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Background: Acute declines in estimated glomerular filtration rate (eGFR) occur commonly after starting angiotensin-converting enzyme inhibitors. Whether declines in eGFR that occur after simultaneously starting angiotensin-converting enzyme inhibitors with other antihypertensive agents modifies the benefits of these agents on cardiovascular outcomes is unclear., Methods and Results: We identified predictors of acute declines in eGFR (>15% over 3 months) during randomization to benazepril plus amlodipine versus benazepril plus hydrochlorothiazide in the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial. We then determined the relation between declines in eGFR (treated as a binary variable, ≤15% versus >15% and separately, as a restricted spline variable) and the composite risk of fatal and nonfatal cardiovascular events using Cox proportional hazards models. We included 10 714 participants (median age 68 years [Q1 63, Q3 73]), of whom 1024 reached the trial end point over median follow-up of 2.8 years. Predictors of acute declines in eGFR>15% over 3 months included assignment to hydrochlorothiazide (versus amlodipine) and higher baseline albuminuria. Overall, declines in eGFR ≥15% (versus <15%) were associated with a 26% higher hazard of cardiovascular outcomes (95% CI, 1.07-1.48). In spline-based analysis, risk for cardiovascular outcomes was higher in the hydrochlorothiazide arm at every level of decline in eGFR compared with the same magnitude of eGFR decline in the amlodipine arm., Conclusion: Combined use of benazepril and amlodipine remains superior to benazepril and hydrochlorothiazide for cardiovascular outcomes, regardless of the magnitude of the decline in eGFR that occurred with initiation of therapy.

Background: The ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension) trial demonstrated that combination therapy using amlodipine, rather than hydrochlorothiazide, in conjunction with benazepril provided greater cardiovascular risk reduction among high-risk hypertensive patients. Few trials have evaluated the effect of prior antihypertensive therapy used among participants on the study outcomes., Methods and Results: In a post hoc observational analysis, we examined the characteristics of the drug regimens taken before trial enrollment in the context of the primary composite outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac death, and coronary revascularization). In the "primary subgroup" (n=4475), patients previously taking any renin-angiotensin system blockade plus either a diuretic or a calcium channel blocker alone or as part of their antihypertensive regimen, there were 206 of 2193 (9.4%) versus 281 of 2282 (12.3%) primary composite events among those randomized to combination therapy involving amlodipine versus hydrochlorothiazide, respectively (adjusted Cox proportional hazard ratio, 0.74; 95% confidence interval, 0.62-0.89; P =0.0015). All other participants (n=6975) previously taking any antihypertensive regimen not included in the primary subgroup also benefited from randomization to amlodipine plus benazepril (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72-0.98; P =0.024). Outcomes among most other subgroups, including patients previously taking lipid-lowering medications or dichotomized by prior blood pressure control status, showed similar results., Conclusions: When combined with an angiotensin-converting enzyme inhibitor, amlodipine provides cardiovascular risk reduction superior to hydrochlorothiazide, largely regardless of prior medication use. These findings add further support for the initial use of this combination regimen among high-risk hypertensive patients., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Pulse pressure (PP) is an independent risk factor for cardiovascular (CV) disease and death but few studies have investigated the effect of antihypertensive treatments in relation to PP levels before treatment. The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial showed that the combination of benazepril+amlodipine (B+A) is superior to benazepril+hydrochlorothiazide (B+H) in reducing CV events. We aimed to investigate whether the treatment effects in the ACCOMPLISH trial were dependent on baseline PP. High-risk hypertensive patients (n=11,499) were randomized to double-blinded treatment with single-pill combinations of either B+A or B+H and followed for 36 months. Patients were divided into tertiles according to their baseline PP and events (CV mortality/myocardial infarction or stroke) were compared. Hazard ratios (HRs) for the treatment effect (B+A over B+H) were calculated in a Cox regression model with age, coronary artery disease, and diabetes mellitus as covariates and were compared across the tertiles. The event rate was increased in the high tertile of PP compared with the low tertile (7.2% vs 4.4% P<.01). In the high and medium PP tertiles, HRs were 0.75 (95% confidence interval [CI], 0.60-0.95; P=.018) and 0.74 (CI, 0.56-0.98, P=.034), respectively, in favor of B+A. There was no significant difference between the treatments in the low tertile and no significant differences in treatment effect when comparing the HRs between tertiles of PP. B+A has superior CV protection over B+H in high-risk hypertensive patients independent of baseline PP although the absolute treatment effect is enhanced in the higher tertiles of PP where event rates are higher., (© 2014 Wiley Periodicals, Inc.)

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended a thiazide-like diuretic, alone or in combination with other antihypertensive drug classes, as initial therapy for hypertension. JNC 7, however, did not specify preferred combinations. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial was completed five years after the JNC 7 and demonstrated a 20 % advantage in cardiovascular risk reduction when blood pressure was lowered using the single-pill combination of benazepril-amlodipine compared to benazepril-hydrochlorothiazide (Jamerson et al. 359(23):2417-28 [1]). This new and significant finding provided compelling evidence that the long-standing preference for diuretics as initial therapy could be refuted, but it may also be relevant to the lower-than-expected reduction in coronary disease related events (compared to stroke) observed for decades prior to the ACCOMPLISH approach to therapy. The JNC 8 panel members recently published their recommendations, and while the group did not recommend benazepril-hydrochlorothiazide over other combinations, they did highlight the findings of ACCOMPLISH, rating the primary ACCOMPLISH paper as "good." The American Society of Hypertension position paper and the European Hypertension Society guidelines endorse such combinations as a first-line agent for patients with stage 2 hypertension. We review the current position of ACCOMPLISH in the guidelines regarding treatment of stage 2 hypertension.

Combination therapy with benazepril 40 mg and amlodipine 10 mg (B+A) has been shown to be more effective than benazepril 40 mg and hydrochlorothiazide (HCTZ) 25 mg (B+H) in reducing cardiovascular (CV) events in high-risk patients with stage 2 hypertension with similar blood pressure reductions. In the present post hoc analysis, we evaluated whether B+A is more effective than B+H for reducing CV events in patients with known coronary artery disease (CAD) at baseline in a subgroup analysis of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) study. The main trial randomized 11,506 patients. Of those, 5,744 received B+A and 5,762 received B+H. Of the 11,506 patients, 5,314 (46%) were classified as having CAD at baseline. The mean patient follow-up period was 35.7 months for the B+A group and 35.6 months for the B+H group. The primary end point was the interval to the first event of composite CV morbidity and mortality. At baseline, significant differences were present between the 5,314 with CAD and the 6,192 without CAD. The patients with CAD had a lower systolic blood pressure and heart rate, a lower incidence of diabetes, and greater incidence of dyslipidemia. However, no baseline differences were found between the randomized B+A and B+H groups. In the patients with CAD, an 18% reduction occurred in the hazard ratio for CV events (primary end point) with B+A versus B+H (p = 0.0016). In a prespecified secondary analysis of the composite end point, including only CV death, myocardial infarction, and stroke, the hazard ratio in the patients with CAD was reduced by 25% (p = 0.0033) in the B+A group compared with the B+H group. B+A was more effective than B+H at comparable blood pressure reductions for reducing CV events in patients, regardless of the presence of CAD. In conclusion, our findings suggest that the combination of B+A should be preferentially used for older patients with high-risk, stage 2 hypertension., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The ACCOMPLISH Trial investigated intensive antihypertensive combination treatment with benazepril + amlodipine (B+A) or benazepril + hydrochlorothiazide (B+H) on cardiovascular outcomes in patients with systolic hypertension. We analyzed the baseline predictors of achieving a systolic blood pressure (SBP) <140 mmHg and achieved SBP level by the end of 12 months in both treatment groups., Methods: Baseline and 12-month SBP was available in 10,506 patients, of whom 6250 had diabetes. Univariate and multivariate logistic regression models were used for SBP control at 12 months and multivariable regression models were used for the prediction of SBP at 12 months. A stepwise procedure was used to select significant (p < 0.001) predictors in multivariate analyses., Results: Mean (± SD) BP fell from 145.4/80.1 (± 18.3/10.7) mmHg at randomization to 132.8/74.7 (± 16.0/9.6) mmHg at 12 months. The main baseline predictors of SBP control <140 mmHg were region (USA >Nordic region) and Caucasian ethnicity in both randomization arms. A higher diastolic BP and the use of lipid lowering agents indicated favorable effects in the B+H arm only. The predictors of uncontrolled SBP were: (i) higher baseline SBP values, (ii) higher number of previous antihypertensive medications in both arms, (iii) the previous use of insulin in the B+A arm, and (iv) pre-trial calcium channel blocker (CCB) use in the B+H arm. Additionally, pre-trial use of thiazides and electrocardiogram (ECG)-left ventricular hypertrophy (LVH) at baseline predicted higher, and smoking lower absolute SBP in the B+A arm and the use of thiazides and proteinuria a higher SBP in the B+H arm., Conclusion: Irrespective of treatment, patients in the USA and Caucasians achieved better SBP control, whereas higher baseline SBP and more previous antihypertensive medications indicated less control. Concomitant use of lipid lowering treatment indicated a better SBP control in the benazepril + hydrochlorothiazide arm. Lastly, insulin use and ECG-LVH in the benazepril + amlodipine arm and proteinuria in the benazepril + hydrochlorothiazide arm indicated poor control.

A high heart rate (HR) predicts future cardiovascular events. We explored the predictive value of HR in patients with high-risk hypertension and examined whether blood pressure reduction modifies this association. The participants were 15,193 patients with hypertension enrolled in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and followed up for 5 years. The HR was assessed from electrocardiographic recordings obtained annually throughout the study period. The primary end point was the interval to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary end point for a 10-beats/min of the baseline HR increment was 1.16 (95% confidence interval 1.12 to 1.20). Compared to the lowest HR quintile, the adjusted hazard ratio in the highest quintile was 1.73 (95% confidence interval 1.46 to 2.04). Compared to the pooled lower quintiles of baseline HR, the annual incidence of primary end point in the top baseline quintile was greater in each of the 5 study years (all p <0.05). The adjusted hazard ratio for the primary end point in the highest in-trial HR heart rate quintile versus the lowest quintile was 1.53 (95% confidence interval 1.26 to 1.85). The incidence of primary end points in the highest in-trial HR group compared to the pooled 4 lower quintiles was 53% greater in patients with well-controlled blood pressure (p <0.001) and 34% greater in those with uncontrolled blood pressure (p = 0.002). In conclusion, an increased HR is a long-term predictor of cardiovascular events in patients with high-risk hypertension. This effect was not modified by good blood pressure control. It is not yet known whether a therapeutic reduction of HR would improve cardiovascular prognosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Added-risk hypertensive patients with co-morbidities such as diabetes and metabolic syndrome often require two or more antihypertensives to achieve blood pressure (BP) targets. The aim of this sub-analysis was to determine the efficacy and safety of telmisartan 40 or 80 mg plus amlodipine 5 or 10 mg in patients with hypertension, stratified according to certain criteria such as type 2 diabetes mellitus and metabolic syndrome., Methods: Patients were treated for 8 weeks with telmisartan 20-80 mg plus amlodipine 2.5-10 mg. This post-hoc analysis included patients treated with higher doses, and stratified according to a number of sub-populations (age, race, diabetes, obesity, metabolic syndrome, elevated baseline systolic BP (SBP), renal impairment)., Results: Eight weeks' treatment with telmisartan plus amlodipine combinations provided consistent reductions in mean SBP/diastolic BP (DBP) across the different sub-populations, similar to the overall population. SBP/DBP reductions ranged from -13.5 to -34.7/-12.6 to -26.1 mmHg and BP goal rates (<140/90 mmHg) ranged from 29.8-100% for the four key dose combinations of telmisartan plus amlodipine. For the highest dose combination of telmisartan 80 mg plus amlodipine 10 mg, SBP/DBP reduction ranged from -19.1 to -34.7/-16.4 to -22.8 mmHg and goal attainment rate from 66.7% to 87.0%. Across the sub-populations, high SBP and DBP response rates were seen with combination treatment (83.3-97.7% and 75.0-95.7%, respectively, with telmisartan 80 mg plus amlodipine 10 mg). The combination was safe and well tolerated across all sub-populations and the incidence of peripheral oedema with telmisartan 40-80 mg plus amlodipine 10 mg was generally lower than with A10 monotherapy., Conclusions: Despite small patient numbers in some sub-populations and the post-hoc nature of the analysis, this does show that the combination of telmisartan plus amlodipine provides an effective, safe and well-tolerated antihypertensive treatment for added-risk hypertensive patients.

The combination of benazepril plus amlodipine was shown to be more effective than benazepril plus hydrochlorothiazide in reducing cardiovascular events in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial. There was a small difference in clinic systolic blood pressure between the treatment arms favoring benazepril plus amlodipine. Ambulatory blood pressure monitoring provides a more rigorous estimate of blood pressure effects. A subset of 573 subjects underwent ambulatory blood pressure monitoring during year 2. Readings were obtained every 20 minutes during a 24-hour period. Between-treatment differences (benazepril plus amlodipine versus benazepril plus hydrochlorothiazide) in mean values were analyzed using ANOVA. Treatment comparisons with respect to categorical variables were made using Pearson's χ². At year 2, the treatment groups did not differ significantly in 24-hour mean daytime or nighttime blood pressures (values of 123.9, 125.9, and 118.1 mm Hg for benazepril plus amlodipine group versus 122.3, 124.1, and 116.9 for the benazepril plus hydrochlorothiazide group), with mean between-group differences of 1.6, 1.8, and 1.2 mm Hg, respectively. Blood pressure control rates (24-hour mean systolic blood pressure <130 mm Hg on ambulatory blood pressure monitoring) were greater than 80% in both groups. Nighttime systolic blood pressure provided additional risk prediction after adjusting for the effects of drugs. The 24-hour blood pressure control was similar in both treatment arms, supporting the interpretation that the difference in cardiovascular outcomes favoring a renin angiotensin system blocker combined with amlodipine rather than hydrochlorothiazide shown in the ACCOMPLISH trial was not caused by differences in blood pressure, but instead intrinsic properties (metabolic or hemodynamic) of the combination therapies.

Objectives: The aim of this study was to determine which combination therapy in patients with hypertension and diabetes most effectively decreases cardiovascular events., Background: The ACCOMPLISH (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension) trial compared the outcomes effects of a renin-angiotensin system blocker, benazepril, combined with amlodipine (B+A) or hydrochlorothiazide (B+H). A separate analysis in diabetic patients was pre-specified., Methods: A total of 6,946 patients with diabetes were randomized to treatment with B+A or B+H. A subgroup of 2,842 diabetic patients at very high risk (previous cardiovascular or stroke events) was also analyzed, as were 4,559 patients without diabetes. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for angina, resuscitated arrest, and coronary revascularization., Results: In the full diabetes group, the mean achieved blood pressures in the B+A and B+H groups were 131.5/72.6 and 132.7/73.7 mm Hg; during 30 months, there were 307 (8.8%) and 383 (11.0%) primary events (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.68 to 0.92, p = 0.003). For the diabetic patients at very high risk, there were 195 (13.6%) and 244 (17.3%) primary events (HR: 0.77, 95% CI: 0.64 to 0.93, p = 0.007). In the nondiabetic patients, there were 245 (10.8%) and 296 (12.9%) primary events (HR: 0.82, 95% CI: 0.69 to 0.97, p = 0.020). In the diabetic patients, there were clear coronary benefits with B+A, including both acute clinical events (p = 0.013) and revascularizations (p = 0.024). There were no unexpected adverse events., Conclusions: In patients with diabetes and hypertension, combining a renin-angiotensin system blocker with amlodipine, compared with hydrochlorothiazide, was superior in reducing cardiovascular events and could influence future management of hypertension in patients with diabetes. (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension [ACCOMPLISH]; NCT00170950)., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting-enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic., Methods: In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization., Results: The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) and 679 in the benazepril-hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001). For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs., Conclusions: The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.), (2008 Massachusetts Medical Society)

We have previously shown that the angiotensin receptor blocker valsartan is associated with a lower incidence of new-onset type 2 diabetes than that with the calcium-channel antagonist amlodipine in the treatment of hypertensive patients at high cardiovascular risk. We have now investigated the benefits of valsartan vs amlodipine in patients of different categories of diabetogenic risk. Some 9995 patients without diabetes at onset participated in VALUE, with average follow-up of 4.2 years. Predictors of new diabetes were analyzed by stepwise logistic regression. A diabetes risk score for each patient was calculated based on a multivariate model. The risk of developing new diabetes in quartiles of risk for the disease was calculated as an odds ratio (OR) with 95% confidence intervals (CI). New diabetes was reported in 580 (11.5%) patients on valsartan and in 718 (14.5%) patients on amlodipine (p<0.0001). There was a more than sevenfold rise in the development of new diabetes from the lowest to the highest quartile of risk. When study treatment was included in the risk model, the odds in favor of valsartan in preventing new diabetes progressively increased with higher risk. Fifty-two (4.03%) patients developed diabetes on valsartan and 50 (4.14%) patients on amlodipine in the lowest quartile of risk, 73 (5.70%) patients on valsartan and 83 (6.81%) patients on amlodipine in the second quartile, and 126 (10.27%) patients on valsartan and 160 (12.58%) patients on amlodipine in the third quartile. The difference between treatments was highly significant in quartile 4 with 329 (26.68%) patients developing new diabetes on valsartan vs 425 (33.57%) patients on amlodipine (OR = 0.72, 95% CI 0.61-0.86, p = 0.0002). The number of patients needed for treatment for the duration of the trial in order to gain the benefit of valsartan over amlodipine in preventing one new case of diabetes was 43 in the third quartile and 15 in the fourth quartile of risk categories. We conclude that valsartan compared with amlodipine reduces the risk of developing diabetes mellitus, particularly in hypertensive patients with the highest susceptibility for development of diabetes.

Context: Type 2 diabetes is emerging as a major health problem, which tends to cluster with hypertension in individuals at high risk of cardiovascular disease., Objective: To test for the first time the hypothesis that treatment of hypertensive patients at high cardiovascular risk with the angiotensin-receptor blocker (ARB) valsartan prevents new-onset type 2 diabetes compared with the metabolically neutral calcium-channel antagonist (CCA) amlodipine., Design: Pre-specified analysis in the VALUE trial. Follow-up averaged 4.2 years. The risk of developing new diabetes was calculated as an odds ratio (OR) with 95% confidence intervals (CI) for different definitions of diabetes., Patients: A sample of 9995 high-risk, non-diabetic hypertensive patients., Interventions: Valsartan or amlodipine with or without add-on medication [hydrochlorothiazide (HCTZ) and other add-ons, excluding other ARBs, angiotensin-converting enzyme (ACE) inhibitors, CCAs]., Main Outcome Measure: New diabetes defined as an adverse event, new blood-glucose-lowering drugs and/or fasting glucose > 7.0 mmol/l., Results: New diabetes was reported in 580 (11.5%) patients on valsartan and in 718 (14.5%) patients on amlodipine (OR 0.77, 95% CI 0.69-0.87, P < 0.0001). Using stricter criteria (without adverse event reports) new diabetes was detected in 495 (9.8%) patients on valsartan and in 586 (11.8%) on amlodipine (OR 0.82, 95% CI 0.72-0.93, P = 0.0015)., Conclusion: Compared with amlodipine, valsartan reduces the risk of developing diabetes mellitus in high-risk hypertensive patients.

The objective of the study was to demonstrate that reduction in mean 24-hour diastolic blood pressure with 160 mg valsartan and 12.5 mg hydrochlorothiazide was not inferior to 10 mg amlodipine in hypertensive blacks. A total of 482 blacks with stage 1 and stage 2 hypertension (mean seated blood pressure 140 to 180/90 to 110 mm Hg) were enrolled in a double-blind, randomized, prospective study. After a placebo run-in period, patients were randomized to 160 mg valsartan or 5 mg amlodipine for 2 weeks, then force-titrated to 160 mg valsartan and 12.5 mg hydrochlorothiazide or 10 mg amlodipine for an additional 10 weeks. Blood pressure was assessed by 24-hour ambulatory blood pressure monitoring. Other assessments included quality of life, peripheral edema, and safety. Noninferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in mean 24-hour diastolic blood pressure with both treatments (-10.2+/-8.6 mm Hg versus -9.1+/-8.3 mm Hg, respectively; P<0.001 for noninferiority), as well as in mean 24-hour systolic blood pressure (-15.9+/-12.1 mm Hg versus -14.5+/-12.2 mm Hg; P<0.001 for noninferiority). The proportion of patients reporting adverse events and the incidence of most events were similar in both treatment groups, although more patients treated with amlodipine reported peripheral edema (5.8% versus 1.7%; P=0.03) and joint swelling (2.9% versus 0%; P=0.008) compared with valsartan/hydrochlorothiazide. We conclude that a starting dose of valsartan/hydrochlorothiazide (160/12.5 mg) is as effective as high-dose amlodipine (10 mg) in reducing blood pressure in blacks with stage 1 and stage 2 hypertension, and valsartan/hydrochlorothiazide is better tolerated.

Current recommendations for the treatment of hypertension clarify the need to achieve lower blood pressure levels in the general population (<140/90 mm Hg) and in specific high-risk patient groups such as patients with diabetes or chronic renal disease (<130/80 mm Hg). Further, it is evident that to reach appropriate blood pressure control, most patients with high blood pressure will require two or more antihypertensive agents. There is scarce clinical trial outcome evidence to guide clinicians in the selection of optimal combinations of antihypertensive classes for high-risk hypertensive patients. A new clinical trial, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), is the first large clinical trial to directly compare cardiovascular mortality and morbidity rates for two fixed-dose combination therapies. Results from ACCOMPLISH should provide much-needed guidance for selecting optimal combination therapy for high-risk hypertensive patients.

In the ACCOMPLISH trial (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension), combining amlodipine, rather than hydrochlorothiazide, with benazepril reduced the primary composite cardiovascular end point by 20% in hypertensive adults.1 Similar results were observed in patients with diabetes, coronary disease, chronic kidney disease, and resistant hypertension.2 As the benefits were not explained by greater blood pressure (BP)- lowering, other cardioprotective attributes of amlodipine/benazepril were likely responsible.2 We aimed to determine if this superior BP-independent cardiovascular risk reduction extends to Black participants, a key population disproportionally suffering from hypertension and the adverse health consequences. [ABSTRACT FROM AUTHOR]

ACCOMPLISH is the first trial designed to compare the effects on major fatal and non-fatal cardiovascular endpoints of two forms of antihypertensive combination therapy: benazepril plus hydrochlorothiazide and amlodipine plus benazepril in hypertensive patients at high cardiovascular risk. Enrollment for this trial is now complete and this report describes the clinical characteristics of the study cohort. Patients with hypertension and a previous history of cardiovascular events, strokes or diabetes mellitus were randomized to double-blind treatment with either of the two combination regimens. The data in this report detail the clinical history and demographic characteristics in patients immediately prior to randomization to study drugs. A total of 11,454 patients were randomized. Mean age (±SD) was 68. 4±6. 9 years, 60% were men, and 1360 (12%) were African American. Mean body mass index (BMI) was 31. 0±6. 3 kg/m2. At study entry, 46% of patients had a history of acute coronary syndromes, coronary artery bypass grafts or percutaneous coronary interventions; 13% had a history of stroke. A history of diabetes mellitus was reported in 6928 (60%) of patients. Mean blood pressure at baseline (on prior hypertension therapy) was 145. 4/80. 0 mmHg; only 38% of patients had a BP less than 140/90mmHg. Overall, 97% of patients had received previous antihypertensive treatment (74% on at least two drugs); 53% were on oral diabetes therapy or insulin, 68% on anti-lipid therapy and 63% on anti-platelet agents. In summary, the ACCOMPLISH trial has recruited hypertensive patients at high risk of cardiovascular morbidity and mortality. It is noteworthy that the mean BMI of 31 in this cohort is clearly above the accepted diagnostic criterion of obesity and that 60% of patients are diabetic, possibly reflecting secular trends in clinical disease. [ABSTRACT FROM AUTHOR]

Context: Incidence of end-stage renal disease due to hypertension has increased in recent decades, but the optimal strategy for treatment of hypertension to prevent renal failure is unknown, especially among African Americans.Objective: To compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a beta-blocker (metoprolol) on hypertensive renal disease progression.Design, Setting, and Participants: Interim analysis of a randomized, double-blind, 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease (glomerular filtration rate [GFR] of 20-65 mL/min per 1.73 m(2)) enrolled between February 1995 and September 1998. This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000.Interventions: Participants were randomly assigned to receive amlodipine, 5 to 10 mg/d (n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d (n = 441), with other agents added to achieve 1 of 2 blood pressure goals.Main Outcome Measures: The primary outcome measure was the rate of change in GFR; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50% or 25 mL/min per 1.73 m(2), end-stage renal disease, or death.Results: Among participants with a urinary protein to creatinine ratio of >0.22 (corresponding approximately to proteinuria of more than 300 mg/d), the ramipril group had a 36% (2.02 [SE, 0.74] mL/min per 1.73 m(2)/y) slower mean decline in GFR over 3 years (P =.006) and a 48% reduced risk of the clinical end points vs the amlodipine group (95% confidence interval [CI], 20%-66%). In the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups (P =.38). However, compared with the amlodipine group, after adjustment for baseline covariates the ramipril group had a 38% reduced risk of clinical end points (95% CI, 13%-56%), a 36% slower mean decline in GFR after 3 months (P =.002), and less proteinuria (P<.001).Conclusion: Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria. [ABSTRACT FROM AUTHOR]

The ACCOMPLISH trial (Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension) was a 3-year multicenter, event-driven trial involving patients with high cardiovascular risk who were randomized in a double-blinded manner to benazepril plus either hydrochlorothiazide or amlodipine and titrated in parallel to reach recommended blood pressure goals. Of the 8125 participants in the United States, 1414 were of self-described Black ethnicity. The composite kidney disease end point, defined as a doubling in serum creatinine, end-stage renal disease, or death was not different between Black and non-Black patients, although the Blacks were significantly more likely to develop a greater than 50% increase in serum creatinine to a level above 2.6 mg/dl. We found important early differences in the estimated glomerular filtration rate (eGFR) due to acute hemodynamic effects, indicating that benazepril plus amlodipine was more effective in stabilizing eGFR compared to benazepril plus hydrochlorothiazide in non-Blacks. There was no difference in the mean eGFR loss in Blacks between therapies. Thus, benazepril coupled to amlodipine was a more effective antihypertensive treatment than when coupled to hydrochlorothiazide in non-Black patients to reduced kidney disease progression. Blacks have a modestly higher increased risk for more advanced increases in serum creatinine than non-Blacks. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the effects of antihypertensive therapy with benazepril plus amlodipine and benazepril plus hydrochlorothiazide on progression of chronic kidney disease. The study is a prespecified secondary analysis of a randomised controlled trial involving patients with systolic hypertension undertaken in several countries, including the U.S., Sweden and Norway. The researchers concluded that benazepril plus amlodipine is more effective in patients with hypertension at high risk for cardiovascular events.