Abstract
Evaluation of: Boutouyrie P, Achouba A, Trunet P, Laurent S; EXPLOR Trialist Group. Amlodipine–valsartan combination decreases central systolic blood pressure more effectively than the amlodipine–atenolol combination: the EXPLOR study. Hypertension 55(6), 1314–1322 (2010).
Not all blood pressure (BP)-lowering agents have the same effect on central BP, but we know that central BP, in itself, is a risk factor for cardiovascular diseases. Therefore, antihypertensive agents should ideally also have a central BP-lowering effect. In this paper the authors evaluate the effect of adding a calcium channel blocker to a β-blocker. The results show this combination does not reverse the lesser effect of β-blockers on central BP, and that the combination of valsartan plus amlodipine is more effective in lowering central BP than a combination of amlodipine plus atenolol.
In the management of hypertensive patients, a cornerstone of good clinical practice is to maintain blood pressure (BP) below the goals recommended by guidelines. Combination therapy of antihypertensive agents is often necessary to achieve such goals. However, do all the combinations have the same effect? Which combination is best? This article evaluates a recent paper by Boutouyrie et al. in which the authors evaluate the effect of different antihypertensive combinations on central BP, a prognostic factor of cardiovascular disease Citation[1].
Since the publication of the Conduit Artery Function Evaluation (CAFE), a substudy of the Anglo–Scandinavian Cardiac Outcomes Trial (ASCOT) Citation[2], we know that antihypertensive agents, despite a similar impact on brachial BP, could have different effects on central BP. Furthermore, these findings could also explain the different clinical outcomes found between the two antihypertensive treatment arms in the ASCOT trial, which showed highly statistically significant reductions in the amlodipine/perindopril arm versus the atenolol/bendroflumethiazide arm on the combined end point, which included nonfatal myocardial infarction (MI) and fatal coronary heart disease Citation[3].
Amlodipine is a calcium channel blocker and therefore acts as a vasodilator. The question that remained unanswered until the publication of the article under evaluation was if this vasodilation would dampen the deleterious effect of β-blockers on central BP. In this article, the authors have found an answer to that question.
Method & results
The authors conducted a prospective, randomized, open-label, blinded end point (PROBE) study, with parallel groups versus the reference medication. The inclusion criteria were: essential hypertension, resistance to two drugs belonging to two different pharmacological classes, and being aged between 18 and 75 years. Exclusion criteria included BP controlled by 5 mg of amlodipine, contraindication to one of the drugs, women of childbearing potential not using effective contraception, any active chronic disease, and systolic BP (SBP) over 180 mmHg or diastolic BP (DBP) over 110 mmHg after the run-in period.
Finally, 200 patients were randomized to atenolol plus amlodipine, and 193 patients to valsartan plus amlodipine. BP measurements and applanation tonometry were performed on all the patients. After randomization, the authors found no differences of age and BP between the two populations. Although 46% of the patients were at high cardiovascular risk, there were no differences between the two groups in terms of all of the main cardiovascular risk factors.
Brachial BP decrease at week 24 was similar between the two groups (SBP decreased by 11.78 and 12.93 mmHg in the amlodipine plus atenolol and amlodipine plus valsartan groups, respectively, and DBP was reduced by 7.9 mmHg with both treatments). Moreover, the rates of BP control were similar for both groups, but heart rate was more reduced in the amlodipine–atenolol group than in the amlodipine–valsartan group, as expected.
As for the central BP values, central SBP decreased significantly more (13.7 vs 9.7 mmHg) in the amlodipine–valsartan group than in the amlodipine–atenolol group (p < 0.0001) despite the similar changes in brachial SBP. By contrast, no significant difference in the fall in aortic DBP was observed between the two groups. The augmentation index (AIx) was significantly decreased after amlodipine–valsartan administration, whereas it was significantly increased after amlodipine–atenolol administration; the difference in rough AIx reduction was 6.5% in favor of amlodipine–valsartan (p < 0.0001). Owing to the differences in heart rate between both groups, AIx was adjusted for a heart rate of 75 beats per minute; after adjustment both drug regimens significantly reduced this parameter, but the difference in AIx at heart rate 75 between the groups remained significant (2.8%; p < 0.01). Both treatments decreased aortic pulse wave velocity (PWV) by 1 m/s; no significant difference was found between the groups. These differences persist in different subgroup analyses; previously treated patients had similar changes as previously untreated patients.
Expert commentary
Blood pressure is a main risk factor for cardiovascular disease, as a main etiology and as modifier of the natural history of cardiovascular disease (CVD). However, when we try to measure and evaluate the effect of BP on CVD, we should not only rely on the office brachial BP, which has, in itself, some limitation such as being a risk factor and outcome predictor for CVD. Over the last few years, many studies have shown that beside the values for office BP, more data are necessary. We have learned that other factors are at least as important as office BP and should be taken into account. With more frequent use of home BP measures, such as ambulatory BP monitoring (ABPM), the superiority of home BP values over office BP values has become relevant. Thus, some aspects, such as the night-time BP values, which have a greater prognostic value in the evolution of CVD than office BP values, can only be measured through ABPM Citation[4,5].
The pathophysiology of hypertension depends on multiple factors, such as heart contraction and artery compliance, and central BP measurement could give a more complete evaluation of all these variables. Therefore, since the measurement of central BP has become more available, and data about these measurements are published, we know that brachial BP is only ‘a little part of the whole history’. Many studies, such as the Strong Heart and the ICARe Dicomano Study, have demonstrated that those factors are at least as relevant in the outcome of cardiovascular risk factors as office BP itself Citation[6,7].
Since the publication of the CAFE study, more is known about the effect of therapies on central BP Citation[2]. This study demonstrated that different BP-lowering agents have different effects on central BP despite a similar effect on brachial BP. These differences are related to the different mechanism of BP lowering. Therefore, β-blockers such as atenolol have a lesser effect on central BP.
With this study the authors provide the answer to a crucial question: whether the less intensive effect of atenolol on central BP will be reversed by the addition of a calcium channel blocker. For these reasons, the authors selected a PROBE design, which since its description by Hansson et al. in 1992 Citation[8] has proved its efficacy for comparison of different regimes of antihypertensive agents in different situations Citation[9].
The answer to the question is clear: the combination of valsartan plus amlodipine has shown its superiority in central BP reduction, even after adjustment for heart rate, and amlodipine added no benefit to atenolol in reducing central BP. Therefore, these results have practical clinical implications that should be taken in account when choosing a better drug combination for hypertensive patients.
Five-year view
These results are in line with the recommendations of the 2009 reappraisal of the guidelines on hypertension of the European Society on Hypertension, where a combination of renin–angiotensin system inhibition and a calcium antagonist is recommended for patients who do not achieve therapeutic goals Citation[10].
Should we therefore not recommend the use of β-blockers? Many trials in the past have shown the positive effect on survival, and in a better outcome, of β-blockers in patients with ischemic heart disease and heart failure. If ischemic heart disease and/or heart failure are the most relevant health problem, a β-blocker has to be included in the treatment strategy.
On the other hand, in this study, as in the CAFE trial, the authors used an ‘old’ β-blocker (atenolol). Some new β-blockers (e.g., nebivolol) are known to be vasodilators due to their nitric oxide donor properties Citation[11]. Whether the results would have been different if a different β-blocker was used remains open to speculation; more data may be necessary to answer this question.
Key issues
• Central blood pressure (BP) is an independent risk factor for cardiovascular disease, and is at least as important as brachial BP measured at the office.
• Different BP-lowering agents have different effects on central BP.
• Atenolol has a lesser lowering effect on central BP.
• Adding amlodipine to atenolol does not compensate for this lower effect.
• Valsartan plus amlodipine combination is superior to atenolol plus amlodipine combination in lowering central BP.
Financial & competing interests disclosure
Miguel Camafort-Babkowski has consulted for MENARINI, and has received honoraria for speakers/chairmanship at meetings from MENARINI and AstraZeneca. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
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