Journal of Human Hypertension (2007) 21, 914–916 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh COMMENTARY Antihypertensive drugs in combination: additive or greater than additive?

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

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

In this edition of the Journal of Human Hyperten- receptor blockers (A) and b-blockers (B), while older sion, Puig et al.1 report a study demonstrating that people and black subjects of all ages tend to have the calcium channel blocker (CCB) lercanidipine and low renin hypertension and respond preferentially the ACE inhibitor enalapril in combination have at to CCBs (C) and diuretics (D).6–10 This is the least an additive effect on systolic blood pressure rationale for the A (B) CD algorithm proposed by (BP) in elderly people with hypertension. Super- the British Hypertension Society.6 The heterogeneity ficially, the findings are unremarkable, but concealed of the response to antihypertensive therapy means within the data is a message of considerable potential that responses in individuals and the identification importance for the evaluation of antihypertensive of factors that determine response require within- drugs and the management of hypertension. patient (crossover) comparisons. Despite a wealth of robust evidence that effective Even with individualized or targeted monother- control of BP significantly reduces the morbidity apy, BP goals are unlikely to be achieved at the and mortality associated with hypertension, control starting dose of the first drug. Upward dose titration rates in many populations remain dismal.2,3 Current allows the patient to remain on a familiar drug but national and international guidelines recommend the modest increase in BP response is at the cost of a rigorous BP targets in all treated individuals, with steep increase in side effects for most drugs11— even more stringent goals in high-risk groups. the law of diminishing returns.12 Sequential mono- For most individuals, drug therapy is initiated therapy is favoured by some13 but requires a lengthy with monotherapy, followed by dose-titration in an period of trial and error with loss of patient attempt to achieve treatment targets. Although there confidence, and an ideal agent for the individual is controversy about the most appropriate first-line may never be found. choice, there is general agreement that for some patients, there are compelling indications or contra- indications for particular drug classes.4–6 This advice is driven more by consideration of benefits Combination therapy or hazards independent of BP lowering (for example Except for those relatively few individuals with b-blockers indicated in angina but contraindicated pretreatment BP close to target, monotherapy is in asthma) rather than expectation of greater or rarely adequate. Most will require two or more drugs lesser antihypertensive efficacy. in combination. A careful meta-analysis of 354 randomized, double-blind, placebo-controlled trials indicates Targeted/sequential monotherapy that the BP-lowering effects of different drug classes are strictly additive.11 Based on this analysis, it is There is marked interindividual variability in estimated that 50% of hypertensives require three or response to any antihypertensive agent. Plasma more drugs and more than 50% require two or three renin profiling, age and gender are useful in drugs to achieve target BP.14 Only one-third of predicting response.7 Young and white individuals participants in the Hypertension Optimal Treatment tend to have high plasma renin activity and respond study achieved target BP on monotherapy; the well to drugs that block the renin–angiotensin remainder required up to five drugs concomitantly. system (RAS), ACE inhibitors or angiotensin Hypertension is heterogeneous in response to treatment, and combination therapy increases the Correspondence: Professor GT McInnes, Division of Cardiovas- likelihood of an adequate response. Combined cular and Medical Sciences, Western Infirmary, University of treatment can block counter-regulatory mechanisms Glasgow, Gardiner Institute, 44 Church street, Glasgow G11 6NT, UK. that are triggered whenever pharmacological inter- E-mail: [email protected] vention is initiated and act to limit the efficacy Published online 16 August 2007 of antihypertensive medication. Potential mutual Antihypertensive drugs in combination GT McInnes 915 enhancement of the antihypertensive efficacy of drug additive or greater than additive effect with combi- classes raises the theoretical possibility of a greater nation therapy. This requires crossover studies with than additive response to certain combinations. drugs at doses that are optimal to allow assessment of the balance between efficacy and side effects. Which combination? What is new in this edition? All antihypertensive medications can be combined as necessary but some combinations make more The study by Puig et al.1 aimed to assess the effect of sense than others. Allegedly rational combinations combined therapy with lercanidipine and enalapril include b-blocker plus diuretic, b-blocker plus CCB, on systolic BP. Such studies are common but the ACE inhibitor plus diuretic and CCB plus ACE design of this trial (a randomized, double-blind, inhibitor.15–17 The only absolute contraindication is four-way comparison of each active therapy, the the combination of a rate-limiting CCB with a b- combination of both drugs at fixed doses and blocker because of the danger of cardiac function placebo) allows evaluation of whether the treat- decompensation and heart block as both classes ments have additive or greater than additive effects have negative inotropic and chronotropic effects; on BP. sudden cardiac deaths have been reported. Compared with placebo, office systolic BP at A practical approach to choosing combinations is trough was reduced significantly by all active proposed by the British Hypertension Society,6 treatments. The response to combination therapy based on the interaction of major classes of anti- was significantly greater than that to either mono- hypertensive drugs with the RAS. Thus, it is logical therapy. Indeed, the reduction in systolic BP to combine an A drug (for example ACE inhibitor) following combined CCB and ACE inhibitor was with a C drug (CCB). significantly greater than the sum of the effect of CCBs are potent vasodilators that induce reflex each drug alone. activation of the sympathetic nervous system and These findings support a favourable interaction the RAS. Combination with an ACE inhibitor leads between two drug classes resulting in potentiation to buffering of this neuroendocrine activation.18 of BP response beyond that expected. Conclusions Increase in angiotensin II and the negative sodium must be qualified since each antihypertensive agent balance caused by CCBs reinforces the antihyper- was administered only at a single sub-maximal dose. tensive efficacy of ACE inhibitors. Also, concomi- Whether a greater than additive effect would be seen tant ACE inhibition attenuates the side effects of at optimal BP-lowering doses cannot be determined CCBs, notably peripheral oedema.18 Some support but, since dose–antihypertensive responses are for combination therapy based on a CCB and ACE generally shallow,11 it is unlikely that a different inhibitor comes from the Anglo Scandinavian relationship would pertain. Cardiac Outcomes Trial19 in which treatment with Of greater importance is the finding that the effect amlodipine plus perindopril was superior to ther- of lercanidipine and enalapril on ambulatory sys- apy based on atenolol and bendroflumethiazide for tolic BP was no more than additive with no BP, cardiovascular outcomes and side effects. 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 The necessary evidence combination assess BP only at single points during the dose interval, results may be unreliable. To Investigation of whether drugs have additive, assess adequately whether antihypertensive agents greater than additive or less than additive effects have additive effects or effects that are more or less is not an easy matter. The classical method is than additive, it appears that the time course of to construct dose–response curves for one drug action of antihypertensive agents over the dose at one or more dose of the second. A dose ratio interval should be taken into consideration. can then be calculated. This is impractical in the clinical setting. The usual parallel group comparison of antihy- Conclusions pertensive agents given alone and in combination cannot provide a measure of each individual’s Despite overwhelming evidence for the benefit of response to treatments, and similarity of average rigorous BP control in reducing morbidity and response to treatments may deflect from the scope mortality, individuals with hypertension seldom for individual variation in response. Thus, differ- achieve the current targets. Individualized mono- ences may appear less marked, combinations may therapy optimizes response to single drug classes appear ‘additive’ or ‘less than additive’ while, in but most people with hypertension require drugs in individuals, the response may be ‘greater than combination to achieve BP goals. Whether antihy- additive’. pertensive agents have a strictly additive effect or The goal is to know how large a proportion whether some combinations have greater or lesser of the hypertensive population demonstrate an than additive responses is controversial.4–6,11,17–20

Journal of Human Hypertension Antihypertensive drugs in combination GT McInnes 916 The findings from the study by Puig et al.1 further disease prevention in the United Kingdom: a practical fuel this controversy. Using single readings during approach to management. J Hum Hypertens 2007; the dose interval (trough values), a standard 21(3): 183–211. approach to assessing antihypertensive drug ac- 9 Deary AJ, Schumann AL, Murfet H, Haydock SF, Foo tions, a CCB and an ACE inhibitor appears to have RS-Y, Brown MJ. Double-blind, placebo-controlled crossover comparison of five classes of antihyperten- a greater than additive effect, supporting some 4–6 sive drugs. J Hypertens 2000; 20: 771–777. recommendations. However, when BP responses 10 ALLHAT Officers and co-ordinators. Major outcomes over 24 h are considered, the combined effect of the in high-risk hypertensive patients randomized to two drugs was strictly additive. Thus, adequate angiotensin-converting enzyme inhibitor or calcium assessment of the BP-lowering effects of antihyper- channel blocker vs diuretic: the Antihypertensive and tensive drugs in combination may be even more Lipid-Lowering Treatment to prevent Heart Attack complicated than hitherto assumed. In addition to Trial (ALLHAT). JAMA 2002; 288: 2981–2997. the dose range of each drug, the BP profile over the 11 Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose interval must be evaluated to allow reliable dose combination treatment with blood pressure low- conclusions. ering drugs: analysis of 354 randomised trials. BMJ 2003; 327: 1427–1435. 12 Fagan TC. Remembering the lessons of basic pharma- References cology. Arch Intern Med 1994; 154: 1430–1431. 13 Dickerson JEC, Hingorani AD, Ashby MJ, Palmer CR, 1 Puig JG, Calvo C, Luurila O, Luurila H, Sulosaari S, Brown MJ. Optimisation of antihypertensive treatment Strandberg A et al. 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