NPC Archive Item: Dual antihypertensive therapy in patients at high risk of CV disease (ACCOMPLISH study)

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The ACCOMPLISH study suggests that in patients at high risk of CV disease, and who require dual antihypertensive therapy to control blood pressure, a combination of an ACE inhibitor (benazepril) and a calcium channel blocker (amlodipine) may be more effective than a combination of benazepril with a thiazide diuretic (hydrochlorothiazide).

Prescribers should not change practice on the basis of this one clinical study and should continue to follow the NICE clinical guideline for the management of hypertension until such time as the evidence can be considered in the context other studies, and guidelines modified, if appropriate. For those patients who are black or over the age of 55, and who have uncomplicated hypertension, a thiazide diuretic (TD) or a calcium channel blocker (CCB) are appropriate first line choices in addition to lifestyle measures. Choice should be based on likely side-effect profiles, patient factors and cost. An ACE inhibitor can be considered in addition where blood pressure is inadequately controlled. Patients whose hypertension is complicated by existing cardiovascular disease, renal disease, or diabetes (type 1 or 2) should continue to be treated for their hypertension according to the existing NICE guidelines that are specific to these conditions.

It is also worth noting that two of the drugs studied here, hydrochlorothiazide (except in combination products) and benazepril, are not available in the UK.

What is the background to this?
The NICE clinical guideline for the management of hypertension recognised that many patients will require more than one drug to achieve adequate blood pressure control. It was considered that adding an ACE inhibitor to a calcium channel blocker (CCB) or thiazide-type diuretic (TD) (or for younger patients adding either a CCB or a TD to an ACE inhibitor) are logical combinations. However, this choice was based on pathophysiological grounds rather than evidence from randomised controlled trials (RCTs) that evaluated their effect on important patient-oriented outcomes. The ACCOMPLISH study examined the relative benefits of using a combination of an ACE inhibitor (benazepril) in combination with a CCB (amlodipine) or a TD (hydrochlorothiazide) in patients who were at high risk of cardiovascular (CV) events.

What does this study claim?
Over a mean follow-up of 36 months, when the trial was stopped early, there were fewer primary-outcome events (either death from CV causes, nonfatal myocardial infarction, nonfatal stroke, hospitalisation for angina, resuscitation after sudden cardiac arrest, or coronary revascularisation) in the benazepril–amlodipine group (9.6%) than in the benazepril–hydrochlorothiazide group (11.8%); this represents an absolute risk reduction with benazepril–amlodipine therapy of 2.2% (NNT=46) and a relative risk reduction of 19.6% (hazard ratio [HR], 0.80, 95% confidence interval [CI] 0.72 to 0.90; P<0.001). Although adverse-effect profiles varied, their rates of discontinuations for any reason, or for those related to drug side effects, were similar.

How does this relate to other studies?
Evidence from large RCTs suggests that there is little to choose between antihypertensive agents for preventing major CV outcomes when blood-pressure lowering effects are taken into account (see the hypertension section on NPC). The NICE clinical guideline for the management of hypertension recommends that in hypertensive patients aged 55 years or older, or black patients of any age, the first choice for initial therapy should be either a CCB or a TD, whereas in hypertensive patients younger than 55, the first choice for initial therapy should be an ACE inhibitor (or an angiotensin-II receptor antagonist [A2RA] if an ACE inhibitor is not tolerated). In the ALLHAT study, TDs were unsurpassed by ACE inhibitors or CCBs as initial antihypertensive therapy in high-risk patients. Side-effect profiles differ however, and this may influence choice. TDs, especially when used with beta-blockers, have been associated with an increased risk of diabetes, whereas CCBs have been associated with an increased risk of heart failure (see MeRec Bulletin 2006 Vol.17. No.1). No previous large RCTs have directly compared these two agents when used in combination with an ACE inhibitors, which effectively represents the two choices for continuation therapy recommended  by NICE for patients whose blood pressure is uncontrolled by their first choice treatment alone.

So what?
Firstly, we should note that two of the drugs studied here, hydrochlorothiazide (except in combination products) and benazepril, are not available in the UK.

The study found that the use of either drug combination provided good blood pressure control in patients who were at high risk of CV disease.  However, there was a small mean difference of about 1mmHg in both systolic and diastolic blood pressures between the groups, and this may account for at least some of the difference in CV outcomes. An accompanying Editorial also raises the possibility that the particular diuretic regimen used may have been inadequate to provide 24-hour blood pressure. Further data from ambulatory blood pressure measurements collected in the study, but not reported in the publication, could address this issue.

Choice of treatment often depends on compelling indications, contraindications, coexisting conditions and other patient factors.  The results of this study do not diminish the value of treatment with the combination of an ACE inhibitor and a diuretic. As stated in the accompanying Editorial, treatment recommendations should be based on the total available evidence rather than the results of any one trial. Both treatment regimens offer an effective means of controlling blood pressure and the absolute difference in the proportion of patients who suffered a CV event was modest; 46 patients would need to be treated with the ACE inhibitor plus CCB regimen for one additional patient to suffer a CV event who would not have done so, if they had received the ACE inhibitor plus TD regimen.

The patients in this study reflect a broad population of patients at high-risk of CV disease, through virtue of existing CV disease, renal disease or diabetes (about 60% had diabetes). Three-quarters were already receiving two or more antihypertensive drugs. One of the consequences of stopping the study early, was that the study had insufficient power to identify if the benefits extended to just some or all of the included subgroups (for example those with diabetes or renal disease) and the published article does not explore this possibility.

In short, prescribers should continue to follow specific NICE guidance for the treatment of hypertension in patients with CV disease, renal disease, and type 1 or type 2 diabetes, until such time as the guidance is reviewed on the basis of all the evidence, and guidance amended as appropriate. The results can also not be generalised to patients whose hypertension is uncomplicated by existing conditions and who require dual antihypertensive therapy to control blood pressure.

Note that hydrochlorothiazide (except in combination products) and benazepril are not available in the UK.

Study details

Jamerson K, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. New Engl J Med 2008;359:2417–28

Design: Prospective, multicentre (USA and Europe), double-blind RCT. Allocation concealed. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the pre-specified stopping rule was exceeded.
Patients: 11,506 patients with hypertension at high risk of CV disease, including patients with coronary heart disease, impaired renal function, left ventricular hypertrophy or diabetes. Mean age 68 years, 60% male, mean BMI 31, 60% with diabetes, 84% white, mean blood pressure 145/80mmHg.
Intervention: Benazepril 20mg and 5mg amlodipine, or benazepril 20mg and 12.5mg hydrochlorothiazide, once daily. After one month, the benazepril was increased to 40mg daily. Thereafter investigators could double the dose of TD or CCB to attain a blood pressure target of 140/90mmHg (130/80mmHg for patients with diabetes or kidney disease). Other antihypertensive agents were permitted (excluding CCBs, ACE inhibitors, A2RAs or TDs).
Outcomes: Time to first event of one of the following: death from CV causes; nonfatal myocardial infarction; nonfatal stroke; hospitalisation for angina; resuscitation after sudden cardiac arrest; coronary revascularisation.
Results: Primary outcome: benazepril-amlodipine group 9.6%, benazepril-hydrochlorothiazide group 11.8%, absolute risk reduction with benazepril-amlodipine therapy of 2.2% (NNT=45), a relative risk reduction of 19.6% (hazard ratio [HR], 0.80, 95% confidence interval [CI] 0.72 to 0.90; P<0.001).  A statistically significant reduction (HR 0.79, (95%CI 0.67 to0.92, P=0.002) was found for the composite of death from CV causes, non-fatal MI and non-fatal stroke.
Discontinuations in both groups were high (about 30%). Adverse event profiles differed, most markedly with regard to peripheral oedema, which was higher in the ACE inhibitor and CCB group compared with the ACE and TD group (31.2% vs. 13.4%). Rates of serious adverse events and drug-related serious adverse events were low in both groups. Rates of hospitalisation for heart failure were also similar between groups (1.7%). Mean blood pressure throughout the study were 131.6/73.3mmHg in the ACE-inhibitor and CCB group and 132.5/74.4 mmHg in the ACE-inhibitor and TD group.
Sponsorship: The study was supported by Novartis.

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