only prespecified sign of HF were used. For the lisinopril/chlorthalidone comparison, the excess risk of HF with lisinopril was less dramatic but larger than that found for hospitalized events reported by ALLHAT investigators and statistically significant using reviewers judgment and ALLHAT criteria (A1-A3). As the most conservative interpretation, the results of the Validation Study provide strong and conclusive evidence that an ACE inhibitor did not offer superior to chlorthalidone benefit in preventing HF. They also strengthen the published main trial result with respect to the post hoc end point of hospitalized and fatal HF (RR 1.10, 95% CI ) and support our earlier conclusion for the ALLHAT prespecified HF end point (treated out of hospital, hospitalized, or fatal) that chlorthalidone-based treatment is superior to lisinoprilbased in preventing new onset HF in both blacks and nonblacks (RR 1.19, 95% CI ). 10,21 ALLHAT findings with respect to the ACE inhibitor seemed surprising given results of placebo-controlled trials. 7,22-24 However, SHEP investigators reported a 49% ( P b.001) decrease in the risk of HF with chlorthalidone versus placebo. 6 For ACE inhibitors, this reduction was only 20% ( P b.001) in SOLVD Prevention (captopril), 23% ( P b.001) in HOPE (ramipril), and 25% ( P =.02) in PEACE (trandolapril) The results of drug comparison trials are mixed but, overall, not inconsistent with the ALLHAT findings. 7,25 Notably, only one trial directly compared a diuretic with an ACE inhibitor. 26 The ANBP2 study, which compared a diuretic-based treatment (hydrochlorothiazide recommended, dose not stated) with an ACE inhibitor (enalapril recommended, dose not stated), was an open-label practice-based trial in 6083 hypertensive participants (compared with in the 2 similar arms in ALLHAT). The HF rates (not stated whether based on all or hospitalized events only) were not statistically different between the 2 first-step drugs (RR 0.85, 95% CI ), and the upper limit of the 95% CI suggests that the HF results of the 2 trials may be consistent. 27 It is also possible that ANBP2 site clinicians, who were aware of treatment assignments, were more conservative in diagnosing HF in those treated with an ACE inhibitor. Similarly, in the open-label ASCOT comparing an amlodipine-based regimen with an atenolol-based regimen, physicians could have diagnosed HF less frequently in the amlodipine-based treatment arm by not considering peripheral edema as a potential symptom of HF, especially in an outpatient setting. 25 This diagnostic/reporting bias is not an issue in ALLHAT where site clinicians were blinded to treatment assignments. In ALLHAT, observed HF differences were larger earlier in the follow-up. Relative risks (95% CIs) for year 1 of follow-up, compared with subsequent years, were respectively 2.08 ( ) versus 0.96 ( ) and 2.22 ( ) versus 1.22 ( ) for the lisinopril and amlodipine comparisons with chlorthalidone, respectively. There was no significant interaction between prior medication use and treatment group, and data on the type of prior antihypertensive medication collected

8 American Heart Journal Volume 153, Number 1 Einhorn et al 49 Figure 3 A, Cumulative hospitalized HF incidence rates reported by site physicians and validated by ALLHAT (A1), Framingham (F1), and Reviewers criteria sets (amlodipine/lisinopril/chlorthalidone). B, Cumulative hospitalized HF incidence rates reported by site physicians and validated by ALLHAT (A1), Framingham (F1), and Reviewers criteria sets (doxazosin/chlorthalidone). at the trial close-out provide no evidence that discontinuation of prior medication, for example, diuretics, at the time of randomization contributed to the 2-fold increase in the incidence of HF hospitalizations in the ACE inhibitor or calcium-channel blocker group during year Various explanations have been entertained to explain the ALLHAT HF results, including over- and misdiagnosis of HF by ALLHAT physician-investigators, a diverse group of clinicians in a variety of practice settings. We believe that this manuscript provides conclusive evidence that ALLHAT findings of chlorthalidone-based treatment s superiority over amlodipine-, lisinopril- and doxazosin-based strategies in preventing the transition from hypertension to symptomatic HF were not due to the misdiagnosis of HF. The ALLHAT protocol did not include a measurement of LVEF either before or at the time of HF diagnosis. Information on LVEF was collected as part of this Validation Study, and a report on these data is in preparation. If the superiority of diuretics is limited to preventing HF in a setting of preserved LVEF, this could explain the equivalent results beyond year 1 of follow-up with interim MIs contributing to a larger number of individuals with impaired LVEF. Phenotypic and prognostic correlates of the various diagnostic algorithms

9 50 Einhorn et al American Heart Journal January 2007 Figure 3 (continued) will also be explored. Small differences in RRs among the criteria sets may be related to preferential identification of HF with impaired LVEF by, for example, F2 (EFb35% is a major criterion) or A4 (preferential documentation on the use of intravenous pressors compared with diuretics). Strengths and limitations It is important to emphasize that HF was not a primary end point in ALLHAT, and therefore, only limited information was collected prospectively for these events. The Validation Study was conducted retrospectively during the trial close-out, but information was available for most patients, and record collection was completed before unblinding any of the study coordinators. In addition, the evaluation was rigorous and conducted by reviewers unrelated to the study and blinded to treatment assignments. To minimize underreporting of the events, all hospital discharge summaries were reviewed by the CTC staff blinded to treatment assignment, and administrative databases were searched for potential events. Furthermore, reporting bias is not of concern because ALLHAT site physicians who were assigning the diagnoses were blinded to treatment assignments. Although for feasibility reasons and given known limitations of outpatient records this central review was limited to hospitalized events only, it included most hospitalized HF events in ALLHAT. Consequently, it is highly unlikely that a prospective adjudication by the end points committee would have

10 American Heart Journal Volume 153, Number 1 Einhorn et al 51 Figure 4 A, All-cause mortality after hospitalization with first HF event; incident fatal events not included (amlodipine/lisinopril/chlorthalidone). B, Allcause mortality after hospitalization with first HF event; incident fatal events not included (doxazosin/chlorthalidone). been more thorough, of higher quality, or more systematic than this retrospective review. Additional clinical data abstracted during the review of the 2778 HF events will provide information for future publications on clinical presentation and circumstances surrounding transition from hypertension to overt HF in these 1935 ALLHAT participants. Implications for future clinical trials Heart failure proved to be a common outcome in ALLHAT and one that was affected differentially by the randomized treatment assignments. In addition, patients who developed HF had significantly poorer survival than those who did not. Whether this poor prognosis can be altered presents an important clinical and public health question. Thus, in planning future hypertension treatment trials (and perhaps also treatment trials in other populations at high risk of HF, such as diabetics and survivors of acute coronary syndromes), 29,30 serious consideration should be given to including HF in the primary end point, along with death, MI, and stroke. In ALLHAT, near equivalent results for treatment effects on the HF outcome were obtained whether using a more specific end point of validated hospitalized HF (RRs between 1.12 and 1.21 across criteria sets) or a broader end point based on site physicians reports of

11 52 Einhorn et al American Heart Journal January 2007 Figure 4 (continued) unadjudicated hospitalized, fatal, or treated out-of-hospital HF (RR 1.19, 95% CI ). Financial considerations make the latter an attractive possibility in trial design. The experience from the ALLHAT Validation Study and from other community-based studies indicates that community physicians can reliably identify HF events. 4,19 In ALLHAT, about one fourth of the patients with HF were never hospitalized, including those treated in an outpatient setting during the last year of follow-up. Whether identification of the incident HF event occurs in an outpatient setting or in a hospital depends on many circumstances, including clinical presentation, access to care, and patient health care seeking behaviors. ALLHAT experience showed that in a diverse demographic and medical setting, limiting the HF outcome to hospitalized events may result in less precise relative risk estimates and insufficient power to detect a treatment difference. Implications for clinical practice The prevention of HF is an important goal of antihypertensive management in clinical practice. New-onset HF is a relatively common complication of hypertension with high subsequent mortality. The results of the ALLHAT Validation Study confirm that thiazide-type diuretics should be the preferred first-step drug therapy for prevention of HF in high-risk patients with hypertension. This indication is further strengthened by the two-fold higher risk of HF for lisinopril and amlodipine compared with chlorthalidone during year 1 of treatment. 28

12 American Heart Journal Volume 153, Number 1 Einhorn et al 53 We thank Dr Jeffrey Cutler, ALLHAT Project Office Director, for his leadership in the design, conduct, and reporting of ALLHAT and for shepherding the Heart Failure Validation Study from its conceptual inception through data collection and reporting. We also thank the members of the ALLHAT Steering Committee 10 for their approval and support of this endeavor and for their leadership in assuring its successful implementation; the reviewers; and Dr Gabriel Habib, Director of Education at the Michael E. DeBakey VA Medical Center, Houston, TX. References 1. Massie BM, Shah NB. Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease management. Am Heart J 1997;133: Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. Circulation 2001;104: Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347: Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004;292: Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA 1996;275: Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA 1997;278: Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomized trials. Lancet 2003;362: Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents. JAMA 2003;289: Davis BR, Cutler JA, Gordon DJ, et al. for the ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 1996;9: The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288: The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension 2003;42: Weber MA. The ALLHAT report: a case of information and misinformation. J Clin Hypertens 2003;5: Messerli FH. ALLHAT, or the soft science of the secondary end point. Ann Intern Med 2003;139: Davis BR, Furberg CD, Wright JT, et al. for the ALLHAT Collaborative Research Group. ALLHAT: setting the record straight. Ann Intern Med 2004;141: Staessen JA, Birkenhager WH. Evidence that new antihypertensives are superior to older drugs. Lancet 2005;366: Piller LB, Davis BR, Cutler JA, et al. Validation of heart failure events in ALLHAT participants assigned to doxazosin. Am J Hypertens 2001;14:180A. 17. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283: Ho KKL, Anderson KM, Kannel WB, et al. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993;88: Peyster E, Norman J, Domanski M. Prevalence and predictors of heart failure with preserved systolic function: community hospital admissions of a racially and gender diverse elderly population. J Card Fail 2004;10: Schellenbaum GD, Rea TD, Heckbert SR, et al. Survival associated with two sets of diagnostic criteria for congestive heart failure. Am J Epidemiol 2004;160: Wright JT, Dunn JK, Cutler JA, et al. Outcomes in hypertensive black and non-black patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA 2005;293: The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327: Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342: Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351: Dahlof B, Sever PS, Poulter NR, et al. for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo- Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366: Wing LMH, Reid CM, Ryan P, et al. for the Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348: Cutler JA. The ANBP2 and ALLHAT: conflicting or consistent? J Clin Hypertens 2003;5: Davis BR, Piller LB, Cutler JA, et al. Role of diuretics in the prevention of heart failure: the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 2006;113: Lewis EF, Moye LA, Rouleau JL, et al. Predictors of late development of heart failure in stable survivors of myocardial infarction: the CARE study. J Am Coll Cardiol 2003;42: Yki-Jarvinen H. The PROactive study: some answers, many questions. Lancet 2005;366:

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