Review of the Design and Initial Findings for Pre-specified Outcomes and Subgroups

1. 1 Review of the Design and Initial Findings for Pre-specified Outcomes and Subgroups 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.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.

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3. 3 This map shows the ALLHAT sites in the United States, Canada, Puerto Rico, and the US Virgin Islands. This map shows the ALLHAT sites in the United States, Canada, Puerto Rico, and the US Virgin Islands.

4. 4 Baseline Characteristics(33, 357 Participants)

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7. 7 Mean Systolic and Diastolic BP,by Treatment Group

8. 8 Biochemical ResultsSr. Cholesterol & Potassium 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. 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.

9. 9 Biochemical ResultsFasting Glucose 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. 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.

10. 10 As you can see here on the primary endpoint of fatal CHD and nonfatal MI, these drugs did not differ from one another. Thus the older drug, diuretic, was unsurpassed by the newer classes. Similarly, in all secondary endpoints, chlorthalidone was unsurpassed, and, in fact when one looks at heart failure, chlorthalidone clearly bests the newer classes.As you can see here on the primary endpoint of fatal CHD and nonfatal MI, these drugs did not differ from one another. Thus the older drug, diuretic, was unsurpassed by the newer classes. Similarly, in all secondary endpoints, chlorthalidone was unsurpassed, and, in fact when one looks at heart failure, chlorthalidone clearly bests the newer classes.

11. 11 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. 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.

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