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MODULE 3: Using Thiazide-Type Diuretics in African Americans with Hypertension
MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension
MODULE 3: Using Thiazide-Type Diuretics in African Americans with Hypertension
Dr Wright is a paid consultant to The Medical Letter, Inc, and Takeda Pharmaceuticals International, Inc. He is on an advisory board of Medtronic, Inc.
Introduction
Hypertension and hypertensive target organ damage are more prevalent and more severe in certain minority populations, especially African Americans. Hypertension is more common, more severe, develops at an earlier age, and leads to greater morbidity and mortality in African Americans than in age-matched non-Hispanic whites.1 African Americans have among the highest rates of hypertension in the world (41% overall, 44% among black women) and develop the condition an average of 5 years earlier than whites.1
A recent report found that although treatment rates between whites and African Americans overall are similar, a smaller percentage of African Americans with hypertension are controlled to <140/90 mm Hg compared with whites.2 This may at least partly explain the 4 to 5 times higher hypertension-related mortality, 2 to 4 times increased risk of left ventricular hypertrophy (LVH), coronary heart disease (CHD), congestive heart failure, and stroke, and the 4 times higher rate of end-stage renal disease (ESRD) in African Americans compared with whites.1,3 The higher prevalence of diabetes mellitus, cigarette smoking, obesity, lipid disorders, and LVH in blacks exacerbates the existing risk posed by hypertension, making the need for aggressive blood pressure (BP) control even more critical.1
Antihypertensive treatment in African Americans
Lifestyle modification is recommended for all hypertensive patients but is especially important for African Americans. This population has a greater prevalence of obesity than whites, so weight loss is critical.4 Further, African Americans tend to have a greater sensitivity to salt because of a combination of obesity, abnormalities in renal salt handling, and a tendency to consume a high salt/low potassium diet.3 African Americans have been shown to benefit at least as much as other subgroups with hypertension from reductions in dietary salt and improvements in diet quality, such as the Dietary Approaches to Stop Hypertension (DASH) diet.5-7
Several studies have documented the efficacy of diuretics in lowering BP in African Americans.3,8-10 In the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT), treatment initiated with the thiazide-type diuretic (THZD) chlorthalidone (CTD) reduced systolic BP (SBP) by 4 mm Hg more than treatment based on the angiotensin-converting enzyme inhibitor (ACEI) lisinopril or the alpha-blocker doxazosin in black ALLHAT participants who were receiving similar background antihypertensive drug treatment.9,10 The greater BP lowering in the THZD arm was associated with a significantly reduced rate in 1 or more cardiovascular disease (CVD) outcomes. Other inhibitors of the renin-angiotensin system (eg, angiotensin-receptor blockers [ARBs], direct renin inhibitors, and beta-blockers) are similarly less effective in lowering BP in African Americans.3 In contrast, when the calcium channel blocker (CCB) amlodipine was compared with CTD in blacks or when CTD was compared with lisinopril or doxazosin in nonblacks, SBP reductions were only ~1 mm Hg.8,10
As a class, diuretics have been shown to decrease hypertension-related morbidity and mortality in both African Americans and whites.10-15 In fact, much of the evidence for the benefits of antihypertensive therapy in preventing hypertension-related morbidity and mortality was conducted with THZDs, with several of the relevant trials containing significant numbers of African American participants (TABLE).8,10,13-16
TABLE
Outcomes of major clinical trials of diuretics in African Americans
| Clinical trial | Relative risk reduction (RRR) or hazard ratio (HR) by endpoint | |||||
|---|---|---|---|---|---|---|
| Mortality | CVD | CHD | Stroke | HF | ESRD | |
| VA Cooperative: HCTZ + RES + HYD vs placebo (RRR)13 | 0.46 | |||||
| HDFP: stepped therapy with CTD vs usual care (HR)14 | 0.76a | |||||
| SHEP: CTD + atenolol vs placebo (HR)15 | 0.68a | |||||
| ALLHAT: All African Americans (RRR)8,10 | ||||||
| AML vs CTD | 0.97 | 1.06 | 1.03 | 0.93 | 1.46a | 1.15 |
| DOX vs CTD | N/A | 1.28a | 1.11 | 1.38a | 1.84a | 0.99 |
| LIS vs CTD | 1.06 | 1.19a | 1.15a | 1.40a | 1.30a | 1.29 |
| ALLHAT: African Americans with diabetes and metabolic syndrome (RRR)16 | ||||||
| AML vs CTD | 1.02 | 1.14a | 1.09 | 1.01 | 1.50 | 1.50 |
| DOX vs CTD | 1.18 | 1.37a | 1.15 | 1.49a | 1.88a | 1.17 |
| LIS vs CTD | 0.96 | 1.24a | 1.19a | 1.37a | 1.49a | 1.70a |
| ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; AML, amlodipine; CHD, coronary heart disease; CTD, chlorthalidone; CVD, cardiovascular disease; DOX, doxazosin; ESRD, end-stage renal disease; HCTZ, hydrochlorothiazide; HDFP, Hypertension Detection and Follow-up Program; HF, heart failure; HYD, hydralazine; LIS, lisinopril; RES, reserpine; SHEP, Systolic Hypertension in the Elderly Program; VA, Veterans Administration aP ≤0.05 | ||||||
In the Veterans Administration (VA) Cooperative Trial, African American men comprised 42% of participants, all of whom were randomized to a combination of hydrochlorothiazide, reserpine, and hydralazine, or to placebo.13 In the Hypertension Detection and Follow-Up Program (HDFP) trial, 44% of participants were African American. All participants were randomized to stepped therapy with CTD, reserpine, methyldopa, and hydralazine, or to usual community care.14 Both of these pioneering trials documented the benefit of a THZD-based regimen in lowering BP and improving clinical outcomes in African Americans with hypertension. The Systolic Hypertension in the Elderly Program (SHEP) trial, in which 14% of participants were African American, extended earlier results from the VA Cooperative and HDFP trials by demonstrating that, compared with placebo, active treatment with CTD and the beta-blocker atenolol produced clinical outcome reductions in African Americans and whites with isolated systolic hypertension as well as in those with elevated diastolic BP.15
In comparative trials with newer classes of antihypertensives, THZDs have remained unsurpassed in preventing complications of hypertension, including in African Americans (TABLE). ALLHAT was the first outcome study to evaluate the relative benefit of antihypertensive treatment initiated with newer classes of antihypertensive agents vs treatment initiated with a THZD in blacks. ALLHAT included more than 15,000 African Americans and Afro-Caribbeans and confirmed the findings of studies in other populations that neither an ACEI, a CCB, or alpha-blocker–initiated therapy surpassed therapy initiated with a THZD (CTD) in lowering BP or in preventing CVD or renal outcomes.8,10 Overall, the THZD-based therapy was superior to the alpha-blocker, ACEI, and CCB-based therapies in preventing 1 or more major forms of CVD, including stroke and heart failure (HF). In blacks, THZD-based therapy was superior to alpha-blocker–based therapy in lowering BP and in preventing overall CVD (especially HF and stroke), and was superior to the ACEI-based regimen in preventing stroke, HF, and overall CVD (a composite of CHD, stroke, and HF endpoints). Compared with CCB-based therapy (ie, amlodipine), THZD (CTD)-based therapy was similar in overall CVD protection but superior in preventing HF.
These results in ALLHAT were even more impressive in blacks with diabetes or the metabolic syndrome (TABLE).16 In addition to the above-mentioned CVD outcomes in black hypertensive patients, neither the CCB-based nor the ACEI-based regimens were superior to the THZD-based regimen in preventing ESRD overall or when stratified by diabetes or baseline estimated glomerular filtration rate.10,16,17 In black ALLHAT participants with diabetes or the metabolic syndrome, CTD was associated with substantially reduced rates of ESRD compared with those randomized to doxazosin, amlodipine, or the ACEI lisinopril.16 It should also be noted that nearly all previous renal outcome trials with renin-angiotensin system inhibitors included background therapy with a diuretic.17
Recommendations
Most national and international guidelines recommend THZDs as first-line therapy in African Americans.18-21 Calcium channel blockers are a reasonable alternate first-line choice in African Americans who are unable to tolerate a diuretic.
In addition, the Joint National Committee (JNC-7) guidelines recommend the use of ACEIs and ARBs as first-line therapy in all patients with hypertension comorbid with chronic kidney disease (CKD) or HF, including African Americans.18 These drugs, along with alpha-blockers and all other agents in the antihypertensive armamentarium, should be used as add-on therapy, as needed, to achieve BP goals in African Americans already receiving a THZD or CCB.
Importantly, multiple drug therapy should be considered for initial treatment in all individuals whose BP is more than 20/10 mm Hg above target.18 In addition, multiple antihypertensive agents are usually required to achieve long-term control in most patients, particularly in African Americans who, as noted earlier, tend to have more-severe hypertension.19
Conclusion
Treatment of hypertension in African Americans should include both lifestyle modifications and pharmacologic intervention, usually with multiple agents. In the absence of compelling indications for alternative therapies, THZD-based regimens should be considered first-line treatment given significant evidence from large randomized studies that document their ability to reduce both BP and hypertensive complications in this population.
Monotherapy with ACEIs, ARBs, direct renin inhibitors, or beta-blockers is less effective in lowering BP in African Americans than in other populations. ACEIs and ARBs should be included in antihypertensive regimens prescribed for African Americans with concomitant CKD or HF. They can also be considered as add-on therapy to regimens containing a THZD or CCB in the absence of these conditions.
1. Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220.
2. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303(20):2043-2050.
3. Johnson EF, Wright JT. Management of hypertension in black populations. In: Oparil S, Weber MA, eds. Hypertension: A Companion to Brenner and Rector’s The Kidney. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2005:587–595.
4. National Center for Health Statistics. Health, United States, 2009: With Special Feature on Medical Technology. Hyattsville, MD. 2010. Table 72.
5. Prather AA, Blumenthal JA, Hinderliter AL, Sherwood A. Ethnic differences in the effects of the DASH diet on nocturnal blood pressure dipping in individuals with high blood pressure. Am J Hypertens. 2011;24(12):1338-1344.
6. Svetkey LP, Simons-Morton D, Vollmer WM, et al. Effects of dietary patterns on blood pressure: subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med. 1999;159(3):285-293.
7. Appel LJ, Moore TJ, Obarzanek E, et al. DASH Collaborative Research Group. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med. 1997;336(16):1117-1124.
8. Wright JT, Jr, Dunn JK, Cutler JA, et al. ALLHAT Collaborative Research Group. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005;293(13):1595-1608.
9. Materson BJ, Reda DJ, Cushman WC, et al. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med. 1993;328(13):914-921.
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(9):832-842.
11. Neal B, MacMahon S, Chapman N. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet. 2000;356(9246):1955-1964.
12. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395):1527-1535.
13. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213(7):1143-1152.
14. Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program: mortality by race-sex and blood pressure level. A further analysis. J Community Health. 1984;9(4):314-327.
15. The Systolic Hypertension in the Elderly Program Cooperative Research Group. Implications of the systolic hypertension in the elderly program. Hypertension. 1993;21(3):335-343.
16. 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(2):207-217.
17. 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(8):936-946.
18. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure; National Heart, Lung, and Blood Insitute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-1252.
19. Flack JM, Sica DA, Bakris G, et al. International Society on Hypertension in Blacks. Management of high blood pressure in blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension. 2010;56(5):780-800.
20. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press. 2009;18(6):308-347.
21. Canadian Hypertension Education Program. The 2012 CHEP Recommendations. Hypertension Canada Web site. http://www.hypertension.ca/chep-recommendations. Published 2012. Accessed April 15, 2012.
MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension
MODULE 3: Using Thiazide-Type Diuretics in African Americans with Hypertension
Dr Wright is a paid consultant to The Medical Letter, Inc, and Takeda Pharmaceuticals International, Inc. He is on an advisory board of Medtronic, Inc.
Introduction
Hypertension and hypertensive target organ damage are more prevalent and more severe in certain minority populations, especially African Americans. Hypertension is more common, more severe, develops at an earlier age, and leads to greater morbidity and mortality in African Americans than in age-matched non-Hispanic whites.1 African Americans have among the highest rates of hypertension in the world (41% overall, 44% among black women) and develop the condition an average of 5 years earlier than whites.1
A recent report found that although treatment rates between whites and African Americans overall are similar, a smaller percentage of African Americans with hypertension are controlled to <140/90 mm Hg compared with whites.2 This may at least partly explain the 4 to 5 times higher hypertension-related mortality, 2 to 4 times increased risk of left ventricular hypertrophy (LVH), coronary heart disease (CHD), congestive heart failure, and stroke, and the 4 times higher rate of end-stage renal disease (ESRD) in African Americans compared with whites.1,3 The higher prevalence of diabetes mellitus, cigarette smoking, obesity, lipid disorders, and LVH in blacks exacerbates the existing risk posed by hypertension, making the need for aggressive blood pressure (BP) control even more critical.1
Antihypertensive treatment in African Americans
Lifestyle modification is recommended for all hypertensive patients but is especially important for African Americans. This population has a greater prevalence of obesity than whites, so weight loss is critical.4 Further, African Americans tend to have a greater sensitivity to salt because of a combination of obesity, abnormalities in renal salt handling, and a tendency to consume a high salt/low potassium diet.3 African Americans have been shown to benefit at least as much as other subgroups with hypertension from reductions in dietary salt and improvements in diet quality, such as the Dietary Approaches to Stop Hypertension (DASH) diet.5-7
Several studies have documented the efficacy of diuretics in lowering BP in African Americans.3,8-10 In the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT), treatment initiated with the thiazide-type diuretic (THZD) chlorthalidone (CTD) reduced systolic BP (SBP) by 4 mm Hg more than treatment based on the angiotensin-converting enzyme inhibitor (ACEI) lisinopril or the alpha-blocker doxazosin in black ALLHAT participants who were receiving similar background antihypertensive drug treatment.9,10 The greater BP lowering in the THZD arm was associated with a significantly reduced rate in 1 or more cardiovascular disease (CVD) outcomes. Other inhibitors of the renin-angiotensin system (eg, angiotensin-receptor blockers [ARBs], direct renin inhibitors, and beta-blockers) are similarly less effective in lowering BP in African Americans.3 In contrast, when the calcium channel blocker (CCB) amlodipine was compared with CTD in blacks or when CTD was compared with lisinopril or doxazosin in nonblacks, SBP reductions were only ~1 mm Hg.8,10
As a class, diuretics have been shown to decrease hypertension-related morbidity and mortality in both African Americans and whites.10-15 In fact, much of the evidence for the benefits of antihypertensive therapy in preventing hypertension-related morbidity and mortality was conducted with THZDs, with several of the relevant trials containing significant numbers of African American participants (TABLE).8,10,13-16
TABLE
Outcomes of major clinical trials of diuretics in African Americans
| Clinical trial | Relative risk reduction (RRR) or hazard ratio (HR) by endpoint | |||||
|---|---|---|---|---|---|---|
| Mortality | CVD | CHD | Stroke | HF | ESRD | |
| VA Cooperative: HCTZ + RES + HYD vs placebo (RRR)13 | 0.46 | |||||
| HDFP: stepped therapy with CTD vs usual care (HR)14 | 0.76a | |||||
| SHEP: CTD + atenolol vs placebo (HR)15 | 0.68a | |||||
| ALLHAT: All African Americans (RRR)8,10 | ||||||
| AML vs CTD | 0.97 | 1.06 | 1.03 | 0.93 | 1.46a | 1.15 |
| DOX vs CTD | N/A | 1.28a | 1.11 | 1.38a | 1.84a | 0.99 |
| LIS vs CTD | 1.06 | 1.19a | 1.15a | 1.40a | 1.30a | 1.29 |
| ALLHAT: African Americans with diabetes and metabolic syndrome (RRR)16 | ||||||
| AML vs CTD | 1.02 | 1.14a | 1.09 | 1.01 | 1.50 | 1.50 |
| DOX vs CTD | 1.18 | 1.37a | 1.15 | 1.49a | 1.88a | 1.17 |
| LIS vs CTD | 0.96 | 1.24a | 1.19a | 1.37a | 1.49a | 1.70a |
| ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; AML, amlodipine; CHD, coronary heart disease; CTD, chlorthalidone; CVD, cardiovascular disease; DOX, doxazosin; ESRD, end-stage renal disease; HCTZ, hydrochlorothiazide; HDFP, Hypertension Detection and Follow-up Program; HF, heart failure; HYD, hydralazine; LIS, lisinopril; RES, reserpine; SHEP, Systolic Hypertension in the Elderly Program; VA, Veterans Administration aP ≤0.05 | ||||||
In the Veterans Administration (VA) Cooperative Trial, African American men comprised 42% of participants, all of whom were randomized to a combination of hydrochlorothiazide, reserpine, and hydralazine, or to placebo.13 In the Hypertension Detection and Follow-Up Program (HDFP) trial, 44% of participants were African American. All participants were randomized to stepped therapy with CTD, reserpine, methyldopa, and hydralazine, or to usual community care.14 Both of these pioneering trials documented the benefit of a THZD-based regimen in lowering BP and improving clinical outcomes in African Americans with hypertension. The Systolic Hypertension in the Elderly Program (SHEP) trial, in which 14% of participants were African American, extended earlier results from the VA Cooperative and HDFP trials by demonstrating that, compared with placebo, active treatment with CTD and the beta-blocker atenolol produced clinical outcome reductions in African Americans and whites with isolated systolic hypertension as well as in those with elevated diastolic BP.15
In comparative trials with newer classes of antihypertensives, THZDs have remained unsurpassed in preventing complications of hypertension, including in African Americans (TABLE). ALLHAT was the first outcome study to evaluate the relative benefit of antihypertensive treatment initiated with newer classes of antihypertensive agents vs treatment initiated with a THZD in blacks. ALLHAT included more than 15,000 African Americans and Afro-Caribbeans and confirmed the findings of studies in other populations that neither an ACEI, a CCB, or alpha-blocker–initiated therapy surpassed therapy initiated with a THZD (CTD) in lowering BP or in preventing CVD or renal outcomes.8,10 Overall, the THZD-based therapy was superior to the alpha-blocker, ACEI, and CCB-based therapies in preventing 1 or more major forms of CVD, including stroke and heart failure (HF). In blacks, THZD-based therapy was superior to alpha-blocker–based therapy in lowering BP and in preventing overall CVD (especially HF and stroke), and was superior to the ACEI-based regimen in preventing stroke, HF, and overall CVD (a composite of CHD, stroke, and HF endpoints). Compared with CCB-based therapy (ie, amlodipine), THZD (CTD)-based therapy was similar in overall CVD protection but superior in preventing HF.
These results in ALLHAT were even more impressive in blacks with diabetes or the metabolic syndrome (TABLE).16 In addition to the above-mentioned CVD outcomes in black hypertensive patients, neither the CCB-based nor the ACEI-based regimens were superior to the THZD-based regimen in preventing ESRD overall or when stratified by diabetes or baseline estimated glomerular filtration rate.10,16,17 In black ALLHAT participants with diabetes or the metabolic syndrome, CTD was associated with substantially reduced rates of ESRD compared with those randomized to doxazosin, amlodipine, or the ACEI lisinopril.16 It should also be noted that nearly all previous renal outcome trials with renin-angiotensin system inhibitors included background therapy with a diuretic.17
Recommendations
Most national and international guidelines recommend THZDs as first-line therapy in African Americans.18-21 Calcium channel blockers are a reasonable alternate first-line choice in African Americans who are unable to tolerate a diuretic.
In addition, the Joint National Committee (JNC-7) guidelines recommend the use of ACEIs and ARBs as first-line therapy in all patients with hypertension comorbid with chronic kidney disease (CKD) or HF, including African Americans.18 These drugs, along with alpha-blockers and all other agents in the antihypertensive armamentarium, should be used as add-on therapy, as needed, to achieve BP goals in African Americans already receiving a THZD or CCB.
Importantly, multiple drug therapy should be considered for initial treatment in all individuals whose BP is more than 20/10 mm Hg above target.18 In addition, multiple antihypertensive agents are usually required to achieve long-term control in most patients, particularly in African Americans who, as noted earlier, tend to have more-severe hypertension.19
Conclusion
Treatment of hypertension in African Americans should include both lifestyle modifications and pharmacologic intervention, usually with multiple agents. In the absence of compelling indications for alternative therapies, THZD-based regimens should be considered first-line treatment given significant evidence from large randomized studies that document their ability to reduce both BP and hypertensive complications in this population.
Monotherapy with ACEIs, ARBs, direct renin inhibitors, or beta-blockers is less effective in lowering BP in African Americans than in other populations. ACEIs and ARBs should be included in antihypertensive regimens prescribed for African Americans with concomitant CKD or HF. They can also be considered as add-on therapy to regimens containing a THZD or CCB in the absence of these conditions.
MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension
MODULE 3: Using Thiazide-Type Diuretics in African Americans with Hypertension
Dr Wright is a paid consultant to The Medical Letter, Inc, and Takeda Pharmaceuticals International, Inc. He is on an advisory board of Medtronic, Inc.
Introduction
Hypertension and hypertensive target organ damage are more prevalent and more severe in certain minority populations, especially African Americans. Hypertension is more common, more severe, develops at an earlier age, and leads to greater morbidity and mortality in African Americans than in age-matched non-Hispanic whites.1 African Americans have among the highest rates of hypertension in the world (41% overall, 44% among black women) and develop the condition an average of 5 years earlier than whites.1
A recent report found that although treatment rates between whites and African Americans overall are similar, a smaller percentage of African Americans with hypertension are controlled to <140/90 mm Hg compared with whites.2 This may at least partly explain the 4 to 5 times higher hypertension-related mortality, 2 to 4 times increased risk of left ventricular hypertrophy (LVH), coronary heart disease (CHD), congestive heart failure, and stroke, and the 4 times higher rate of end-stage renal disease (ESRD) in African Americans compared with whites.1,3 The higher prevalence of diabetes mellitus, cigarette smoking, obesity, lipid disorders, and LVH in blacks exacerbates the existing risk posed by hypertension, making the need for aggressive blood pressure (BP) control even more critical.1
Antihypertensive treatment in African Americans
Lifestyle modification is recommended for all hypertensive patients but is especially important for African Americans. This population has a greater prevalence of obesity than whites, so weight loss is critical.4 Further, African Americans tend to have a greater sensitivity to salt because of a combination of obesity, abnormalities in renal salt handling, and a tendency to consume a high salt/low potassium diet.3 African Americans have been shown to benefit at least as much as other subgroups with hypertension from reductions in dietary salt and improvements in diet quality, such as the Dietary Approaches to Stop Hypertension (DASH) diet.5-7
Several studies have documented the efficacy of diuretics in lowering BP in African Americans.3,8-10 In the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT), treatment initiated with the thiazide-type diuretic (THZD) chlorthalidone (CTD) reduced systolic BP (SBP) by 4 mm Hg more than treatment based on the angiotensin-converting enzyme inhibitor (ACEI) lisinopril or the alpha-blocker doxazosin in black ALLHAT participants who were receiving similar background antihypertensive drug treatment.9,10 The greater BP lowering in the THZD arm was associated with a significantly reduced rate in 1 or more cardiovascular disease (CVD) outcomes. Other inhibitors of the renin-angiotensin system (eg, angiotensin-receptor blockers [ARBs], direct renin inhibitors, and beta-blockers) are similarly less effective in lowering BP in African Americans.3 In contrast, when the calcium channel blocker (CCB) amlodipine was compared with CTD in blacks or when CTD was compared with lisinopril or doxazosin in nonblacks, SBP reductions were only ~1 mm Hg.8,10
As a class, diuretics have been shown to decrease hypertension-related morbidity and mortality in both African Americans and whites.10-15 In fact, much of the evidence for the benefits of antihypertensive therapy in preventing hypertension-related morbidity and mortality was conducted with THZDs, with several of the relevant trials containing significant numbers of African American participants (TABLE).8,10,13-16
TABLE
Outcomes of major clinical trials of diuretics in African Americans
| Clinical trial | Relative risk reduction (RRR) or hazard ratio (HR) by endpoint | |||||
|---|---|---|---|---|---|---|
| Mortality | CVD | CHD | Stroke | HF | ESRD | |
| VA Cooperative: HCTZ + RES + HYD vs placebo (RRR)13 | 0.46 | |||||
| HDFP: stepped therapy with CTD vs usual care (HR)14 | 0.76a | |||||
| SHEP: CTD + atenolol vs placebo (HR)15 | 0.68a | |||||
| ALLHAT: All African Americans (RRR)8,10 | ||||||
| AML vs CTD | 0.97 | 1.06 | 1.03 | 0.93 | 1.46a | 1.15 |
| DOX vs CTD | N/A | 1.28a | 1.11 | 1.38a | 1.84a | 0.99 |
| LIS vs CTD | 1.06 | 1.19a | 1.15a | 1.40a | 1.30a | 1.29 |
| ALLHAT: African Americans with diabetes and metabolic syndrome (RRR)16 | ||||||
| AML vs CTD | 1.02 | 1.14a | 1.09 | 1.01 | 1.50 | 1.50 |
| DOX vs CTD | 1.18 | 1.37a | 1.15 | 1.49a | 1.88a | 1.17 |
| LIS vs CTD | 0.96 | 1.24a | 1.19a | 1.37a | 1.49a | 1.70a |
| ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; AML, amlodipine; CHD, coronary heart disease; CTD, chlorthalidone; CVD, cardiovascular disease; DOX, doxazosin; ESRD, end-stage renal disease; HCTZ, hydrochlorothiazide; HDFP, Hypertension Detection and Follow-up Program; HF, heart failure; HYD, hydralazine; LIS, lisinopril; RES, reserpine; SHEP, Systolic Hypertension in the Elderly Program; VA, Veterans Administration aP ≤0.05 | ||||||
In the Veterans Administration (VA) Cooperative Trial, African American men comprised 42% of participants, all of whom were randomized to a combination of hydrochlorothiazide, reserpine, and hydralazine, or to placebo.13 In the Hypertension Detection and Follow-Up Program (HDFP) trial, 44% of participants were African American. All participants were randomized to stepped therapy with CTD, reserpine, methyldopa, and hydralazine, or to usual community care.14 Both of these pioneering trials documented the benefit of a THZD-based regimen in lowering BP and improving clinical outcomes in African Americans with hypertension. The Systolic Hypertension in the Elderly Program (SHEP) trial, in which 14% of participants were African American, extended earlier results from the VA Cooperative and HDFP trials by demonstrating that, compared with placebo, active treatment with CTD and the beta-blocker atenolol produced clinical outcome reductions in African Americans and whites with isolated systolic hypertension as well as in those with elevated diastolic BP.15
In comparative trials with newer classes of antihypertensives, THZDs have remained unsurpassed in preventing complications of hypertension, including in African Americans (TABLE). ALLHAT was the first outcome study to evaluate the relative benefit of antihypertensive treatment initiated with newer classes of antihypertensive agents vs treatment initiated with a THZD in blacks. ALLHAT included more than 15,000 African Americans and Afro-Caribbeans and confirmed the findings of studies in other populations that neither an ACEI, a CCB, or alpha-blocker–initiated therapy surpassed therapy initiated with a THZD (CTD) in lowering BP or in preventing CVD or renal outcomes.8,10 Overall, the THZD-based therapy was superior to the alpha-blocker, ACEI, and CCB-based therapies in preventing 1 or more major forms of CVD, including stroke and heart failure (HF). In blacks, THZD-based therapy was superior to alpha-blocker–based therapy in lowering BP and in preventing overall CVD (especially HF and stroke), and was superior to the ACEI-based regimen in preventing stroke, HF, and overall CVD (a composite of CHD, stroke, and HF endpoints). Compared with CCB-based therapy (ie, amlodipine), THZD (CTD)-based therapy was similar in overall CVD protection but superior in preventing HF.
These results in ALLHAT were even more impressive in blacks with diabetes or the metabolic syndrome (TABLE).16 In addition to the above-mentioned CVD outcomes in black hypertensive patients, neither the CCB-based nor the ACEI-based regimens were superior to the THZD-based regimen in preventing ESRD overall or when stratified by diabetes or baseline estimated glomerular filtration rate.10,16,17 In black ALLHAT participants with diabetes or the metabolic syndrome, CTD was associated with substantially reduced rates of ESRD compared with those randomized to doxazosin, amlodipine, or the ACEI lisinopril.16 It should also be noted that nearly all previous renal outcome trials with renin-angiotensin system inhibitors included background therapy with a diuretic.17
Recommendations
Most national and international guidelines recommend THZDs as first-line therapy in African Americans.18-21 Calcium channel blockers are a reasonable alternate first-line choice in African Americans who are unable to tolerate a diuretic.
In addition, the Joint National Committee (JNC-7) guidelines recommend the use of ACEIs and ARBs as first-line therapy in all patients with hypertension comorbid with chronic kidney disease (CKD) or HF, including African Americans.18 These drugs, along with alpha-blockers and all other agents in the antihypertensive armamentarium, should be used as add-on therapy, as needed, to achieve BP goals in African Americans already receiving a THZD or CCB.
Importantly, multiple drug therapy should be considered for initial treatment in all individuals whose BP is more than 20/10 mm Hg above target.18 In addition, multiple antihypertensive agents are usually required to achieve long-term control in most patients, particularly in African Americans who, as noted earlier, tend to have more-severe hypertension.19
Conclusion
Treatment of hypertension in African Americans should include both lifestyle modifications and pharmacologic intervention, usually with multiple agents. In the absence of compelling indications for alternative therapies, THZD-based regimens should be considered first-line treatment given significant evidence from large randomized studies that document their ability to reduce both BP and hypertensive complications in this population.
Monotherapy with ACEIs, ARBs, direct renin inhibitors, or beta-blockers is less effective in lowering BP in African Americans than in other populations. ACEIs and ARBs should be included in antihypertensive regimens prescribed for African Americans with concomitant CKD or HF. They can also be considered as add-on therapy to regimens containing a THZD or CCB in the absence of these conditions.
1. Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220.
2. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303(20):2043-2050.
3. Johnson EF, Wright JT. Management of hypertension in black populations. In: Oparil S, Weber MA, eds. Hypertension: A Companion to Brenner and Rector’s The Kidney. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2005:587–595.
4. National Center for Health Statistics. Health, United States, 2009: With Special Feature on Medical Technology. Hyattsville, MD. 2010. Table 72.
5. Prather AA, Blumenthal JA, Hinderliter AL, Sherwood A. Ethnic differences in the effects of the DASH diet on nocturnal blood pressure dipping in individuals with high blood pressure. Am J Hypertens. 2011;24(12):1338-1344.
6. Svetkey LP, Simons-Morton D, Vollmer WM, et al. Effects of dietary patterns on blood pressure: subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med. 1999;159(3):285-293.
7. Appel LJ, Moore TJ, Obarzanek E, et al. DASH Collaborative Research Group. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med. 1997;336(16):1117-1124.
8. Wright JT, Jr, Dunn JK, Cutler JA, et al. ALLHAT Collaborative Research Group. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005;293(13):1595-1608.
9. Materson BJ, Reda DJ, Cushman WC, et al. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med. 1993;328(13):914-921.
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(9):832-842.
11. Neal B, MacMahon S, Chapman N. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet. 2000;356(9246):1955-1964.
12. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395):1527-1535.
13. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213(7):1143-1152.
14. Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program: mortality by race-sex and blood pressure level. A further analysis. J Community Health. 1984;9(4):314-327.
15. The Systolic Hypertension in the Elderly Program Cooperative Research Group. Implications of the systolic hypertension in the elderly program. Hypertension. 1993;21(3):335-343.
16. 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(2):207-217.
17. 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(8):936-946.
18. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure; National Heart, Lung, and Blood Insitute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-1252.
19. Flack JM, Sica DA, Bakris G, et al. International Society on Hypertension in Blacks. Management of high blood pressure in blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension. 2010;56(5):780-800.
20. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press. 2009;18(6):308-347.
21. Canadian Hypertension Education Program. The 2012 CHEP Recommendations. Hypertension Canada Web site. http://www.hypertension.ca/chep-recommendations. Published 2012. Accessed April 15, 2012.
1. Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220.
2. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303(20):2043-2050.
3. Johnson EF, Wright JT. Management of hypertension in black populations. In: Oparil S, Weber MA, eds. Hypertension: A Companion to Brenner and Rector’s The Kidney. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2005:587–595.
4. National Center for Health Statistics. Health, United States, 2009: With Special Feature on Medical Technology. Hyattsville, MD. 2010. Table 72.
5. Prather AA, Blumenthal JA, Hinderliter AL, Sherwood A. Ethnic differences in the effects of the DASH diet on nocturnal blood pressure dipping in individuals with high blood pressure. Am J Hypertens. 2011;24(12):1338-1344.
6. Svetkey LP, Simons-Morton D, Vollmer WM, et al. Effects of dietary patterns on blood pressure: subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med. 1999;159(3):285-293.
7. Appel LJ, Moore TJ, Obarzanek E, et al. DASH Collaborative Research Group. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med. 1997;336(16):1117-1124.
8. Wright JT, Jr, Dunn JK, Cutler JA, et al. ALLHAT Collaborative Research Group. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005;293(13):1595-1608.
9. Materson BJ, Reda DJ, Cushman WC, et al. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med. 1993;328(13):914-921.
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(9):832-842.
11. Neal B, MacMahon S, Chapman N. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet. 2000;356(9246):1955-1964.
12. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395):1527-1535.
13. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213(7):1143-1152.
14. Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program: mortality by race-sex and blood pressure level. A further analysis. J Community Health. 1984;9(4):314-327.
15. The Systolic Hypertension in the Elderly Program Cooperative Research Group. Implications of the systolic hypertension in the elderly program. Hypertension. 1993;21(3):335-343.
16. 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(2):207-217.
17. 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(8):936-946.
18. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure; National Heart, Lung, and Blood Insitute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-1252.
19. Flack JM, Sica DA, Bakris G, et al. International Society on Hypertension in Blacks. Management of high blood pressure in blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension. 2010;56(5):780-800.
20. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press. 2009;18(6):308-347.
21. Canadian Hypertension Education Program. The 2012 CHEP Recommendations. Hypertension Canada Web site. http://www.hypertension.ca/chep-recommendations. Published 2012. Accessed April 15, 2012.