Fixed antihypertensive drug combinations and prognostic benefits: what is the evidence?




Jean-Jacques MOURAD
MD, PhD
Department of Internal Medicine and Arterial Hypertension, Avicenne University Hospital
Assistance Publique Hôpitaux de Paris/Université Paris 13
Bobigny, FRANCE

by J.-J. Mourad,France

Elevated blood pressure is an important cardiovascular risk factor. Achieving control of systolic blood pressure together with further reduction in cardiovascular morbidity and mortality are the current challenges for modern antihypertensive strategies. Hypertension frequently resists control with monotherapy, necessitating combination therapy with two or more antihypertensive agents. Many currently available antihypertensive fixed-dose combinations combine drugs with different, but complementary, mechanisms of action to improve overall efficacy and tolerability. Antihypertensive fixed-dose combinations may provide significant advantages over high-dose monotherapy, such as improved blood pressure–lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs, and shorter time to blood pressure control.We have reviewed the latest evidence demonstrating the need for better blood pressure control. In addition, results from studies with different combinations strategies are outlined. In specific situations, such as in patients at high risk of experiencing coronary ischemic events, an angiotensin-converting enzyme inhibitor/ calcium channel blocker combination has demonstrated beneficial effects on hard end points, reducing cardiovascular morbidity and mortality and inhibiting the development and progression of type 2 diabetes mellitus and the progression of renal disease.

Medicographia. 2010;32:294-301 (see French abstract on page 301)


Numerous studies have shown that elevated blood pressure (BP) is a major risk factor for cardiovascular morbidity and mortality. This relationship, which has been demonstrated in a range of patient populations and age groups, is strong and continuous.1 BP is a continuous variable with a normal distribution in the population.2,3 Thus, by necessity, any definition of “hypertension” is arbitrary. However, there is a consensus among many of the major guidelines for the treatment of hypertension that individuals with a BP ≥140/90 mm Hg should be regarded as hypertensive and that attempts should be made to keep BP below this threshold in all individuals.3,4 A number of large, well-validated studies have shown that systolic blood pressure (SBP) is a better predictor of cardiovascular risk than diastolic blood pressure (DBP) in most of the subjects allocated to chronic antihypertensive therapy in clinical practice. In addition to these observations, the increase in life expectancy observed over the last few decades in many developed countries means that the paradigmhas shifted towards SBP.5 Arterial stiffness, endothelial dysfunction, atherosclerosis, and oxidative stress all contribute to an increase in SBP with age.6,7 Drugs that have proven to be particularly useful in the treatment of elevated SBP are calcium channel blockers (CCBs), thiazides, and agents that target the renin-angiotensin system (RAS), ie, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), because these agents improve the large artery stiffness and early wave reflection that are major characteristics of this condition.8-11

In spite of the growing recognition that adequate control of SBP is fundamental to reducing cardiovascular risk, a substantial proportion of patients still fail to achieve the target levels defined by current guidelines. For example, data from NHANES (National Health And Nutrition Examination Survey) III show that SBP was controlled to <140 mm Hg in only 34% of hypertensive patients (treated or untreated).12 In contrast, 73% of patients achieved DBP control (<90 mm Hg). A similar bias was reported in the HYDRA (HYpertension and Diabetes scReening and Awareness) study, which analyzed data from 45125 primary-care patients in Germany.13 In this study, elevated SBP levels were tolerated by doctors in 51% of affected patients. In contrast, elevated DBP levels were tolerated in 41% of affected patients. These results are confirmed by the results of Mancia and Grassi (2002), who used data from 10 controlled trials to show that far fewer patients achieve the level of SBP recommended by guidelines than the DBP level recommended. Overall, DBP <90 mm Hg and SBP <140 mm Hg were achieved by approximately 90% and 50% of treated patients, respectively.14 Control of SBP and DBP was even worse in patients with diabetes.

The EUROASPIRE (EUROpean Action on Secondary and Primary prevention by Intervention to Reduce Events) III survey15 demonstrated that in patients with overt coronary disease, control of elevated BP is still problematic; more than 60% of patients do not achieve BP goals, despite the fact that antihypertensive drugs are being used increasingly.

Current challenges for modern antihypertensive strategies

Current guidelines for the management of hypertension emphasize the need to improve long-term cardiovascular outcomes as well as to increase the proportion of patients achieving target BP.3,4 Despite the fact that literature shows that SBP is an extremely important target for BP lowering, many physicians remain focused on achieving the DBP target. Thus, hypertension remains poorly controlled. However, there have been changes in the understanding of the necessary treatment algorithm. It is now well recognized that most patients will require combination therapy, initiated first-line or at least early, to achieve guideline BP targets.16

Since there is an inverse relationship between regimen complexity and patient adherence,17,18 treatment regimens that involve administration of multiple drugs have consistently been associated with reduced compliance and adherence.18,19 Fixed-dose combinations (FDCs) represent an alternative approach to multiple drug therapy that has been shown to improve patient adherence.20,21 They also offer the possibility of combining agents with different pharmacological profiles to achieve additive effects with enhanced tolerability. In this regard, the 2009 reappraisal of the European guidelines on hypertension management recommends a more individually tailored approach for the management of hypertension.16 The approaches of using FDCs either as a first-line treatment or earlier in the treatment of patients with comorbidities that require rapid BP reduction are endorsed by current guidelines.3,4,16

A number of two-drug fixed combinations are available for clinical use. These include ACE inhibitor/thiazide diuretic, ARB/ thiazide diuretic, β-blocker/thiazide diuretic, ACE inhibitor/ CCB, ARB/CCB, and β-blocker/CCB combinations. However, the most substantial trial evidence of outcome reduction has been obtained for combinations of a thiazide diuretic with an ACE inhibitor, ARB with thiazide, and in recent large-scale trials ACE inhibitor with CCB. As a result, these combinations have been recommended for priority use by the recent reappraisal of the European guidelines on hypertension.16 This also includes a reappraisal of fixed combinations of ARB with ACE inhibitor or direct renin inhibitor, which offer an alternative to classic pharmacological approaches. This strategy needs a large “proof of concept” trial to determine its efficacy as well as its tolerability in unselected hypertensive patients (Figure 1).

Figure 1
Figure 1. Summary of head-to-head trials using combination
strategies in hypertensive patients.

The arrows represent the second step of the strategy in all the trials except for ACCOMPLISH, in which both agents were given at the first stage of titration.
Abbreviations: ACCOMPLISH, Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; INVEST, INternational VErapamil-trandolapril STudy; LIFE, Losartan Intervention For Endpoint reduction in hypertension; VALUE, Valsartan Antihypertensive Long-term Use Evaluation.

Clinical evidence of morbidity and mortality reduction with different antihypertensive combination strategies based on RAS inhibition

The RAS plays a central physiological role in the regulation of cardiovascular, renal, and adrenal function; overactivity of the RAS is implicated in hypertension and other cardiovascular and renal disease states.22,23 Inhibitors of the RAS, including ACE inhibitors and ARBs, have demonstrated efficacy in treating hypertension and preventing or reducing cardiovascular morbidity, such as stroke events. For ACE inhibitors, a reduction in myocardial infarction (MI) has also been proven. Thus RAS inhibitor–based combinations have gained increasing support as an initial treatment in recent years.24,25

The combination of a RAS inhibitor and a diuretic, an effective BP-lowering regimen, protects against hypertension-associated complications, such as cardiovascular events and stroke. This has been partly demonstrated in intervention studies, such as PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study), where the combination of an ACE inhibitor and a diuretic (perindopril plus indapamide) reduced the risk of stroke, MI, and heart failure in patients with previous stroke or transient ischemic attack.26 This was also the case for the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study,27 where an ARB (losartan) in combination with hydrochlorothiazide (HCTZ) reduced stroke, but not MI, other cardiovascular outcomes, or mortality in hypertensive patients with confirmed left ventricular hypertrophy (LVH) (Table I).

Table I
Table I. LIFE: effects on primary and secondary trial end points.

The effects of losartan and atenolol on cardiovascular mortality, stroke, myocardial infarction, and other prespecified end points.
Abbreviations: CI, confidence interval; LIFE, Losartan Intervention For Endpoint reduction in hypertension [study].
Modified from reference 27: Dahlöf et al. Lancet. 2002;359:995-1003. © 2002, Elsevier Ltd.

In ADVANCE (Action in Diabetes and Vascular disease: Preter- Ax and DiamicroN MR Controlled Evaluation),28 the significantly greater antihypertensive effect of perindopril/indapamide given in addition to current therapy in patients with diabetes and hypertension was associated with improvement in morbidity and mortality compared with standard therapy, which included RAS inhibitors, alone. Perindopril/indapamide reduced cardiovascular mortality by 18%, all-cause mortality by 14%, and new microalbuminuria by 21% (Figure 2).28 HYVET (HYpertension in the Very Elderly Trial) provided the first definite demonstration of the benefits of effective BP reduction and reduction in cardiovascular outcomes with indapamide (in combination with perindopril in the majority of patients) in very elderly hypertensive patients.29 The trial demonstrated that even in patients 80 years of age or older, antihypertensive treatment not only prevents cardiovascular events, but contributes to prolonging life.16

Figure 2
Figure 2.
ADVANCE: effects on primary and selected secondary trial end points.

Effects of study treatment on deaths, coronary events,
cerebrovascular events, and renal events.
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; CI, confidence interval. After reference 28: Patel et al. Lancet. 2007;370:829-840. © 2007, Elsevier Ltd.

The administration of a CCB with a RAS inhibitor (ACE inhibitor or ARB) is another rational approach for the management of hypertension that enhances antihypertensive efficacy compared with equivalent monotherapies.30-32 The largest ever trial in this field was the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Some 19257 hypertensive patients with at least 3 prespecified cardiovascular risk factors were enrolled in a randomized prospective trial comparing an amlodipine/perindopril– based regimen to a βblocker/bendroflumethiazide– based regimen.32 The trial was stopped prematurely when evidence for lower all-cause mortality (–11%; P=0.00247) and cardiovascular mortality (–24%; P=0.001) was demonstrated in the CCB/ACE inhibitor arm. Other secondary end points also favored amlodipine/perindopril, with a 23% reduction in fatal and nonfatal stroke (P=0.0003), a 13% reduction in total coronary events (P=0.007), a 16% reduction in total cardiovascular events and procedures (P<0.001), a 13% reduction in nonfatal MI (excluding silent) and fatal coronary heart disease (P=0.0458), and a 30% reduction in new-onset diabetes (P<0.0001). The primary end point (all nonfatal MI plus fatal coronary heart disease) was reduced by 10%with perindopril/ amlodipine, although the difference did not reach statistical significance due to early termination, as mentioned (Figure 3, page 298).33

Various substudies of ASCOT have provided further information to support the superior efficacy of an amlodipine/perindopril regimen in patients at moderate risk of experiencing cardiovascular events. In the Conduit Artery Function Evaluation (CAFE) substudy, although brachial SBP was comparable between the groups, the amlodipine/perindopril regimen was associated with substantial reductions in central aortic pressures compared with the atenolol/HCTZ regimen.34 Central aortic BP reflects the effects of conduit artery stiffness on pulse wave morphology and central hemodynamics more accurately than brachial BP,35,36 which suggests that a differential effect of perindopril/amlodipine on central aortic pulse pressure may be a factor in the protective efficacy of the treatment strategy.

Figure 3
Figure 3. Summary of all end points in ASCOT-BPLA.

Effects of study treatment on deaths, coronary events, cerebrovascular events, and renal events.
Abbreviations: ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm; CHD, coronary heart disease; MI, myocardial infarction.
Modified from reference 33: Dahlöf et al. Lancet. 2005;366:895-906. © 2005, Elsevier Ltd.

A recent substudy of ASCOT also demonstrated11 that directly measured central carotid SBP is lower (and associated with a lesser magnitude of wave reflection) with an amlodipine/ perindopril regimen than with an atenolol-based regimen.11 This difference was explained by the investigators as being related to the enhanced improvement in arterial structure and decrease in peripheral arterial resistance seen with amlodipine/ perindopril. In addition, clinical confirmation of 24-hour BP control with an amlodipine/perindopril regimen, demonstrated by its superior nighttime SBP reduction, was provided by an ambulatory BP measurement substudy of ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure– Lowering Arm) that examined the impact of the two ASCOT treatment regimens on ambulatory BP.37

Finally, recent evidence suggests that in ASCOT, the regimen based on amlodipine that added perindopril as required was more beneficial in reducing BP variability than the β-blocker/ diuretic regimen.38 Authors also found a strong correlation between increased SBP variability and the risk of both stroke and cardiovascular events.39 From a clinical point of view, this new ASCOT substudy draws attention to patients with sporadically elevated BP who, although not considered hypertensive, are already at high risk of CV complications. For these “hypertensives,” it is prognostically important not only to decrease BP to target level, but also to make sure that antihypertensive treatment works throughout the 24-hour postdosing period and that it also reverses structural arterial changes (such as arterial stiffening and remodeling), which are considered to be responsible for excess BP variability.38

The results of the ASCOT trial contrast with those of INVEST (INternational VErapamil-trandolapril STudy),40 in which stepwise treatment strategies based on trandolapril/verapamil SR and β-blocker (atenolol)/diuretic (HCTZ) were evaluated in 22576 patients with essential hypertension and documented evidence of coronary artery disease. Although 85% of patients in INVEST were treated with antihypertensive medication at baseline, BP was controlled in only approximately 20%. After two years, BP control was similar in each group (71.7% with the trandolapril/verapamil regimen and 70.7% with the atenolol/HCTZ regimen). After a mean follow-up of 2.7 years, similar rates of primary outcome (first occurrence of all-cause death, nonfatal MI, or nonfatal stroke) were observed with both treatment regimens (9.9% vs 10.2%); overall rates from each component were also similar, and there were no betweenstrategy differences in secondary outcomes of cardiovascularrelated death or hospitalization.40

The results of INVEST lead to the hypothesis that the ASCOT findings may not be due to a class effect. This idea is particularly plausible for CCBs, since the pharmacological actions of dihydropyridines and verapamil differ substantially.

Recent results from the ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension) trial give an insight into the effectiveness of combinations containing CCB relative to those containing HCTZ. The results demonstrate that therapy with a fixed-dose ACE inhibitor/CCB combination (benazepril/amlodipine) was superior to standard ACE inhibitor/diuretic (benazepril/ HCTZ) therapy in reducing cardiovascular events, despite similar BP lowering.41,42

Figure 4
Figure 4. Hazard ratios for the primary outcome and individual
components in ACCOMPLISH.

Only the first event in an individual patient was counted in the analysis of the primary end point. For subsequent analysis of the component
end points, one event per category was counted if a patient had events in more than one category.
Abbreviations: ACCOMPLISH, Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension; CI, confidence interval.
Modified from reference 41: Jamerson et al. N Engl J Med. 2008;359:2417-2428. © 2008, Massachusetts Medical Society.

ACCOMPLISH enrolled 11506 hypertensive patients with evidence of cardiovascular or renal disease or target organ damage; 60% of patients had diabetes. The primary end point was a composite of fatal and nonfatal events from cardiovascular causes (individual components are presented in Figure 4).41 At baseline, 97.2%of patients were being treated for hypertension and 74.7% were being treated with two or more antihypertensive agents, but only 37.3% had BP below 140/ 90 mm Hg. At the end of the study, BP control (<140/90 mm Hg) had been attained in an average of 75.4%of patients in the benazepril/amlodipine group and 72.4% in the benazepril/ HCTZ group. After a mean follow-up of 36 months, the relative risk reduction in the combined primary outcome of the benazepril/ amlodipine strategy versus the conventional therapy strategy was 19.6%(hazard ratio [HR], 0.80; 95%confidence interval [CI], 0.72 to 0.90; P<0.001) (Figure 4).41 However, ACCOMPLISH does not provide evidence of reduced mortality or improvements in the majority of secondary end points.

here is also established evidence of the antihypertensive efficacy of ARBs and their activity in reversing or inhibiting vasoconstriction, myocardial hypertrophy, vascular hypertrophy, and aldosterone secretion.43 They also reduce proteinuria in patients with renal impairment, as do ACE inhibitors.43 Compelling indications for their use include heart failure, diabetes, and chronic kidney disease.3,4 The combination of ARBs and CCBs provides better BP control with a more favorable tolerability profile than the componentmonotherapies and enhances the regression of some subclinical organ damage.16,44,45 However, no intervention studies to date have assessed whether this combination reduces the risk of cardiac or cerebrovascular morbidity and mortality.

Due mainly to the LIFE study27 and ASCOT trials, guidelines have recently placed less prominence on β-blocker–based therapy4,46 in patients without overt coronary heart disease. It is unclear to what extent these findings relate to other FDCs containing diuretic or CCBs; however, it would seem to support the use of FDC therapy containing an ACE inhibitor and a CCB in hypertensive patients at high risk of experiencing coronary ischemic events. Aliskiren, an oral renin inhibitor, represents another approach to the management of hypertension that has recently become available. Aliskiren is available as monotherapy; an FDC with HCTZ or valsartan is also available in some countries.47 There is no ongoing trial for aliskirenbased combinations versus any other acknowledged standard combination for hypertensive patients. However, recent results of the ALLAY (ALiskiren Left ventricular Assessment of hypertrophY) study in hypertensive patients with LVH show that the effect on LVH reduction of adding aliskiren 300 mg to losartan 100 mg versus losartan 100 mg alone was neutral. Furthermore, BP values obtained with the combination were not lower than those obtained with either component.48

Conclusion

Hypertension frequently resists control with monotherapy, necessitating combination therapy with two or more antihypertensive agents.Many currently available antihypertensive FDCs combine drugs with different, but complementary, mechanisms of action to improve overall efficacy and tolerability. Antihypertensive FDCs may provide significant advantages over high-dose monotherapy, such as improved BP-lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs, and shorter time to BP control. Combination therapy has been recommended as potential first-line therapy in recent consensus guideline statements, especially for higher-risk patients such as those with stage 2 hypertension. The combination of a renin-angiotensin- aldosterone system–targeting agent, such as an ACE inhibitor or ARB (in the case of ACE inhibitor intolerance), with a diuretic or CCB provides synergy with regard to BP lowering. In specific situations, such as in patients at high risk of experiencing coronary ischemic events, ACE/CCB combinations have demonstrated beneficial effects on hard end points, reducing cardiovascular morbidity and mortality and inhibiting the development and progression of type 2 diabetes mellitus and the progression of renal disease. _

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Keywords: antihypertensive fixed-dose combination; cardiovascular risk factor; BP-lowering efficacy; lower treatment cost