Editorial N° 131



First-line antihypertensive
treatment options: should we
move on from monotherapy?

by E. Agabiti-Rosei, Italy

 

E. AGABITI-ROSEI, MD
Department of Clinical and
Experimental Sciences
University of Brescia
Brescia, ITALY

Experimental and clinical research in hypertension has produced extraordinary results, which represent one of the major successes of modern medicine. However, despite the availability of effective and well-tolerated antihypertensive drugs, blood pressure (BP) control in the hypertensive population remains far from optimal. In fact, only approximately half of those who take antihypertensive treatment have BP <140/90 mm Hg.1 Although several factors may be responsible, poor adherence to antihypertensive treatment and therapeutic inertia by doctors represent main causes of poor BP control.

It has been widely recognized that the majority of hypertensive patients require two or more drugs in combination in order to reach BP target. However, current guidelines for the management of hypertension, particularly European guidelines,2 recommend initiation of treatment with combination therapy only for patients with moderate- to-severe hypertension or for those at high/very high cardiovascular risk. They nevertheless suggest that a single-pill combination may simplify treatment and hence favor adherence to the prescribed therapeutic regimen.3 Better adherence to treatment may translate into better cardioprotection and reduced morbidity and mortality.4

Recent evidence indicates that initiation of antihypertensive treatment with a combination may also be useful in patients with mild hypertension.5,6 First-step combination therapy offers several advantages compared with monotherapy. In addition to better adherence, it may provide faster BP control, thus avoiding the frustration of a long-lasting search for effective monotherapy. Combination therapy with lower doses of each component drug often leads to a greater antihypertensive effect and fewer side effects.

BP is, in fact, regulated by multiple mechanisms, and the effect of a given drug may be modified by activation of compensatory pathways. A meta-analysis by Wald et al indicated that combining two drugs of different classes with different mechanisms of action produces a BP reduction approximately five times greater than doubling the dose of one drug.7 Information from randomized trials on drug combinations that may effectively reduce cardiovascular outcomes is only indirect. A two-drug combination has been used systematically in only three trials: the Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE),8 which compared the angiotensin-converting enzyme (ACE) inhibitor perindopril plus the diuretic indapamide versus placebo; FEVER (Felodipine EVEnt Reduction),9 which compared the calcium antagonist felodipine plus the diuretic hydrochloro-thiazide versus the diuretic plus placebo; and ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension),10 which compared the same ACE inhibitor benazepril with either the diuretic hydrochlorothiazide or the calcium antagonist amlodipine.

In all other trials treatment was initiated with monotherapy and another drug was added if needed. In summary, the combinations that were associated with significant benefit in randomized clinical trials and hence those that should be considered preferred combinations include: ACE inhibitor + calcium antagonist or diuretic; angiotensin receptor blocker + diuretic; and calcium antagonist + diuretic. Although the combination of angiotensin receptor blocker + calcium antagonist seems rational, effective, and well tolerated, it has never been systematically used in an outcome trial. A β-blocker + diuretic combination was as effective as other combinations in several trials, but it appears to induce more cases of new-onset diabetes in some predisposed patients, compared with other combinations. The only combination that cannot be indicated, on the basis of the results of ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial)11 and ALTITUDE (ALiskiren Trial In Type 2 diabetes Using carDio-renal Endpoints),12 is two blockers of the renin-angiotensin system (RAS). In about 15% to 20% of patients, BP cannot be adequately controlled by a two-drug combination. In these cases a three drug combination is required and the most rational choice here seems to be a blocker of the RAS, a calcium antagonist, and a diuretic.2 This was the most commonly used combination in the intensive treatment arm of SPRINT (Systolic blood PRessure INtervention Trial),13 a recent trial that suggested that lower systolic BP targets may be of benefit in at least some subgroups of patients.

Thus, earlier treatment with combination therapy may help to reach lower BP targets in a more effective way. Indeed, it has been proposed that a simplified antihypertensive algorithm using initial low-dose combination therapy may be useful for the treatment of patients with hypertension, including mild hypertension.5-7 Recently, two large studies assessed the efficacy and tolerability of a single-pill first-line strategy combination of perindopril + amlodipine, starting with a low dose of each component.

In the first study,14 a perindopril/amlodipine combination initiated at a low dose and then uptitrated to higher doses was compared with a stepped-care strategy, initiated with monotherapy of an ARB and then uptitrated in combination with amlodipine. The conclusion of this three-month study was that the three-step strategy of initiation with single-pill perindopril/ amlodipine produced greater lowering of BP and a more rapid rate of control of hypertension. In the second study,15 a low- and fixed-dose combination of perindopril/amlodipine was more effective than either component given singly and was noninferior to both component drugs given at their initial clinically approved doses. Adverse events with the low-dose combination were also less frequent.

In conclusion, first-line combination treatment given at adapted dosages even to patients with mild hypertension enables treatment via a dual mode of action, which is more effective than monotherapy and may possibly have fewer side effects. It is reasonable to expect that this will provide benefits beyond better BP control, such as improved compliance and more effective cardioprotection. ■

References
1. Hypertension: an urgent need for global control and prevention. Lancet. 2014; 383(9932):1861. Editorial.
2. Mancia G, Fagard R, Narkiewicz K, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31:1281-1357.
3. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixeddose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55:399-407.
4. Burnier M. Antihypertensive combination treatment: state of the art. Curr Hypertens Rep. 2015;17:51.
5. Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53:646-653.
6. Byrd JB, Zeng C, Tavel HM, et al. Combination therapy as initial treatment for newly diagnosed hypertension. Am Heart J. 2011;162:340-346.
7. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
8. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
9. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A; FEVER Study Group. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-con- trolled trial in Chinese hypertensive patients. J Hypertens. 2005;23:2157-2172.
10. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in highrisk patients. N Engl J Med. 2008;359:2417-2428.
11. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET Investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547-553.
12. Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012; 367:2204-2213.
13. Wright JT Jr, Williamson JD, Whelton PK et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-2116.
14. Mancia G, Asmar R, Amodeo C, et al. Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine. J Hypertens. 2015;33:401-411.
15. Laurent S, Parati G, Chazova I, et al. Randomized evaluation of a novel, fixeddose combination of perindopril 3.5 mg/amlodipine 2.5 mg as a first-step treatment in hypertension. J Hypertens. 2015;33:653-661.