European Heart Journal (2011) 32, 2499–2506 REVIEW doi:10.1093/eurheartj/ehr177Novel therapeutic conceptsHypertension management 2011: optimalcombination therapyPeter S. Sever 1* and Franz H. Messerli 21 International Centre for Circulatory Health, Imperial College London, 59 North Wharf Road, London W2 1LA, UK; and 2Division of Cardiology, St Luke’s and Roosevelt Hospitals,Columbia University College of Physicians and Surgeons, New York, NY, USAReceived 11 August 2010; revised 16 March 2011; accepted 13 May 2011; online publish-ahead-of-print 22 June 2011 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 7, 2012Raised levels of blood pressure result from the complex interplay of environmental and genetic factors. The complexity of blood pressurecontrol mechanisms has major implications for individual responsiveness to antihypertensive drugs. The underlying haemodynamic disorderin the majority of cases is a rise in peripheral vascular resistance. This observation led to the discovery and development of increasinglysophisticated and targeted vasodilators, although many of the earlier antihypertensive drugs, by virtue of their actions blocking the sympath-etic nervous system, had a vasodilator component to their mode of action. A recent meta-analysis of placebo controlled trials of monother-apy in unselected hypertensives, reports average (placebo-corrected) blood pressure responses to single agents of 9.1 mmHg systolic and5.5 mmHg diastolic pressure. These average values disguise the extremely wide ranging responses in individuals across a fall of 20– 30 mmHgsystolic at one extreme, to no effect at all, or even a small rise in blood pressure at the other. The second factor determining individualresponses to monotherapy is the extent to which initial falls in pressure are opposed by reﬂex responses in counter regulatory mechanismsthat are activated following the blood pressure reduction. Thus, a satisfactory blood pressure response is rarely reached with monotherapyalone. What then is the next step if blood pressure is not a goal after the patient has been treated with monotherapy for a few weeks? Shouldyou uptitrate, substitute or combine?-----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords Hypertension † Combination therapy earlier antihypertensive drugs, by virtue of their actions blockingIntroduction the sympathetic nervous system, had a vasodilator component toRaised levels of blood pressure result from the complex interplay their mode of action. The ﬁrst non-speciﬁc vasodilator, hydrala-of environmental and genetic factors leading to the activation or zine, was followed by vasodilatation which involved blockadesuppression of one or more of a host of physiological systems of calcium channels on vascular smooth muscle cells [theinvolved in blood pressure regulation (Figure 1). The complexity calcium channel blockers (CCBs)], blockade of post-synapticof blood pressure control mechanisms, ﬁrst hypothesized by alpha-adrenoceptors on peripheral sympathetic neurones (theIrvine Page,1 has major implications for individual responsiveness alpha blockers) and, ﬁnally, vasodilatation achieved byto antihypertensive drugs (Figure 2), because of the inevitable blockade of the renin–angiotensin –aldosterone system (RAAS)variety of hypertensive phenotypes, the identiﬁcation of which, [angiotensin-converting enzyme (ACE) inhibitors, angiotensinwith some notable exceptions, remains elusive to the practicing receptor blockers (ARBs), direct renin inhibitors (DRIs)] (Figure 3).physician involved in making treatment decisions for individual The nature of these molecules, and in most cases their single sitepatients.2 of action, dictates that when administered to a heterogeneous Hypertension is, by deﬁnition, a haemodynamic disorder. The population, encompassing many hypertensive phenotypes, bloodmajor haemodynamic ﬁnding associated with higher levels of pressure responses will be largely unpredictable and wideblood pressure is a rise in peripheral vascular resistance. This ranging (Figure 4). If, in a particular case, blood pressure levelsobservation led to the discovery and development of increasingly are largely determined by activation of the RAAS, for example insophisticated and targeted vasodilators, although many of the renal artery stenosis, marked falls in blood pressure with* Corresponding author. Tel: +44 207 594 1100, Fax: +44 207 594 1145, Email: firstname.lastname@example.orgPublished on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: email@example.com
2500 P.S. Sever and F.H. Messerli Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 7, 2012 Figure 1 A schematic to demonstrate the interaction of environmental factors with underlying genetic predisposing factors to increase blood pressure through the activation of a variety of pathogenetic mechanisms. Figure 2 A modiﬁed and updated mosaic theory of blood pressure regulation derived from the original Paige mosaic.1impairment of renal function may follow the administration of an systolic and 5.5 mmHg diastolic pressure. These average values dis-ACE-Inhibitor.3 On the other hand, in the elderly and in those guise the extremely wide ranging responses in individuals across aof African origins, where the activity of the RAAS is generally sup- fall of 20–30 mmHg systolic at one extreme, to no effect at all, orpressed, blood pressure reductions4,5 with an ACE-Inhibitor may even a small rise in blood pressure at the other7 (Figure 4).be small. In general, however, the phenotype is not known. The second factor determining individual responses to mono- A recent meta-analysis of placebo-controlled trials of monother- therapy is the extent to which initial falls in pressure areapy, in unselected hypertensives,6 reports average (placebo cor- opposed by reﬂex responses in counter regulatory mechanismsrected) blood pressure responses to single agents of 9.1 mmHg that are activated following the blood pressure reduction. In
To uptitrate, to substitute, or to combine drugs 2501 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 7, 2012 Figure 3 The history of development of antihypertensive drugs reproduced with kind permission of Thomas Unger. Figure 4 The frequency distribution of changes in diastolic blood pressure produced by three different antihypertensive Figure 5 Response to the vasodilator hydralazine followed by drugs. Negative values represent placebo-corrected reductions the co-administration of the beta-blocker, atenolol. in diastolic pressure. Modiﬁed from reference.7 antihypertensive drugs have a rather shallow dose–responseextreme cases, these reﬂex responses can nullify any fall in curve. In particular, with RAAS inhibitors doubling the dose haspressure (Figure 5). minimal incremental effect on blood pressure. In contrast, with Thus, a satisfactory blood pressure response is rarely reached CCBs, additional antihypertensive efﬁcacy can be gained when, forwith monotherapy alone. What then is the next step if blood example, the starting dose of amlodipine is doubled from 5 topressure is not at goal after the patient has been treated with 10 mg. However, the incidence of pedal oedema also is dose depen-monotherapy for a few weeks? Should you uptitrate, substitute, dent and increases with a higher dose of amlodipine. Importantly, theor combine? additional blood pressure fall from combining drugs from two differ- ent classes is 5 times greater than the one from doubling the doseUptitration of a single drug.8 Thus, the odds of getting blood pressure to goal areUptitration of the initial drug is reasonable only if deﬁnitive, several times greater with combining drugs than with up titration ofenhanced antihypertensive efﬁcacy of the higher dose has been monotherapy. From a sheer efﬁcacy point of view, combinationdocumented and the cost is not prohibitive. Regrettably, most therefore takes precedence over uptitration.
2502 P.S. Sever and F.H. MesserliSubstitution Although there are some differences between guidelines, severalSubstituting an antihypertensive drug from a different class should be now recommend the initiation of combination therapy as ﬁrst lineconsidered only if there is no antihypertensive effect with a reason- in particular circumstances, in view of the associated risks of moreable dose, as is occasionally observed with beta-blockers or RAAS severe hypertension, the recognition that dual (or triple therapy) isblockers in black patients, or if there are any intolerable adverse invariably needed to achieve target blood pressures of ,140/effects such as angioedema. Fortunately, most modern antihyperten- 90 mmHg, and that there is a degree of urgency in reducingsive drugs are generally well tolerated and serious adverse effects are blood pressure to more acceptable levels to combat this risk.few. However, before resorting to drug substitution one may con- JNC-7 recommends initiating therapy with two drugs whensider that the addition of another drug may unmask the antihyperten- blood pressure is .20 mmHg above systolic goal or 10 mmHgsive efﬁcacy of the initial agent. For instance, the addition of a thiazide above diastolic goal.10 The European Guidelines,12 including theirdiuretic in a patient previously unresponsive to RAAS blockade is most recent update,13 conﬁrm such a recommendation and alsoprone to stimulate the renin–angiotensin system to the extent proposes the initiation of combination therapy in those withthat now both drugs, the RAAS inhibitor as well as the diuretic, milder degrees of blood pressure elevation in the presence of mul-have an additive antihypertensive effect.9 tiple risk factors, subclinical organ damage, diabetes, renal, or associated cardiovascular disease. Although combination therapy is not speciﬁcally advocated as initial therapy in the 2004 BritishRationale for combination therapy Hypertension Society Guidelines14 (largely based on the fact that there is a lack of randomized controlled trial evidence to Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 7, 2012The rationale for combination therapy in hypertension is therefore support such practice), it is probable that the results of ongoingstraightforward. First, it is to combine drugs acting on different trials will provide new evidence in favour of their early introduc-physiological systems in a situation where the phenotype is not tion into treatment strategies.known and where a pharmacological ‘attack’ on two (or more) Inevitably, there are concerns that initiating therapy with moresystems will have a greater impact on blood pressure reduction than one drug could induce signiﬁcant hypotension and increasethan blind monotherapy. Second, it is an attempt to block counter- coronary risk. An analysis of intervention trials in hypertension15,16regulatory responses that are activated by the perturbation of the provides some evidence for a ‘J-curve’ relationship between theblood pressure regulatory mechanisms when a physiological magnitude of blood pressure lowering and coronary heartsystem is blocked with single-drug therapy (Figure 6). disease outcome, but this seems to be conﬁned to high-risk indi- Third, the hypertensive population includes many with levels of viduals including those with established coronary artery disease,blood pressure categorized as moderate or severe (stage 2 hyperten- in whom excessive blood pressure lowering compromises coron-sion).10 There is general consensus that those with systolic blood ary perfusion. In uncomplicated hypertension, lower pressures arepressures .160 mmHg and/or diastolic pressures .100 mmHg fall well tolerated, for example, as seen in the Systolic Hypertension ininto this category. They constitute 10–15% of hypertensive popu- the Elderly Study, in which diastolic pressures as low as 60 mmHglations and are at substantially greater risk of a future cardiovascular were achieved in the active treatment group.17 Ongoing trials com-event. For every 20 mmHg increase in systolic blood pressure, paring initiation of dual therapy vs. sequential monotherapy inthere is an approximate doubling of cardiovascular risk.11 hypertension will aim to clarify the safety of the former. Obviously the proportion of the population with hypertension Fourth, blood pressure variability has been shown to decreaseincreases with age and this also applies to those with stage 2 hyperten- with combination therapy18 when compared with monotherapy.sion. As age advances systolic hypertension predominates and is In an extensive analysis of several randomized trials, visit-to-visitlargely accounted for by loss of elasticity and increasing rigidity of variability of systolic blood pressure was documented to be alarge arteries. strong predictor of both stroke and myocardial infarction and this was independent of mean in-trial blood pressure.18 Interest- ingly enough, CCBs and diuretics were most efﬁcacious in reducing visit-to-visit blood pressure variability and also were associated with the most efﬁcacious stroke prevention.19 In contrast, beta- blockers were shown to increase variability of systolic pressure in a dose-dependent way and also were the least efﬁcacious in stroke prevention. The addition of a CCB or to a lesser extent of a diuretic to a RAAS inhibitor diminishes variability of systolic pressure, which makes another strong argument for combination therapy. Trial evidence for and against Figure 6 Renin– angiotensin– aldosterone system and sym- speciﬁc combinations pathetic nervous system activation and suppression by different classes of antihypertensive drugs. An extensive review of ﬁrst-line drug choices has been published by the Blood Pressure Lowering Treatment Trialists’
To uptitrate, to substitute, or to combine drugs 2503Collaboration20,21 and is based upon prospective meta-analyses of cardiovascular outcome, and differentially affected by differenttrials comparing different drug regimens. Similar analyses have been ´ treatment strategies. For example, in the CAFE substudy ofundertaken by the National Institute for Clinical Excellence (NICE) ASCOT, the amlodipine/perindopril regimen lowered centralin the UK.22 The difﬁculty in extending these analyses to evaluate aortic blood pressure to a greater extent than the atenolol/thia-the comparative effects of different combinations of drugs is that in zide regimen (by 4 mmHg systolic), and the level of centralmany trials it is not possible to establish which add-on drugs were pressure was related to cardiovascular and renal outcomes28. Inused and in what doses. The evidence base for making claims about another substudy, various measures of blood pressure variabilitythe comparable or superior efﬁcacy of one regimen vs. another during the trial were strongly associated with both stroke andcomes from trials where the treatment algorithm was clearly coronary outcomes, in that the amlodipine-based treatmentdeﬁned and one could conclude with reasonable assuredness regimen reduced blood pressure variability compared with thethat a particular regimen was similar to, better than or worse atenolol-based regimen. These differences largely accounted forthan another. The best evidence, from which claims can be the observed differences in cardiovascular outcomes betweenmade of outcomes in favour of a particular regimen, comes from the two-drug regimens.29four trials, the Losartan Intervention For Event Reduction Trial In the third trial, ACCOMPLISH,25 11 506 hypertensive patients(the LIFE Trial,23 the Anglo-Scandinavian Cardiac Outcomes Trial were randomized to a combination of the ACE-Inhibitor, benaze-(ASCOT).24 The Avoiding Cardiovascular Events through Combi- pril, with either hydrochlorothiazide, or the CCB, amlodipine.nation Therapy in Patients Living with Systolic Hypertension Trial Patients were followed for 3 years. Blood pressure levels were(ACCOMPLISH)25 and the Valsartan Antihypertensive Long-term reduced similarly in the two arms of the trial. Cardiovascular Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 7, 2012Use Evaluation Trial (VALUE).26 events were signiﬁcantly reduced by 20% in benazepril/amlodipine In the LIFE Trial,23 9193 hypertensive patients were random- arm compared with the benazepril/hydrochlorothiazide arm.ized to initial treatment with either an ARB (losartan) or a beta- Myocardial infarction was reduced signiﬁcantly (22%) and strokeblocker (atenolol). Hydrochlorothiazide was added in the non-signiﬁcantly (16%) by benazepril/amlodipine compared withmajority of patients to achieve blood pressure control, along benazepril/hydrochlorothiazide. The beneﬁts of the benazepril/with the further addition of common third-line agents in a min- amlodipine combination over benazepril/hydrochlorthiazide wereority of patients. After an average follow-up of 5 years during seen in both diabetic and non-diabetic patients.30which there was no discernable difference in blood pressure In the fourth study, VALUE,26 15 245 hypertensive patientsbetween the two regimens, the composite primary cardiovascu- were randomized to either the ARB, valsartan, or the CCB,lar endpoint was reduced by 13% in the losartan-based group amlodipine. Hydrochlorothiazide was added to each limb incompared with the atenolol-based group. The major beneﬁt attempting to achieve goal blood pressures. Other add-onwas seen in the secondary stroke endpoint (a component of drugs were similar in the two treatment arms. Mean follow-upthe primary) which was reduced by 25% in the losartan-based was 4.2 years. Blood pressures were more effectively and moregroup. rapidly reduced in the amlodipine-based treatment arm. Although In the second trial, ASCOT,24 over 19 000 hypertensive patients the primary composite endpoint of cardiac morbidity and mor-with no prior history of coronary heart disease were randomized tality was similar in the two arms of the trial, myocardial infarc-to either a CCB, amlodipine, or a beta-blocker, atenolol. The tion occurred signiﬁcantly less frequently (risk reduction 19%)ACE-Inhibitor perindopril or the diuretic bendroﬂumethiazide and strokes non-signiﬁcantly less often (risk reduction 15%) inwas added to each arm, respectively, in an attempt to achieve the amlodipine-based treatment arm compared with theblood pressure targets. Again, common third-line drugs could be valsartan-based arm. The authors of the trial attributed earlyadded to each arm in a minority of patients. After an average differences in blood pressure as an explanation for the differentialfollow-up of 5.5 years, the trial was stopped prematurely on the effects of the two treatments on myocardial infarction andadvice of the Data Safety Monitoring Committee, because of stroke.highly signiﬁcant outcome beneﬁts in favour of the amlodipine- The cumulative evidence from these trials strongly supports thebased regimen. All cardiovascular events were reduced by 26%, view that, in hypertensive patients, combination therapy with CCB/stroke by 23%, and all-cause mortality by 11% by the amlodipine- ACE-I or CCB/ARB is likely to be associated with better cardiovas-based regimen compared with the atenolol-based regimen. The cular outcomes, including myocardial infarction and stroke, thanprimary endpoint of non-fatal myocardial infarction and fatal cor- regimens containing beta-blockers and thiazide diuretics and thatonary disease was reduced non-signiﬁcantly by 10% in favour of CCB/ACE-I combinations are preferable to diuretic/ACE-I combi-the amlodipine-based regimen, best explained by the early termin- nations on major cardiovascular endpoints. Added to this shouldation of the trial before the required number of primary endpoints be the cost-effectiveness analysis from the NICE Guidelineshad been reached. In the event, a more comprehensive coronary which clearly demonstrates that CCBs and ACE-Is or ARBs areendpoint which included coronary revascularizations was more cost-effective treatment choices than beta-blockers orreduced signiﬁcantly by 13%. thiazide diuretics.22 In several subsequent analyses, the small blood pressure differ- The above recommendations apply, in general, to those subjectsences observed early in the trial did not explain the outcome with uncomplicated hypertension. In hypertensives with associatedbeneﬁts in favour of amlodipine-based treatment.27 In recent cardiovascular disease such as heart failure or coronary heartreports, however, it has been shown that additional haemo- disease, the guidelines are consistent in recommending speciﬁcdynamic measurements may be better determinants of drugs with compelling indications, based on randomized controlled
2504 P.S. Sever and F.H. Messerlitrial evidence, that should be incorporated into treatment therefore be the preferred agent to be combined with a RAASstrategies. blocker. Unfortunately most RAAS inhibitors are available only in a ﬁxed-dose combination (FDC) with hydrochlorthiazide. In a recently reported study in a very elderly (.80 years) hyper-Speciﬁc drug combinations tensive population, the Hypertension in the Very Elderly StudyGiven that there are seven major classes of antihypertensive drugs (HYVET),34 a thiazide-like diuretic, indapamide, to which anand numerous members of each class, the number of possible ACE-Inhibitor, perindopril, was added, was found to reducecombinations is extensive. In the following, we subdivide combi- stroke incidence (30%) and the incidence of heart failure (64%),nations as preferred, acceptable or unacceptable/ineffective combi- compared with placebo.nations, based on outcome, antihypertensive efﬁcacy, safety, and/ortolerability. Acceptable combinations Beta-blockers and diureticsPreferred combinations The addition of diuretics has been shown to improve the antihy-Renin–angiotensin –aldosterone system inhibitors pertensive efﬁcacy of beta-blockers in African-American patientsand calcium channel blockers and other populations with low-renin hypertension. However,Additive blood pressure reduction has been documented with the both of these drug classes have been shown to have similarcombination of an ACE-Inhibitor, ARB, or DRI with a CCB. The adverse effects in that they increase the risk of glucose intolerance,common dose-dependent adverse effect of CCB monotherapy is the development of new-onset diabetes,22 fatigue, and sexual dys- Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 7, 2012peripheral oedema. The addition of a RAAS blocker has been function. Outcome studies have shown a morbidity and mortalityshown to mitigate this adverse effect. A recent meta-analysis has reduction with diuretics and beta-blockers in combination.22shown that ACE-Inhibitors are somewhat more efﬁcacious thanARBs in decreasing peripheral oedema associated with CCB Calcium channel blockers and diureticstherapy.31 As stated above, the ACCOMPLISH trial showed that Most physicians are somewhat reluctant to combine a CCB with aﬁxed combination of an ACE-Inhibitor (benazapril) with a CCB diuretic. However, in the VALUE trial,26 hydrochlorthiazide was(amlodipine) was more beneﬁcial with regard to morbidity and added as a second step in patients randomized to amlodipinemortality reduction than the ﬁxed combination of the same and the diuretic/CCB combination was well tolerated, althoughACE-Inhibitor with hydrochlorthiazide.25 Generally, similar end- there was a higher risk of new onset diabetes and hyperkalaemiapoint reductions have been demonstrated with ACE-Inhibitors when compared with the valsartan arm. Nevertheless, morbidityand ARBs, although there is a suggestion that ACE-Inhibitors and mortality reductions were at least as good in the amlodipinemay be slightly more cardioprotective and that ARBs may confer as in the valsartan arm of the VALUE study.some advantages in stroke prevention.32 The International Verapamil-Trandolapril Study (INVEST)33 was Calcium channel blockers and beta-blockersa comparison of ‘new’ vs. ‘old’ drugs in that a regimen of the non- The combination of a beta-blocker with a dihydropyridine CCBdihydropyridine, verapamil, to which trandolapril was added if has additive blood pressure reduction and, in general, is well toler-necessary, was compared with atenolol to which hydrochlorthia- ated. In contrast, beta-blockers should not be combined with non-zide was added if necessary to achieve blood pressure goals. A dihydropyridine calcium blockers such as verapamil or diltiazem.total of 22 576 hypertensives with established coronary artery The negative chronotropic effect of both of these drugs maydisease were enrolled and followed up for a mean of 2.7 years. result in heart block or bradycardia.The combined cardiovascular outcome was similar in the twogroups. Perhaps the most logical explanation for these ﬁndings is Dual calcium channel blockadethat the disadvantage of the beta-blocker regimen observed in The combination of a dihydropyridine CCB with either verapamilhypertension trials in uncomplicated patients was offset by the or diltiazem has been shown in a recent meta-analysis 35 to haveknown advantages of beta blockade in the context of established an additive effect on blood pressure lowering without signiﬁcantlycoronary artery disease. increasing adverse events. Dual CCB blockade may be useful in patients with documented angioedema on RAAS inhibitors or inRenin–angiotensin –aldosterone system inhibitors patients with advanced renal failure at risk for hyperkalaemia.and diuretics However, no outcome data are available with dual CCB therapyNumerous factorial design studies have shown that the combi- and long-term safety remains undocumented.nation of a thiazide diuretic with an ACE-Inhibitor, an ARB, or aDRI result in fully additive blood pressure reduction. Diuretics, Unacceptable/ineffective combinationsby depleting intravascular volume, activate the RAAS which Dual renin –angiotensin –aldosterone system blockadecauses salt and water retention as well as vasoconstriction. The For the treatment of hypertension per se, dual RAAS blockade, inaddition of a RAAS blocker attenuates this counter regulatory general, is not recommended.36 In the ONTARGET study,37 thereresponse. Moreover, diuretic induced hypokalaemia as well as were more adverse events with a combination of telmisartan andglucose intolerance is mitigated by the addition of a RAAS ramipril than with individual agents and cardiovascular endpoints,blocker. Chlorthalidone has been shown to be more effective despite a small additional blood pressure reduction, were notthan hydrochlorthiazide in reducing blood pressure and should improved compared with monotherapy. Thus, there is little if any
To uptitrate, to substitute, or to combine drugs 2505reason to combine an ARB with an ACE-Inhibitor for the treatment Adverse effectsof hypertension. However, as blockade of the renin–angiotensincascade by either an ACE-Inhibitor or an ARB increases plasma The adverse reactions associated with combination treatments arerenin activity, the argument has been put forward that the addition largely predicted from the known side effects of the individualof a DRI could have additional beneﬁts. Indeed, the combination of components. However, in older combinations of vasodilatorsaliskiren with an ARB has been shown to have a small, signiﬁcant (hydralazine) with beta-blockers and diuretics, the side effects ofadditional effect on blood pressure in a double-blind study of 1797 vasodilatation (tachycardia and ﬂuid retention) were mitigated bypatients.38 However, this fall in blood pressure with dual RAAS the additional drugs. There is some evidence that the oedemablockade was less than one would have expected by the addition commonly associated with dihydropyridine CCBs is partiallyof either a thiazide diuretic or a CCB. Of note, in an open label pro- relieved by co-administration of RAAS blockers44,45 and RAASspective crossover study in patients with resistant hypertension, the blockers may reduce the incidence of hypokalaemia induced byaldosterone antagonist spironolactone was shown to lower blood thiazides.46 On the other hand, it seems likely that the increasepressure more effectively than conventional dual RAAS blockade.39 in incidence of new-onset diabetes commonly associated withAt the present time, no outcome data are available to support beta-blockers is exacerbated when these drugs are given in con-beneﬁts of the combination of a DRI with either an ACE-Inhibitor junction with thiazide diuretics. A meta-analysis of the increasedor an ARB. Nevertheless, a randomized double-blind trial (ALTI- incidence of new-onset diabetes with beta-blocker and thiazideTUDE) has been designed to look into this question and is currently treatment, compared with ‘newer’ drugs, is provided by thein progress. NICE Guidelines.22 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 7, 2012 These conclusions assume that there are no differences between individual drugs within a particular drug class in relationRenin –angiotensin –aldosterone system blockers to their effects on long-term morbidity and mortality. Amongand beta-blockers the CCBs, the best evidence is for amlodipine. Among theIn patients having suffered a myocardial infarction or in those in ACE-Is and ARBs, several different drugs have been used bothheart failure, these two drug classes are commonly combined within and without combination trials in hypertensive patientsbecause both have been shown to reduce reinfarction rates and and in other cardiovascular patient groups, and no clear beneﬁtsto improve survival. However, their combination produces little of one drug over another are evident. For thiazide and thiazide-likeadditional blood pressure reduction compared with either mono- diuretics, there persists an opinion that the evidence base for long-therapy. Thus, for the treatment of blood pressure per se, there is term beneﬁts is best for moderate doses of chlorthalidone,17,42,47no reason to combine these two drug classes. compared with other thiazides in lower doses. Regrettably, there are unlikely to be future trials comparing drugs within this class.Beta-blockers and antiadrenergic drugs For the beta-blockers, atenolol has been the drug most oftenLittle if any antihypertensive efﬁcacy can be gained when beta- used and claims have been made that had other drugs in thisblockers are combined with antiadrenergic drugs such as clonidine. class been used in the trials then perhaps different results wouldIn fact, an exaggerated rebound in BP has been observed with this have occurred.48 This is unlikely since the adverse effects of ateno-combination.40 lol, observed in ASCOT, on blood pressure variability,29 and an increase in central aortic pressures compared with amlodipine 28Other drug classes in combination therapy: alpha-blockers (both of which were associated with an increase in cardiovascularand spironolactone risk), would be likely to occur with most other beta-blockers.Alpha-adrenoceptor antagonists have been widely used as add-on Outcome trials in hypertension with beta-blockers possessingdrugs in combination regimens to achieve target blood pressures. additional pharmacological properties have not been conducted.The availability of extended release formulations has improvedtheir tolerability proﬁle. Data from an observational analysis ofthe ASCOT trial showed that doxazosin gastrointestinal thera-peutic system (GITS) used as third-line therapy lowered blood Fixed-dose combinations andpressure and caused a modest reduction in serum lipids.41 In con-trast to earlier ﬁndings in ALLHAT,42 doxazosin use in ASCOT was outcome beneﬁtsnot associated with an increased incidence of heart failure. In a recent review of the potential advantages of FDC formulations For subjects with resistant hypertension, deﬁned as failure over their corresponding free drug components given separately, itto achieve target blood pressure (,140/90 mmHg) despite was shown that the FDCs were associated with signiﬁcantly bettermaximum doses or maximum tolerated doses of three antihyper- compliance and a non-signiﬁcant improvement in persistence withtensive drugs including a RAAS blocker, a CCB, and a thiazide treatment.49 Similarly, in a meta-analysis of nine studies comparingdiuretic, quadruple therapy is frequently required. Recent reports the administration of FDCs with their separate components, thedemonstrate that spironolactone added to triple therapy is associ- adherence rate was improved by 26% in patients receiving FDCs.50ated with substantial further reductions in blood pressure of, In trials in which blood pressure data were reported, use ofon average, 22/9.5 mmHg.43 Spironolactone is therefore rec- FDCs was associated with a non-signiﬁcant lowering of systolicommended as a component of combination therapy in patients and diastolic pressure (4.1 and 3.1 mmHg, respectively) comparedwith resistant hypertension. with the corresponding drugs administered separately.49 Such
2506 P.S. Sever and F.H. Messerlidifferences in blood pressure if sustained long term wouldundoubtedly confer advantages on cardiovascular outcomes. Table 1 Drug combinations in hypertension: recommendationsBlood pressure control in practice Preferred ACEInhibitor/diureticWorldwide surveys of blood pressure control to targets rec- ARB/diureticommended by national and international guidelines have consist- ACE-Inhibitor/CCBently revealed that in clinical practice the conventional goal of a ARB/CCBblood pressure ,140/90 mmHg is reached by only a minority of ................................................................................patients.51 Data from several countries are shown in Figure 5. AcceptableWhile there are several explanations for physicians failing to Beta-blocker/diureticachieve target blood pressures, including poor compliance or con- CCB (dihydropyridine)/beta-blockercordance with drug taking by patients, white coat hypertension, CCB/diureticundiagnosed secondary causes of hypertension, and true resistant Renin inhibitor/diuretichypertension, in the majority of cases therapeutic inertia on the Renin inhibitor/CCBpart of the physician plays a major role. There is good evidence Dihydopyridine CCB/non-dihydropyridine CCB ................................................................................that when physicians are faced with patients on treatment for Unacceptablehypertension, but who have not reached goal blood pressures, ACE-Inhibitor/ARB Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 7, 2012they are reluctant to increase drug doses or initiate second- and Renin inhibitor/ARBthird-line combination therapy.52 Renin inhibitor/ACE-Inhibitor The issues surrounding these observations are complex. Clearly RAS inhibitor/beta-blockerlack of education and failure to appreciate the importance of CCB (non-dihydropyridine)/beta-blockerlowering blood pressure to targets to prevent cardiovascular Centrally acting agent/beta-blockeroutcomes associated with uncontrolled blood pressure are impor-tant issues. The historical focus on diastolic pressure as the basisfor initiation of therapy and as a treatment target is another. Inpractice, diastolic targets of ,90 mmHg are far more commonly often the norm rather than the exception. In hypertension, theattained than systolic targets of ,160 mmHg.53 underlying rationale for combination therapy is somewhat differ- Lastly, and importantly, true therapeutic inertia—the reluctance ent. Since we do not know the cause of the blood pressureto change medications when faced with a patient whose blood elevation, therapy is essentially blind and a shotgun approachpressures remain above goals. Excuses such as the following may be more efﬁcacious than targeted therapy. This is particularlyexample—‘It’s a little bit higher today (cold weather, rush to true because monotherapy invariably triggers a variety of counterclinic, stress at work, domestic problems etc) but we will see regulatory mechanisms which are mitigated by combinationwhat it’s like in a few weeks/months time’ are all too frequent. therapy. Thus, a strong case can be made for the early introductionThis major problem can be overcome (as we observe in trials) of combination therapy and conceivably, the time will come whenwhen physicians or nurses are obliged to follow goal directed combination therapy in low doses will be the preferred option fortreatment algorithms dictated by a trial protocol, and when ﬁrst-line treatment in patients with hypertension.‘excuses’ cannot be made to avoid changes in medications whenblood pressures are not at target. Take home message and An alternative scheme, practised in the UK since 2004, has been recommendationsto remunerate doctors based on the extent to which they achieve (1) Many, if not most patients, need two or more drugs froma number of clinical targets, one of which is dictated by the pro- different classes to achieve blood pressure control.portion of their hypertensive patients whose blood pressures are (2) Combination therapy should be initiated if the patient’s bloodlowered to an audit standard of ,150/90 mmHg. This has contrib- pressure is .20/10 mmHg above target level unless cardiovas-uted to improvements in the levels of blood pressure control in cular status is brittle.the population and has been accompanied by the increasing use (3) Preferred or acceptable two drug combinations should beof combination therapies.54 used (Table 1).Conclusions (4) Whenever convenience and cost outweigh other consider- ations ﬁxed-dose combinations rather than individual drugsThe use of combinations of drugs in therapeutic practice is should be used.common place in contemporary medicine in a wide variety ofdisease categories, for example, in infectious disease, to cover mul-tiple organisms and to overcome drug resistance; in respiratory Conﬂict of interest: P.S.S. has received grant income and honor-illness such as chronic bronchitis or asthma to target multiple aria from Pﬁzer and Servier. F.H.M. is an ad hoc consultant for thepathophysiological mechanisms of disease and in neurological con- following organizations: Novartis, Daiichi Sankyo, Pﬁzer, Takeda,ditions to interfere with different abnormalities of neurotransmit- Abbott. F.H.M. received grant support from Forest, Daiichiter function. In fact throughout medicine, combination therapy is Sankyo and Boehringer Ingelheim.
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