Angiotensin‐Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in African‐American Patients With Hypertension

Abstract

African‐American patients with hypertension are less responsive to blockers of the renin‐angiotensin system than white patients. The relative efficacy of angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers and the extent of cross‐resistance to these agents has not been studied. Fifty‐one African‐American patients with stage 1–2 hypertension were randomly assigned to enalapril or candesartan cilexetil for 8 weeks and then crossed over to the other treatment. Nonresponders to enalapril and candesartan used a combination of the two. Of the 51 patients randomized (average age 61.2±9 years, blood pressure 148/100 mm Hg, heart rate 74 bpm, and body weight 92.8 kg), 44 completed the study. At Week 8, systolic blood pressure (SBP) was reduced by 4.8 mm Hg with enalapril and by 4.7 mm Hg with candesartan (p=NS), and diastolic blood pressure (DBP) was reduced by 4.4 mm Hg and 5.6 mm Hg, respectively (p<0.04). Of these 44 patients, 11 (25%) responded to enalapril by SBP criteria and 19 (43%) by DBP criteria. Seven patients (16%) responded by both SBP and DBP criteria, and 21 patients (48%) were nonresponders. With candesartan, 13 patients (29%) responded by SBP criteria, 20 (45%) by DBP criteria and 12 (27%) by both SBP and DBP criteria (p<0.04, compared with enalapril). Only six patients (14%) responded to both enalapril and candesartan by both SBP and DBP criteria. Of the 18 nonresponders to either enalapril or candesartan, the combination of the two had minimal additional effect. Significant changes in plasma‐renin activity and angiotensin II levels were noted only with the high dose of each drug. In this small group of patients, treatment with candesartan resulted in slightly higher response and control rates than enalapril, more than 40% of patients who responded to enalapril did not respond to candesartan and vice versa, and in nonresponders, a combination of candesartan and enalapril offered little additional antihypertensive effect.

The prevalence of hypertension is higher in African Americans (32%) than in the rest of the US population (24%). African Americans have more severe forms of hypertension and experience more frequent and more debilitating cardiovascular complications than white patients of similar age. ¹ , ² Hypertension appears at an earlier age in African Americans; produces more pronounced end organ damage; and in general, is more difficult to treat. ³ Efficacy of various pharmacologic therapies is also different. African‐American patients appear to respond better to diuretics and calcium channel blockers, whereas the response to β blockers and other blockers of the renin‐angiotensin‐aldosterone system (RAAS) is less than in white patients. This has been attributed partially to the fact that African‐American patients more frequently have low‐renin, high‐volume hypertension. ⁴

Several studies have shown poor response of African Americans to angiotensin‐converting enzyme (ACE) inhibitors, ⁵ , ⁶ , ⁷ , ⁸ , ⁹ whereas others suggested that African‐American patients require higher doses of ACE inhibitors. ⁵ , ⁸ More recently, studies with angiotensin receptor blockers (ARBs) have shown blood pressure (BP) response in African Americans that is less than that in whites, ¹⁰ , ¹¹ but this difference was eliminated when ARBs were combined with low‐dose diuretics. ¹² , ¹³ This has also been shown to be true for ACE inhibitors when given in combination with a diuretic. ⁷

While ACE inhibitors and ARBs have been studied separately in African Americans, ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ comparative studies are scarce. Furthermore, it is not known whether these patients who do not respond to ACE inhibitors are also resistant to ARBs and vice versa and whether there is an additive antihypertensive effect when ACE inhibitors and ARBs are combined at their highest recommended doses.

This study was designed to assess the relative efficacy of the ACE inhibitor enalapril and the ARB candesartan cilexetil on resting BP in African‐American patients with hypertension, and to address potential cross‐resistance, possible pathophysiologic mechanisms of resistance, and or synergistic effects of the two agents.

Patients

For the purpose of this study, 51 patients with hypertension of African‐American descent with stage 1–2 hypertension were enrolled from the hypertension research clinic at the Veterans Affairs Medical Center in Washington, DC. Patients were eligible for the study if they were newly diagnosed with stage 1–2 hypertension (diastolic blood pressure [DBP] 90–110 mm Hg), or treated hypertensives who met inclusion criteria after 2–4 weeks of washout and had none of the exclusion criteria. Patients with a history of myocardial infarction; symptomatic coronary artery disease; congestive heart failure; significant liver, kidney, or lung disease; or patients unable to provide informed consent were excluded from the study.

STUDY PROTOCOL

The crossover design of the protocol is shown in Figure 1. Following the qualifying period, eligible patients were randomized to candesartan 16 mg daily or to enalapril 10 mg daily for 4 weeks. BP was measured in the sitting position following at least 5 minutes of rest in a quiet room. The patient was seated with his back supported and legs uncrossed. A mercury sphygmomanometer was used, and three measurements, taken 1 minute apart, were averaged to provide the BP for that visit. Patients were seen, and BP measured every 2 weeks, but changes in medication dosage were made at 4 weeks of therapy. In nonresponders, doses were increased to 32 mg daily for candesartan or 20 mg for enalapril for another 4 weeks. At the end of this period, following a 2‐week washout period, patients were crossed to the opposite arm (enalapril 10 mg daily or candesartan 16 mg daily), and the same protocol was repeated. At the end of the second phase, patients not responding to either enalapril or candesartan were treated with the combination of the two: initially, 16 mg candesartan plus 10 mg enalapril increased to 32 mg candesartan plus 20 mg enalapril if not controlled on the lower dose. Laboratory workup, including plasma renin activity (PRA) and angiotensin II levels (A‐II) were performed at baseline at 4 and 8 weeks of each monotherapy and at the end of each phase of the combination therapy.

Figure 1.

Following an initial washout period of 2–4 weeks, qualified patients were randomized to enalapril 10 mg daily or candesartan 16 mg daily for 4 weeks. Doses were increased if patients not controlled. Following a second washout period, patients were crossed to the other treatment. Patients not controlled on either therapy progressed to phase 3, combination therapy.

PRA and A‐II

Blood samples were collected following a 30‐minute rest, and samples were analyzed by a commercial research laboratory (Quest Diagnostics) following standard techniques and procedures.

Efficacy Measures

All BP measurements were taken by the same fully certified nurse coordinator. BP was measured in the sitting position with a conventional mercury sphygmomanometer, after at least 5 minutes of rest. At each visit, sitting systolic blood pressure (SBP) and DBP were measured at least three times, 1 minute apart, and values were averaged. The primary end point of the study was change of DBP at 8 weeks of treatment. Secondary end points included changes in SBP, PRA and A‐II levels.

Statistical Analysis

Due to the crossover design of the study, all patients were treated with candesartan and enalapril. Based on BP responses from previous studies, this study was powered to detect differences of 2 mm Hg between groups.

The Student t test was used to assess differences in efficacy between treatment groups and placebo or differences between treatment groups. To assess differences between responders or patients controlled in each group, the χ ² test was utilized.

RESULTS

All patients in this study were African‐American men with hypertension. Of the 51 patients randomized into the study, 44 completed the two monotherapy phases and 18 patients completed the combination phase. Baseline characteristics of these patients are shown in Table I.

The average age of patients was 61.2 years, with an average height and weight of 175.3 cm and 92.8 kg, respectively. The average baseline sitting BP at the end of the washout period was 148/100 mm Hg, and the average standing BP was 154/108 mm Hg. Renal and liver function tests, electrolytes, and other biochemical measures were within normal limits. Approximately one third of patients were on statin therapy and low‐density lipoprotein (LDL) cholesterol averaged 98 mg/dL. High‐density lipoprotein levels averaged 53 mg/dL, which is consistent with findings from other studies. PRA was on the low end of normal, but A‐II levels were within normal ranges.

Table II shows the change from baseline in sitting SBP and DBP at Weeks 4 and 8 of treatment. All patients progressed from the low dose of each monotherapy at Week 4 to the higher dose. Changes in BP at Week 4, using the low dose of each monotherapy, were small and not significantly different from placebo. At Week 8 on higher dosages, the average change from baseline with enalapril was 4.8 mm Hg for SBP and 4.4 mm Hg for DBP (p<0.01 for both). For candesartan, changes were 4.7 mm Hg and 5.6 mm Hg, respectively (p<0.01 for both). At Week 8, average change in DBP with candesartan was significantly greater than the change with enalapril (p<0.04).

The percentages of responders to each monotherapy using SBP or DBP criteria were only slightly higher for candesartan than enalapril; p values did not reach statistical significance. When both criteria were used together in the same patient, more patients met the criteria with candesartan than with enalapril (p<0.04) (Figure 2). Similarly, when the criteria for reaching target BP control (<140/90 mm Hg) were considered, more patients were controlled with candesartan than with enalapril (p<0.04) (Figure 3).

Figure 2.

Percent of responders to enalapril or candesartan cilexetil for systolic blood pressure (SBP), diastolic blood pressure (DBP), or both pressure values. Response for SBP was considered a decrease of ≥10 mm Hg and response for DBP was considered a decrease of ≥5 mm Hg.

Figure 3.

Percentage of controlled patients on each monotherapy. Treatment effect was assessed during both phases of monotherapy (patients considered controlled when both systolic and diastolic blood pressures were below target of140/90 mm Hg).

Eighteen of the 44 patients in this study did not respond to either monotherapy and participated in the third phase of the study, which was combination therapy. In these patients, baseline SBP was slightly higher and DBP slightly lower than the total group (150/99 mm Hg). Treatment with monotherapy resulted in only a 1–2 mm Hg change in SBP or DBP. There was no improvement in BP response (Table II) with combination therapy for either the low or high dose.

Table II.

Mean Change in Blood Pressure From Baseline (mm Hg)

Therapy	4 Weeks	8 Weeks
Monotherapy (n=44)
SBP/enalapril	−0.1	−4.8*
DBP/enalapril	−5.7*	−4.4*
SBP/candesartan	1.4	−4.7*
DBP/candesartan	−2.9	−5.6**
Combination therapy (n=18)
SBP/enalapril + candesartan	5.1	1.3
DBP/enalapril + candesartan	−1.1	−1.2
SBP=systolic blood pressure; DBP=diastolic blood pressure; *p<0.01 compared with placebo; **p<0.04 compared with enalapril

Table III shows the changes in serum potassium, serum creatinine, PRA, and A‐II levels. No significant changes were noted with either monotherapy or combination therapy in serum potassium or creatinine. PRA increased significantly only at 8 weeks with the high dose of enalapril or candesartan therapy. A‐II was reduced significantly only with the high dose of enalapril at Week 8 of therapy (p<0.05).

Figure 4 shows the degree of overlap of nonresponders to each monotherapy. Of the patients who responded either by SBP or DBP criteria to enalapril, only about half responded to candesartan, and of those patients who initially responded to candesartan, only about 60% responded to enalapril (p=nonsignificant).

Figure 4.

Panels A and B demonstrate the overlap in responders between the two monotherapies. Approximately 40% of patients who responded to one monotherapy did not respond to the other and vice versa. SBP=systolic blood pressure; DBP=diastolic blood pressure

DISCUSSION

African‐American patients with hypertension have been shown to respond less than white patients to blockers of the RAAS. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ Although no good explanation has been proposed, low‐renin/high‐volume hypertension has been implicated. Some research suggests these patients may respond adequately to higher doses or to the combination of the two classes of agents. Our study was designed to assess and compare the effect of the ACE inhibitor enalapril to the effect of the ARB candesartan on BP in African Americans with stage 1–2 hypertension. The doses chosen were those that are commonly used in daily practice. Patients who did not respond to either monotherapy were treated with the combination of the two agents to assess whether higher levels of blockade would be beneficial. In general, the changes seen with either enalapril or candesartan were small, and only enalapril produced significant DBP reduction at the low dose. At the higher dose, each monotherapy was only minimally effective in reducing SBP and DBP. The reduction of DBP was somewhat greater with candesartan than with enalapril, and more patients were controlled to target with candesartan than with enalapril. Changes noted in this study are consistent with previous trials in African Americans, and they confirm the lesser response of these patients to blockers of the RAAS. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ This study provided a number of interesting observations, including that candesartan was slightly more effective than enalapril at the doses used, suggesting that AT₁ receptor blockade may be more important than ACE inhibition in this group of patients; that approximately 40% of patients not responding to enalapril responded to candesartan and vice versa, suggesting that the mechanism by which BP is reduced may be different between ACE inhibitors and ARBs; that a low dose of either drug was essentially ineffective in reducing BP, attesting to the previous suggestion that African‐American patients may not respond to even high doses (in nonresponders to monotherapy, combination of the two was ineffective, suggesting a minimal role of the RAAS in this subgroup of patients); and that the effect of either treatment on PRA and A‐II levels was minimal.

PRA is expected to increase substantially with use of both ACE inhibitors and ARBs. In this study, the low dose of either drug failed to significantly influence PRA, thus corroborating the lack of effect on BP. The high dose of either monotherapy increased PRA as expected, by four‐fold, but the effect was less than is usually seen in white patients. Furthermore, A‐II decreased marginally and only with the high dose of enalapril. It is possible that higher doses might have produced different results, but this is speculative. We cannot exclude the possibility that the levels of A‐II had returned toward baseline, since levels were measured at 4 and 8 weeks of therapy. Previous studies have shown that levels of A‐II are significantly reduced within 24 hours post‐ACE inhibition, but gradually returned toward baseline. ¹⁴ This process, however, may take up to 6 months. The fact that we saw no change with the low dose of enalapril and only marginal reduction with the high dose suggests either suboptimal blockade with ACE inhibitors in African Americans or very active alternative pathways for the production of A‐II. ¹⁵ Either way, this may, in part, explain the lesser BP‐lowering effect of ACE inhibitors in this group of patients. Similarly, treatment with candesartan increased PRA significantly only with the higher dose and had no effect on A‐II levels, again suggesting that higher doses are needed in this group of patients. In this study, we had no white patients, and direct comparison cannot be made.

Disclosure: This study was supported by an unrestricted grant from AstraZeneca Pharmaceuticals LP.