Health and Human Services National Heart, Lung, and Blood Institute U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute ALLHAT 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) Treatment and complications among the 50-60 million Americans with hypertension are estimated to cost the nation $37 billion annually, with antihypertensive drug costs alone accounting for an estimated $15.5 billion/year. There is conclusive evidence that antihypertensive drug therapy can substantially reduce the risk of hypertension-related morbidity and mortality. However, the optimal choice for initial pharmacotherapy of hypertension is uncertain. Earlier clinical trials documented the benefit of lowering blood pressure (BP) using primarily thiazide diuretics or beta-blockers. After these studies, several newer classes of antihypertensive agents, i.e. angiotensin-converting-enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), alpha-adrenergic blockers, and more recently angiotensin receptor blockers (ARBs) became available. Over the past decade, major placebo-controlled trials have documented that ACEIs and CCBs reduce cardiovascular events in hypertensive individuals. However, their relative value compared with older, less expensive agents remains unclear. There has been considerable uncertainty regarding effects of some classes of antihypertensive drugs on risk of coronary heart disease (CHD). The relative benefit of various agents in high-risk subgroups such as older, diabetic, and Black hypertensive persons also needed to be established. The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) www.allhat.org JAMA 2002;288:2981-2997

Antihypertensive Trial Design ALLHAT Antihypertensive Trial Design Randomized, double-blind, multi-center clinical trial Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic 42,418 high-risk hypertensive patients ≥ 55 years The Antihypertensive and Lipid‑Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double‑blind, multi‑center, clinical trial sponsored by the National Heart Lung and Blood Institute (NHLBI), was designed to determine whether the occurrence of fatal CHD or nonfatal myocardial infarction (MI) is lower for high‑risk hypertensive patients treated with a CCB (represented by amlodipine), an ACEI (represented by lisinopril), or an alpha blocker (represented by doxazosin), each compared with diuretic treatment (represented by chlorthalidone). 42,418 high-risk hypertensive patients age 55 and older were randomized.

Background ALLHAT In addition to their BP lowering potential all antihypertensive agents have other important mechanisms of action and indications. These actions may convey benefits or risks independent of BP lowering By having a common BP goal for all treatment arms, ALLHAT aimed to evaluate the health effects of these non-BP actions

ALLHAT Secondary Outcomes All-cause mortality Stroke Combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina Combined CVD – (CHD, stroke, coronary revascularizations, heart failure [treated non-hospitalized, hospitalized, fatal], angina (treated non-hospitalized, hospitalized), peripheral arterial disease (revascularization procedure) Other secondary objectives were to examine effects on all-cause mortality fatal and nonfatal stroke, and other cardiovascular (CVD) events. Definitions were: combined CHD (the primary outcome, coronary revascularization, hospitalized angina), and combined CVD (combined CHD, stroke, other treated angina, HF [fatal, hospitalized, or treated non-hospitalized], and peripheral arterial disease). Coronary revascularization included coronary artery bypass graft, percutaneous angioplasty, insertion of stents, and atherectomy. Other secondary objectives were to examine effects on renal outcomes (including dialysis, renal transplant, renal death, or slope of the reciprocal of longitudinal serum creatinine measurements) and cancer. Individual components of the combined outcomes were pre-specified and examined. Estimated glomerular filtration rate was examined post-hoc.

Secondary Outcomes (Continued) ALLHAT Secondary Outcomes (Continued) HQOL (Health-related quality of life) GI Bleeding Costs

Step 1 Treatment Protocol ALLHAT Step 1 Treatment Protocol Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3* Chlorthalidone 12.5 25 Amlodipine 2.5 5 10 Lisinopril 20 40 Doxazosin 1 2 4 8 * mg/day Step 1 drugs were encapsulated and identical in appearance, so that the identity of each agent was double-masked at each dosage level. Dosages were 12.5, 12.5 (sham titration), and 25 mg/d for chlorthalidone; 2.5, 5, and 10 mg/d for amlodipine; and 10, 20, and 40 mg/d for lisinopril.

Step Up Treatment Protocol ALLHAT Step 2 Agents: Dose 1* Dose 2* Dose 3* Reserpine 0.05 qd or 0.1 qod 0.1 qd 0.2 qd Clonidine (oral) 0.1 bid 0.2 bid 0.3 bid Atenolol 25 qd 50 qd 100 qd Step 3 Agent: Hydralazine 25 bid 50 bid 100 bid *All doses in mg Doses of study-supplied open-label drugs were: step 2 -- atenolol, 25-100 mg/d; reserpine, 0.05-0.2 mg/d; or clonidine, 0.1-0.3 mg twice/day, and step 3 -- hydralazine, 25-100 mg twice/day. Other drugs, including low doses of open-label step 1 drug classes, were permitted if clinically indicated. After initial titration visits, participants were seen every 3 months during the first year and every 4 months thereafter.

Baseline Characteristics ALLHAT Baseline Characteristics Chlorthalidone 15,255 Amlodipine 9,048 Lisinopril 9,054 Mean SBP/DBP 146 / 84 Treated (90%) Untreated (10%) 145 / 83 156 / 89 157 / 90 145 / 84 Mean age, y 67 Black, % 35 36 Women, % 47 46 Current smoking % 22 History of CHD, % 26 24 25 Type 2 diabetes, % 37 There were nearly identical distributions of baseline factors in the three treatment groups. The mean baseline blood pressure was 146/84 mm Hg. The mean age was 67 years; 35% were Black, 47% were women, 22% were current cigarette smokers, 25% had a history of CHD, and 36% were diabetic.

On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group ALLHAT On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group Among participants in the chlorthalidone group who were contacted in the clinic or by telephone within 12 months of annual scheduled visits, 87% were taking chlorthalidone or another diuretic at 1 year, decreasing to 80% at 5 years. Among participants in the amlodipine group, 88% were taking amlodipine or another CCB at 1 year, decreasing to 80% at 5 years. Among participants in the lisinopril group, 82% were taking lisinopril or another ACEI at 1 year, decreasing to 73% at 5 years. The most common reasons for not taking step 1 medication at 5 years in the chlorthalidone, amlodipine, and lisinopril groups, respectively, were unspecified refusals [41%, 40%, and 38%], and symptomatic adverse effects [15%, 16%, and 18%]. Elevated BP [4%, 4%, and 9%] or other adverse effects such as abnormal laboratory values [4%, 2%, and 2%] were other reasons given for discontinuation of step 1 medications.

BP Results by Treatment Group ALLHAT BP Results by Treatment Group BL 6M 1Y 3Y 5Y C 84.0 80.1 79.2 77.1 75.4 A 83.9 79.7 78.5 76.1 74.5 L 84.1 80.8 77.2 BL 6M 1Y 3Y 5Y C 146.2 138.2 136.6 134.6 134.1 A 140.0 138.3 135.4 134.9 L 146.4 141.4 139.7 136.4 136.1 Mean seated BP at randomization was about 146/84 mm Hg in all three groups, with 90% of participants reporting current antihypertensive drug treatment. Among participants returning for follow-up visits, the mean BP at 1 year was 137/79 mm Hg, 138/79 mm Hg, and 140/80 in the chlorthalidone, amlodipine, and lisinopril groups, respectively; at 5 years, the corresponding BP’s were 134/75, 135/75, and 136/75 mm Hg. Compared to chlorthalidone. SBP was significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg). Compared to chlorthalidone, DBP was significantly lower in the amlodipine group (~1 mm Hg). At the initial visit, the proportion of participants at or below the BP goal (<140/90 mm Hg) was 26-28%; at 5 years, it was 68%, 66%, and 61% for the chlorthalidone, amlodipine, and lisinopril groups, respectively. Compared to chlorthalidone: SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg). Compared to chlorthalidone: DBP significantly lower in the amlodipine group (~1 mm Hg).

Blood Pressure Control ALLHAT 1.6 = mean number of drugs 2.0 1.8 1.7 1.6 1.4 @ 5 years: 62% were on >2 drugs 30% were on 1 drug and controlled Cushman, et al. J Clin Hypertens 2002;4:393-404

ALLHAT Biochemical Results Chlorthalidone Amlodipine Lisinopril Serum cholesterol- mg/dL Baseline 216.1 (43.8) 216.5 (44.1) 215.6 (42.4) 4 Years 197.2 (42.1) 195.6 (41.0)* 195.0 (40.6)* Serum cholesterol - > 240 mg/dL Baseline 3838 (26.5) 2284 (26.6) 2178 (25.4) 4 Years 1223 (14.4) 673 (13.4) 603 (12.8) Serum potassium – mmol/L 4.3 (0.7) 4.4 (0.7)* 4.1 (0.7) 4.5 (0.7)* Serum potassium – <3.5mEq/L 493 (3.4) 292 (3.4) 223 (2.6) 707 (8.5) 93 (1.9) 37 (0.8) Mean total serum cholesterol levels at baseline were about 216 mg/dL (5.58-5.61 mmol/L) in all three groups. At 4 years, the respective mean levels were 197.2 (chlorthalidone), 195.6 (amlodipine), and 195.0 (lisinopril) mg/dL (5.10, 5.07, and 5.05 mmol/L). Both comparisons with the chlorthalidone group were statistically significant at p<.05. By 4 years, about 35-36% of participants in all three groups reported taking lipid-lowering drugs, largely HMG CoA reductase inhibitors, some as a result of participation in the ALLHAT lipid trial. Mean serum potassium levels at baseline were 4.3-4.4 mmol/L; at 4 years, the respective mean levels were 4.1, 4.4, and 4.5 mmol/L for those in the chlorthalidone, amlodipine, and lisinopril groups, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05. About 8% of the chlorthalidone group were on potassium supplementation at 5 years, compared with 4% in the amlodipine group and 2% in the lisinopril group. Mean estimated GFR at baseline was about 78 mL/min/1.73 m2 in all groups. At 4 years, it was 70.0, 75.1, and 70.7 mL/min/1.73 m2 in the chlorthalidone, amlodipine, lisinopril groups, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05. The slopes of the reciprocal of serum creatinine over time, which are not shown here, were virtually identical in the chlorthalidone and lisinopril groups, whereas the decline in the amlodipine slope was less than that of the chlorthalidone slope. * p<.05 compared to chlorthalidone † Ann Intern Med. 1999;130:461-470

ALLHAT USE OF POTASSIUM SUPPLEMENTATION % on potassium suppl.

Biochemical Results – Fasting Glucose – mg/dL ALLHAT Biochemical Results – Fasting Glucose – mg/dL Chlorthalidone Amlodipine Lisinopril Total Baseline 123.5 (58.3) 123.1 (57.0) 122.9 (56.1) 4 Years 126.3 (55.6) 123.7 (52.0) 121.5 (51.3)* Among baseline nondiabetics with baseline <126 mg/dL 93.1 (11.7) 93.0 (11.4) 93.3 (11.8) 104.4 (28.5) 103.1 (27.7) 100.5 (19.5)* Diabetes Incidence (follow-up fasting glucose  126 mg/dL) 11.6% 9.8%* 8.1%* The respective mean fasting serum glucose levels at baseline were 123.5, 123.1, and 122.9 mg/dL (6.9, 6.8 and 6.8 mmol/L); at 4 years, the respective mean levels were 126.3, 123.7, and 121.5 mg/dL (7.0, 6.9, and 6.7 mmol/L). The comparison of the lisinopril and chlorthalidone groups was statistically significant at p<.05. Among individuals classified as nondiabetic at baseline, with baseline fasting serum glucose less than 126 mg/dl (7.0 mmol/L), incidence of diabetes (fasting serum glucose 126 mg/dl) at four years was 11.6%, 9.8%, and 8.1%, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05. *p<.05 compared to chlorthalidone

Renal Outcomes ALLHAT C A L A/C L/C ESRD (Rate/100 # events) 1.8 (0.1) 193 2.1 (0.2) 129 2.0(0.2) 126 RR=1.12 p=.98 RR=1.11 p=0.38 GFR (4 Year) Mean (sd) 70.0 (19.7) 75.1 (20.7) 70.7 (20) p<.001 p=0.03 C = Chlorthalidone; A = Amlodipine; L = Lisinopril

ALLHAT Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Years to CHD Event 1 2 3 4 5 6 7 Cumulative CHD Event Rate .04 .08 .12 .16 .2 RR (95% CI) p value A/C 0.98 (0.90-1.07) 0.65 L/C 0.99 (0.91-1.08) 0.81 Chlorthalidone Amlodipine Lisinopril No significant difference was observed between amlodipine (the red line) and chlorthalidone (the blue line) for the primary outcome. The relative risk for amlodipine compared to chlorthalidone was 0.98, with a 95% confidence interval of 0.90-1.07. Also, no significant difference was observed between lisinopril (the green line) and chlorthalidone for the primary outcome. The relative risk was 0.99, with a 95% confidence interval of 0.91-1.08. Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209 Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195

ALLHAT Cumulative Event Rates for Stroke by ALLHAT Treatment Group Cumulative Stroke Rate Years to Stroke 1 2 3 4 5 6 7 .02 .04 .06 .08 .1 RR (95% CI) p value A/C 0.93 (0.81-1.06) 0.28 L/C 1.15 (1.02-1.30) 0.02 Chlorthalidone Amlodipine Lisinopril There was no difference for stroke between the amlodipine and chlorthalidone groups. The lisinopril group had a 15% higher risk for stroke. Number at risk: Chlor 15,255 14,515 13,934 13,309 11,570 6,385 3,217 567 Amlo 9,048 8,617 8,271 7,949 6,937 3,845 1,813 506 Lisin 9,054 8,543 8,172 7,784 6,765 3,891 1,828 949

ALLHAT Stroke – Subgroup Comparisons – RR (95% CI) Amlodipine Better Chlorthalidone Better 0.50 1 2 Non-Diabetic 0.96 (0.81, 1.14) Diabetic 0.90 (0.75, 1.08) Non-Black 0.93 (0.79, 1.10) Black 0.93 (0.76, 1.14) Women 0.84 (0.69, 1.03) Men 1.00 (0.85, 1.18) Age >= 65 0.93 (0.81, 1.08) Age < 65 0.93 (0.73, 1.19) Total 0.93 (0.82, 1.06) Lisinopril Better Chlorthalidone Better 1.23 (1.05, 1.44) 1.07 (0.90, 1.28) 1.00 (0.85, 1.17) 1.40 (1.17, 1.68) 1.22 (1.01, 1.46) 1.10 (0.94, 1.29) 1.13 (0.98, 1.30) 1.21 (0.97, 1.52) 1.15 (1.02, 1.30) P = .01 for interaction There was no difference across the pre-defined subgroups for the amlodipine vs chlorthalidone comparison. For stroke, there was a significant differential effect by race, with p = .01 for interaction. The relative risks (lisinopril versus chlorthalidone) for stroke were 1.40 (p < .001) in Blacks and 1.00 (p=.96) in non-Blacks. The mean follow-up systolic BP for all participants was 2 mm Hg higher in the lisinopril group than the chlorthalidone group, 4 mm Hg higher in Blacks. Adjustment for follow-up BP as time-dependent covariates in a proportional hazards model slightly reduced the relative risks for stroke (RR 1.15 to 1.11), overall and in the Black subgroup (stroke RR 1.40 to 1.36), but the results remained statistically significant. For various reasons, such adjusted analyses need to be interpreted cautiously.

ALLHAT Cumulative Event Rates for All-Cause Mortality by ALLHAT Treatment Group Cumulative Mortality Rate Years to Death 1 2 3 4 5 6 7 .05 .1 .15 .2 .25 .3 RR (95% CI) p value A/C 0.96 (0.89-1.02) 0.20 L/C 1.00 (0.94-1.08) 0.90 RR (95% CI) p value A/C 0.96 (0.89-1.02) 0.20 L/C 1.00 (0.94-1.08) 0.90 Chlorthalidone Amlodipine Lisinopril For all-cause mortality, neither the amlodipine vs chlorthalidone or the lisinopril vs chlorthalidone comparison were statistically significant. Number at risk: Chlor 15,255 14,933 14,564 14,077 12,480 7.185 3,523 428 Amlo 9,048 8,847 8,654 8,391 7,442 4,312 2,101 217 Lisin 9,054 8,853 8,612 8,318 7,382 4,304 2,121 144

Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group Cumulative Combined CVD Event Rate Years to Combined CVD Event 1 2 3 4 5 6 7 .1 .2 .3 .4 .5 RR (95% CI) p value A/C 1.04 (0.99-1.09) 0.12 L/C 1.10 (1.05-1.16) <0.001 Chlorthalidone Amlodipine Lisinopril The amlodipine vs chlorthalidone comparison for combined CVD was not statistically significant. The lisinopril group had a 10% higher risk of combined CVD (p < .001), with a 6-year absolute risk difference of 2.4%. Included in this were a 19% higher risk of HF (p < .001), a 10% higher risk of hospitalized/fatal HF (p = .11), an 11% higher risk of hospitalized/non-hospitalized treated angina (p= .01), and a 10% higher risk of coronary revascularization (p= .05). Number at risk: Chlor 15,255 13,752 12,594 11,517 9,643 5,167 2,362 288 Amlo 9,048 8,118 7,451 6,837 5,724 3,049 1,411 153 Lisin 9,054 7,962 7,259 6,631 5,560 3,011 1,375 139

ALLHAT Combined CVD – Subgroup Comparisons – RR (95% CI) Amlodipine Better Chlorthalidone Better 0.50 1 2 Non-Diabetic 1.02 (0.96, 1.09) Diabetic 1.06 (0.98, 1.15) Non-Black 1.04 (0.97, 1.10) Black 1.06 (0.96, 1.16) Women 1.04 (0.96, 1.13) Men 1.04 (0.98, 1.11) Age >= 65 1.05 (0.99, 1.12) Age < 65 1.03 (0.94, 1.12) Total 1.04 (0.99, 1.09) Lisinopril Better Chlorthalidone Better 1.12 (1.05, 1.19) 1.08 (1.00, 1.17) 1.06 (1.00, 1.13) 1.19 (1.09, 1.30) 1.12 (1.03, 1.21) 1.08 (1.02, 1.15) 1.13 (1.06, 1.20) 1.05 (0.97, 1.15) 1.10 (1.05, 1.16) P = .04 for interaction There was no difference across the pre-defined subgroups for the amlodipine vs chlorthalidone comparison. There was a significant differential effect for combined CVD by race, with p=.04 for interaction. The relative risks (lisinopril versus chlorthalidone) were 1.19 (p<.001) and 1.06 (p=.05) in Blacks and non-Blacks, respectively.

ALLHAT Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group RR (95% CI) p value A/C 1.38 (1.25-1.52) <.001 L/C 1.19 (1.07-1.31) Cumulative CHF Rate Years to HF 1 2 3 4 5 6 7 .03 .06 .09 .12 .15 Chlorthalidone Amlodipine Lisinopril The amlodipine group had a 38% higher risk of HF (p<.001) with a 6-year absolute risk difference of 2.5%. The lisinopril group had a 19% higher risk of HF (p < .001). Number at risk: Chlor 15,255 14,528 13,898 13,224 11,511 6,369 3,016 384 Amlo 9,048 8,535 8,185 7,801 6,785 3,775 1,780 210 Lisin 9,054 8,496 8,096 7,689 6,698 3,789 1,837 313

Overall Conclusions ALLHAT Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy. Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.