Antihypertensive combinations: what is missing?

Faculty of Medicine
Paris-Descartes University

Antihypertensive combinations: what is missing?

by J. Blacher, France

All the epidemiological studies show that hypertension remains inadequately screened, treated, and controlled. It has been shown that when antihypertensive monotherapy is not sufficient to control blood pressure, the combination of two agents from any two classes of antihypertensive drugs increases the level of blood pressure reduction much more than doubling the dose of one agent. Most of the existing guidelines focus on combinations that use a blocker of the renin-angiotensin-aldosterone system and either a thiazide diuretic or a calcium channel antagonist. Other combinations are underpromoted; specifically, the combination of a thiazide diuretic and a calcium channel antagonist. However, this combination has been used in several therapeutic trials and has shown similar or greater benefits than comparator drugs. In VALUE (Valsartan Antihypertensive Long-Term Use Evaluation), ELSA (European Lacidipine Study on Atherosclerosis), FEVER (Felodipine EVEnt Reduction), and COPE (COmbination therapy of hypertension to Prevent cardiovascular Events), the calcium channel antagonist/thi-azide combinations were effective both in terms of systolic blood pressure reduction and prevention of cardiovascular complications. Furthermore, in addition to a wellaccepted effect on systolic blood pressure, this combination could also have beneficial effects over and above blood pressure reduction; namely, its effects on central blood pressure and on systolic blood pressure variability. Finally, therapeutic innovation in hypertension will perhaps come more from the combination of older drugs than from the discovery of new drugs.

Medicographia. 2013;35:395-402 (see French abstract on page 402)

Hypertension is the leading chronic disease worldwide.1 It is known to increase the risk of stroke, coronary heart disease, heart failure, renal failure, and cognitive disorders, and was responsible for between 7 and 8 million deaths worldwide in 2011.2 Antihypertensive treatment has been shown to reduce cardiovascular complications.3 In France, an estimated 12 million patients receive pharmacological treatment for hypertension, most of them receiving combination therapy.4

For over 30 years, national and international societies have issued numerous sets of guidelines for the management of hypertension, yet hypertension still remains inadequately screened, treated, and controlled.5 In France, 20% of patients known to be hypertensive are not treated, and 50% of treated hypertensive patients are not controlled, thus showing that the impact of the guidelines is insufficient at the population level.6

To improve the management of hypertension, combination therapies need to be promoted. Most of the existing guidelines focus on combinations using a blocker of the renin-angiotensin aldosterone system and another drug (thiazide diuretic or calcium channel antagonist), whereas others combinations are under promoted; namely, the combination of a thiazide diuretic and a calcium channel antagonist. This article will focus on the existing data in favor of such a combination.

Which strategy after the failure of an initial monotherapy?

According to the 2007 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines,7 antihypertensive treatment should most of the time start with a single drug, which should initially be administered at a low dose. If blood pressure is not controlled, either a full dose of the initial agent can be given or patients can be switched to an agent of a different class (which should also be administered first at a low dose and then at full dose). Switching to an agent from a different class is mandatory in cases where the first agent had no blood pressure–lowering effect or induced important side effects. This ‘‘sequential monotherapy’’ approach allows one to find the drug to which any individual patient best responds, both in terms of efficacy and tolerability. However, although the so-called ‘‘responder rate’’ for any agent in monotherapy is approximately 50% (response meaning here systolic and diastolic blood pressure reduction of >20 mm Hg and >10 mm Hg, respectively), the ability of any agent used alone to achieve target blood pressure values (<140/90 mm Hg) does not exceed 20%-30% in the overall hypertensive population, except in subjects with grade 1 hypertension. Furthermore, the procedure is laborious and frustrating for both doctors and patients, leading to low compliance.

In its 2009 reappraisal,8 the ESH task force tempered its position, mostly because of the publication of an important meta-analysis.9 This meta-analysis of 42 studies showed that combining two agents from any two classes of antihypertensive drugs increases the blood pressure reduction much more (5 times) than doubling the dose of one agent.9 Admittedly, the advantage of combination therapy over monotherapy may partly be due to the fact that if any agent used in monotherapy is ineffective or scarcely effective in a number of patients, thus its combination with an agent that is effective in these patients must induce a greater response than doubling the dose of an ineffective agent. However, although it is possible that the use of two drugs together implies the administration of one drug that is futile, searching for the most effective monotherapy in every given patient is painstaking, and, as mentioned, may discourage compliance.

It is also important to note that in most trials, a combination of two or more drugs has been the most widely used treatment regimen to effectively reduce blood pressure and reach the predetermined goal. Use of combination therapy has been found to be even more frequently needed in diabetic, renal, and high-risk patients, and in general whenever lower blood pressure targets are pursued.8 For example, in a large-scale trial on high-risk hypertensives, the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial), about 9 out of 10 patients were given two or more antihypertensive drugs in order to reduce blood pressure to <140/90 mm Hg.10

Furthermore, there are physiological and pharmacological synergies that justify the greater effectiveness of drug combinations, and this strategy appears to be that on which the selection of antihypertensive medication may increasingly be based. From a public health perspective, it would seem desirable to see a substantial increase in the use of combination treatment in clinical practice from the relatively low prevalence of today.4,6 This could help attain the goal of substantially improving blood pressure control in the hypertensive population from its present low rate of control worldwide.2

Finally, for all these reasons, in the 2013 French Society of Hypertension guidelines, we have proposed a direct switch to combination therapy when blood pressure is not adequately controlled by initial monotherapy.11

What is the ideal combination therapy?

The ideal combination therapy should be: (i) effective in terms of systolic blood pressure reduction, with at least complete (not partial) additive effects of both monotherapies, and at best, synergistic effects; (ii) pertinent in terms of pathophysiological effects: this should be achieved by combining agents that either interfere with distinctly different pressor mechanisms or effectively block counterregulatory responses; and (iii) evidence- based; that is to say that this combination should have demonstrated a beneficial effect on cardiovascular morbid and fatal events in comparison with a monotherapy, or best, another combination treatment.

Table I
Table I. 2009 European Society of Hypertension position concerning
combination therapy.

After reference 8: Mancia G et al; European Society of Hypertension. J Hypertens.
2009;27:2121-2158. © 2009, Lippincott Williams & Wilkins.

Unfortunately, the blood pressure effects of combination therapies in hypertension are frequently underadditive, pathophysiological considerations are frequently contradicted by different clinical trials, and there are very few therapeutic trials comparing two different bitherapies with clinical events outcomes. Thus, preferences should take into account a combination of the previous criteria and a large degree of uncertainty.

In their 2009 guidelines, the ESH/ESC reported that (Table I):

Trial evidence of outcome reduction has been obtained particularly for the combination of a diuretic with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor antagonist or a calcium antagonist, and in recent large-scale trials for the ACE inhibitor/calcium antagonist combination.8

In a recent position paper, Gradman et al, on behalf of the American Society of Hypertension (ASH), differentiated the possible drug combinations in hypertension into three groups: the preferred, the acceptable, and the less-effective combinations (Table II).12 It is important to note that the calcium channel blocker (CCB)/diuretic combination was considered as “preferred” by the European guidelines and just “acceptable” by the ASH. It will be interesting to see if such discrepancy still exists in the forthcoming European and American guidelines.

Focus on an “acceptable bitherapy”: the calcium channel blocker/diuretic combination

Despite the fact that small pharmacological studies have raised doubts about the synergistic effects of adding a diuretic to a calcium channel antagonist (for review see reference 8), this combination was included in the meta-analysis by Wald et al9 and did not detract from the demonstration of a greater blood pressure–lowering effect of combining calcium channel antagonists with other drugs compared with doubling the calcium channel antagonist dose in monotherapy. Even more importantly, the association of a calcium channel antagonist with a diuretic has been used in several therapeutic trials, where it has shown similar or greater benefits than the comparators. These trials are detailed hereafter and summarized in Table III.

Table II
Table II. 2011 American Society of Hypertension position concerning
combination therapy.

Abbreviations: ARB, angiotensin receptor blocker; ACE, angiotensin-converting
enzyme; CCB, calcium channel blocker.
After reference 12: Gradman AH et al; American Society of Hypertension Writing
Group. J Am Soc Hyper. 2010;4:42-50. © 2010 American Society of Hypertension.

Table III
Table III. The calcium
channel blocker/diuretic
combination is at least as
effective as or superior to
other antihypertensive

Abbreviations: ARB, angiotensin
receptor blocker; BB, β-blocker;
CCB, calcium channel blocker;
COPE, COmbination therapy of
hypertension to Prevent cardiovascular
Events (trial); CV, cardiovascular;
DIU, diuretic; ELSA,
European Lacidipine Study on
Atherosclerosis; FEVER, Felodipine
EVEnt Reduction (trial); MI,
myocardial infarction; PEP, primary
end point; VALUE, Valsartan Antihypertensive
Long-Term Use
Evaluation (trial).

◆ The VALUE trial
The VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation) included patients with high-risk hypertension, most with previous histories of coronary disease, stroke, or diabetes. Patients were randomized to either a valsartan-based or amlodipine- based treatment, and were followed-up for as long as 6 years. Most patients were on previous antihypertensive therapy, and at the start of the study were switched immediately to the starting dose of their randomly assigned drug. If needed, to achieve blood pressure control (<140/90 mm Hg), doses could be titrated (valsartan 80 mg to 160 mg; amlodipine 5 mg to 10 mg) and hydrochlorothiazide (12.5 mg to 25 mg) and other drugs added during the first 6 months of the study. The primary study end point was a composite of fatal and nonfatal cardiac events (including sudden cardiac death, myocardial infarction, hospitalization for heart failure, and death associated with percutaneous or surgical coronary interventions). Although there was no statistically significant difference in the primary end point between groups at the end of the trial, the greater blood pressure reduction (–3.8/–2.2 mm Hg) seen in amlodipine- versus valsartan-treated patients in the first 6 months was accompanied by a statistically significant difference in cardiovascular event rate in favor of the more effectively- treated group.13

◆ The FEVER trial>
The FEVER trial (Felodipine EVEnt Reduction) was a multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. It enrolled 9800 Chinesepatients, of either sex, aged 50 to 79 years, with one or two additional cardiovascular risk factors or disease, whose blood pressure was in the range of 140-180 mm Hg (systolic) or 90-100 mm Hg (diastolic) 6 weeks after switching from their previous antihypertensive therapy to low-dose (12.5 mg a day) hydrochlorothiazide. These patients were randomly assigned to either low-dose felodipine extended release or placebo, and followed at 3-month intervals for an average of 40 months. The intention-to-treat analysis included 9711 patients. Add-on therapy was given to 33.9% of the hydrochlorothiazide + felodipine patients and to 42.3% of the hydrochlorothiazide + placebo patients. In the felodipine group, systolic blood pressure/diastolic blood pressure decreased (from randomization to study end) from 154.2/ 91.0 mmHg to 137.3/82.5 mm Hg, and in the placebo group from 154.4/91.3 mm Hg to 142.5/85.0 mm Hg, with an average difference throughout the trial of 4.2/2.1 mm Hg. In the felodipine group, the primary end point (fatal and nonfatal stroke) was reduced by 27% (P<0.001). Among the secondary end points, all cardiovascular events were reduced by 27% (P<0.001), all cardiac events by 35% (P=0.012), death by any cause by 31% (P=0.006), coronary events by 32% (P=0.024), heart failure by 30% (P=0.239), and cardiovascular death by 33% (P=0.019) in the felodipine group.14

◆ The ELSA study>
The ELSA trial (European Lacidipine Study on Atherosclerosis) was a randomized, double-blind trial in 2334 patients with hypertension that compared the effects of 4 years of treatment based on either lacidipine or atenolol on an index of carotid atherosclerosis: the mean of the maximum intima-media thickness in far walls of common carotids and bifurcations (CBMmax). This index has been shown by epidemiological studies to be predictive of cardiovascular events. If blood pressure was not at goal, after increasing the study drug dose in each group, 12.5 mg hydrochlorothiazide was added. Although clinic blood pressure reductions were identical in both groups, a significant (P<0.0001) effect of lacidipine was found compared with atenolol, with a treatment difference in 4-year CBMmax progression of 0.0227 mm (intention-to-treat population) and 0.0281 mm (completers). No significant difference between treatments was found for any cardiovascular events, although the relative risk for stroke, major cardiovascular events, and mortality showed a trend favoring lacidipine (plus hydrochlorothiazide).15

◆ The COPE study>
In COPE (COmbination therapy of hypertension to Prevent cardiovascular Events), a randomized, open-label, blinded end point trial, 3501 hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (<140/90 mm Hg) with the CCB benidipine 4 mg/day were randomly equally assigned to receive an angiotensin receptor blocker, a β-blocker, or a thiazide diuretic in addition to benidipine. Median follow-up was 3.61 years. At the end of the treatment, 64.1%, 66.9%, and 66.0% of patients in the benidipine+angiotensin receptor blocker, benidipine+β-blocker, and benidipine+thiazide groups, respectively, achieved target blood pressure. The cardiovascular composite end point occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively; the hazard ratio was 1.26 in the benidipine + angiotensin receptor blocker group (P=0.3505) and 1.54 in the benidipine + β-blocker group (P=0.0567) compared with the benidipine + thiazide group. The secondary analyses revealed that benidipine + thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P=0.0109) and benidipine + angiotensin receptor blocker significantly reduced new-onset diabetes (P=0.0240) compared with benidipine + β-blocker. Finally, there was a trend toward a superior net benefit in the benidipine + thiazide group.16

Figure 1
Figure 1. Typical pressure
waveforms and characteristics
related to reflected waves in
high and low arterial stiffness.

Tr: arrival time (msec) of reflected waves
at central aorta (time from the onset of left
ventricular ejection (T0) to inflection point
A). AP=P1-P2 the augmentation of aortic
systolic pressure induced by the return
of the reflected wave, where P1 is the
pressure at the first inflection point A and
P2 is the pressure at the second inflection
point B. Augmentation index (AIx) (%) is
defined by the formula: AIx = 100 AP/PP,
where PP is the aortic pulse pressure
(systolic minus diastolic pressure). Ts: the
end of systole (ejection duration).
After reference 17: Protogerou AD et al.
J Hypertens. 2007;25:265-272. © 2007,
Lippincott Williams & Wilkins.

Beneficial effects of calcium channel blocker/
diuretic combination over and above blood
pressure reduction

The main benefits of antihypertensive treatment are due to lowering of blood pressure per se, and are largely independent of the drugs employed. Nevertheless, several therapeutic trials have shown differences in the rate of cardiovascular complications between groups without any significant blood pressure difference. Thus, some strategies are undoubtedly associated with a cardiovascular benefit that goes above and beyond blood pressure reduction. The two best candidates to explain part of this benefit are the concepts of central hemodynamics and blood pressure variability.

◆ Central blood pressure
The blood pressure waveform varies substantially between the peripheral conduit (brachial) and the central elastic (aorta) arteries, mainly due to a gradual increase in systolic blood pressure as the wave propagates distally. This phenomenon is called blood pressure amplification and is principally generated by the presence of an arterial stiffness gradient and wave reflections along the arterial bed (Figure 1).17 More and more clinical studies suggest that central blood pressure may provide additional information regarding cardiovascular risk beyond peripheral blood pressure. Recent evidence suggests, beyond any doubt, that antihypertensive drugs affect peripheral and central blood pressure differentially and alter pressure amplification. We previously published a review paper showing that18: (i) it is clear that there are important differences between the classes of antihypertensive drugs regarding their effects on blood pressure amplification; (ii) it seems that the newer antihypertensive drugs (ACE inhibitors, angiotensin receptor blockers, and dihydropyridine CCBs), as well as nitrates, have a more beneficial effect on blood pressure amplification than the older drugs (diuretics and β-blockers); and (iii) there is compelling evidence regarding the detrimental effect of β-blockers (mainly atenolol) on central blood pressure.

Nevertheless, very few comparative studies have been performed that focus on central blood pressure parameters. In a double-blind crossover study, the effects on central aortic pressure of the four major drug classes were measured and compared with placebo. Central aortic pressure and various indices were determined using the SphygmoCor® apparatus. The study was undertaken in patients aged 65 to 85 years with systolic blood pressure of >150 mm Hg at study entry. Results were reported for 32 patients who had satisfactory applanation tonometry in all five periods. This study revealed that CCBs and diuretics caused a greater fall in brachial artery systolic blood pressure than ACE inhibitors or β-blocker drugs. On placebo, central aorta augmentation pressure and index were 23 mm Hg and 33.3%; on ACE inhibitors the values were 18 mm Hg and 30%; on β-blockers, 26 mm Hg and 38.5%; on CCBs, 16 mm Hg and 28%; and on diuretics, 17 mm Hg and 28.8%. The augmentation pressure on β-blocking drugs was greater than on the other three drug classes (P<0.05), and augmentation pressures on ACE inhibitors, CCBs, and diuretics were less than on placebo (P<0.05). The lowest central aortic pressures were achieved with CCBs and diuretics.19

To my knowledge, the effects of combination therapies on central hemodynamics have never been assessed.

◆ Blood pressure variability
Unexplained differences between classes of antihypertensive drugs in their effectiveness in terms of cardiovascular prevention might be due to class effects on intra-individual variability in blood pressure. In order to test this hypothesis, Webb et al performed a systematic review to assess any such effects in randomized controlled trials.20 In their meta-analysis, blood pressure variability was expressed as the ratio of the variances or as coefficient of variation. Compared with other drugs, inter-individual variation in systolic blood pressure was reduced by CCBs (variance ratio 0.81; 95% confidence interval, 0.76-0.86; P<0.0001) and nonloop diuretic drugs (variance ratio 0.87; 95% confidence interval, 0.79-0.96; P=0.007), and increased by ACE inhibitors (variance ratio 1.08; 95% confidence interval, 1.02-1.15; P=0.008), angiotensin receptor blockers (variance ratio 1.16; 95% confidence interval, 1.07- 1.25; P=0.0002), and β-blockers (variance ratio 1.17, 95% confidence interval, 1.07-1.28, P=0.0007). CCBs followed by thiazide diuretics could thus be considered as the two best drugs in terms of reduction of blood pressure variability (Figure 2).

As with central hemodynamics, to my knowledge, the effects of combination therapies on blood pressure variability have never been assessed.

Which calcium channel blocker, which diuretic?

In the absence of therapeutic trials comparing drugs within a single antihypertensive class, preferences have to take into account indirect comparisons, level of proof for every single drug, and a large degree of uncertainty.

With regard to thiazide or thiazide-like diuretics, among the four previously described therapeutic trials,13-16 three used hydrochlorothiazide. We could thus believe that hydrochlorothiazide should be the primary recommended thiazide diuretic. However, some data are at odds with such a statement. First, recently reviewed old data are in favor of a superiority of chlortalidone over hydrochlorothiazide.21 Second, indapamide has been tested in two major therapeutic trials, HYVET (HYpertension in the Very Elderly Trial)22 and ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation),23 and was associated with both a net benefit in terms of cardiovascular end points and also in terms of total mortality. Finally, the most recent National Institute for Health and Care Excellence (NICE) guidelines recommend favoring chlortalidone and indapamide over hydrochlorothiazide.24

Figure 2
Figure 2. Changes in systolic blood pressure group variation at
follow-up compared with baseline as variance ratio (A) and percentage
increase in coefficient of variation (B) in clinical trials of
various antihypertensive drugs.

Error bars represent the 95% confidence intervals. (A) is plotted on a logarithmic
scale. The apparent increase in variance ratio and coefficient of variation (CV)
from baseline to follow-up was mainly a consequence of the requirement in
many trials for narrow ranges of blood pressure at randomization, which tended
to lead to an increase in group standard deviation on follow-up; however, this
effect applied almost equally to all drug classes.
Abbreviations: AB, &alpha:;1-blocker; ACEI, angiotensin-converting enzyme inhibitor;
ARB, angiotensin receptor blocker; BB, β-blocker; CCB, calcium channel
blocker; CCBND, non-dihydropyridine calcium channel blocker; DIU, nonloop
diuretic drug.
After reference 20: Webb AJ et al. Lancet. 2010;375:906-915. © 2010,
Elsevier Ltd.

With regard to calcium channel antagonists, amlodipine undoubtedly has the highest level of proof, with the results of four major therapeutic trials in the field of hypertension: VALUE, described previously13; ALLHAT (Antihypertensive and Lipid- Lowering treatment to prevent Heart Attack Trial), which did not find any difference in the composite of fatal coronary heart disease plus nonfatal myocardial infarction compared with lisinopril (primary end point) and also found a decrease in stroke of 23% (secondary end point)25; ASCOT, with a significant decrease in all end points including all-cause mortality in the amlodipine/perindopril group compared with the atenolol/thiazide group10; and finally, the ACCOMPLISH trial (Avoiding Cardiovascular events in COMbination therapy in Patients LIving with Systolic Hypertension), which found that amlodipine in combination with benazepril was superior to the combination of benazepril plus hydrochlorothiazide in a high-risk population.26


Poor blood pressure control at the population level motivates promotion of new therapeutic strategies. Since the vast majority of hypertensive patients need more than one drug to control their blood pressure, the emphasis should be on combination therapy evaluation rather than duplication of conventional therapeutic trials evaluating monotherapies. Among the different possible combination therapies, there is one that has been insufficiently evaluated and promoted: the CCB/thiazide diuretic combination. This combination is considered as “preferred” by the ESH but just as “acceptable” by the ASH. Nevertheless, several therapeutic trials have shown that this combination is at least as effective as comparators, and sometimes superior. Furthermore, in addition to a well-accepted systolic blood pressure–lowering effect, this combination could also have beneficial effects over and above blood pressure reduction; namely, its effects on central blood pressure and systolic blood pressure variability. Finally, therapeutic innovation in hypertension will perhaps come more from the combination of older drugs than from the discovery of new ones.

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Keywords: blood pressure variability; calcium channel blocker; central hemodynamics; combination therapy; thiazide diuretic