Differing Mechanisms of Action of Angiotensin-Converting Enzyme Inhibition in Black and White Hypertensive Patients
Abstract The antihypertensive effect of the angiotensin-converting enzyme inhibitor trandolapril administered in doses of 1, 2, and 4 mg/d was compared in 207 white patients and 91 black patients with mild to moderate hypertension following a double-blind, randomized, placebo-controlled, parallel study design. Trandolapril is a prodrug that is rapidly hydrolyzed to its active diacid metabolite, trandolaprilat. After 6 weeks of double-blind treatment, trandolapril lowered baseline sitting diastolic pressure in both white and black patients. A comparison of the antihypertensive response of the two populations revealed that the black patients required between two and four times the dose of trandolapril to obtain a response similar to that observed in the white patients. A dose of 1 mg/d trandolapril resulted in a 6.1 mm Hg mean decrease in baseline sitting diastolic pressure for white patients; a similar response (−6.5 mm Hg) was observed in the black patients at 4 mg/d. In contrast to the population differences in blood pressure, the decreases in angiotensin-converting enzyme activity were similar for both populations. An evaluation of trandolaprilat levels revealed that there were no racial differences in the trandolaprilat concentrations required to achieve a given degree of angiotensin-converting enzyme inhibition. Therefore, it appears that the antihypertensive response of black patients is not completely explained by a reduction in angiotensin-converting enzyme activity. The lack of response at a lower dose but increasing response at a higher dose could reflect another vasodepressor activity of trandolapril or just be evidence of reduced sensitivity of high blood pressure in blacks to angiotensin-converting enzyme inhibition.
Previous clinical trials have demonstrated that black hypertensive patients do not respond as well to angiotensin-converting enzyme (ACE) inhibitors as do nonblack hypertensive patients.1 2 3 This differential response may be explained by the greater tendency toward plasma volume expansion and a low-renin, more sodium-sensitive profile in hypertensive patients of African American descent.4 5 ACE inhibitors result in a better clinical response in patients who have increased renin levels such as commonly seen in white hypertensive patients.6
This study examined the efficacy of a new second-generation non–sulfhydryl-containing ACE inhibitor in a population of white and black hypertensive patients in relation to its effects on the renin-angiotensin-aldosterone axis. Trandolapril is a substituted octahydro-indole-2-carboxylic acid. It is a prodrug that in vivo is rapidly hydrolyzed to its active diacid, trandolaprilat. Several clinical trials have shown its clinical safety and efficacy in lowering both diastolic blood pressure (DBP) and systolic blood pressure (SBP) in patients with mild to moderate essential hypertension.7 8 Because of the lipophilic nature of the active moiety, which results in a steady-state half-life of 16 to 24 hours, it has the advantage of offering therapeutic activity with a once-a-day dosing schedule.
This was a randomized, double-blind, parallel-group, placebo-controlled study in which the dose-response characteristics of trandolapril were evaluated in populations of white and black patients. Patients who had been newly diagnosed with or had previously been treated for mild to moderate hypertension discontinued all antihypertensive medications and entered into a single-blind, placebo run-in period of 4 weeks.
Only patients with mild to moderate hypertension (supine DBP between 95 and 114 mm Hg) during the final 2 weeks of this run-in period (based on readings at each of the final two visits of the placebo lead-in period) were randomized to receive double-blind medication.
After the 4-week placebo run-in period, patients entered a 6-week double-blind period during which they were randomized to one of four treatment groups: placebo or 1, 2, or 4 mg trandolapril. Patients were monitored on a weekly basis during the placebo run-in period and during the first 2 weeks of the double-blind treatment period. The patients were seen at 2-week intervals for weeks 6 to 10 of the treatment period. Patients consumed their usual ad libitum dietary sodium intake.
Patients could be enrolled in the study if they were older than 21 years of age and had nonlabile, mild to moderate hypertension. Patients were not enrolled if they had any other form of hypertension (eg, malignant or severe); had suffered a cerebrovascular accident, convulsion, or hypertensive encephalopathy within the previous year; experienced a myocardial infarct within 3 months of the study or had a history of severe cardiac abnormalities (such as congestive heart failure, arrhythmias, conduction abnormalities, or atrioventricular block); been treated with antihypertensive medication within 4 weeks or spironolactone within 6 weeks of starting double-blind treatment; had evidence of renal, hepatic, hematologic, or other metabolic abnormalities that could interfere with study drug absorption, metabolism, or excretion; or had a history of drug abuse or addiction. Patients were excluded if they needed concomitant medications such as antidepressants, antiarrhythmic drugs, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory drugs, digitalis, major tranquilizers, or estrogen-containing drugs. The patients gave written informed consent as approved by the local Institutional Review Board.
Patients were monitored on a regular basis over the duration of the study. The time of day at which blood pressure was measured and trandolapril was administered was standardized between 8 and 10 am throughout the study. At each visit, an interim physical examination was done, vital signs and blood pressure were measured, compliance was evaluated, and the patient was questioned about the occurrence of adverse experiences. Special laboratory tests, including ACE activity, serum aldosterone levels, and serum renin activity, were measured at baseline and after 6 weeks of double-blind treatment. Samples were obtained with patients in the recumbent position after patients had been supine for 30 to 45 minutes. During the double-blind period, blood pressures were measured at “trough,” just before study drug dosing, and approximately 4 to 5 hours after administration, which coincides with peak plasma trandolaprilat concentrations and peak effect.9 Blood samples were also taken during double-blind treatment for measurement of trough and peak (4 to 5 hours after dosing) plasma levels of trandolapril and trandolaprilat.
Blood pressure measurements were made in the arm with the highest blood pressure readings. SBP was recorded at phase I of the Korotkoff sounds, and DBP at phase V. The mean of three consecutive (2 minutes apart) blood pressure measurements with patients in the supine, sitting, and standing positions was reported.
Methodology for Assays of Renin, Aldosterone, ACE Activity, Trandolapril, and Trandolaprilat
Plasma renin determinations were based on competitive binding principles of radioimmunoassay as previously described.10 Serum aldosterone determinations were performed with the use of radioimmunoassay procedures as described by Chattoraj and Watts.11 The methodology for spectrophotometric determination of serum ACE activity was as described by Lieberman.12 All assays were performed by SmithKline Beecham Clinical Laboratories, Van Nuys, Calif. Plasma concentrations of trandolapril and its diacid metabolite trandolaprilat were measured by radioimmunoassay. All samples were analyzed blindly by Analytical Solutions, Inc, Sunnyvale, Calif.
Patients were withdrawn from the study if supine DBP rose above 114 mm Hg at any point during the study and remained elevated above 114 mm Hg at a follow-up visit within 48 to 72 hours or if the physician investigator felt it was in the patient’s best medical interest.
Measures of Clinical Effectiveness
We used two criteria to measure clinical effectiveness. The first was the change in sitting DBP and SBP from baseline to end point. End point was defined as the end of the double-blind period or the last visit during which the patient received double-blind medication. The second was the number of patients who had a “satisfactory therapeutic response” at end point, which was defined as a reduction in baseline sitting DBP to less than 90 mm Hg or a decrease in sitting DBP of 10 mm Hg or more compared with baseline.
Statistical and Analytic Methods
The values of parameters at week 4 were used as the baseline values for the purposes of analyzing the differences between study populations in their responses to the various trandolapril doses. An intent-to-treat analysis was performed, in which mean end-point values for sitting DBP and SBP were used for measurement of the change from baseline. Baseline values for the two study populations were compared with a one-way ANOVA. Postbaseline differences between populations were compared with a one-way ANCOVA, with baseline values as covariates. Data are expressed as mean±SEM. Comparison of the numbers of responsive patients in each study population was performed with Fisher’s exact test.
Two hundred and ninety-eight patients of either sex with nonlabile, mild to moderate hypertension were enrolled at 21 study sites. Two hundred seven of the patients were white, and 91 patients were black. Ages ranged between 27 and 84 years (mean, 57.2±11.6 years) for the white population and between 28 and 77 years (mean, 53.3±10.2 years) for the black population.
Table 1⇓ summarizes the demographic and baseline data for each patient population. The biggest difference between the populations was the number of patients; the white population was 2.3 times larger than the black population. There were no significant differences between the treatment groups within each population nor between the treatment groups of each population. Four black patients and 12 white patients receiving trandolapril were withdrawn before completion of the study, as was 1 black patient and 10 white patients on placebo treatment. These patients were included in the efficacy analyses.
After 6 weeks of double-blind treatment, trandolapril lowered baseline sitting DBP in both white and black patients. For the white patients, mean decreases of 6.1, 8.1, and 8.9 mm Hg were observed for the 1-, 2-, and 4-mg dosage groups, respectively. These decreases were statistically significant (P<.05) compared with the decrease observed for the white placebo group (−3.1 mm Hg). The mean decreases in baseline sitting DBP observed for the black patients (2.0, 3.8, and 6.5 mm Hg for the 1-, 2-, and 4-mg dosage groups, respectively) were not statistically significant compared with the decrease observed for the black placebo group (−3.2 mm Hg), primarily because of the smaller sample size for the black group (see Fig 1⇓).
A comparison of the antihypertensive response of white and black patients revealed that black patients required between two and four times the dose to obtain a response similar to that observed in white patients. As shown in Table 2⇓, 1 mg/d trandolapril resulted in a 6.1 mm Hg mean decrease in baseline sitting DBP for white patients, whereas a similar response (−6.5 mm Hg) was observed in black patients at 4 mg/d. The changes observed for SBP followed patterns similar to those observed for DBP.
Analyses of patient responder rates gave results similar to those obtained from the change in DBP. A responder was defined as a patient who had a sitting DBP of less than 90 mm Hg or who had a decrease of 10 mm Hg of more at end point compared with baseline. Table 3⇓ shows the number of patients in each treatment group who met the requirements for a responder. The placebo-treated patients showed a 20% responder rate for the white population and 27% for the black population. For the white population the three trandolapril doses gave a dose response, which ranged from a 39% to 55% responder rate. The responder rate was significantly greater for the white population compared with the black population at trandolapril doses of 1 and 2 mg/d; the difference in response rates for the dose of 4 mg/d was not significantly different.
Renin, ACE Activity, Aldosterone, and Trandolaprilat Values
In marked contrast to the population differences in blood pressure, the decreases in ACE activity with trandolapril dose were similar for both study populations (Fig 1⇑). None of the serum ACE decreases were significantly different between populations. In addition, as shown in Table 4⇓, plasma trandolaprilat concentrations for both black and white patients were evaluated at ≤75%, ≤50%, and ≤25% ACE activity remaining for 1, 2, and 4 mg trandolapril. The results show that there were no racial differences in trandolaprilat concentrations required to achieve identical degrees of ACE inhibition. For a given ACE activity, trandolaprilat concentrations were the same for both populations. Based on these data, it appears that the antihypertensive effectiveness of trandolapril administered to black patients is not completely explained by a reduction in serum ACE activity.
As depicted in Fig 2⇓, relation curves comparing percent ACE activity remaining and trough trandolaprilat concentration were similar for the white and black populations. There was no statistical difference between black and white hypertensive patients for both the intercept (P=.54) and slope (P=.57) in this response.
Fig 3⇓ depicts the changes in plasma renin and aldosterone concentrations for each treatment group from baseline to end point. Renin showed a dose-related increase for both patient populations. Although the increases for the white treatment groups were greater than those for the corresponding black treatment groups, none of the differences between populations were significant. The changes in aldosterone levels show significant racial differences. While aldosterone levels showed a slight increase from baseline for all treatment groups in the white patient population, there was a dose-related decrease in the black population. The changes in aldosterone levels at end point for the two populations were significantly different for the 2-mg (P=.01) and 4-mg (P<.05) groups.
Safety was evaluated in all patients who received trandolapril. At the doses studied, trandolapril was well tolerated by both white and black patients. Table 5⇓ shows the most common adverse events reported by patients in this study. Adverse events necessitating patient withdrawal from the study occurred in 5 white patients: 3 during trandolapril therapy (atrial flutter, blurred vision, thrombocytopenia) and 2 during placebo lead-in.
Hypertensive disease in African Americans is an important clinical problem in that these patients have a greater frequency and intensity of hypertension, resulting in accelerated target-organ damage.13 14 15 16 17 18 19 Additionally, prior clinical studies have suggested that hypertensive blacks do not respond to all antihypertensive therapies to the same degree that nonblack hypertensive patients respond, perhaps because of different pathophysiological factors that characterize their hypertensive disease.4 5 Black hypertensive patients, both young and old, tend to be more sensitive to dietary sodium, with greater blood pressure increases, and have a variable tendency toward expanded plasma volume and increased peripheral and renal vascular resistances.4 5 These characteristics may explain why hypertensive blacks respond more effectively to medications that facilitate natriuresis, such as diuretics and calcium channel blockers.1 2 3 Likewise, prior studies have demonstrated that blacks do not respond as well to β-blockers or ACE inhibitors as do nonblack hypertensive patients because these therapies have proved to be more effective in patients who have higher renin levels and less of a tendency toward expanded plasma volume.1 2 3 One clinical trial has demonstrated that doubling ACE inhibitors doses will facilitate blood pressure control in black hypertensive patients.20
Prior clinical trials have addressed neither the comparative efficacy of ACE inhibitors in white and black hypertensive patients nor the question of whether inhibition of serum ACE is part of the antihypertensive activity of these drugs in blacks or whether there is another property of the drug that at higher doses facilitates blood pressure reduction. The antihypertensive properties of ACE inhibitors are largely believed to be related to the ability of these drugs to block serum ACE and thereby inhibit the formation of the vasoconstrictive peptide angiotensin II.21 However, it is also known that these drugs can increase bradykinin production21 and vasodilator prostaglandins of the E series21 as well as inhibit the formation of tissue ACE.22 23 Yet it is also possible that there may be other activities of ACE inhibitors that may be important for blood pressure reduction, including their ability to enhance sodium and water excretion by the kidney through the modulation of the renal/adrenal response to dietary sodium loading.24
The results from the present study show that greater doses of ACE inhibitors are needed for blood pressure control in black compared with white hypertensive patients. Only one clinical trial2 compared an ACE inhibitor with other therapies, including a cardioselective β-blocker and a calcium channel blocker in black hypertensive patients. The trial demonstrated an adequate but not equivalent therapeutic response with an ACE inhibitor compared with a calcium channel blocker. However, a full dose titration was not performed. Even at the lower doses used, a dose response was noted, with increasing efficacy with increasing dose. No prior studies have determined just how much more ACE inhibitor is required for blood pressure control in blacks, although there is evidence that larger doses can be effective.20
The results of this clinical trial demonstrate that black hypertensive patients will require approximately two to four times the dose of an ACE inhibitor as similarly age- and sex-matched white hypertensive patients for similar DBP and SBP reduction to be achieved. Moreover, in white hypertensive patients, DBP and SBP reductions correlate with serum ACE inhibition, whereas in black hypertensive patients, despite similar reductions in serum ACE activity, blood pressure reduction does not occur until the highest dose of trandolapril (4 mg) is administered. Thus, there is disassociation between serum ACE inhibition and the antihypertensive activity of trandolapril in black hypertensive patients. Consequently, another property of the ACE inhibitor trandolapril is likely responsible for the blood pressure reduction seen in black hypertensive patients. These data could also be reflective of reduced sensitivity of high blood pressure in blacks to ACE inhibition. This study does not answer the question as to what effect of the ACE inhibitor causes this blood pressure reduction. However, the reduction in serum aldosterone concentration observed with the higher trandolapril doses in the black hypertensive patients may be important, particularly in this population, which has a tendency toward mild volume expansion and a low-renin, sodium-sensitive profile. In addition, prior studies have demonstrated abnormalities in aldosterone responsiveness in black hypertensive patients.25 26 However, there is no clinical evidence to suggest that aldosterone reduction correlates with blood pressure reduction.
Another interesting question not answered by the present study is whether one would achieve similar blood pressure reduction with higher doses of trandolapril (16 mg) in blacks, as would be seen with 4 mg trandolapril in whites. In general, ACE inhibitors have flat dose-response curves with regard to adverse events,27 suggesting that significantly higher doses can be safely administered.
One drawback to the interpretation of the results of the present study is that dietary sodium and potassium was not assessed. If the black patients consumed significantly more sodium than the white patients, this could account for some of the resistance to the antihypertensive effect of the ACE inhibitor. However, our large study cohorts (n=91 blacks and n=207 whites) would minimize some of the variability in diet among and between groups. Furthermore, data from the INTERSALT study28 demonstrate no consistent evidence of higher dietary sodium intake among blacks compared with whites.
The importance of our observations is that they establish the premise that ACE inhibitors do possess antihypertensive properties independent of their ability to block serum ACE. Moreover, these observations establish the fact that in general ACE inhibitors do need to be administered in higher doses in hypertensive patients of African American descent for satisfactory blood pressure reduction to be achieved.
This study was supported by a grant from Knoll Pharmaceutical Co, Whippany, NJ. We wish to acknowledge the expert secretarial assistance of Karyl Fleck and Rosemaria Jackson and the editorial review of Beverly Novrit and Edward Kirsten, PhD.
The Trandolapril Multicenter Study Group included John W. Allen, MD, Hospital of the Good Samaritan, Los Angeles, Calif; Paula Barden, MD, Warwick Charlton, MD, Frank F. Synder, MD, Lovelace Scientific Resources, Albuquerque, NM; Joan Ryder Benz, MD, PhD, PC, Cedar Rapids, Iowa; Robert Goldstein, MD, Florida West Coast Clinical Research Group, Tampa; P. Michael Kaihlanen, MD, Dennis Ruff, MD, San Antonio, Tex; David Kelley, MD, Angela Bowen, MD, Olympia, Wash; Jon H. Levine, MD, Rosalyn McGuire, RN, Richard D. Pinson, MD, Clinical Research Associates, Nashville, Tenn; F. Gilbert McMahon, MD, Adesh Jain, MD, Clinical Research Center, New Orleans, La; R. Zorba Paster, MD, Brenda Gehin, RTRR, Barb Bryant, RN, Dean Medical Center, Oregon, Wis; Warren W. Pleskow, MD, Asthma, Allergy and Internal Medicine, Encinitas, Calif; C. Venkata S. Ram, MD, Norman M. Kaplan, MD, Alexander F. Khoury, MD, Lena Farrell, RN, Diane Veath, LVN, University of Texas, Southwestern Medical Center, Dallas; Robert Reeves, MD, Barbara Guller, MD, Olympia, Wash; Steven Savran, MD, Scott MacDonald, MD, Charles Spielman, MD, Southwest Medical Associates, Las Vegas, Nev; Harold W. Schnaper, MD, E.E. Eddleman, Jr, MD, Scientific Applications Co, Inc, Birmingham, Ala; David J. Shaw, MD, Margaret McCracken, MD, Connie Caro, RN, Internal Medicine Associates, San Diego, Calif; Harold M. Silberman, MD, Jeffrey B. Rosen, MD, Maria M. Milanes, RMA-CRT, Clinical Research of South Florida, Coral Gables; L. Kent Smith, MD, Arizona Heart Institute, Phoenix; William J. Stein, MD, Richard E. Abbott, MD, James J. Budd, MD, Carl Oshrain, MD, Rochester, NY.
Reprint requests to Matthew R. Weir, MD, Division of Nephrology, University of Maryland Hospital, 22 S Greene St, Baltimore, MD 21201. E-mail firstname.lastname@example.org.
- Received November 9, 1994.
- Revision received November 28, 1994.
- Accepted February 6, 1995.
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