Combining RAAS and calcium channel blockade: ACCOMPLISH in perspective

Abstract

The Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial was the first trial to compare the cardiovascular outcomes of initial fixed‐dose combination angiotensin‐converting enzyme inhibitor (ACEI)/calcium channel blocker (CCB) and ACEI/diuretic therapy in patients with hypertension and high risk of cardiovascular events. The initial combination therapy was effective in this population, with ACEI/CCB therapy providing the greatest benefit (reduction in risk of cardiovascular events). Whether or not the findings of ACCOMPLISH can be applied to other renin–angiotensin–aldosterone system (RAAS) inhibitor/CCB combinations, such as angiotensin receptor blocker (ARB)/CCB combinations, has yet to be investigated. The present report reviews the results of ACCOMPLISH, data from trials comparing ARB and ACEI therapies, and findings from studies of ARB/CCB combination therapy that support the use and further study of combination therapy with RAAS inhibitors and CCBs.

• Angiotensin II type 1 receptor blockers
• angiotensin‐converting enzyme inhibitors
• antihypertensive agents
• calcium channel blockers
• hypertension
• renin–angiotensin system

Introduction

Hypertension affects up to 1 billion individuals worldwide [1]. Target organ damage caused by uncontrolled hypertension can lead to a host of adverse outcomes [1]. Worldwide, it is estimated that elevated blood pressure (BP) (systolic blood pressure [SBP] >115 mmHg) is responsible for 62% of cerebrovascular disease and 49% of ischemic heart disease [2]. Hypertension contributes to more than 7 million deaths annually, making it the number one risk factor for death worldwide. Despite our knowledge of the significance of hypertension and the availability of numerous treatment options, many patients are not controlled adequately [3]. In the USA, it is estimated that two‐thirds of the 73 million hypertensive individuals have SBP/diastolic blood pressure (DBP) above the recommended goal of <140/90 mmHg [4].

Current treatment guidelines recognize the need for effective BP lowering and recommend treatment goals of SBP/DBP <130/80 mmHg for patients with diabetes or chronic kidney disease and <140/90 mmHg for all others [1], [5]. They also recommend that pharmacological therapy be initiated if lifestyle modifications fails to achieve these BP goals. Combination therapy typically is recommended for patients who have more severe hypertension or who fail first‐line monotherapy [1], [5]. Further, trial evidence suggests that most patients require two or more pharmacological agents to achieve BP control [6]. This awareness has intensified the search for optimized combination regimens, which potentially could be implemented earlier in the course of hypertension to achieve more rapid control and cardioprotective effects. Fixed‐dose combinations have multiple potential advantages over single‐drug regimens in the hypertensive population. Regimens that combine drugs from different therapeutic classes can result in improved antihypertensive efficacy, reduced adverse events, enhanced convenience and adherence, prolonged duration of action, and/or better protection against target organ damage [7].

Renin–angiotensin–aldosterone system (RAAS) inhibitors and calcium channel blockers (CCBs) are well‐established classes of antihypertensive agents. Their efficacy and tolerability have been demonstrated in a wide range of patients. Therapeutic benefits include reductions in BP and the risk of cardiovascular events. Direct effects on vasculature and atherosclerotic plaques may contribute to their cardioprotective effects [8–17]. Therefore, it has been hypothesized that for the same BP‐lowering effects, RAAS inhibitor/CCB combinations may have additional cardiovascular advantages over diuretic‐based therapies. To this end, the effects of combination angiotensin‐converting enzyme inhibitor (ACEI)/CCB therapy on cardiovascular outcomes were examined in a trial of 11,463 patients with hypertension and high risk of cardiovascular events. The Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial [18–23] used fixed‐dose combinations at trial outset, in contrast to the traditional add‐on approach. The major finding of ACCOMPLISH was a greater reduction in cardiovascular morbidity and mortality in patients treated with the ACEI/CCB combination vs ACEI/diuretic combination in this high‐risk population where a comparable BP reduction and control rate were achieved in both groups [21]. The objectives of the present report are to (i) review the results of the ACCOMPLISH trial, (ii) describe the comparative efficacy of ACEIs and angiotensin receptor blockers (ARBs) in large randomized controlled trials, and (iii) discuss the potential role of fixed‐dose ARB/CCB combination therapy in the management of patients at risk of cardiovascular events.

The ACCOMPLISH trial

The ACCOMPLISH trial was a randomized, double‐blind, 5‐year trial designed to test the theory that therapy with fixed dose combination ACEI/CCB therapy (benazepril/amlodipine titrated up to 40/10 mg) would be more efficacious than combination ACEI/diuretic therapy (benazepril/hydrochlorothiazide titrated up to 40/25 mg) in reducing cardiovascular morbidity and mortality in patients with high‐risk hypertension (Figure 1) [18]. The primary endpoint was the time to first event of a composite of cardiovascular morbidity and mortality. The secondary endpoints were [1] composite cardiovascular morbidity/mortality and [2] composite of cardiovascular mortality, fatal/non‐fatal stroke, and fatal/non‐fatal myocardial infarction (MI). A total of 11,463 patients with hypertension and high risk of cardiovascular events were randomized in the trial in the USA and Europe [19]. Inclusion criteria included age ⩾60 years, SBP⩾160 mmHg or currently on antihypertensive therapy, and evidence of cardiovascular or renal disease or target organ damage [18]. Younger patients (aged 55–59 years) were permitted in the trial if they had evidence of two or more cardiovascular disease risk factors or target organ damage.

Figure 1 Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension(ACCOMPLISH) trial design. Reprinted with permission from Jamerson et al. [18].

Baseline observations attest to the suitability of the population (Table I) [19]. The majority of subjects (97%) were treated with antihypertensive medication and 74% of them were treated with two or more antihypertensive medications at entry, but only 37.5% were controlled. Hypertension was longstanding in the majority of patients, with 92% taking antihypertensive medication for more than 1 year. Diabetes mellitus was common among participants (baseline prevalence, 60%), as was obesity (baseline prevalence, 50%). Nearly half the patients (46%) had a history of acute coronary syndromes, coronary artery bypass grafts, or percutaneous coronary interventions, and 13% had a history of stroke.

Table I. Baseline characteristics of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) population.

Characteristic	Randomized population (n = 11,463)
Mean (SD) age, years	68.4 (6.9)
Gender, % male	60.7%
Race, % white/black/other	83.9/11.9/4.2
Mean (SD) BMI, kg/m^2	31.0 (6.3)
Duration of hypertension, % <1 year/1–5 years/>5 years	8/29/63
Previous antihypertensive treatment (⩾1), %	97
Mean SBP/DBP, mmHg*	145.5/80.0
History of coronary events, %	46.0
History of stroke, %	12.9
Diabetes mellitus, %	60.4
Renal disease, % with proteinuria or raised serum creatinine/% with estimated GFR <60 ml/min/1.73 m^2	6.1/18

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; GFR, glomerular filtration rate. *n = 11,402. Reprinted with permission from Weber et al. [19].

Results of an interim blinded analysis using 6‐month data (n = 10,704) indicated that fixed‐dose combination ACEI/CCB or ACE/diuretic therapy substantially reduced BP from baseline [22]. During this period, mean SBP/DBP decreased from 145.5/80.2 to 132.5/74.3 mmHg (p<0.001 vs baseline). Control rates at the 6‐month timepoint (Figure 2) were the highest of any multinational trial to date. Nearly three‐fourths of all patients achieved SBP/DBP <140/90 mmHg (73% overall; 78% of the US population). The more stringent control rate of <130/80 mmHg was achieved by 43% of diabetics [16.3% controlled at baseline [19]] and 40% of patients with renal disease [18.3% controlled at baseline [19]] [22]. Of the patients who did not achieve control, 61% were taking submaximal therapy. Hypotension was uncommon, occurring in less than 2% of patients. Patients in the USA, Caucasians and patients taking lipid‐lowering therapy were most likely to reach BP targets with combination therapy. [Nordic‐area review boards only allowed enrollment of patients with BP not currently controlled (not a requirement for US enrollment), which resulted in a lower baseline BP control rate for the Nordic countries than for the USA.] [19] At 12 months, mean SBP/DBP remained low (132.7/74.7 mmHg overall) and control rates remained high (73% overall) [20]. Strong predictors of uncontrolled hypertension were more severe hypertension, an established need for more antihypertensive drugs, and target organ damage.

Figure 2 Proportion of patients achieving systolic/diastolic blood pressure (SBP/DBP) <140/90 mmHg at 6 months in the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial. Reprinted with permission from Jamerson et al. [22]. 16.3% of diabetics and 18.3% of patients with chronic kidney disease had SBP/DBP <130/80 mmHg at baseline. *43% achieved SBP/DBP <130/80 mmHg; †40% achieved SBP/DBP <130/80 mmHg.

After the mean follow‐up of 39 months, BP reduction from baseline was comparable between the ACEI/CCB combination and the ACEI/HCTZ combination therapy groups, and BP control (SBP/DBP <140/90 mmHg) was achieved in 80% of all treated patients [21], indicating that early BP reductions were sustained even after 1 year and through the end of the trial. However, ACEI/CCB combination therapy was superior to ACEI/diuretic combination therapy in reducing cardiovascular morbidity and mortality in this high‐risk population [22], [23]. Specifically, the reduction in risk of cardiovascular morbidity and mortality was 20% greater in the ACEI/CCB group relative to the ACEI/diuretic group (p = 0.0002; Figure 3). Similarly, the ACEI/CCB group had a 20% greater reduction in the hard cardiovascular endpoint (cardiovascular death, fatal/non‐fatal stroke or fatal/non‐fatal MI) (p = 0.007). These results provide compelling evidence for initial combination therapy with ACEI/CCB in this patient population.

Figure 3 Kaplan–Meier curves for the primary endpoint (cardiovascular morbidity and mortality) in the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial. Reprinted with permission from Jamerson et al. [21].

ACCOMPLISH was the first trial to evaluate cardiovascular outcomes using a single‐pill, fixed‐dose combination for the initial treatment of high‐risk hypertensive patients. It utilized a strong and scientifically based design to provide robust data [18]. The trial was an enriched trial, conducted in hypertensive patients with concomitant evidence of cardiovascular disease and high risk of future events [19]. The trial was stopped prematurely because the DSMB determined that the prespecified efficacy boundary had been crossed with 60% of the trial information [23].

Other trials supporting combination RAAS inhibitor/CCB therapy

The findings of ACCOMPLISH add to a growing body of evidence supporting early use of fixed‐dose combination therapy. The results of multiple clinical trials have demonstrated that RAAS inhibitor/CCB combinations are well tolerated and efficacious [7], [24–28]. In general, their use has been associated with significant BP‐lowering effects and high rates of BP control, with tolerability profiles similar to or better than those of monotherapy. Response rates (sitting DBP<90 mmHg or reduction from baseline ⩾10 mmHg) at 8 weeks were as high as 90% in factorial design studies of combination therapies (valsartan/amlodipine, olmesartan/amlodipine and benazepril/amlodipine combinations) [25], [27], [28]. Because RAAS inhibitors promote both arterial and venous dilation and often provide BP control without the need for high CCB doses, reduced rates of peripheral edema have been reported with RAAS inhibitor/CCB combinations relative to CCB monotherapy [26].

RAAS inhibitor/CCB combinations have demonstrated utility in patients who have failed to respond to antihypertensive monotherapy. In a direct‐switch trial (Exforge in Failure After Single Therapy Trial, EX‐FAST; n = 894), the administration of combination valsartan/amlodipine therapy to patients with hypertension not controlled by several different classes of antihypertensive monotherapy was associated with control rates of >70% at 16 weeks (control was defined as SBP/DBP <140/90 mmHg for non‐diabetics and <130/80 mmHg for diabetics). Control rates were 72.7% in the valsartan/amlodipine 160/5‐mg group and 74.8% in the valsartan/amlodipine 160/10‐mg group [24]. The combination was generally well tolerated, and the most frequently reported treatment‐related adverse event was peripheral edema (occurring in 6.8% and 22.2% of the 160/5‐mg and 160/10‐mg groups, respectively).

Combination RAAS inhibitor/CCB therapy also may provide greater BP‐lowering effects and cardiovascular benefits relative to BB/diuretic combination therapy in some patients. In the Anglo‐Scandinavian Cardiac Outcomes Trial‐Blood Pressure Lowering Arm (ASCOT‐BPLA; n = 19,257), CCB‐based therapy (amlodipine±perindopril) provided greater BP‐lowering and cardiovascular benefits relative to beta‐blocker (BB)–based therapy (atenolol±bendroflumethiazide and potassium) in adults with hypertension and at least three other cardiovascular risk factors (but no previous history of coronary heart disease) [29], [30]. Mean SBP/DBP reductions from baseline to final visit were −27.5/−17.7 mmHg in the CCB‐based therapy group and −25.7/−15.6 mmHg in the BB‐based therapy group (p<0.0001). CCB‐based therapy reduced the risk of coronary events by 13% and stroke events by 23%. [Adjusted hazard ratios (95% CI) for coronary events and stroke events were 0.87 (0.79–0.96) and 0.77 (0.66–0.89), respectively.] Whereas the results of this trial provide evidence of the benefits of CCB‐based therapy vs BB‐based therapy, they do not provide definitive evidence of the relative merits of ACEI/CCB therapy over BB/diuretic therapy because a substantial number of patients received CCB or BB monotherapy only.

It may be that the cardiovascular benefits of combination RAAS inhibitor/CCB therapy are attributable to factors other than just BP lowering. In patients with mild to moderate hypertension, the administration of combination benazepril/amlodipine therapy (20/5 mg), benazepril (40 mg) or amlodipine (10 mg) for 26 weeks produced mean SBP/DBP changes of −19.2/−11.4, −13.9/−8.6, and −16.7/−11.6 mmHg, respectively). Benefits on cardiovascular surrogate endpoints (improvement in arterial stiffness and left ventricular hypertrophy) were greater in the combination therapy group relative to the monotherapy groups [31]. RAAS inhibitors and CCBs have individual and combined (potentially synergistic) vasoprotective properties and beneficial actions on endothelial function that likely contribute to this finding [8–15]. Benefits may include structural and functional changes in resistance arteries (media:lumen ratio), effects on atherosclerosis progression, atherosclerotic plaque stabilization and fibrinolysis.

Implications of results: can ACCOMPLISH ACEI/CCB data be applied to ARB/CCB combination therapy?

In the absence of direct comparisons of ACEI/CCB and ARB/CCB combinations on morbidity and mortality, the relative benefits of these combinations in patients with high cardiovascular risk remain unknown. However, data from multiple clinical studies indicate that ACEI and ARB provide similar cardiovascular benefits (Table II). Comparable morbidity and mortality outcomes have been reported for patients with vascular disease or high‐risk due to diabetes [32], acute MI [33–35] and heart failure [33], [36–40]. Furthermore, in patients with heart failure, the ARB candesartan was as effective as enalapril in preventing left ventricular remodeling [41]. In hypertensive patients, treatment with ARBs appears to provide more consistent improvement in stroke prevention beyond BP‐lowering effects [42]. In general, tolerability was comparable or better in the ARB (vs ACEI) treatment groups in these studies. In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)‐Alternative trial [38], the ARB candesartan was used successfully in patients intolerant to ACEI therapy.

Table II. Major findings from studies comparing cardiovascular outcomes of angiotensin receptor blocker (ARB) and angiotensin‐converting enzyme inhibitor (ACEI) therapy.

Trial	n	Interventions/target doses	Design/duration	Major findings
ONTARGET [32]	25,620 patients with vascular disease or high‐risk diabetes	Telmisartan 80 mg qd vs ramipril 10 mg qd vs terlmisartan+ramipril	R, DB, multinational, median follow‐up, 56 months	Primary outcome (composite of death from cardiovascular causes, MI, stroke, or hospitalization for heart failure) occurred in a similar proportion of patients in each group (16.7%, 16.5%, and 16.3%, respectively). Fewer patients in the telmisartan group than in the ramipril group discontinued therapy because of cough (1.1% vs 4.2%; p<0.001) or angioedema (0.1% vs 0.3%; p = 0.01). More patients in the combination and telmisartan groups than in the ramipril group discontinued therapy because of hypotensive symptoms (4.8%, 2.7% and 1.7%, respectively; p<0.001 for telmisartan vs ramipril and combination vs ramipril). Combination therapy was associated with greater discontinuation rates related to syncope (p = 0.03), diarrhea p<0.001), and renal impairment (p<0.001) vs ramipril
VALIANT [34]	14,703 patients with MI complicated by left ventricular systolic dysfunction and/or heart failure	Valsartan 80 mg BID, captopril 25 mg tid, or valsartan 40 mg BID+captopril 25 mg tid	R, DB, multinational, median follow‐up, 24.7 months	Valsartan was as effective as captopril in preventing cardiovascular morbidity in patients following an acute MI. HR (97.5% CI) for death from cardiovascular causes, 0.98 (0.87, 1.09); p‐value for non‐inferiority = 0.001. HR (97.5% CI) for death from CV causes, MI, HF, resuscitation after cardiac arrest, or stroke, 0.96 (0.89, 1.04); p‐value for non‐inferiority <0.001. There were fewer discontinuations because of cough (0.6% vs 2.5%), rash (0.3% vs 0.8%), and taste disturbance (0.2 vs 0.4%) for valsartan vs captopril (all p<0.05). There were more discontinuations because of hypotension in the valsartan group (1.4 vs 0.8; p<0.05)
CHARM [33], [36–38]	7601 adults (>18 years) with heart failure	Candesartan 32 mg daily or placebo in addition to standard therapy (ie, BBs, diuretics, digoxin, spironolactone, or ACEI)	R, multinational, median follow‐up, 37.7 months	Candesartan reduced cardiovascular morbidity and mortality 10% in patients with heart failure; adjusted RR in candesartan group, 0.90 (p = 0.032). Among patients intolerant of ACEIs (n = 2028), candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity (adjusted HR [95% CI] for cardiovascular death or hospital admission for CHF, 0.70 (0.6, 0.81); p<0.0001). Similar proportions of patients in the candesartan and placebo groups discontinued therapy because of AEs
RESOLVD [41]	768 adults (mean age, 63 years) with heart failure and left ventricular dysfunction	Candesartan (4 to 16 mg daily), enalapril (10 mg BID), or candesartan (4 to 8 mg daily+enalapril 10 mg daily)	R, DB, multicenter, 43‐week trial	Candesartan was as effective as enalapril in terms of safety, tolerability, and preventing left ventricular remodeling in patients with heart failure. Combined therapy provided additional benefits (greater prevention of left ventricular remodeling)
ELITE I [39]	722 elderly patients (⩾65 years) with heart failure and decreased left ventricular ejection fraction	Losartan 50 mg qd vs captopril 50 mg tid	R, DB, multinational, 48‐week trial	Losartan was associated with lower overall mortality relative to captopril. All‐cause mortality was 4.8% with losartan vs 8.7% with captopril (p = 0.035). Note: trial was not designed to have the statistical power to detect a difference in mortality. Trend toward fewer deaths or hospitalizations for heart failure with losartan (9.4% vs 13.2%, p = 0.075). Losartan and captopril affected renal function equally. Losartan was better tolerated than captopril, with fewer discontinuations because of intolerance
ELITE II [40]	3152 elderly patients (⩾60 years) with heart failure and decreased left ventricular ejection fraction	Losartan 50 mg qd or captopril 50 mg tid	R, multinational, mean duration of follow‐up, 1.5 years	Losartan and captopril decreased cardiovascular events, sudden death, resuscitated arrests, and all‐cause mortality to a similar extent. No difference in all‐cause mortality (11.7% vs 10.4%, respectively). No difference in sudden death or resuscitated arrest (9.0% vs 7.3%, respectively). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects
OPTIMAAL [35]	5477 patients with MI complicated by heart failure or left ventricular dysfunction	Losartan 50 mg qd vs captopril 50 mg tid	R, DB, multicenter (Europe); Average follow‐up, 2.7 years	No significant difference between losartan and captopril in all‐cause mortality in patients following an acute MI (relative risk, 1.13 (0.99, 1.28); p = 0.069. Losartan was better tolerated and associated with fewer discontinuations (p<0.0001). Losartan was associated with less hypotension (13.3% vs 16.3%; p = 0.002), cough (9.3% vs 18.7%; p<0.0001), skin rash (3.1% vs 4.6%; p = 0.005), angioedema (0.4% vs 0.8%; p = 0.034), and taste disturbance (0.6% vs 2.7%; p<0.0001) relative to captopril

ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; VALIANT, Valsartan in Acute Myocardial Infarction Trial; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; RESOLVD, Randomized Evaluation of Strategies for Left Ventricular Dysfunction; ELITE, Evaluation of Losartan in the Elderly Study, I and II; OPTIMAAL, Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan.

R, randomized; DB, double‐blind; MI, myocardial infarction; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; BB, beta‐blocker; CHF, congestive heart failure; AE, adverse events.

Data from two large, international, randomized trials support the equivalence of ARBs and ACEIs in these populations. In the recently published Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET; n = 25,620), the ARB telmisartan was as effective as the ACEI ramipril in preventing cardiovascular morbidity and mortality in patients at high risk of vascular events (patients with coronary, peripheral, or cerebrovascular disease or diabetes with end‐organ damage) [32]. Specifically, the primary composite outcome of death from cardiovascular causes, MI, stroke or hospitalization for heart failure occurred in a similar proportion of patients in the telmisartan and ramipril treatment groups (16.7% and 16.5%, respectively). In the Valsartan in Acute Myocardial Infarction Trial (VALIANT; n = 14,703 patients with MI complicated by left ventricular systolic dysfunction and/or heart failure), valsartan was as effective as captopril in preventing cardiovascular morbidity in patients following an acute MI [hazard ratio (97.5% CI) for death from cardiovascular causes, 0.98 (0.87–1.09); p‐value for non‐inferiority = 0.001; hazard ratio (97.5% CI) for death from cardiovascular causes, MI, heart failure, resuscitation after cardiac arrest, or stroke, 0.96 (0.89–1.04); p‐value for non‐inferiority <0.001] [34].

Results of a systematic review of data from 61 comparative studies involving individuals with hypertension indicate that ACEIs and ARBs provide similar BP control and effects on death, cardiovascular events, major adverse events, quality of life and cardiovascular risk factors including lipid levels, diabetes mellitus, and left ventricular mass and function (Figure 4) [43]. The only clinically significant difference between ACEIs and ARBs found in this analysis was the rate of cough, which was higher with ACEIs [mean rate, 10% (ACEI) vs 3% (ARB)]. ARBs also were associated with higher rates of persistence (determined by the pattern of filled prescriptions) during initial therapy.

Figure 4 Risk of death and major cardiovascular events in angiotensin‐converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) monotherapy studies (A) and withdrawals because of adverse events (B). Reprinted with permission from Matchar et al. [43].

A systematic review of all six large prospective randomized outcomes trials comparing treatment with ACEIs with ARBs came to similar conclusions except that ARBs may be slightly more protective than ACEIs on the risk of stroke [44].

Two fixed‐dose ARB/CCB combinations are currently commercially available (olmesartan/amlodipine and valsartan/amlodipine). Both have demonstrated BP‐lowering effects greater than component monotherapies. In an 8‐week factorial design trial, 35.0–53.2% of patients treated with olmesartan/amlodipine achieved the target SBP/DBP (<140/90 mmHg) vs 20.0–36.3% of the olmesartan monotherapy group and 21.1–32.5% of the amlodipine monotherapy group [28]. In other factorial design trials, valsartan/amlodipine lowered DBP to a significantly greater extent than placebo and either component alone, facilitating response (sitting DBP <90 mmHg or ⩾10 mmHg reduction from baseline) in a high proportion of patients (80–90%) [27]. Both combinations were generally well tolerated in clinical trials, with a lower incidence of peripheral edema relative to amlodipine monotherapy.

Conclusions

Hypertension is a challenging condition to manage, despite the availability of a wide variety of treatment options. The benefits of combination therapy are widely accepted; however, current guidelines recommend that, for most patients, such therapy be implemented only after failure of first‐line monotherapy. The ACCOMPLISH trial was the first to compare the benefits of initial combination ACEI/CCB and ACEI/diuretic therapy in patients with hypertension and high risk of cardiovascular events. Results indicate that initial combination therapy is beneficial in this population, with ACEI/CCB therapy providing the greater benefit (reduced cardiovascular morbidity and mortality relative to initial ACEI/diuretic combination therapy). ARB/CCB combinations may provide similar benefits. In monotherapy studies, ARBs and ACE inhibitors have demonstrated comparable BP‐lowering effects and cardiovascular benefits, with similar or improved tolerability. Therefore, combination ARB/CCB therapy may be better tolerated than ACEI/CCB therapy and may be particularly useful in patients unable to tolerate ACEI. Additional clinical research is needed to establish the efficacy of initial ARB/CCB therapy and the relative benefits of ARB/CCB vs ACEI/CCB combinations in the high‐risk hypertensive population.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.