Magnetic Resonance Imaging Left Ventricular Mass Reduction With Fixed-Dose Angiotensin-Converting Enzyme Inhibitor–Based Regimens in Patients With High-Risk Hypertension
Left ventricular hypertrophy, a major cardiovascular risk factor for morbidity and mortality, is commonly caused by arterial hypertension. The renin-angiotensin-aldosterone system may contribute to the pathogenesis of left ventricular hypertrophy. The Assessment of Lotrel in Left Ventricular Hypertrophy and Hypertension Study compared a single-pill combination of amlodipine/benazepril at doses 5.0/20.0 mg, 5.0/40.0 mg, and 10.0/40.0 mg with hydrochlorothiazide/benazepril at doses 12.5/20.0 mg, 12.5/40.0 mg, and 25.0/40.0 mg on the reduction of left ventricular mass index measured by cardiac MRI in stage 2 hypertensive patients over 52 weeks of treatment in a randomized clinical trial. A total of 125 male and female patients, ≥55 years of age, with echocardiographic left ventricular hypertrophy and high-risk hypertension defined as blood pressure ≥160/100 mm Hg or current antihypertensive treatment were enrolled. After 52 weeks of treatment, left ventricular mass index was significantly reduced from baseline with amlodipine/benazepril (mean: 10.16 g/m2) or hydrochlorothiazide/benazepril (mean: 6.74 g/m2; both P<0.0001), with a mean difference between treatment groups of 3.36 g/m2 (P=0.16). No significant treatment differences were observed in subgroups defined by age, male gender, race, diabetes status, or dose level. However, in female patients, left ventricular mass index reduction was greater with amlodipine/benazepril (P=0.02). Both treatments were well tolerated.
- left ventricular hypertrophy regression
- combination therapy
Left ventricular (LV) hypertrophy (LVH), the cardinal target organ damage in hypertension,1 is a strong independent predictor of cardiovascular events and all-cause mortality.2–4⇓⇓ LVH regression is associated with improved cardiovascular outcomes independent of blood pressure (BP) reduction.5–8⇓⇓⇓ Consequently, LVH regression is considered a goal of effective antihypertensive treatment.9
LVH regression may differ between agents for a similar BP reduction.10 Data suggest that inhibition of the renin-angiotensin-aldosterone system or calcium channel blockade achieves the greatest reduction in LVM.11,12⇓ Thus, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors (ACEIs), and long-acting calcium channel blockers (CCBs) appear most effective, followed by diuretics, β-blockers, and other agents.13
Current guidelines recommend combination therapy to control BP in high-risk hypertensive individuals.14,15⇓ The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a diuretic combined with an ACEI, angiotensin receptor blocker, CCB, or β-blocker.14 In the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm, amlodipine with perindopril prevented more major cardiovascular events than atenolol with diuretic, suggesting that CCB/renin-angiotensin-aldosterone system inhibition may be particularly effective for LVH regression.16 In a previous pilot study, ACEI (benazepril) with long-acting CCB (amlodipine) increased arterial compliance and reduced LV mass more than individual monotherapies.17
The Assessment of Lotrel in Left Ventricular Hypertrophy and Hypertension (ALIVE) Study was a randomized, active comparator study comparing a single-pill CCB/ACEI (amlodipine/benazepril [A/B]) with a diuretic/ACEI (hydrochlorothiazide [HCTZ]/benazepril) on the reduction of LV mass (LVM) index (LVMI) measured by cardiac MRI (CMR) in stage 2 hypertensive patients with echocardiographically confirmed LVH.
Study Design and Patient Population
This was a 52-week multicenter, double-blind, randomized, parallel group study to assess the efficacy and tolerability of once-daily therapy with a single-pill A/B 5.0/20.0, 5.0/40.0, or 10.0/40.0 mg versus HCTZ/benazepril (HCTZ/B) 12.5/20.0, 12.5/40.0, or 25.0/40.0 mg. The study was approved by institutional review boards at all of the sites, and all of the patients signed informed consents.
Eligible patients were men or women ≥55 years old with stage 2 hypertension and echocardiographic LVH, either untreated, with mean pre-enrollment sitting BP of ≥160/100 mm Hg, or taking antihypertensive medication. Exclusions included the following: history of secondary hypertension; LVH with another etiology; refractory hypertension (systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg unresponsive to combination therapy); unstable angina within 6 months of study entry; symptomatic heart failure (New York Heart Association classes II through IV) or ejection fraction <40%; myocardial infarction with coronary revascularization; stroke or transient ischemic event within 3 months of study entry; pacemaker, defibrillator, other ferromagnetic device or severe claustrophobia that precluded CMR; serum creatinine >2.5 mg/dL; glycosylated hemoglobin >9.5%; serum potassium >5.2 mEq/L; significant cardiac arrhythmias; valvular disease requiring surgery during the expected study duration; severe hepatic disease; malignancy within 5 years; significant autoimmune disorder; allergy and/or hypersensitivity to amlodipine, benazepril, or HCTZ; or history of alcohol or other drug/substance abuse within 12 months.
Patients were screened 2 weeks before randomization, and consenting eligible treated patients were asked to discontinue antihypertensive medications, but no formal washout period or threshold BP off treatment was required. Randomization and a 52-week treatment period followed (Figure 1). Patients were randomly assigned to receive either A/B 5.0/20.0 mg or HCTZ/B 12.5/20.0 mg for 4 weeks. Those not achieving target BP (<140/90 mm Hg) were then up-titrated to A/B 5.0/40.0 mg or HCTZ/B 12.5/40.0 mg for 4 weeks. At week 8, patients whose BP was not <140/90 mm Hg were up-titrated to A/B 10.0/40.0 mg or HCTZ/B 25.0/40.0 mg for 4 additional weeks. At week 12 and subsequent visits, β-blockers, α-blockers, loop diuretics, and clonidine or other centrally acting antihypertensives could be added in patients not meeting target BP. Patients who achieved target BP at week 4 or thereafter were maintained at the same dose levels. Downward adjustments to the previous dose level were permitted in patients unable to tolerate the protocol-specified dosing schedule. ACEI, angiotensin receptor blockers, other renin-angiotensin-aldosterone system inhibitors, CCBs, and thiazide-like diuretics were prohibited from initiation of the washout period to the conclusion of the study.
Echocardiograms were performed before enrollment to establish eligibility. LV visualization was obtained following recommendations of the American Society of Echocardiography.18 Measurements of interventricular septal and LV posterior wall thicknesses and LV internal dimension were obtained from M-mode or 2D recordings at midcavity level at end diastole, choosing the view that obtained the maximum correctly oriented chamber diameter and allowed exclusion of trabeculae and false tendons from wall thicknesses. LV mass was calculated using a necropsy-validated formula.18,19⇓ LV mass was indexed for body surface area, using partition values within 5% of 125 g/m2 in men and 110 g/m2 in women to identify LVH.20
Magnetic Resonance Measurements
CMR studies were acquired using 1.5-T scanners. After scout imaging, volumetric breath-hold cine steady-state free precessing LV imaging was performed, acquiring contiguous 8-mm LV short-axis sections from beyond the LV apex to above the mitral annulus with temporal resolution ≤40 ms and maximal spatial resolution achievable. Aortic valve imaging was performed to permit the use of aortic valve closure to define end systole. Short-axis cine imaging of the aorta at the bifurcation of the pulmonary artery was performed with automated BP recording before and after to estimate aortic distensibility. Phase-contrast through-plane cine velocity imaging of transmitral flow was performed to assess LV filling. At the central core laboratory, a trained, experienced image analyst blinded to clinical findings or treatment determined the areas encompassed by the LV endocardium and epicardium on each short-axis section using commercial software (MASS, Medis) and summed the product of the differences between endocardial and epicardial areas multiplied by section thickness to determine LV myocardial volume, which was multiplied by 1.05 to yield LV mass. Measurements included papillary muscles and protuberant LV trabeculae in the cavity volume, the prevailing method used in CMR. In addition, transmitral flow was determined on each frame of the diastolic phase-contrast images and relative E wave volume, A wave volume, and the early diastolic mitral inflow volume/standard late-diastolic mitral inflow volume ratio determined.21 All of the analyses were overread by the core laboratory technical director and the first author, blinded to clinical findings and treatment.
Efficacy and Safety Outcomes
The primary efficacy outcome was change from baseline in LVMI assessed by CMR, adjusted for body surface area, between treatment groups at week 52. Secondary efficacy outcomes were changes from baseline in end-diastolic and end-systolic LV volumes, unindexed LV mass, LV ejection fraction, the ratio of peak E to A diastolic transmitral flow, and an index of aortic compliance (percentage of cross-sectional area change per millimeter of mercury of pulse pressure) from baseline to week 52. Safety and tolerability of the 2 regimens were assessed by monitoring and recording all of the adverse events, clinical laboratory test results, and findings from physical examinations.
A total of 168 randomized patients (84 per group) was planned, allowing for a 10% dropout rate and 90% power, assuming an expected between-group difference of 8 g/m2 in change in LVMI from baseline to week 52, an SD of 15 g/m2, with a 2-sided significance of 0.05.
Baseline demographics and clinical characteristics were summarized using appropriate descriptive statistics. χ2 tests for categorical variables and 2-sample t tests for continuous variables were used to test for homogeneity between the treatment groups. Categorical data are expressed as numbers and percentages and continuous data as the mean and SD. As appropriate, the hypothesis of no mean change from baseline to week 52 was tested using a paired t test with earlier observations carried forward if week-52 data were missing. ANCOVA models with baseline measurement, diagnosis of diabetes (yes or no), and center as covariates were used to analyze the primary efficacy variable. Also, 95% CIs for differences between treatment groups were reported on the basis of the fitted model. Because primary and secondary efficacy variables were only assessed once postbaseline assessment, at week 52, only an observed-case analysis was performed.
Prespecified subgroup analyses were performed on the basis of sex, age, race, achieved dose level of randomized treatment, and achievement of target BP. Associations of baseline LVMI and its change from baseline at week 52 with demographics, baseline characteristics, LVM, and measures of diastolic function and aortic compliance were explored using Spearman correlation coefficients. To determine the main factors involved in LVH regression, a multivariate analysis was applied. Sex, age, body mass index, BP at baseline, diabetes mellitus, BP decrease, diastolic dysfunction, aortic compliance, LVM, and the presence of CMR LVH at baseline were included as potential predictive factors. CMR LVH was defined as >89 g/m2 in men and >73 g/m2 in women on the basis of the upper 95% normal confidence limit obtained at the MRI Core Laboratory (St Francis Hospital Research Department, Roslyn, NY) in carefully screened normotensive nonobese controls. Statistical significance was set at P<0.05. Time to goal (BP <140/90 mm Hg) was analyzed by the Kaplan-Meier method.
Safety analyses were performed using all of the randomized patients who received ≥1 dose of study medication during active treatment. The overall incidences of adverse events, severity, and relationship to study drugs were recorded. Incidences of death, other serious adverse events, and adverse events leading to study discontinuation were summarized separately. Other safety data, including clinical laboratory tests, ECGs, and physical examinations, were also reviewed.
Of 277 patients screened, 152 were not randomized, most commonly because of lack of echocardiographic LVH and/or not meeting hypertension requirements for study entry. The study included 125 patients with stage 2 hypertension and confirmed echocardiographic LVH (63 in the A/B group and 62 in the HCTZ/B group), with an average age of 66±8 years; 53% were women. Thus, because of challenges in patient recruitment, the target number of patients was not achieved. In all, 29 patients (23%) withdrew before study completion: 17 in the A/B group and 12 in the HCTZ/B group. The most common reasons for withdrawal were adverse events (6 each in each group) and patient withdrawal of consent (5 in the A/B and 3 in the HCTZ/B group). Other reasons for withdrawal were protocol violation (1 in the A/B and 2 in the HCTZ/B group), administrative problems (2 in the A/B group), death (1 in the A/B group), and loss to follow-up (2 in the A/B and 1 in the HCTZ/B group). Overall, 96 patients (46 in the A/B and 50 in the HCTZ/B group) completed the study. The population considered in safety analyses included 62 patients in each group, and the intention-to-treat population included 46 patients in the A/B group and 51 in the HCTZ/B group. One patient in the HCTZ/B arm included in the intention-to-treat population experienced cough and did not complete the study. Clinical characteristics of included patients are shown in Table 1. There were no differences between treatment groups in baseline systolic and diastolic BPs or other baseline variables (all P>0.10). Previous antihypertensive therapies were similar in both groups.
Both systolic BP and diastolic BP decreased in both treatment groups, with significant reductions observed at week 12 to week 52 without significant differences between groups (P<0.05 from baseline; P value not significant between groups; Figure 2). At week 12, a majority of patients in both groups achieved BP goal of <140/90 mm Hg (<130/80 mm Hg in diabetics): 26 (57%) of 46 patients in the A/B group and 33 (65%) of 51 patients in the HCTZ/B group. By week 52, 93% and 98% patients, respectively, in the A/B and HCTZ/B groups achieved the prespecified BP goal. Although other agents affecting the renin-angiotensin-aldosterone system were excluded, 3 patients, 1 on A/B and 2 on HCTZ/B, received an aldosterone antagonist as adjunctive treatment.
CMR measures at baseline and follow-up and changes therein are shown in Table 2. There were no statistically significant differences in baseline CMR findings between groups (P=0.09 to 0.97). Overall, mean end-diastolic and end-systolic volumes were 141 mL and 54 mL, respectively; mean LVM was 156 g, mean ejection fraction was 63%, mean early diastolic mitral inflow volume/standard late-diastolic mitral inflow volume ratio was 1.42, and mean systolic compliance index was 0.11% area per millimeter of mercury. There were significant reductions in both LV mass and LVMI (primary end point) from baseline to follow-up (P<0.0001; Table 2), which did not differ between treatment groups (P=0.16 for LVMI; Figure 3).
There were no treatment differences in the primary end point of LVMI reduction between prespecified treatment subgroups defined by age, male gender, race, diabetes status, dose level, or baseline LVMI more than the median. LVMI fell significantly in patients with and without CMR LVH but fell more in those with CMR LVH. However, the interaction between treatment and sex was statistically significant (P=0.035), and, in women, there was a significant difference in favor of A/B (P=0.02; please see Table S1 in the online Data Supplement at http://hyper.ahajournals.org).
In an exploratory analysis, changes from baseline in mean arterial pressure and cardiac output did not differ between treatments at week 52, but total peripheral resistance was significantly reduced in both male and female patients in the A/B arm (from 1906 at baseline to 1464 dyne·cm·sec−5) and increased slightly (from 1939 to 2063) in the HCTZ/B group (P=0.0002 for between-treatment difference) In addition, an exploratory multiple linear regression analysis was performed to identify determinants of LV mass regression. Only baseline LVM (r=−0.127; P=0.009) and change in end-systolic volume (r=−0.464; P=0.01) were significantly related to change in LVM, whereas age, sex, body mass index, systolic BP, and diabetes status were not.
Because there was a nonsignificant trend toward end diastolic volume (EDVi) index increase in the A/B group with an EDV index decrease in the HCTZ/B group (Table 2), an exploratory analysis also assessed effects on LV mass/volume ratio. There was a significant reduction in the LVM/EDV ratio in the A/B group (1.17 to 1.03; −0.14; P<0.0017) but not the HCTZ/B group (1.13 to 1.07; −0.06; P=0.096). The LVMI/EDV reduction in A/B occurred in patients >65 years of age (P<0.004) and in men, but in women both regimens reduced the LVM/EDV ratio significantly.
Thirteen patients (7 in the A/B group and 6 in the HCTZ/B group) discontinued because of adverse events. Most common adverse events are shown in Table S2. There were no differences between groups, except for peripheral edema, which was more common in the A/B arm (P<0.05). During the study, one patient randomized to A/B died from a cerebrovascular accident. This event was considered not related to the study drug. Serious adverse events were recorded in 19 patients (9 in the A/B group and 10 in the HCTZ/B group). Two serious adverse events (moderate-to-severe syncope) related to the study drug occurred in the HCTZ/B group.
Current guidelines emphasize the importance of a combination treatment for patients with high-risk hypertension (Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, European Society of Hypertension and European Society of Cardiology 2007), but few data address whether combinations of antihypertensive agents differ in their ability to reverse LVH.22 To the best of our knowledge, this study is the first comparison of the effects of single-pill antihypertensive combination therapies on LVH regression. Using highly reproducible CMR methodology,23 we found significant reduction of LVMI by both A/B and HCTZ/B treatments, with a mean difference between treatment arms of 3.5 g/m2 (4.5%) that fell short of the hypothesized difference of 8.0 g/m2 and was not statistically significant.
Previous studies have compared antihypertensive monotherapies to each other, to placebo, or to no treatment, mostly using echocardiography.12,22,24,25⇓⇓⇓ In a meta-analysis of 80 studies, including >4000 patients assigned to active treatments or placebo, LV mass was reduced with all of the major classes of antihypertensive medication.11 After correction for treatment duration and change in diastolic BP, the average reduction in LVMI was 13% with angiotensin receptor blockers, 11% with CCBs, 10% with ACEIs, and 8% with diuretics but only 5% with β-blockers (P<0.05 versus other agents). An earlier meta-analysis showed similar findings.26
Few studies have compared diuretics with CCBs for LV mass reduction. On the basis of meta-analyses, diuretics are somewhat inferior to CCBs.13,27⇓ A small study compared combined therapy with and ACEI and a CCB (20 mg of lisinopril in combination with 30 mg of nifedipine gastrointestinal therapeutic system) to an ACEI with diuretic (20 mg of lisinopril + 25 mg of HCTZ) in the regression of LVH.28 After 6 months, LVMI decreased significantly in both groups but decreased more with ACEI/CCB than with ACEI/diuretic treatment.
Because both treatments in the ALIVE Study included benazepril, the difference in LVH regression between treatment arms reflects the effects of amlodipine versus the diuretic HCTZ. However, effects of these agents when used in combination with an ACEI may not be similar to those found when they are used alone. The nonsignificant difference between the treatment arms of 3.5 g/m2, although less than the hypothesized difference of 8.0 g/m2, was consistent with the difference of 3% in the LVM reduction between CCB- and diuretic-treated patients derived from previous meta-analyses.11,26⇓
Of note, in a prespecified subset analysis in this study population, A/B treatment was associated with greater LVH regression than that achieved on HCTZ/B among women, whereas there was no difference among men. Furthermore, within the A/B treatment group, LVH regression was numerically greater for women than men. In the previous Losartan Intervention for Endpoint (LIFE) Study and the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement, no preferential treatment effect on LVMI was noted in women.12,29⇓ In the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement, women had similar reductions in LVMI with enalapril and nifedipine. Although women had numerically greater LVH regression than men with either treatment in the LIFE Study, the differences were not statistically significant (P>0.3).26 A recent LIFE Study exploratory analysis, using Sokolow-Lyon voltage and Cornell product criteria, reported less LVH regression in women than in men regardless of treatment.30 These differences in results versus the LIFE Study and the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement may be related to our use of MRI rather than ECG or echocardiography to assess LVH.
Although our result favoring A/B in women could be a chance occurrence, the possibility of a true biological difference is supported by the finding that different genes may be responsible for ventricular remodeling in female and male rats31 and the finding that hypertension induces mainly concentric hypertrophy in women but eccentric hypertrophy in men in some populations.32,33⇓ Women with aortic stenosis may also have more marked concentric hypertrophy and less fibrosis than men.34,35⇓ The mechanisms associated with sex differences in cardiac remodeling have been reviewed recently,36 with the suggestion that, as we observed, drugs may have different effects in men and women. This hypothesis requires further prospective evaluation.
Recently, results of the Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension Trial have been reported.37 Patients were randomly assigned to receive fixed-dose A/B or HCTZ/B as in the ALIVE Study. At 30 months, BP reduction was similar in both groups, but those receiving A/B experienced 20% less cardiovascular morbidity and mortality than the HCTZ/B group. Given the strong associations between the reduction of echocardiographic or ECG LVH and outcomes in the LIFE Study,8 even a small difference in LVH regression in favor of A/B versus HCTZ/B in the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension Study could have contributed to the significant outcome benefit observed with the former regimen.37
Given the modest, albeit significant, differences in LVH regression achieved by different antihypertensive treatments for similar BP lowering, the present study population was relatively small. With the observed SD of 12.0 g/m2 of LV mass change within treatment groups, 250 patients per group would have been needed to detect the observed LVMI reduction difference of 3.5 g/m2 with 90% power and 186 per group for 80% power. The difference in LVH regression between treatment arms in the ALIVE Study may also have been attenuated by the relatively low mean LVMI present at enrollment. All of the subjects had at least borderline echocardiographic LVH, but many did not have CMR LVH. One factor affecting LVMI differences between screening echocardiography and CMR in the ALIVE Study was exclusion of papillary muscles and trabeculae from myocardial volume in CMR. In recent studies, papillary muscles and trabeculae composed 12.6% to 16.6% of LVM in patients with LVH or LV systolic dysfunction but only 6.0% in controls,38,39⇓ so that their contribution to LVH regression may be important. Effects of alternative measurement methodologies on apparent LVH regression merit future study.
In this study, single-pill combinations of CCB/ACE inhibitor (A/B at doses 5.0/20.0 mg, 5.0/40.0 mg, and 10.0/40.0 mg) and diuretic/ACEI (HCTZ/benazepril at doses 12.5/20.0 mg, 12.5/40.0 mg, and 25.0/40.0 mg) reduced LVMI measured by CMR in stage 2 hypertensive patients over 52 weeks of treatment. In female patients, there was a significant difference in LVMI reduction in favor of A/B (P=0.02). This finding should be viewed as hypothesis generating and will require further confirmation.
We thank Kanaka Sridharan of Novartis Pharmaceuticals Corporation for providing editorial assistance.
Sources of Funding
This study was sponsored by Novartis Pharmaceuticals Corporation.
N.R. serves as a consultant to Novartis Pharmaceuticals Corporation, Timaq Medical Imaging Inc, and GlaxoSmithKline. R.B.D. receives honoraria for lectures from Merck & Co, and serves as a consultant to Merck & Co, Novartis Pharmaceuticals Corporation, and NovoNordisk. B.P. serves as a consultant to Novartis Pharmaceuticals Corporation, Pfizer, Merck & Co, Astra Zeneca, Takeda, Bayer Corporation, and Boehringer Ingelheim USA. R.A.R., R.H., D.H., and D.P. are employees at Novartis Pharmaceuticals Corporation.
- Received February 10, 2009.
- Revision received February 23, 2009.
- Accepted July 10, 2009.
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