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
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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