EDITOR'S PAGE
Three new intervention trials in hypertension presented:
ONTARGET, ACCOMPLISH and HYVET - what is the evidence?

 

Recently at the American College of Cardiology (ACC) in Chicago, USA, on 31st March, three new landmark clinical trials were presented, with great implications for the treatment of hypertension in risk patients and in the elderly.

Firstly, in the HYVET trial 3845 elderly hypertensives, aged 80 years and above, with a baseline systolic blood pressure over 160 mmHg and no dementia or serious illness, were randomised to receive either a combination of perindopril and indapamide or placebo [1]. The results showed that active treatment was associated with reduction of all stroke (-30%), total mortality (-21%) and congestive heart failure (-64%) after a mean blood pressure reduction of 15/6 mmHg versus placebo after 2 years. The risk ratio for total mortality was RR 0.79 (95% CI: 0.65-0.95; p = 0.019). This means that the benefits of blood pressure control should not be withheld from elderly hypertensives that are in a fairly good health condition with more remaining life years expected. Especially the impressive reduction of heart failure is important as this condition is associated with a very poor quality of life. On the other hand, both ethical aspects and possible contraindications have to
 be taken into consideration in all elderly patients of such high age (mean 83 years in the study).

Secondly, the ONTARGET was a very large, randomised, controlled intervention study in patients (n = 25,620) at high cardiovascular risk (69% hypertensives), recruited at 733 centres in 40 countries, which means that the results are globally applicable [2]. The primary aim was to show non-inferiority of treatment with the angiotensin-2 receptor blocker telmisartan 80 mg in comparison with the ACE-inhibitor ramipril 10 mg. It also included the aim to show if a combination of temisartan and ramipril was more effective than ramipril alone.

The primary composite end-point was cardiovascular mortality, myocardial infarction, stroke, and hospitalisation for congestive heart failure. The main results showed non-inferiority for telmisartan but no added benefits with the combination treatment as compared to ramipril alone. In fact, the combination was associated with more adverse effects and study termination of patients with renal failure, as defined by the participating physicians themselves.

This was the first large clinical trial to compare two different, but related, methods to block the renin-angiotensin system. As no difference was shown between the drugs this means that both ramipril and telmisartan can be used, and that other factors such as tolerability, side effects and pricing should guide prescription. There is no need to combine the two drugs, but further analyses in relation to changes in proteinuria will possibly shed more light on this. Not all data have been published in the first publication.

In many countries national or local guidelines propose that ACE-inhibitors should be used in the first place because of documentation in the HOPE trial for ramipril and that this drug now is cheap [3]. However, if patients can not tolerate it, there is a strong case to use telmisartan as the most well-proven angiotensin-2 receptor antagonist for high risk patients.

Finally, in the ACCOMPLISH trial [4] the use of fixed combinations was tried in a randomised controlled trial in 5721 patients randomised to an ACE-inhibitor and a calcium antagonist (benazepril and amlodipin) or in 5741 patients given an ACE-inhibitor and a diuretic (benazepril and hydrochlorothiazide) for evaluation of non-fatal myocardial infarction or stroke, as well as hospitalisation for unstable angina or revascularisation). Inclusion criteria were age over 60 years and systolic blood pressure above 160 mh Hg or on antihypertensive therapy, and a history of cardiovascular disease or signs of target organ damage.
 
Results showed that the first combination (benazepril and amlodipin) was clinically better than the comparative combination for the primary end-point, RR 0.80 (95% CI: 0.72-0.90; p = 0.002). These results underline that the combination of an ACE-inhibitor and a dihydropyridine type of calcium antagonist is very effective and should be used more widely in risk patients. A similar result was obtained two years ago in the ASCOT study. The full publication of the ACCOMPLISH trial has to await the ajudication of a few remaining end-points, as the study was stopped prematurely due to a significant difference between the two treatment arms.
 
In summary, these three important new hypertension trials will certainly influence clinical practice as well as the revision of guidelines. In short the message is:

  • do not let elderly hypertensives be without effective blood pressure control if they are reasonably healthy for their age (no dementia or cancer).
  • use even more than previously the fixed combination of an ACE-inhibitor and a calcium antagonist in risk patients
  • as ramipril and telmisartan are equally effective, the choice between them can be determined by other factors (side effects, pricing). If ramipril is not tolerated, telmisartan is a good choice.

Based on these findings we should improve the standards of care for hypertensive patients across Europe, and also widen the age range for active interventions.


Peter M Nilsson                               Krzysztof Narkiewicz,
Malmö, Sweden                                 Gdansk, Poland

References:

  1. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al; the HYVET Study Group. Treatment of Hypertension in Patients 80 Years of Age or Older. N Engl J Med 2008 Mar 31.
  2. Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events.
    The ONTARGET Investigators. N Engl J Med 2008 Mar 31.
  3. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53.
  4. Jamerson KA; Avoiding Cardiovascular events through Combination therapy in
    Patients Living with Systolic Hypertension Trial. The first hypertension trial comparing the effects of two fixed-dose combination therapy regimens on cardiovascular events: Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH). J Clin Hypertens (Greenwich) 2003;5(4 Suppl 3):29-35.