Optimal Treatment of Hypertension and Cardiovascular Risk Reduction in African Americans: Treatment Approaches for Outpatients

Authors

  • Jackson T. Wright Jr. MD, PhD,

    1. From the Clinical Hypertension Program1 and the Division of Hypertension,2 University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH
    Search for more papers by this author
  • and 1 Janice Douglas MD 2

    1. From the Clinical Hypertension Program1 and the Division of Hypertension,2 University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH
    Search for more papers by this author

Jackson T. Wright, Jr., MD, PhD, Department of Medicine, Case Western Reserve University, 10901 Euclid Avenue, Medical Center, Room W-165 School of Medicine, Cleveland OH 44106-4982
E-mail: jxw20@po.cwru.edu

Abstract

African Americans have a higher prevalence and greater severity of hypertension compared with whites and therefore have a higher prevalence of many disease-related complications, such as coronary heart disease, stroke, and end-stage renal disease. Minorities have been, until recently, underrepresented in large clinical trials, leading to a lack of outcome data for these patient groups. However, accumulating data confirm the benefit of aggressive blood pressure-lowering therapy in this population. These studies also show that most patients require combination therapy to achieve adequate blood pressure reduction, particularly high-risk patient groups that have lower target blood pressure goals. All of the available antihypertensive agents are effective in African Americans. Recent studies suggest that regimens containing a thiazide-type diuretic are unsurpassed in blood pressure lowering and prevention of major clinical complications, and they cost less. Thus, while other agents may be required for selected clinical indications or for blood pressure control, diuretics should be drugs of first choice or included in most antihypertensive regimens especially in African American hypertensives.

Hypertension is a significant public health problem with a disproportionate effect among certain racial/ethnic populations. Hypertension is more prevalent in African Americans (32%) than in other racial groups such as whites (23%) and Mexican Americans (23%).1 In addition, hypertension tends to occur earlier in life in African Americans and is more severe than in their white counterparts.2 Only 25% of African Americans with hypertension have their blood pressure adequately controlled (an overall control rate in the United States is 27%).1 Not surprisingly, there is a higher prevalence of many hypertension-related complications such as coronary heart disease, stroke, and end-stage renal disease in this population.3 Because of the well-established link between blood pressure level and the development of hypertension-related complications,4 improved control of blood pressure has the potential to substantially improve clinical outcomes. This report reviews the results from studies evaluating the effect of hypertension treatment in African American patients and discusses treatment approaches for outpatients with hypertension, with an emphasis on target organ risk reduction.

REVIEW OF CLINICAL TRIALS

Although minority patients were underrepresented in many of the large-scale hypertension treatment trials, data on the efficacy of treatment in these patients have begun to accumulate. These studies generally confirm that there are some differences between racial groups regarding optimal therapeutic strategies; however, they also confirm the efficacy of antihypertensive therapy in meeting target blood pressure goals and the benefit of aggressive therapy in reducing target organ damage. The study designs and objectives of major hypertensive trials that include African-American cohorts are summarized in Table I.

Table I.  Summary of Large Randomized Antihypertensive Therapy Trials Involving African American Cohorts
StudyDesignPatient CharacteristicsDosage Regimen (mg/day)No. of PatientsObjective
AASK12R, DB, ACAA hypertensives 18–70 years old with renal insufficiencyRamipril 2.5–10*436Impact of treatment on progression of hypertensive kidney disease
   Amlodipine 5–10*217 
   Metoprolol 50–200*441 
ALLHAT15,16R, DB, ACHigh-risk hypertensives 55 years or older +geqslant R: gt-or-equal, slanted1 other cardiovascular risk factor (35% AA)Chlorthalidone 12.5–2515,255Impact of treatment on combined incidence of fatal coronary heart disease and nonfatal myocardial infarction
   Amlodipine 2.5–109048 
   Lisinopril 10–409054 
HDFP5R, ACHypertensives 30–69 years old (44% AA)Aggressive (stepped care)5485Impact of treatment on 5-year mortality rate
   Usual (referred care)5455 
LIFE9R, DB, ACHypertensives with left ventricular hypertrophy 55–80 years old (11% AA)Losartan 50–100533Impact of treatment on cardiovascular morbidity and death
   Atenolol 50–1004588 
SHEP7R, DB, PC60 years or older with isolated systolic hypertension (14% AA)Chlorthalidone 12.5–25 ±
atenolol 25–50
2365Impact on risk of total stroke (nonfatal and fatal)
   Placebo2371 
*Other agents added to achieve usual or low mean arterial pressure goal; additional agents (reserpine, clonidine, atenolol, and hydralazine) could be added if the maximum tolerable dose of a first-line agent provides inadequate blood pressure control; hydrochlorothiazide and other antihypertensives added as needed to achieve blood pressure goal. AA=African American; AASK=African American Study of Kidney Disease and Hypertension; AC=active control; ALLHAT=Antihypertension and Lipid-Lowering Treatment to Prevent Heart Attack Trial; DB=double blind; HDFP=Hypertension Detection and Follow-up Program; LIFE=Losartan Intervention for Endpoint Reduction; PC=placebo controlled; R=randomized; SHEP=Systolic Hypertension in the Elderly Program

Hypertension Detection and Follow-Up Program (HDFP)

The HDFP5 was a randomized controlled trial designed to determine the efficacy of aggressive and systematic antihypertensive therapy (stepped care) compared with usual care (referred care) in reducing mortality in different subgroups of patients. The study enrolled 10,940 hypertensive adults, including 4850 African Americans. Patients were stratified according to severity of hypertension: stratum I, diastolic blood pressure (DBP) 90–114 mm Hg; stratum II, DBP 105–114 mm Hg; stratum III, DBP geqslant R: gt-or-equal, slanted115 mm Hg.

After 5 years of follow-up, blood pressure control was consistently better in patients randomized to stepped care than for those in the referred care group.6 More than one half of patients receiving stepped care achieved the target DBP goal of <90 mm Hg.

Stepped care was also associated with lower morbidity and mortality than referred care.5 Mortality rates were lower among African Americans receiving stepped care than those in the referred care group for all DBP strata.5 Five-year mortality rates ranged from 9.9%–11.2% and 4.6%–5.7%, respectively, for African American men and women receiving stepped care compared with 12.2%–15.4% and 7.2%–7.9%, respectively, for men and women receiving referred care. The stepped-care strategy also decreased the difference in mortality between black and white subjects. Indeed, mortality among African Americans in the stepped-care group was lower than for whites receiving stepped care in three of the six subgroups (DBP stratum II and III women and DBP stratum III men). These data provide strong evidence for the value of aggressive therapy in African Americans with hypertension, regardless of the severity of disease.

Systolic Hypertension in the Elderly Program (SHEP)

The SHEP7,8 was designed to determine whether treatment with chlorthalidone with or without atenolol could reduce the risk of nonfatal and fatal stroke in elderly patients with isolated systolic hypertension.7,8 This study included 4736 individuals (14% African American) aged 60 years or older with a systolic blood pressure (SBP) between 160–219 mm Hg and a DBP <90 mm Hg. Patients were randomized to an active stepped-care regimen or placebo. All patients receiving active treatment were treated with chlorthalidone 12.5 mg/day, increasing to 25 mg/day for those not reaching their blood pressure goal (a reduction in SBP of at least 20 mm Hg). Atenolol 25–50 mg/day could be added if maximal doses of chlorthalidone did not produce the desired blood pressure reduction.

Active treatment was associated with mean reductions in SBP and DBP of 26 and 9 mm Hg, respectively, compared with baseline.7 The corresponding declines for the placebo group were 15 and 4 mm Hg (a difference of −11/5 mm Hg). The blood pressure goal was achieved in 65%–72% of patients receiving active treatment.7

After an average follow-up of 4.5 years, active treatment produced significant reductions in a number of clinical outcomes.7 Active treatment was associated with a relative risk of 0.64 for total stroke (reduction of 36%), 0.73 for nonfatal myocardial infarction plus coronary death (reduction of 27%), 0.68 for major cardiovascular events (32% reduction), and 0.87 for all-cause mortality (13% reduction) compared with the placebo group. The benefit of active treatment for stroke risk reduction was evident irrespective of the baseline SBP. A favorable effect was also seen in three of the four sex-race groups (African American women, white men, and white women). The apparent lack of benefit in African American men was likely due to the small number of stroke events in this patient group.

Losartan Intervention for Endpoint Reduction (LIFE)

The LIFE study9,10 was designed to determine the relative effects of a losartan-based, compared to an atenolol-based, treatment regimen in reducing cardiovascular morbidity and mortality in patients with hypertension and signs of left ventricular hypertrophy (LVH). The study included more than 9000 patients aged 55–80 years with essential hypertension and electrocardiographic signs of LVH. The treatment arms were losartan (50–100 mg/day) or atenolol (50–100 mg/day) with dosage increases and the addition of other antihypertensive agents (hydrochlorothiazide ± other agents) dependent on reaching a target blood pressure of 140/90 mm Hg. Patients were followed-up for at least 4 years.

Blood pressure was substantially decreased in both treatment groups with reductions of 30.2 and 16.6 mm Hg, respectively, in SBP and DBP for the losartan group compared with decreases of 29.1 and 16.8 mm Hg, respectively, for the atenolol group. Target blood pressure was achieved in 49% of losartan-treated patients compared with 46% of those in the atenolol group. The angiotensin receptor blocker (ARB)-based program was significantly more effective than the β blocker regimen in reducing the primary composite end point of cardiovascular death, stroke, and myocardial infarction, with a 13% relative risk reduction after adjustment for Framingham risk score and degree of LVH at baseline (most of the benefit for difference in outcome was accounted for by the difference in stroke events).9 Death from cardiovascular disease (11% relative risk reduction), fatal or nonfatal stroke (25% relative risk reduction), and new-onset diabetes was also reduced in the losartan group compared with the atenolol group.9 Similar benefit was seen in the subgroup of patients with diabetes.10

However, in a subsequent subgroup analysis, it was discovered that, unlike in other patient groups, losartan was significantly less effective than atenolol in the 533 black patients included in the trial. These patients had a lower risk of cardiovascular death, myocardial infarction, and stroke in the atenolol-based group than in patients receiving losartan (11% vs. 17%), despite similar blood pressure lowering with both drugs and a greater reduction in LVH with losartan.11

African American Study of Kidney Disease and Hypertension (AASK)

The AASK was designed to assess the impact of three different treatment regimens (ramipril, amlodipine, and metoprolol) and two different blood pressure goals (low and usual) on the progression of hypertensive kidney disease.12–14 A total of 1094 adult African Americans with a glomerular filtration rate between 20 and 65 mL/min/1.73 m2 with hypertension and no other identifiable cause of kidney disease were included. Patients were randomized to receive ramipril (2.5–10 mg/day), amlodipine (5–10 mg/day), or sustained-release metoprolol (50–200 mg/day) with mean arterial pressure goals of 102–107 mm Hg and <92 mm Hg, respectively, for the usual-and low-goal groups. Additional agents (furosemide, doxazosin, clonidine, hydralazine, and minoxidil) were added if the mean arterial pressure goal was not met.

No difference in renal outcomes was noted in those randomized to the higher blood pressure goal (mean achieved blood pressure of 141/85 mm Hg) compared with those assigned to the lower goal (mean achieved blood pressure of 128/78 mm Hg). While the primary analysis based on the rate of decline in glomerular filtration rate did not establish a definitive difference between the three drug regimens, the main clinical analysis that was based on the composite of a 50% or >25 mL/min/173 m2 decline in glomerular filtration rate, deaths, and end-stage renal disease suggested that the ramipril-based treatment regimen retarded the progression of renal disease to a significantly greater extent than amlodipine and metoprolol (Figure 1 and Table II).

Figure 1.

Figure 1.

Change in glomerular filtration rate (GFR; mL/min/1.73 m2) according to baseline urinary protein/creatine (UP/Cr) ratio in patients receiving a regimen based on amlodipine or ramipril in the African American Study of Kidney Disease and Hypertension (AASK). Reprinted with permission from JAMA. 2001;285:2719–2728.12

Table II.  Decline in Glomerular Filtration Rate (GFR), Death, and End-Stage Renal Disease (ESRD) in the AASK Trial
OutcomesUsual vs. Low BP GoalAmlodipine vs. MetoprololRamipril vs. MetoprololRamipril vs. Amlodipine*
SBP (achieved)141 vs. 128133 vs. 135135 vs. 1351354 vs. 133
DBP (achieved)85 vs. 7881 vs. 8182 vs. 8182 vs. 81
GFR slope analysisNot definitiveNot definitiveNot definitiveNot definitive
GFR, ESRD, or death (RR)−2 (−31 to 20)
p=0.85
20 (−10 to 41)22 (1–38)38 (14–56)
GFR event or ESRD (RR)−2 (−31 to 20)24 (−9 to 47)22 (−2 to 41)40 (14–59)
ESRD alone (RR)6 (−29 to 31)59 (36–74)22 (−10 to 45)59 (36–74)
AASK=African American Study of Kidney Disease and Hypertension
*Secondary comparison described in previous publication; all risk reductions (RR) adjusted for prespecified covariates: baseline proteinuria, mean arterial pressure, gender, history of heart disease, and age. Risk difference for ESRD or death composite and ESRD alone also adjusted for baseline GFR; GFR event, ESRD, or death: main secondary composite clinical outcome with 340 events, including 179 declining GFR events, 84 additional participants with ESRD event, and 77 deaths; GFR event or ESRD; composite end point with 263 events, including 179 declining GFR events and 84 additional participants with ESRD events; ESRD or death; composite end point with 251 events, including 171 ESRD events and 80 deaths; and ESRD alone: end point with 171 events and deaths censored in this analysis. Adapted with permission from JAMA. 2002;288:2421–2431.15

Of note, a high proportion of patients in this study were able to achieve target blood pressure levels.14 Almost 80% of patients in the low mean arterial pressure goal group were able to achieve a blood pressure of <140/90 mm Hg after 14 months of treatment. Effective blood pressure control was achieved irrespective of age, sex, body mass index, education, insurance or employment status, income, or marital status.14 Multiple drugs were necessary to achieve goal pressures in a large majority of patients. More than three quarters of the patients received a diuretic as part of the treatment regimen.

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

The ALLHAT was designed to assess the effect of treatment (chlorthalidone, amlodipine, lisinopril, or doxazosin) on the combined incidence of fatal coronary heart disease and nonfatal myocardial infarction.16–18 This study also contained an open-label component to assess whether lowering low-density lipoprotein cholesterol levels with pravastatin would reduce all-cause mortality compared to patients receiving usual care. The study was conducted in a clinic-based setting; more than one half of the sites (54%) were private practices, and about one fourth had no previous research experience.

More than 42,000 patients (15,133 blacks) with hypertension who were at least 55 years old and had at least one other risk factor for cardiovascular disease were randomized to receive chlorthalidone (12.5–25 mg/day), amlodipine (2.5–10 mg/day), lisinopril (10–40 mg/day), or doxazosin (2–8 mg/day). Additional antihypertensive medications were allowed for patients who did not attain satisfactory blood pressure control with maximum tolerated doses of the randomized medication. However, because diuretics, ACE inhibitors, calcium channel antagonists, and α blockers were among the blinded agents, these drugs were not allowed to be used as add on or as second-step drugs.19 The primary end point was combined fatal coronary heart disease and nonfatal myocardial infarction. The planned mean duration of treatment and follow-up was 6 years.

Overall, more than 65% of patients achieved SBP levels <140 mm Hg. More than 90% achieved goal DBP levels. In ALLHAT, with more than 15,000 diabetic patients, chlorthalidone was also unsurpassed by either amlodipine, doxazosin, or lisinopril in cardiovascular event reduction in this subgroup.18 In addition, despite previous reports of an increased rate of coronary events associated with the dihydropyridine calcium channel blockers in patients with diabetes, this was not supported by ALLHAT.

There was no difference in rates of myocardial infarctions and fatal coronary heart disease (the primary end point) or in mortality. Participants randomized to the thiazide-type diuretic were more likely to achieve a blood pressure <140/90 mm Hg and remain on their assigned drug. Furthermore, the diuretic was unsurpassed in preventing one or more of several major clinical end points. Chlorthalidone was significantly better in reducing heart failure compared to doxazosin, lisinopril, and amlodipine, and in reducing stroke compared to lisinopril and doxazosin. These differences in outcome were even greater in the black ALLHAT cohort, especially in the comparisons between the chlorthalidone and lisinopril groups (Table III). While the differences in outcome between the chlorthalidone and lisinopril groups were not significantly reduced by statistically adjusting for the blood pressure difference, an effect of the blood pressure difference to the difference in treatment outcomes cannot be excluded.18 These guidelines may need to be reevaluated in light of ALLHAT, especially in African Americans.

Table III.  Clinical Outcomes in ALLHAT by Antihypertensive Treatment Group18
 ChlorthalidoneAmlodipineDoxazosinLisinopril
Whole Cohort
  Mean SBP (4 year)134135135136
  Mean DBP (4 year)77767677
  Percent <140/90 mm Hg67.165.8 63.1
   (Chl vs. Dox)(64) (58) 
  ESRD1.01.12 (0.89–1.40) 1.11 (0.88–1.38)
Black subgroup
  RR fatal/nonfatal myocardial infarction (vs. Chl)1.00.98 (0.90–1.07) 0.99 (0.91–1.08)
  Mortality1.00.97 (0.87–1.09) 1.06 (0.95–1.18)
  Cardiovascular disease1.01.06 (0.96–1.16)1.4 (1.25–1.57)1.19 (1.09–1.30)
  Coronary heart disease1.01.02 (0.90–1.15) 1.16 (1.03–1.31)
  Cerebrovascular accident1.00.93 (0.76–1.14) 1.4 (1.17–1.68)
  Heart failure1.01.47 (1.24–1.74)2.18 (1.73–2.74)1.32 (1.11–1.58)
ALLHAT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; RR=relative risk

APPROACH TO TREATMENT

Combination Therapy

Monotherapy is ineffective in achieving adequate blood pressure reductions in most high-risk patients with hypertension.20 Such patients usually require combination therapy to achieve target blood pressure levels.21 Indeed, a large percentage of patients in the previously discussed trials required multiple medications to reach target goals. For example, the high degree of success in achieving blood pressure targets in AASK14 was primarily due to the aggressive use of combination therapy. In this study,14 an average of three agents was required to reach target levels. Similarly, in the LIFE trial,9 only 11%–12% of patients were receiving monotherapy with the primary study medications at the end of the trial. This is consistent with the results from other trials. A review of clinical trials involving patients with diabetes or renal impairment showed that an average of 3.2 different antihypertensive agents were required to achieve a low blood pressure goal (Figure 2).20

Figure 2.

Figure 2.

The number of antihypertensive drugs required for blood pressure control in recent clinical trials. AASK=African American Study of Kidney Disease and Hypertension; ABCD=Appropriate Blood Pressure Control in Diabetes; HOT=Hypertension Optimal Treatment Trial; MDRD=Modification of Dietary Protein in Renal Disease; UKPDS=United Kingdom Prospective Diabetes Study; MAP=mean arterial pressure Reprinted with permission of Elsevier Science from Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646–661.20

The use of combination therapy is especially important for African Americans, who have a higher prevalence of more severe (stage 3) hypertension and a suboptimal blood pressure response to monotherapy with many antihypertensive agents (e.g., ACE inhibitors and β blockers). Appropriate combinations can often provide additive antihypertensive effects while minimizing adverse events.22 These beneficial drug interactions are particularly appropriate for African Americans. For example, although ACE inhibitors are less effective in these individuals when used as monotherapy, the response is similar to that of white patients when ACE inhibitors are given in combination with a diuretic.23 In addition, the combination of an ACE inhibitor plus a dihydropyridine calcium antagonist is associated with less pedal edema than the calcium antagonist alone.

Specific Patient Groups

Because there is a clear correlation between the degree of blood pressure reduction and the reduction of clinical events, the ability to achieve target blood pressure goals is likely to have a substantial effect on outcome. For patients with uncomplicated hypertension, the blood pressure goal established by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)22 is <140/90 mm Hg, with lower levels desirable if treatment is tolerated. For certain high-risk patient groups with coexisting conditions, a blood pressure goal of 140/90 mm Hg may not be optimal; lower target blood pressure levels are recommended for patients with diabetes, proteinuric renal disease, and heart failure.22

For hypertensive patients, especially African Americans, with uncomplicated hypertension, thiazide-type diuretics are the preferred antihypertensive agents based on their proven ability to decrease hypertensive-related morbidity and mortality.18,22 However, in patients with certain concomitant conditions there may also be indications for other antihypertensive agents.

In patients with diabetes, the new American Diabetes Association guidelines24 recommend that ACE inhibitors, ARBs, β blockers, calcium channel blockers, and diuretics are all appropriate as initial drug therapy for patients with hypertension. For diabetic hypertensive patients with microalbuminuria, an ACE inhibitor or an ARB should be used (usually with a diuretic).24 ACE inhibitor therapy should also be considered for hypertensive patients with renal disease.15,22

In patients with heart failure, the JNC VI recommends the use of ACE inhibitors and diuretics.22 Additionally, the importance of β blockers for reducing heart failure mortality has recently been established in these patients.25 The benefits of these agents for the treatment of blacks with heart failure seem to be of a similar magnitude to that observed in whites.26 The combination of a β blocker and a diuretic are also highly effective for producing blood pressure control.

LVH is a substantial problem for African Americans; this group has a higher risk for progression of heart failure and death than whites.27 For these patients, diuretics seem to have the greatest efficacy in reducing left ventricular mass. Isolated systolic hypertension and prior myocardial infarction are other compelling indications for using specific antihypertensive classes of drugs. For patients who have had a myocardial infarction, β blockers without intrinsic sympathomimetic activity are recommended. Among the subset of postmyocardial infarction patients with systolic dysfunction, ACE inhibitors should be used.28

Despite concerns regarding the lower response to ACE inhibitors, ARBs, and β blockers in African Americans compared with white patients when used as monotherapy, these agents are indicated as part of a treatment regimen for the above indications regardless of race or ethnicity.22 Clinicians should be aware that the addition of diuretics to ACE inhibitor therapy is required to achieve a blood pressure reduction similar to that in whites.

SUMMARY

Aggressive blood pressure control has been shown to decrease target organ damage and reduce clinical events and death in patients with hypertension. Because African Americans have a higher prevalence of hypertension and its related complications, appropriate treatment can have a substantial clinical impact for these patients. Achievement of target blood pressure goals requires the selection of the appropriate agents(s) for the given clinical indication and the use of appropriate dosages and drug combinations.

For most hypertensive patients, especially African Americans, this regimen should include a thiazidetype diuretic. Calcium channel blockers, ACE inhibitors, and β blockers can be considered as first-step therapy in the unusual circumstance in which the patient cannot take a diuretic. The vast majority of African American hypertensive patients will require multiple agents to achieve recommended blood pressure goals, and aggressive lifestyle intervention is critical to successful management.

Ancillary