Low‐dose combination therapy to control sustained ambulatory hypertension—Basic principles and future directions

Recently released international guidelines on the management of hypertension reclassify hypertension and reappraise the previously established blood pressure (BP) goals and targets.1, 2 The 2018 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines, for example, recommend that in the vast majority of hypertensives, on‐treatment BP should be targeted to levels <130/80 mm Hg, provided that intensive antihypertensive therapy is well‐tolerated.2 These lower BP goals are recommended for hypertensives at any level of cardiovascular risk and regardless of the presence or absence of established cardiovascular disease.2 Support to these guideline recommendations is provided by “hard” clinical‐trial evidence showing that compared with a standard systolic BP target of <140 mm Hg, intensive therapy targeting to lower systolic BP <120 mm Hg offers additive cardiovascular risk reduction.3 Wide use of combination therapy—preferably single‐pill combinations—is recommended as a principle strategy to enhance adherence to the prescribed antihypertensive regimen, overcome therapeutic inertia and facilitate the achievement of these lower BP targets.1, 2

In this issue of the Journal of Clinical Hypertension, Xu et al4 report the results of a prespecified sub‐analysis of an open‐label, randomized, controlled trial comparing the effect of low‐dose, single‐pill combination of valsartan/amlodipine (80/5 mg/day) versus nifedipine GITS (30 mg/day) on ambulatory BP and arterial stiffness. According to the inclusion/exclusion criteria, this sub‐analysis enrolled 150 hypertensives with uncontrolled office BP, despite the administration of monotherapy for at least 4 weeks prior to study enrollment. Over a‐12‐week‐long follow‐up, in the overall population, valsartan/amlodipine combination was not superior to monotherapy with nifedipine GITS in lowering 24‐hour ambulatory BP (between‐group difference: −2.1/‐1.7 mm Hg, P > 0.20).4 Combination therapy with valsartan/amlodipine exerted a more potent BP‐lowering action during night‐time than during day‐time. In subgroup analysis stratified according to the dipping status, combination therapy was superior to monotherapy in lowering night‐time BP in non‐dippers, but not in dippers.4 When the analysis was stratified according to the ambulatory BP control status of participants at baseline, the BP‐lowering effect of combination therapy was similar to that of monotherapy in the subgroup of white‐coat uncontrolled hypertension. By contrast, in those with sustained uncontrolled hypertension, combination therapy lowered more effectively 24‐hour ambulatory BP relative to monotherapy (between‐group difference: −4.9/‐3.8 mm Hg, P < 0.05). Valsartan/amlodipine combination therapy was also associated with improvement in arterial stiffness, assessed by measuring brachial‐ankle pulse wave velocity (PWV).4

Interpretation of the above findings requires a careful evaluation of the study design and participant characteristics. The absence of a statistically significant benefit of low‐dose combination therapy with valsartan/amlodipine versus monotherapy with nifedipine GITS on 24‐hour ambulatory BP in the study of Xu et al4 does not come in contrast with the results of large‐scale outcome trials and meta‐analyses showing that combination therapy is more effective in controlling high BP. The findings of this study are rather expectable if we take into consideration that sustained uncontrolled hypertension, confirmed with 24‐hour ambulatory BP monitoring, was not a prespecified inclusion criterion in this sub‐analysis. Accordingly, approximately one‐third of study participants (53 out of 150 participants) had uncontrolled office BP but adequately controlled 24‐hour ambulatory BP.4 This phenotype is described with the term “white‐coat” uncontrolled hypertension. In accordance with earlier observations,5 the study of Xu et al4 showed that intensified combination therapy in the subgroup of white‐coat uncontrolled hypertension provoked significant reductions in office BP but had no effect on ambulatory BP. Whether antihypertensive therapy should be intensified in order to control on‐treatment white‐coat hypertension is a question that is not yet properly answered. Prospective cohort studies have shown that white‐coat uncontrolled hypertension among drug‐treated hypertensives is not associated with higher long‐term risk for cardiovascular events and mortality,6, 7 possibly because these patients have sustained and adequate hypertension control when BP is recorded with home or ambulatory BP monitoring. Despite the fact that patients with on‐treatment white‐coat hypertension are routinely enrolled in large‐scale outcome trials, identification of these patients and quantification of the efficacy of intensified antihypertensive therapy in this setting is difficult or even impossible, mainly due to the fact that out‐of‐office BP recordings are unavailable.

Indeed, the results of the study of Xu et al4 provide support to the concept of single‐pill combination therapy in management of hypertension. In the subgroup of sustained uncontrolled hypertension, valsartan/amlodipine combination therapy lowered 24‐hour ambulatory BP by 4.9/3.8 mm Hg relative to monotherapy with nifedipine GITS. This BP‐lowering effect was statistically significant and was consistent during both day‐time and night‐time periods. This BP‐lowering effect was paralleled with an improvement in brachial‐ankle PWV,4 suggesting that low‐dose combination therapy is superior to monotherapy in causing regression of hypertension‐related target organ damage. These findings are even more important because this study did not actually enroll patients with newly diagnosed hypertension. According to the baseline characteristics, the duration of pre‐existing hypertension was 14.7 ± 7.0 years in the group of valsartan/amlodipine combination and 15.2 ± 8.0 years in the group of nifedipine GITS.4 Accordingly, we hypothesize that these patients might have remained on monotherapy for a long period despite the lack of adequate BP control. Absence of proper intensification of antihypertensive therapy in patients with uncontrolled hypertension may be of multi‐factorial origin, but therapeutic inertia is an important barrier to achieve BP goals and targets.9 In this direction, initiation of antihypertensive therapy with the use of low‐dose combinations—as recommended by international guidelines—is a principle strategy to overcome therapeutic inertia and improve BP control rates.1, 2 A real‐world observational study enrolling 125 635 Italian hypertensives supports this notion showing that compared with initial monotherapy, patients who initiated combination therapy had a markedly greater covariate‐adjusted prosperity of being prescribed a multi‐drug antihypertensive regimen over a 3‐year‐long follow‐up.10 These patients had also 20% lower risk for all‐cause mortality and 16% lower risk for hospitalization due to cardiovascular events,10 a benefit possibly mediated through optimized antihypertensive therapy and adequate BP control during the observational period.

The therapeutic strategy of initiating pharmacotherapy of hypertension with the use of two‐drug combinations for the majority of patients is supported by a growing body of evidence. Meta‐analyses of randomized trials have shown that the BP‐lowering effect of two‐drug combination therapy is approximately 5 times greater than that of doubling the dose of monotherapy.11, 12 Observational studies have shown that compared with monotherapy, the use of single‐pill combination therapy is associated with lower discontinuation rates,13 improved adherence to the prescribed antihypertensive regimen and better BP control rates during the first year of follow‐up.14 Most importantly, real‐world, large‐scale observational studies provide evidence that these benefits of initial combination therapy on intermediate endpoints are translated into reduction in the risk of major cardiovascular events and all‐cause mortality.15, 16 Randomized controlled trials evaluating “hard” clinical endpoints are now warranted to provide additional strength to the notion that initial combination therapy offers greater cardiovascular risk reduction than initial monotherapy.

In conclusion, the study of Xu et al4 showed that among patients with sustained uncontrolled ambulatory hypertension, low‐dose valsartan/amlodipine combination (80/5 mg/day) was superior to monotherapy with nifedipine GITS (30 mg/day) in lowering 24‐hour, day‐time and night‐time BP; this BP‐lowering effect was shown to be accompanied by a parallel regression of arterial stiffness. These findings are clinically meaningful and provide support to the concept of initial combination therapy as a strategy to optimize the overall management of hypertension and facilitate the achievement of the lower BP targets, as reappraised in recent international guidelines.1, 2

CONFLICT OF INTEREST

All authors have no conflicts of interest to disclose.