Journal of Human Hypertension (2007) 21, 914–916; doi:10.1038/sj.jhh.1002272; published online 16 August 2007

Antihypertensive drugs in combination: additive or greater than additive?

G T McInnes1

1Division of Cardiovascular and Medical Sciences, Western Infirmary, University of Glasgow, Glasgow, UK

Correspondence: Professor GT McInnes, Division of Cardiovascular and Medical Sciences, Western Infirmary, University of Glasgow, Gardiner Institute, 44 Church street, Glasgow G11 6NT, UK. E-mail:

In this edition of the Journal of Human Hypertension, Puig et al.1 report a study demonstrating that the calcium channel blocker (CCB) lercanidipine and the ACE inhibitor enalapril in combination have at least an additive effect on systolic blood pressure (BP) in elderly people with hypertension. Superficially, the findings are unremarkable, but concealed within the data is a message of considerable potential importance for the evaluation of antihypertensive drugs and the management of hypertension.

Despite a wealth of robust evidence that effective control of BP significantly reduces the morbidity and mortality associated with hypertension, control rates in many populations remain dismal.2, 3 Current national and international guidelines recommend rigorous BP targets in all treated individuals, with even more stringent goals in high-risk groups.

For most individuals, drug therapy is initiated with monotherapy, followed by dose-titration in an attempt to achieve treatment targets. Although there is controversy about the most appropriate first-line choice, there is general agreement that for some patients, there are compelling indications or contraindications for particular drug classes.4, 5, 6 This advice is driven more by consideration of benefits or hazards independent of BP lowering (for example beta-blockers indicated in angina but contraindicated in asthma) rather than expectation of greater or lesser antihypertensive efficacy.


Targeted/sequential monotherapy

There is marked interindividual variability in response to any antihypertensive agent. Plasma renin profiling, age and gender are useful in predicting response.7 Young and white individuals tend to have high plasma renin activity and respond well to drugs that block the renin–angiotensin system (RAS), ACE inhibitors or angiotensin receptor blockers (A) and beta-blockers (B), while older people and black subjects of all ages tend to have low renin hypertension and respond preferentially to CCBs (C) and diuretics (D).6, 7, 8, 9, 10 This is the rationale for the A (B) CD algorithm proposed by the British Hypertension Society.6 The heterogeneity of the response to antihypertensive therapy means that responses in individuals and the identification of factors that determine response require within-patient (crossover) comparisons.

Even with individualized or targeted monotherapy, BP goals are unlikely to be achieved at the starting dose of the first drug. Upward dose titration allows the patient to remain on a familiar drug but the modest increase in BP response is at the cost of a steep increase in side effects for most drugs11—the law of diminishing returns.12 Sequential monotherapy is favoured by some13 but requires a lengthy period of trial and error with loss of patient confidence, and an ideal agent for the individual may never be found.


Combination therapy

Except for those relatively few individuals with pretreatment BP close to target, monotherapy is rarely adequate. Most will require two or more drugs in combination.

A careful meta-analysis of 354 randomized, double-blind, placebo-controlled trials indicates that the BP-lowering effects of different drug classes are strictly additive.11 Based on this analysis, it is estimated that 50% of hypertensives require three or more drugs and more than 50% require two or three drugs to achieve target BP.14 Only one-third of participants in the Hypertension Optimal Treatment study achieved target BP on monotherapy; the remainder required up to five drugs concomitantly.

Hypertension is heterogeneous in response to treatment, and combination therapy increases the likelihood of an adequate response. Combined treatment can block counter-regulatory mechanisms that are triggered whenever pharmacological intervention is initiated and act to limit the efficacy of antihypertensive medication. Potential mutual enhancement of the antihypertensive efficacy of drug classes raises the theoretical possibility of a greater than additive response to certain combinations.


Which combination?

All antihypertensive medications can be combined as necessary but some combinations make more sense than others. Allegedly rational combinations include beta-blocker plus diuretic, beta-blocker plus CCB, ACE inhibitor plus diuretic and CCB plus ACE inhibitor.15, 16, 17 The only absolute contraindication is the combination of a rate-limiting CCB with a beta-blocker because of the danger of cardiac function decompensation and heart block as both classes have negative inotropic and chronotropic effects; sudden cardiac deaths have been reported.

A practical approach to choosing combinations is proposed by the British Hypertension Society,6 based on the interaction of major classes of antihypertensive drugs with the RAS. Thus, it is logical to combine an A drug (for example ACE inhibitor) with a C drug (CCB).

CCBs are potent vasodilators that induce reflex activation of the sympathetic nervous system and the RAS. Combination with an ACE inhibitor leads to buffering of this neuroendocrine activation.18 Increase in angiotensin II and the negative sodium balance caused by CCBs reinforces the antihypertensive efficacy of ACE inhibitors. Also, concomitant ACE inhibition attenuates the side effects of CCBs, notably peripheral oedema.18 Some support for combination therapy based on a CCB and ACE inhibitor comes from the Anglo Scandinavian Cardiac Outcomes Trial19 in which treatment with amlodipine plus perindopril was superior to therapy based on atenolol and bendroflumethiazide for BP, cardiovascular outcomes and side effects.


The necessary evidence

Investigation of whether drugs have additive, greater than additive or less than additive effects is not an easy matter. The classical method is to construct dose–response curves for one drug at one or more dose of the second. A dose ratio can then be calculated. This is impractical in the clinical setting.

The usual parallel group comparison of antihypertensive agents given alone and in combination cannot provide a measure of each individual's response to treatments, and similarity of average response to treatments may deflect from the scope for individual variation in response. Thus, differences may appear less marked, combinations may appear 'additive' or 'less than additive' while, in individuals, the response may be 'greater than additive'.

The goal is to know how large a proportion of the hypertensive population demonstrate an additive or greater than additive effect with combination therapy. This requires crossover studies with drugs at doses that are optimal to allow assessment of the balance between efficacy and side effects.


What is new in this edition?

The study by Puig et al.1 aimed to assess the effect of combined therapy with lercanidipine and enalapril on systolic BP. Such studies are common but the design of this trial (a randomized, double-blind, four-way comparison of each active therapy, the combination of both drugs at fixed doses and placebo) allows evaluation of whether the treatments have additive or greater than additive effects on BP.

Compared with placebo, office systolic BP at trough was reduced significantly by all active treatments. The response to combination therapy was significantly greater than that to either monotherapy. Indeed, the reduction in systolic BP following combined CCB and ACE inhibitor was significantly greater than the sum of the effect of each drug alone.

These findings support a favourable interaction between two drug classes resulting in potentiation of BP response beyond that expected. Conclusions must be qualified since each antihypertensive agent was administered only at a single sub-maximal dose. Whether a greater than additive effect would be seen at optimal BP-lowering doses cannot be determined but, since dose–antihypertensive responses are generally shallow,11 it is unlikely that a different relationship would pertain.

Of greater importance is the finding that the effect of lercanidipine and enalapril on ambulatory systolic BP was no more than additive with no indication of a significant interaction. Thus, trough BP may not be representative of the profile over 24 h. Since most studies of antihypertensive drugs in combination assess BP only at single points during the dose interval, results may be unreliable. To assess adequately whether antihypertensive agents have additive effects or effects that are more or less than additive, it appears that the time course of action of antihypertensive agents over the dose interval should be taken into consideration.



Despite overwhelming evidence for the benefit of rigorous BP control in reducing morbidity and mortality, individuals with hypertension seldom achieve the current targets. Individualized monotherapy optimizes response to single drug classes but most people with hypertension require drugs in combination to achieve BP goals. Whether antihypertensive agents have a strictly additive effect or whether some combinations have greater or lesser than additive responses is controversial.4, 5, 6, 11, 17, 18, 19, 20

The findings from the study by Puig et al.1 further fuel this controversy. Using single readings during the dose interval (trough values), a standard approach to assessing antihypertensive drug actions, a CCB and an ACE inhibitor appears to have a greater than additive effect, supporting some recommendations.4, 5, 6 However, when BP responses over 24 h are considered, the combined effect of the two drugs was strictly additive. Thus, adequate assessment of the BP-lowering effects of antihypertensive drugs in combination may be even more complicated than hitherto assumed. In addition to the dose range of each drug, the BP profile over the dose interval must be evaluated to allow reliable conclusions.



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