Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial

doi:10.1016/S0140-6736(09)62100-0

The Lancet

Volume 375, Issue 9721, 3–9 April 2010, Pages 1173-1181

https://doi.org/10.1016/S0140-6736(09)62100-0 Get rights and content

Summary

Background

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease.

Methods

ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12·5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1·73 m² or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950.

Findings

The trial was terminated early (mean follow-up 2·9 years [SD 0·4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2·0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3·7%) in the benazepril plus hydrochlorothiazide group (HR 0·52, 0·41–0·65, p<0·0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33·7%; benazepril plus hydrochlorothiazide, 85 of 532, 16·0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group.

Interpretation

Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent.

Funding

Novartis.

Introduction

Current guidelines for management of hypertension in Europe and the USA recommend initial antihypertensive therapy with a combination of two drugs for patients whose blood pressure is 20/10 mm Hg above their treatment goal.1, 2 The US guidelines recommend that a thiazide diuretic be included in the initial combination,¹ whereas experimental and clinical evidence suggests that other combinations—ie, a renin-angiotensin system blocker such as an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker—effectively reduce blood pressure and have vasculoprotective effects.3, 4

Patients with chronic kidney disease usually need combination antihypertensive therapy to achieve the recommended blood pressure goal of less than 130/80 mm Hg;5, 6 however, patients with this disease who were treated with three antihypertensive agents did not achieve the recommended blood pressure goals in clinical trials.⁷ Patients with albuminuria above 33·9 mg/mmol, whether or not they have chronic kidney disease, need additional antihypertensive treatment to achieve blood pressure goals, whereas those with normoalbuminuria do not need such treatment.8, 9

Most studies in patients with advanced stage nephropathy support the initial use of renin-angiotensin system blockers in combination with diuretics to reduce blood pressure.5, 6, 10 However, no studies have compared the effect of initial treatment with two different fixed-dose combinations of antihypertensive drugs on progression of chronic kidney disease. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial compared the effectiveness of a maximally titrated, fixed-dose combination of the ACE inhibitor benazepril and the dihydropyridine calcium-channel blocker amlodipine with the combination of benazepril and hydrochlorothiazide in reducing cardiovascular morbidity and mortality. The trial was stopped early because of a 20% reduction in cardiovascular risk recorded in the benazepril plus amlodipine group.¹¹

As part of the prespecified analyses of the ACCOMPLISH trial,¹² we examined the effects of the drug combinations at the approved maximum doses on chronic kidney disease outcomes in a large population of patients who were at high risk for cardiovascular events. We report the frequency of the composite endpoint of progression of chronic kidney disease, defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate [eGFR] <15 mL/min/1·73 m² or need for dialysis). Additionally, we report this outcome in combination with cardiovascular mortality or all-cause mortality, and report changes in surrogate markers of progression of chronic kidney disease, such as changes in eGFR and albuminuria.

Section snippets

Patients

The rationale and study design for the ACCOMPLISH trial have been reported in detail elsewhere.¹² Briefly, ACCOMPLISH was a prospective, randomised, double-blind clinical trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). Men or women aged 55 years or older of any ethnic background were eligible for enrolment. All enrolled patients had hypertension and were at high risk for cardiovascular events; patients were included if they had a history of coronary events,

Results

In the main trial, 13 782 patients were screened and 11 506 were randomly assigned to treatment (benazepril plus amlodipine, n=5744; benazepril plus hydrochlorothiazide, n=5762). Mean follow-up was 2·9 years (SD 0·4). At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). Patients who were lost to follow-up did not differ from those who completed the study in terms of

Discussion

This trial shows that in patients with hypertension at high risk for cardiovascular events, combination treatment with benazepril plus amlodipine reduces progression of chronic kidney disease more effectively than does benazepril plus hydrochlorothiazide. This benefit was also seen when cardiovascular or all-cause mortality were assessed with progression of chronic kidney disease. Differences in blood pressure control throughout the study could not account for these findings.

Although reduction

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ArticlesRenal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Am J Kidney Dis

J Am Coll Cardiol

Am J Hypertens

Am J Kidney Dis

Kidney Int

Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Hypertension

2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension

J Hypertens

Beneficial effects of combined benazepril-amlodipine on cardiac nitric oxide, cGMP, and TNF-alpha production after cardiac ischemia

J Cardiovasc Pharmacol

Amlodipine releases nitric oxide from canine coronary microvessels: an unexpected mechanism of action of a calcium channel-blocking agent

Circulation

Lessons learned from recent hypertension trials about kidney disease

Clin J Am Soc Nephrol

Influence of microalbuminuria in achieving blood pressure goals

Curr Opin Nephrol Hypertens

Differential effects of beta-blockers on albuminuria in patients with type 2 diabetes

Hypertension

Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review

BMJ

Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients

N Engl J Med

Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy

N Engl J Med

Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial

JAMA

Articles
Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial