Curr Opin Cardiol 25: ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins

Transcription

1 ALLHAT: still providing correct answers after 7 years Paula T. Einhorn a, Barry R. Davis b, Jackson T. Wright Jr c, Mahboob Rahman c, Paul K. Whelton d, Sara L. Pressel b, for the ALLHAT Cooperative Research Group a National Heart, Lung, and Blood Institute, Bethesda, Maryland, b University of Texas Health Science Center at Houston School of Public Health, Houston, Texas, c Case Western Reserve University, Cleveland, Ohio and d Loyola University Medical Center and Health System, Maywood, Illinois, USA Correspondence to Sara L. Pressel, MS, University of Texas Health Science Center at Houston School of Public Health, 1200 Herman Pressler St, Suite E801, Houston, TX 77030, USA Tel: ; Sara.L.Pressel@uth.tmc.edu Funding/support: This study was supported by contract NO1-HC with the National Heart, Lung, and Blood Institute (NHLBI). ALLHAT investigators received contributions of study medications supplied by Pfizer (amlodipine besylate and doxazosin mesylate), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer. Current Opinion in Cardiology 2010, 25: Purpose of review The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is re-evaluated considering information from recent subgroup and exploratory analyses, other new clinical trials, and meta-analyses. The ALLHAT analyses specifically emphasize heart failure findings, results in Black participants and those with chronic kidney disease, selection and doses of thiazide and similar diuretics, and the association of antihypertensive drug use with new-onset diabetes and its cardiovascular consequences. Recent findings The initial ALLHAT conclusion, that thiazide diuretics are superior to angiotensinconverting enzyme inhibitors (ACEIs), calcium antagonists (CCBs) and a-blockers in preventing one or more major clinical outcomes, including heart failure and stroke, and unsurpassed in significantly preventing any cardiovascular or renal outcome, has been further validated for patients with diabetes, renal disease, and/or metabolic syndrome. The evidence is even more compelling for Black patients. New-onset diabetes associated with thiazides did not increase cardiovascular outcomes. The diuretic was superior to all in preventing heart failure with preserved left-ventricular ejection fraction (LVEF) and similar to the ACEI in preventing heart failure with impaired LVEF. It was also unsurpassed in preventing atrial fibrillation. Summary The totality of evidence re-affirms the initial ALLHAT conclusion that thiazide and similar diuretics (at evidence-based doses) are the preferred first-step therapy in most patients with hypertension. Keywords ACE inhibitors, alpha blockers, antihypertensive therapy, calcium channel blockers, diuretics, thiazides Curr Opin Cardiol 25: ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction The Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT) a major randomized active-controlled (comparative effectiveness) trial published its main findings in December 2002 and September 2003 [1 3]. The largest hypertension clinical trial ever conducted, it enrolled demographically and clinically diverse high-risk patients with hypertension. The results of the trial influenced clinical practice [4,5,6 9 ] and generated considerable discussion, as some of the results seemed unexpected [10 14]. Since the initial publications, new clinical trials and metaanalyses have been reported, and ALLHAT data have continued to be analyzed [15 17,18,19,20 32,33,34, 35,36,37]. In May 2009, the ALLHAT Steering Committee published a review manuscript to reassess the trial s conclusions in light of up-to-date information [38 ]. Here, we summarize and update this review with special emphasis on heart failure findings, results in Black participants, selection and doses of thiazide and similar diuretics (simply termed thiazides), patients with chronic kidney disease (CKD), and the association of antihypertensive drug use with new-onset diabetes and its cardiovascular consequences. ALLHAT: background and objectives When the ALLHAT trial was funded in 1993, it was well established that treatment of hypertension with thiazides compared with placebo or usual care reduces mortality by up to 20% and prevents stroke, heart failure, and myocardial infarction (MI) by about 40, 50, and 20%, respectively [39 42]. New drugs developed in the late 70s and in the 80s calcium antagonists (CCBs), angiotensinconverting enzyme inhibitors (ACEIs), and a-receptor blockers were shown to have more favorable metabolic profiles in short-term studies than the well established ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /HCO.0b013e32833a8828

2 356 Hypertension thiazides. Therefore, a logical expectation was that these newer agents would have better long-term cardiovascular outcomes, especially for coronary heart disease (CHD). The objective of ALLHAT was to compare three new classes of drugs: the CCBs [represented by amlodipine besylate ( mg/day)], the ACEIs [by lisinopril (10 40 mg/day)], and the a-blockers [by doxazosin mesylate (2 8 mg/day)] with the established thiazide [represented by chlorthalidone ( mg/day)], in the strongest possible design a randomized, double-blind trial [43]. Each drug was used as first-step treatment with other drugs added to achieve a blood pressure (BP) goal of less than 140/90 mmhg. A composite of CHD death and nonfatal MI was designated as the primary endpoint. Prespecified secondary endpoints included combined cardiovascular disease and its components (the primary endpoint, heart failure, stroke, coronary revascularization, angina, and peripheral vascular disease) as well as end-stage renal disease (ESRD). To optimize statistical power for multiple comparisons, the randomization ratio was 1.7 : 1 for the thiazide versus each of the comparator drugs. As noted by Neaton and Kuller [44], ALLHAT was the only hypertension trial with adequate power to detect moderate (i.e. 16% relative difference in CHD) but important differences in several major clinical outcomes. ALLHAT: principal findings After up to 8 years of follow-up (average 4.9 years in the CCB or ACEI versus thiazide comparison and 3.2 years in the a-blocker versus thiazide comparison, which was terminated early), we concluded that the thiazide-based treatment was superior to each of the three comparator drugs in significantly preventing one or more major forms of cardiovascular disease (CVD) and unsurpassed in preventing any outcome. Specifically (Fig. 1), thiazide was superior to a-blocker in preventing combined CVD [CCVD; relative risk (RR) ¼ 1.20; 95% confidence interval (CI) ¼ ]. Notably, thiazide was especially superior to a-blocker in preventing heart failure (HF) (RR ¼ 1.80; 95% CI ¼ ) and stroke (RR ¼ 1.26; 95% CI ¼ ), as well as cardiovascular and stroke mortality [RR (95% CI) ¼ 1.15 ( ) and 1.39 ( ), respectively]. Thiazide was also superior to ACEI in preventing CCVD [1.10 ( )], including stroke in Black individuals [1.15 ( ) overall; 1.40 ( ) Blacks and 1.00 ( ) non-blacks; interaction P ¼ 0.01] and HF [1.20 ( ) overall; 1.32 ( ) Blacks and 1.15 ( ) non-blacks; interaction not significant] [30]. Furthermore, thiazide was superior to CCB in preventing HF [1.38 ( )]. Despite, as expected, better metabolic profiles of the newer drugs, especially ACEI and a-blocker, the newer drugs were not superior to thiazides for either the primary outcome or an expanded CHD outcome (including angina and revascularization) [1,3]. Demographic and clinical subgroups By design, ALLHAT recruited a very diverse patient population, both demographically and clinically. They were men and women, aged 55 years or older, with elevated BP or treated with one or two antihypertensive drugs, and one additional CHD risk factor, including diabetes, diagnosed CVD, LVH, and/or cigarette smoking. Of participants, were women; were Black and 8072 Hispanic (mostly from Puerto Figure 1 Major treatment group comparisons in ALLHAT (hazard ratio and 95% confidence interval) CHD, coronary heart disease; CVD, cardiovascular disease; ESRD, end-stage renal disease.

3 ALLHAT: still providing correct answers Einhorn et al. 357 Rico); were 70 years of age or older; had a history of type II diabetes and 7175 had CKD defined by estimated glomerular filtration rates (egfrs) below 60 ml/ min/1.73 m 2. Except for race (see below), results in prespecified subgroups (age, sex, and diabetes) were remarkably consistent(fig. 2)[1,3,27]. Post-hoc subgroup analyses by metabolic syndrome at baseline, with and without diabetes [25,26], were consistent with the overall results and with the results in those with diabetes at baseline [1,27]. Similarly, outcomes stratified by egfr at baseline were consistent with the overall results [24]. These subgroup results provide further support for the ALLHAT and the Seventh Report of Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommendation that thiazides should be preferred for first-step antihypertensive treatment in most patients, including those with diabetes, metabolic syndrome and renal impairment. Black patients with hypertension Black individuals have been long recognized to have the highest prevalence and earliest onset of hypertension. Hypertension is also a major contributor to the racial gap in cardiovascular mortality between Whites and Blacks in the US. Notably, in Black individuals aged 40 and over, awareness of hypertension is high (71 83% across sex/age groups) and a large majority of those aware of their hypertension report being treated (83 97% across sex/ age groups). However, the proportion of treated Black patients with BP controlled to below 140/90 mmhg remains low [45,46]. With Black participants, ALLHAT is the only randomized clinical trial to provide long-term BP control and major cardiovascular outcomes data on treatment of hypertension with drugs other than thiazides in this subgroup. The results are very clear: the use of thiazides as initial treatment of hypertension is even more compelling for Blacks because of the 40% increased risk of stroke (P < 0.001) and 19% increased risk of CCVD (P < 0.001) with ACEI versus thiazide. For both Blacks and non-blacks, there was a lower risk of heart failure for chlorthalidone versus all three comparator drugs and of CCVD and stroke versus a-blocker. Notably, the newer drugs were not significantly superior to chlorthalidone for any of the major clinical outcomes (Figs 2 and 3) [30]. Figure 2 Treatment comparisons (hazard ratio, 95% confidence interval) by prespecified subgroups CCVD, combined cardiovascular disease; CHD, coronary heart disease.

4 358 Hypertension Figure 2. (Continued). We have also shown that these findings extend to individuals with metabolic syndrome, both Black and non- Black (Table 1) [25,26]. Unlike the other two classes, there was little difference [less than 1 mmhg at 4 years (P < 0.05)] in BP lowering between the thiazide and the CCB and the only difference in outcomes was a significantly higher rate of heart failure. However, compared with the thiazide, the ACEI was less effective in lowering BP, primarily in Black participants, and associated with significantly higher risks of stroke, heart failure, and overall CVD. At 4 years, SBP/ DBP was 3.5/1.0 mmhg higher in Black participants versus SBP 0.6 mmhg higher and DBP 0.2 mmhg lower in non-blacks. Overall, SBP/DBP was 1.6/0.1 higher in the ACEI compared with the thiazide. Similarly, the a-blocker was less effective than the thiazide in lowering BP (þ2.1/þ0.1 mmhg at 4 years) and associated with significantly higher risks of HF, stroke and CCVD, as well as cardiovascular and stroke mortality (Figs 2 and 3) [30,38 ]. Prevention of heart failure The prevention of heart failure is an important goal of antihypertensive management in clinical practice. Newonset heart failure is a common complication of hypertension, the most common diagnosis-related group (DRG) for hospitalized Medicare beneficiaries [47], and is associated with very high subsequent mortality. In ALLHAT, 6-year incidence rates of centrally adjudicated hospitalized heart failure were comparable in magnitude to those of stroke (5.6%) and to about half those of CHD (11.4%). The magnitude of the mortality rates

5 ALLHAT: still providing correct answers Einhorn et al. 359 Figure 3 Kaplan Meier plots for outcomes by treatment group by race (solid line, chlorthalidone; dotted line, amlodipine besylate; dashed line, lisinopril; dot-dash line, doxazosin mesylate) subsequent to hospitalized heart failure (more than 50% at 5 years) further underscores the importance of prevention [32,48 50]. Heart failure validation study In the main results manuscripts, we reported that the risk of developing new-onset heart failure was higher for each of the comparator drugs than for the thiazide by 38 (P < 0.01), 20 (P < 0.001), and 80% (P < 0.001) for the CCB, ACEI, and a-blocker, respectively (Fig. 1) [1,3]. Some found these results unexpected, especially with respect to the ACEI, and raised questions about validity of the results [10,11,51,52]. An extensive validation study, which centrally adjudicated all hospitalized heart failure events, confirmed the initial results [32]. Importantly, reporting bias was not an issue because ALLHAT was double-blinded and procedures were in place to prevent under-reporting of events [32]. Heart failure with preserved versus reduced ejection fraction Among source documentation, the ALLHAT Heart Failure Validation Study collected information on LVEF during heart failure hospitalizations [32]. These data provided further information on prevention of new-onset heart failure in high-risk hypertensive patients [34]. We reported that the thiazide significantly reduced the risk of heart failure with preserved LVEF (50%) compared with the CCB, ACEI, or a-blocker; the hazard ratios were 0.69 (P ¼ 0.009), 0.74 (P ¼ 0.032), and 0.53 (P < 0.001), respectively. The risk of heart failure with reduced LVEF was also decreased by the thiazide compared with

6 360 Hypertension Table 1 ALLHAT findings in participants with the metabolic syndrome (previously published, from [38 ]) RR (95% CI) versus thiazide Nonfatal MI/fatal CHD All-cause mortality Combined CHD Stroke HF Combined CVD ESRD Participants without MetS a-blocker 1.00 ( ) 0.99 ( ) 1.14 ( ) 1.19 ( ) 1.91 ( ) 1.17 ( ) 0.81 ( ) ACEI 1.02 ( ) 1.02 ( ) 1.07 ( ) 1.20 ( ) 1.02 ( ) 1.07 ( ) 0.76 ( ) CCB 1.05 ( ) 0.93 ( ) 1.03 ( ) 1.04 ( ) 1.45 ( ) 1.05 ( ) 0.81 ( ) Participants with MetS a-blocker 1.11 ( ) 1.08 ( ) 1.06 ( ) 1.31 ( ) 1.83 ( ) 1.23 ( ) 1.18 ( ) ACEI 1.01 ( ) 1.01 ( ) 1.04 ( ) 1.09 ( ) 1.28 ( ) 1.14 ( ) 1.22 ( ) CCB 0.95 ( ) 0.97 ( ) 1.00 ( ) 0.87 ( ) 1.32 ( ) 1.05 ( ) 1.27 ( ) Nondiabetic participants with MetS a-blocker 1.15 ( ) 1.10 ( ) 1.07 ( ) 1.34 ( ) 1.86 ( ) 1.24 ( ) 0.86 ( ) ACEI 1.05 ( ) 1.04 ( ) 1.04 ( ) 1.22 ( ) 1.31 ( ) 1.19 ( ) 1.08 ( ) CCB 0.96 ( ) 0.98 ( ) 1.01 ( ) 0.84 ( ) 1.09 ( ) a 1.03 ( ) 0.69 ( ) Black participants with MetS a-blocker 1.18 ( ) 1.09 ( ) 1.15 ( ) 1.49 ( ) 1.88 ( ) 1.37 ( ) 1.17 ( ) ACEI 1.17 ( ) 1.14 ( ) 1.19 ( ) 1.37 ( ) 1.49 ( ) 1.24 ( ) 1.70 ( ) b CCB 0.96 ( ) 1.02 ( ) 1.09 ( ) 1.01 ( ) 1.50 ( ) 1.14 ( ) 1.50 ( ) c ACEI, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; ESRD, end-stage renal disease; HF, heart failure; MetS, metabolic syndrome; MI, myocardial infarction; RR, relative risk. a For diabetic participants without MetS, 1.55 ( ), P ¼ 0.03 for interaction. b For Black participants without MetS, 0.75 ( ), P ¼ 0.03 for interaction. c For Black participants without MetS, 0.67 ( ), P ¼ 0.04 for interaction. the CCB or a-blocker (hazard ratios 0.74; P ¼ and 0.61; P < 0.001, respectively), and similar to the ACEI (hazard ratio 1.07; P ¼ 0.596). These results are remarkably consistent with placebo-controlled trials: for the thiazide, 49% decreased risk (P < 0.001) based on SHEP (chlorthalidone atenolol) and 64% based on HYVET (P < 0.001, sustained release indapamide perindopril, participants aged 80 years); for ACEI, 20% (P < 0.001) risk reduction in SOLVD Prevention (captopril, participants with reduced LVEF), 23% (P < 0.001) in HOPE (ramipril), and 25% (P ¼ 0.02) in PEACE (trandolapril, participants with preserved LVEF) [19,42,53 56]. Early benefit of chlorthalidone for preventing new-onset heart failure The greatest benefit of the thiazide for hospitalized or fatal heart failure prevention occurred during year 1. The relative risk of developing heart failure in those assigned the CCB, ACEI, or a-blocker was substantially greater than in those on the thiazide. After year 1, there was no further increase in relative risk in the ACEI versus thiazide arm [31]. In the CCB and a-blocker arms, the risk of developing new-onset heart failure versus thiazide continued to increase beyond year 1, though at slower rates (RR 1.22; 95% CI and 1.28; 95% CI , respectively) [31,38,57]. In seeking explanations for the early benefit of the thiazide, we also explored an issue of whether discontinuation of medications at study entry could contribute to the excess new-onset heart failure in the other drugs compared with the thiazide. Whereas information about prior medications was not collected at ALLHAT baseline, using infrastructure provided by the ALLHAT Heart Failure Validation Study [32], we obtained pretrial medication history from the clinics to conduct a case-only analysis within those who developed new-onset heart failure. We found that pre-entry drug type did not explain the observed excess of new-onset heart failure in the ACEI, CCB, or a-blocker-based treatments compared with the thiazide-based therapy [33,58,59]. Atrial fibrillation Atrial fibrillation, the most common clinically significant cardiac arrhythmia, is associated with markedly increased risks of stroke, heart failure and death. Hypertension is an important risk factor for atrial fibrillation. We have just published the results of an ALLHAT ancillary study of atrial fibrillation at baseline and during follow-up [36 ]. There were two important findings in this report. First, the report confirmed both the lesser prevalence and lower new-onset incidence of atrial fibrillation in Black versus non-black individuals. The odds of having atrial fibrillation on baseline ECGs were two-fold higher for

7 ALLHAT: still providing correct answers Einhorn et al. 361 non-black versus Black participants, even after adjustment for relevant demographic and clinical characteristics. (Of note, ALLHAT recruitment criteria excluded those with symptomatic heart failure or LVEF <35%.) Also, the odds of developing new-onset atrial fibrillation during follow-up in Black individuals were about 60% compared with non-black individuals. Second, except for the a-blocker versus thiazide comparison, the ECG-based incidence of atrial fibrillation did not differ by antihypertensive treatment group. In those randomized to the a-blocker-based treatment, the risk of developing atrial fibrillation was 35% higher compared with those assigned to the thiazide-based regimen (P ¼ 0.02). Patients with chronic kidney disease Among antihypertensive treatment trials, ALLHAT had one of the largest cohorts of patients with at least stage 2 CKD. Though known serum creatinine above 2 mg/dl was an exclusion criterion, approximately 17% of participants (N ¼ 7175) had an entry egfr below 60 ml/min/ 1.73 m 2, consistent with CKD [22]. ALLHAT has provided important information in this area: participants with CKD are much more likely to have prevalent CVD [22] and also to develop CVD over time compared with participants without CKD [24]. In fact, older patients with CKD are much more likely to develop or die of CVD than to progress to ESRD requiring dialysis. Neither the CCB nor the ACEI was superior to the thiazide in preventing significant declines in GFR or progression to ESRD [23]. While these results may seem inconsistent with previous studies showing beneficial effects of the renin angiotensin axis inhibitors (RAS inhibitors) [60 62], there are important differences between ALLHAT and traditional renal studies. Most ACEI/ARB studies used thiazides as second-line agents or in combination rather than in direct comparison with RAS inhibitors. In addition, the renal studies often had patients with more advanced CKD and proteinuria. ALLHAT provides the most robust cardiovascular outcome data in CKD currently available in the literature. Most previous studies were either underpowered or did not adequately ascertain cardiovascular outcomes. In ALLHAT, neither the CCB nor the ACEI-based therapy was superior to the thiazide-based therapy in preventing cardiovascular outcomes in the CKD subgroup [24]. Most CKD patients require multiple drug therapy to achieve BP goals. The National Kidney Foundation guidelines on hypertension management in CKD recommend that Most patients with CKD should be treated with a diuretic ; thiazide diuretics are recommended in patients with GFR at least 30 ml/min/1.73 m 2, and loop diuretics in those with more advanced CKD [63]. Glucose metabolism and incident diabetes An important ALLHAT rationale was to determine whether newer drugs with more favorable effects on glucose and other metabolic parameters would result in a lower incidence of major clinical outcomes, especially coronary events. As described above, they did not. We explored this issue in detail in a separate manuscript and in the recent review. The evidence was consistent in showing no increase in CVD outcomes associated with diuretic-induced new-onset diabetes [29,38 ]. Although counterintuitive, it is important to recognize that the increase in glucose levels with the use of thiazides and contributing to incident diabetes is relatively small (4 6 mg/dl). Though some have suggested that the follow-up may have been of inadequate duration [64], neither in ALLHAT nor in meta-analyses of thiazide cardiovascular outcome trials has a signal for adverse effect of these agents on CVD been appreciated [38 ]. In ALLHAT, overall new-onset diabetes was associated with a 64% increase in CHD (CI ) compared with nondiabetics, and the hazard ratio was 2.23 ( ) in those randomized to the ACEI [29]. Notably, the majority of new-onset type II diabetes occurring with the use of thiazides, as with other antihypertensives, may be due to factors such as aging and weight gain with little additional drug-specific (drug-induced) effect. In ALLHAT at 2 years of follow-up, 9.3% of participants had developed new-onset diabetes mellitus in the chlorthalidone groups versus 7.2% in the amlodipine group, suggesting that, among participants on chlorthalidone, about 80% of incident diabetes at 2 years was not due to chlorthalidone [29]. The issue is difficult to study because it is not possible to randomize participants to develop or not develop diabetes. ALLHAT findings based on postrandomization stratification by incident diabetes suggest that incident diabetes occurring in the thiazide arm may be heterogeneous, with the thiazide-induced cases having less adverse outcomes. It is also possible that drug combinations that would prevent thiazide-induced diabetes, including potassium supplementation, may result in even better long-term clinical outcomes. Mechanistic studies in the context of properly designed clinical trials are needed to address this important clinical issue [65]. It is also important to recognize that no evidence exists to support better clinical outcomes in relationship to prevention of diabetes with ACEIs or, as noted by Mendoza and Stevermer [66], lisinopril (in ALLHAT) reduced the onset of diabetes over 5 years at the cost of increase in HF and CCVD.

8 362 Hypertension Results from recent clinical trials On the basis of results of recently reported comparative trials, prominent hypertension researchers raised questions about a fixed relationship between BP lowering and outcome benefit at least at all BP ranges, at all levels of cardiovascular risk and with all drug combinations [67]. ALLHAT results also raised this issue, and so did other trials reported shortly afterwards [16,17]. We have addressed this topic in the Wright et al. [38 ] review and concluded that small BP differences seen in ALLHAT may account for some, but not all, of the advantages seen with the thiazide. Other trials Two more recent trials deserve special mention. Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) was the first double-blind randomized trial designed to compare two fixed-dose double-drug combinations. In one arm, benazepril was combined with amlodipine besylate (5 10 mg), in the other with hydrochlorothiazide ( mg) [18 ]. The dose of amlodipine besylate was the same as in ALLHAT; the dose of the thiazide was roughly equivalent to half of the mg of chlorthalidone used in ALLHAT. The trial was stopped early by its data and safety monitoring board for marked benefit in the ACEI/CCB arm of the trial on CVD outcomes. It highlighted the need for the treatment recommendations to include evidence-based dosing and revived decades-old discussion about the type and the dose of diuretics [68 ]. For the purpose of this review, it is important to note that trials in which hydrochlorthiazide was associated with favorable reductions in cardiovascular events used higher doses (25 50 mg/day) than currently advocated and used in fixed-dose drug combinations [38,68 ]. The Hypertension in the Very Elderly Trial (HYVET) addressed a very important clinical question of whether antihypertensive treatment of individuals aged 80 and over is beneficial [19 ]. There was a concern that antihypertensive therapy in the very elderly may reduce the risk of stroke but increase the risk of death from other causes. A double-blinded, randomized, placebocontrolled trial, HYVET enrolled 3845 patients who were 80 years of age or older and had sustained SBP between 160 and 199 mmhg. Patients were randomized to receive a thiazide (sustained release indapamide 1.5 mg) or a matching placebo. The ACEI (perindopril 2 or 4 mg), or matching placebo, was added if necessary to achieve the target BP of 150/80 mmhg or less. (The use of additional antihypertensive agents for more than 3 months resulted in withdrawal of patients from double-blinded follow-up.) After an average follow-up of 2.1 years, the investigators reported a 21% statistically significant reduction in total mortality (P ¼ 0.02). There was also a 64%, highly significant (P < 0.001), reduction in fatal and nonfatal heart failure and a 34% reduction (P < 0.001) in combined major CVD events. The primary endpoint, fatal or nonfatal stroke, was reduced by 30%, but failed to reach a nominal statistical significance of less than (Stroke mortality was reduced by 39%; P ¼ ) Fewer adverse events were reported in the active-treatment versus placebo group. Thus, HYVET demonstrated that antihypertensive treatment with a thiazide, with or without ACEI, in persons 80 years or older is beneficial. ALLHAT enrolled participants aged 70 and above (2765 aged 80 and above). Although more detailed presentation of ALLHAT data in older hypertensive individuals is forthcoming, we have already reported similarity of treatment effects in the prespecified subgroups of above and below age 65 (Fig. 2) [1]. Conclusion In summary, the up-to-date evidence remains consistent in confirming the initial ALLHAT findings that neither a-blockers nor ACEIs or CCBs surpass thiazides (at appropriate dosage) as initial antihypertensive therapy for the reduction of cardiovascular or renal risk. Thiazides are superior in preventing one or more major forms of CVD, including heart failure, versus all three comparator drugs, and stroke and combined cardiovascular outcome versus ACEIs and a-blockers. The recommended dose of the thiazide is an equivalent of mg of chlorthalidone (roughly mg of hydrochlorothiazide). The dose may be especially important for stroke prevention. Longer-acting thiazides may have added outcome benefits, but even without that evidence they are more forgiving of missed doses. We also hypothesized based on many clinical trials that adding an ACEI to a thiazide may optimize heart failure prevention [34]. Recommendation Given the totality of evidence, we re-affirm the initial ALLHAT conclusion that thiazide and similar diuretics (at evidence-based doses) are the preferred first-step therapy in most patients with hypertension. Future analyses of biomarkers and genes in the ALLHAT population may set the stage for development of more personalized treatment recommendations. Acknowledgements Drs Einhorn and Whelton and Ms Pressel report no financial disclosures. Dr Davis has served as a consultant for Takeda. Dr Wright has served as a consultant for CVRx, Novartis, Daiichi-Sanyo, Pfizer, and Sanofi-Aventis.

9 ALLHAT: still providing correct answers Einhorn et al. 363 Dr Rahman has received compensation from Boehringer Ingelheim. We thank the ALLHAT Steering Committee for scientific leadership and continued commitment to optimizing ALLHAT s contribution to research and clinical practice. The complete list of ALLHAT investigators can be found in reference [1]. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 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: ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs. usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial 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: Chobanian AV, Bakris GL, Black HR, et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. National High Blood Pressure Education Program Coordinating Committee. Hypertension 2003; 42: Muntner P, Krousel-Wood M, Hyre AD, et al. Antihypertensive prescriptions for newly treated patients before and after the main Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial results and Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines. Hypertension 2009; 53: This study examines trends in thiazide and similar diuretic prescribing following publication of the ALLHAT main results (December 2002) and JNC-7 guidelines (May 2003) in a single medical system. The sustained increase in the use of thiazide diuretics reported by the authors identified an existing opportunity to increase adherence to JNC-7 guidelines. 7 Feldman RD, McAlister FA. Postgame wrap of the ultimate blood pressure megatrial: did it score an ALLHAT trick or was it three strikes and you re out?. Hypertension 2009; 53: This is an editorial to ref. [6 ] above. The editorialists recommend that it is incumbent on developers of guidelines to foster active implementation process to incorporate proven implementation strategies to ensure that the outstanding contributions of trialists such as ALLHAT team move beyond the printed page and into clinical practice. 8 Bartholomew LK, Cushman WC, Cutler JA, et al. Getting clinical trial results into practice: design, implementation, and process evaluation of the ALLHAT Dissemination Project. Clin Trials 2009; 6: This study describes the design, implementation and process evaluation of a multicomponent program to disseminate ALLHAT results in a context of JNC-7 guidelines. The reported experience demonstrates that a large multimethod dissemination of clinical trial results is feasible. Thus, planning for dissemination efforts, including evaluation research, should be considered as a part of the funding and design of the clinical trial and should begin early in trial planning. 9 Stafford R, Bartholomew L, Cushman W, et al. Impact of the ALLHAT/JNC7 Dissemination Project on thiazide-type diuretic use. Arch Intern Med 2010; 170: This study evaluates the impact of the ALLHAT/JNC-7 Dissemination Project s academic detailing component on thiazide and similar diuretics prescribing using two complementary national databases available from IMS Health (Plymouth Meeting, PA). The outcomes were analyzed at a county level by intensity (dose) of intervention. The results showed that the program was associated with a small increase in diuretic prescribing, which was consistent with the small dose of intervention (1698 presentations by 147 investigator-educators reached physicians), and thus demonstrated that academic detailing has the potential to increase physicians implementation of clinical trial results, thereby making prescribing more consistent with evidence. 10 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: Zanchetti A, Mancia G. The ALLHAT trial: a verdict or a challenge? J Hypertens 2003; 21: Liberati A, Magrini N. Information from drug companies and opinion leaders. BMJ 2003; 326: Davis BR, Furberg CD, Wright JT Jr, et al., ALLHAT Collaborative Research Group. ALLHAT: setting the record straight. Ann Intern Med 2004; 141: Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003; 348: Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: Dahlof B, Sever PS, Poulter NR, et al. 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: Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359: This trial evaluated in a randomized, double-blind design two fixed-dose antihypertensive drug combinations (benazepril hydrochlorothiazide and benazepril amlodipine) in high-risk hypertensive patients. The primary endpoint was a composite of major cardiovascular outcomes. This was the first well designed trial to compare fixed-dose drug combinations. 19 Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358: This double-blind clinical trial randomized 3845 hypertensive patients aged 80 and over to a thiazide diuretic with or without an ACE inhibitor or to placebo for the purpose of informing clinical practice on whether treatment of hypertension in the very elderly is beneficial. The primary endpoint was fatal and nonfatal stroke. Secondary endpoints included mortality and heart failure. 20 Turnbull F, Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003; 362: Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005; 165: Rahman M, Brown CD, Coresh J, et al. The prevalence of reduced glomerular filtration rate in older hypertensive patients and its association with cardiovascular disease: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Arch Intern Med 2004; 164: Rahman M, Pressel S, Davis BR, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs. a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005; 165: Rahman M, Pressel S, Davis BR, et al. Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med 2006; 144: Black HR, Davis B, Barzilay J, et al. Metabolic and clinical outcomes in nondiabetic individuals with the metabolic syndrome assigned to chlorthalidone, amlodipine, or lisinopril as initial treatment for hypertension: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Diabetes Care 2008; 31: Wright JT Jr, Harris-Haywood S, Pressel S, et al. Clinical outcomes by race in hypertensive patients with and without the metabolic syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2008; 168: Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005; 165: Barzilay JI, Davis BR, Bettencourt J, et al. Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study. J Clin Hypertens 2004; 6:

10 364 Hypertension 29 Barzilay JI, Davis BR, Cutler JA, et al. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2006; 166: Wright JT Jr, Dunn JK, Cutler JA, et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA 2005; 293: 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: Einhorn PT, Davis BR, Massie BM, et al. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Heart Failure Validation Study: diagnosis and prognosis. Am Heart J 2007; 153: Grimm RH, Davis BR, Piller LB, et al. Heart failure in ALLHAT: did blood pressure medication at study entry influence outcome? J Clin Hypertens (Greenwich) 2009; 11: This analysis used an infrastructure provided by the Heart Failure Validation Study to address speculations that the heart failure results in ALLHAT could have been due to persistent effects of antihypertensive drugs ALLHAT participants were treated with prior to enrollment. The results of this case-only analysis did not provide significant evidence that pre-entry drug type explained observed differences in the hospitalized heart failure outcome (see also reference [32]). 34 Davis BR, Kostis JB, Simpson LM, et al. Heart failure with preserved and reduced left ventricular ejection fraction in the Antihypertensive And Lipid- Lowering Treatment To Prevent Heart Attack Trial. Circulation 2008; 118: Margolis KL, Dunn K, Simpson LM, et al. Coronary heart disease in moderately hypercholesterolemic, hypertensive black and nonblack patients randomized to pravastatin versus usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Am Heart J 2009; 158: ALLHAT Lipid-Lowering Trial (LLT) compared in a randomized, open-label design statin (pravastatin) with usual care. The main results manuscript (ref [2] above) reported statistically significant differential outcomes by race for CHD and stroke; there was no difference by race for the primary outcome of total mortality. Whereas the findings by race could be due to chance, given the fact that ALLHAT-LLT is the only trial that included meaningful representation of Black participants, they merit careful exploration. This prespecified subgroup analysis failed to find an explanation for the observed beneficial effect of the statin in Black but not in non-black individuals, suggesting that pravastatin may be more effective than usual care in preventing CHD in black individuals despite the observed modest differential in achieved cholesterol levels. 36 Haywood LJ, Ford CE, Crow RS, et al. Atrial fibrillation at baseline and during follow-up in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). J Am Coll Cardiol 2009; 54: Limited information is available on whether atrial fibrillation is affected differentially by antihypertensive drug classes or treatment with statins. This study examines baseline prevalence and in-trial incidence of new-onset atrial fibrillation or atrial flutter and their influence on clinical outcomes, and compares incidence of atrial fibrillation or atrial flutter across randomized treatment groups in ALLHAT. 37 Cushman WC, Ford CE, Einhorn PT, et al. Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens 2008; 10: Wright JT Jr, Probstfield JL, Cushman WC, et al. ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses. Arch Intern Med 2009; 169: This study re-evaluated ALLHAT findings in the context of up-to-date evidence. The current study is intended to complement and update the 2009 review. 39 Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990; 335: Hypertension Detection and Follow-up Program Cooperative Group. Fiveyear findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: Hypertension Detection and Follow-up Program Cooperative Group. Fiveyear findings of the Hypertension Detection and Follow-Up Program. II. Mortality by race-sex and age. JAMA 1979; 242: Kostis JB, Davis BR, Cutler J, et al., for the SHEP Cooperative Research Group. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1997; 278: 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: Neaton JD, Kuller LH. Diuretics are color blind. JAMA 2005; 293: Einhorn PT. National Heart, Lung, and Blood Institute-initiated program Interventions to Improve Hypertension Control Rates in African Americans : background and implementation. Circ Cardiovasc Qual Outcomes 2009; 2: Hypertension is a major contributor to the racial gap in cardiovascular mortality between Black and White Americans. This manuscript describes the background and implementation of an NHLBI-initiated program to improve hypertension control in African Americans. Concept and design manuscripts of the funded projects can be found in the same issue of the Circulation: Cardiovascular Quality and Outcomes journal. ALLHAT informed the treatment of hypertension in Blacks. 46 Cutler JA, Sorlie PD, Wolz M, et al. Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between and Hypertension 2008; 52: Yu W, Ash AS, Levinsky NG, Moskowitz MA. Intensive care unit use and mortality in the elderly. J Gen Internal Med 2000; 15: Lee DS, Gona P, Vasan RS, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham Heart Study of the National Heart, Lung, and Blood Institute. Circulation 2009; 119: Henkel DM, Redfield MM, Weston SA, et al. Death in heart failure: a community perspective. Circ Heart Failure 2008; 1: Shotan A, Garty M, Blondhein DS, et al. Atrial fibrillation and long-term prognosis in patients hospitalized for heart failure: results from Heart Failure Survey in Israel (HFSIS). Eur Heart J 2010; 31: Sjoholm A. ALLHAT: a critical assessment. Blood Press 2004; 13: Unger T. Lessons from ALLHAT. Are low budget diuretics first line therapy in hypertension? Z Kardiol 2004; 93: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991; 325: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigators. N Engl J Med 1992; 327: Yusuf S, Sleight P, Pogue J, et al., for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. 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: Davis BR, Cutler JA, Furberg CD, et al. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Ann Intern Med 2002; 137: Pitt B. The role of chlorthalidone in patients with high-risk hypertension. J Clin Hypertens (Greenwich) 2009; 11: Massie BM. Prevention of heart failure with chlorthalidone in ALLHAT: placing the results into perspective. J Clin Hypertens (Greenwich) 2009; 11: Berl T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med 2003; 138: Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: Agodoa LY, Appel L, Bakris GL, African American Study of Kidney Disease and Hypertension (AASK) Study Group et al.. Effect of ramipril vs. amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285: Guideline 7: pharmacological therapy: use of antihypertensive agents in CKD. Available at: guide_7.htm [Accessed 10 February 2010]. 64 Almgren T, Wilhelmsen L, Samuelsson O, et al. Diabetes in treated hypertension is common and carries a high cardiovascular risk: results from a 28-year follow-up. J Hypertens 2007; 25: Carter BL, Einhorn PT, Brands M, et al., Working Group from the National Heart, Lung, and Blood Institute. Thiazide-induced dysglycemia: call for research from a working group from the National Heart, Lung, and Blood Institute. Hypertension 2008; 52:30 36.