The Combination of Perindopril/ Amlodipine for the Management of Hypertension With or Without Coronary Artery Disease

Roberto Ferrari, MD, PhD; Claudio Ceconi, MD

Introduction Hypertension is a massive drain on the world’s health-care resources. The World Health Organization ranks hypertension the number one mortality risk factor, with 13% of deaths worldwide (7 million) attributable to hypertension-related diseases each year.1 Over a quarter of the world’s population suffers from hypertension,2 and of the 70% of patients whose hypertension has actually been diagnosed, only 34% are at recommended target systolic blood pressure (SBP) (< 140 mm Hg) and diastolic blood pressure (DBP) (< 90 mm Hg) levels.3 Furthermore, the relationship between blood pressure (BP) and cardiovascular (CV) risk is strong—the higher the BP, the higher the CV risk. Further down the CV continuum, coronary artery disease (CAD) is the principal cause of angina, and estimates predict that about 0.5% of the Western population aged > 40 years has uncomplicated angina pectoris.4 In Europe, angina affects 20,000 to 40,000 individuals per million of the general population. Annual mortality in stable angina ranges from 0.9% to 1.4%, while the incidence of non-fatal myocardial infarction (MI) is between 0.5% and 2.6%.4 Despite the enormous health-care burden associated with hypertension, management remains less than adequate. Failings in management can usually be attributed to inadequate treatment with regard to dosage or choice of agent, problems with compliance, or absence of synergy when combinations are used.5 The administration of fixed combinations is recommended by international guidelines to help optimize the management of hypertension,3,6,7 and may also be useful in CAD. Indeed, fixed-combination strategies, including the angiotensin-converting enzyme (ACE) inhibitor/calcium channel blocker (CCB) combination, are advocated in the most recent European Society of Cardiology (ESC)/ European Society of Hypertension (ESH) guidelines on the management of arterial hypertension, from 2007.6 More recently, the 2009 Reappraisal of ESH Guidelines8 endorsed the need for a patient-oriented approach to CV risk in each patient. In those with high CV risk, the reappraisal called for faster BP control via the priority use of certain fixed combinations, including ACE inhibitor/CCB, when treatment is initiated. It also backed the use of fixed combinations following failure of monotherapy to control BP, where an additional drug is required. Evidence-based medicine currently suggests that renin-angiotensin system (RAS) inhibitors and CCBs are among the best components of an antihypertensive combination.6 Over and above the improved compliance and side effect profile associated with fixed combination treatments, they may also have advantages in terms of improved efficacy. The guidelines highlight combinations of ACE inhibitor/CCB as being supported by the strongest evidence, from the ACCOMPLISH9 (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension) trial and, particularly, the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) trial.10 The latter was considered a breakthrough in hypertension management owing to the reduction in all-cause mortality seen in hypertensive patients treated with a combination of amlodipine and perindopril— a first for a modern antihypertensive treatment. The last breakthrough of this size in hypertension was seen in 1991 in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension), when active antihypertensive treatment consisting of β-blockade or diuretics significantly reduced cardiovascular morbidity and mortality versus placebo.11 Moreover, recent trials such as ADVANCE (Action in Diabetes and Vascular disease: Preterax and Diamicron MR Controlled Evaluation)12 and HYVET (Hypertension in the Very Elderly Trial)13 have confirmed the ASCOT finding of a reduction in all-cause mortality with antihypertensive treatment that includes perindopril. This review will examine the suitability of a fixed-dose combination of the ACE inhibitor perindopril and the CCB amlodipine for the management of hypertension with or without concomitant CAD. Rationale for the Use of Fixed combination Perindopril/ Amlodipine Endothelial Disruption and Apoptosis: Effect of Perindopril A key component of the efficacy of perindopril in CV disease is its effect on the endothelium at the cellular level. The endothelium, the lining of blood vessels, is made up of a continuous layer of cells. In humans, it has a surface area of over 800 m2 and weighs approximately 1.5 kg. The human endothelium, which is capable of producing more than 250 biologically active, vasoregulating substances, has a lifespan of 1–3 months and continuously regenerates throughout life. ACE, which is present in the endothelium and smooth muscle, is primarily a tissue enzyme (80–90%). Consistently high levels of tissue ACE in the endothelium result in the overproduction of angiotensin II, a potent vasoconstrictor and growth factor, leading to a host of negative vascular effects, including endothelial cell apoptosis, vasoconstriction, inflammation, vascular remodelling, thrombosis, and eventually plaque rupture. ACE increases BP by promoting not only the formation of angiotensin II from angiotensin I in the RAS, but also the degradation of bradykinin.14 As bradykinin is degraded,15 its protective actions (vasodilation, antioxidation, profibrinolysis, anti-apoptosis, and anti-remodelling) versus the effects of angiotensin II are reduced. Endothelial function can be determined clinically by measuring levels of the procoagulant von Willebrand factor (vWf), a marker of endothelial damage, or by evaluating endothelium-dependent dilation or ischaemia-induced flow-mediated dilation. The effect of perindopril on endothelial function in stable CAD was determined using these criteria in PERTINENT (Perindopril- Thrombosis Inflammation, Endothelial Dysfunction and Neurohormonal Activation Trial), a substudy of EUROPA (European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease).16,17 Elevated vWf at baseline (ie, higher than the median level of 142% per unit) was found to significantly correlate with the occurrence of CV events in EUROPA over 4 years (P = 0.013). Moreover, levels of vWf also significantly decreased after 1 year’s treatment with perindopril (P < 0.01).16 Perindopril also appears to protect the vascular endothelium from apoptosis-mediated damage. The PERTINENT investigators explored the effects of circulating blood on endothelial function by measuring endothelial nitric oxide synthase (eNOS) protein expression and activity, and the rate of apoptosis. When isolated human endothelial cells were incubated with serum from EUROPA patients with stable CAD (perindopril, n = 43; placebo, n = 44) and with serum from healthy age-matched controls (n = 45), significant differences were found between the rates of apoptosis for controls and CAD patients (1.3% ± 0.6% vs 7.8% ± 2.9%; P < 0.01).16 This suggests that serum from patients with stable CAD includes agents that promote endothelial apoptosis. Treatment with perindopril for 1 year reduced the rate of apoptosis to 4.7% ± 2.2% (P < 0.05 vs baseline). It also appears that perindopril may be able to reverse new atherosclerotic plaque formation if it occurs. An excess rate of apoptosis versus regeneration causes disruption of endothelial continuity, which in turn leads to pathological sequelae, such as the onset of atherosclerosis and plaque erosion and rupture. A post hoc analysis18 of the PERSPECTIVE (Perindopril’s Prospective Effect on Coronary Atherosclerosis by Intravascular Ultrasound Evaluation) substudy19 of EUROPA found that perindopril was able to regress the size of non-calcified plaques compared with placebo. Coronary plaque with no or little calcium (0–25%) regressed with perindopril, but did not change with placebo (-0.33 ± 1.74 vs -0.03 ± 1.66 mm2; P = 0.04). The size of plaques containing moderate amounts of calcium (25–50%) did not change with perindopril, but severely calcified plaques (50–100%) continued to progress. Endothelial regeneration may also be positively affected by perindopril. The drug appears to correct the damage of pathologically augmented apoptosis by increasing the production and incorporation of endothelial progenitor cells. Endothelial progenitor cells are incorporated in vessel walls, allowing the physiological renewal of the endothelium.20 Experimental data21 and preliminary clinical data22 in acute coronary syndrome suggest that perindopril increases the production of endothelial progenitor cells in bone marrow. In contrast, valsartan does not increase endothelial renewal nor does it counter serum-induced proapoptosis. Calcium channel blockade may modestly reduce endothelial apoptosis too, possibly via a calcium-mediated reduction in caspase activity.23 Perindopril and Amlodipine: Complementary Modes of Action Perindopril and amlodipine have different but complementary modes of action, which may work in synergy to reduce BP (Figure 1).24 The vasodilating properties of ACE inhibitors like perindopril are related to its inhibition of the formation of angiotensin II from angiotensin I, which leads to a decrease in the level of the hormone aldosterone, the synthesis and release of which is stimulated by angiotensin II. A decrease in the level of aldosterone leads to diminished sodium reabsorption and water retention and, thus, to decreased blood volume and BP. Perindopril, being a highly effective tissue ACE inhibitor, counteracts the vasoconstrictive effect of angiotensin II, whose direct action on vascular smooth muscle tissue causes BP to rise.25 In addition, perindopril prevents bradykinin degradation, which increases bradykinin levels and vasodilation and prevents remodelling, in consequence. It also increases eNOS levels, leading to an increase in the vasodilator nitric oxide (Figure 1 and Table 1),24,26,27Furthermore, perindopril increases the bioavailability of bradykinin,24 which increases levels of the vasodilators prostacyclin and endothelium-derived hyperpolarizing factor, further reinforcing vasodilation. Dihydropyridine CCBs like amlodipine, on the other hand, work differently. At the level of endothelial cells, no calcium channels are found. The main antihypertensive action of CCBs takes place at the level of vascular smooth muscle. CCBs counteract excess calcium entry through voltage- and receptor-operated calcium channels of vascular smooth muscle.28 The decrease in intracellular calcium in the vascular smooth muscle of arteries decreases contraction and leads to vasodilation, an increase in arterial diameter, which in turn decreases total peripheral resistance, causing BP to drop. Both classes of agents are vasoprotective and cardioprotective. The vasoprotective efficacy of perindopril is mainly due to its protection of endothelial function and structure via a decreased rate of endothelial cell apoptosis, leading to a reduction in atherosclerotic plaque development and progression.16,19 A secondary effect of perindopril on vasculature is related to its anti-remodelling effect, its reduction of arterial stiffness, and its protection of target organs.29,30 ACE inhibitors appear to have extra cardioprotective properties in vivo due to their ability to regulate the kallikrein–kinin and sympathetic nervous systems, and prostaglandin levels. They also slow post-ischaemic left ventricular (LV) remodelling.31,32 At a cellular level, CCBs maintain myocyte function and delay irreversible ischaemic damage.33 These effects rely on an adenosine triphosphate (ATP)-sparing capacity and a reduction in ischaemic cytosolic calcium overload.33,34 In addition, CCBs produce coronary vasodilation and relieve exercise-induced vasoconstriction.5,35 Potential Synergy of Perindopril/ Amlodipine The potential for synergy of fixedcombination perindopril/amlodipine is wide-ranging, and may contribute to more efficient BP reduction, better fibrinolytic balance, and decreased side effects (Table 1).26 As well as treating hypertension, the combination of perindopril and amlodipine may be useful for treating ischaemic heart disease. ACE inhibition–mediated vasodilation of perindopril counteracts rebound stimulation of the RAS and the sympathetic nervous system as a consequence of amlodipine-induced vasodilation, leading to improved BP lowering. The failure of the verapamil/ trandolapril combination to reduce BP versus atenolol/hydrochlorothiazide in the International Verapamil- Trandolapril Study (INVEST)36 indicates that this might be a combinationspecific effect. ACE inhibitors and CCBs may correct fibrinolytic dysfunction, which helps decrease the risk of atherosclerosis and CV disease in hypertensive and CAD patients. When these agents are co-administered, they improve fibrinolytic balance via complementary modes of action.37 Both agents increase tissue plasminogen activator (t-PA) activity, while ACE inhibitors also decrease plasminogen activator inhibitor type 1 (PAI-1) levels. Low t-PA and high PAI-1 levels are indicators of impaired fibrinolytic function. This effect was demonstrated in a 6-week study in 38 hypertensive diabetic patients with impaired fibrinolysis comparing separate versus combined administration of the ACE inhibitor benazepril and CCB amlodipine.38 Lastly, ACE inhibition is known to reduce peripheral oedema, a wellknown side effect of CCBs, by dilating venous capacitance vessels, thus normalizing intracapillary pressure and reducing interstitial fluid exudation. With amlodipine, this side effect normally occurs in about 22% of patients39 and in women more often than men, but in a trial in 500 hypertensive patients treated with fixed-combination perindopril/amlodipine, there were no reports of ankle oedema.40 The vasodilatory properties of ACE inhibitors appear to make them more effective at reducing CCBrelated oedema than either diuretics41 or angiotensin receptor blockers.42 It has even been suggested that adding an ACE inhibitor, rather than a diuretic, to CCB monotherapy is the optimal way to further reduce BP while attenuating lower limb oedema. Clinical Evidence for Fixed combination Perindopril/ Amlodipine in Hypertension Mortality Benefits With an Antihypertensive Regimen ASCOT, the first head-to-head study of two antihypertensive regimens to demonstrate a difference in total mortality and CV morbidity,10 was the driving force behind the development of a fixed-dose combination of perindopril and amlodipine. ASCOT included 19,257 hypertensive patients who had at least three other CV risk factors, but no cardiac disease. The study compared the effect of an antihypertensive regimen based on amlodipine, plus perindopril as required, with a regimen based on atenolol, plus bendroflumethiazide and potassium as required.10 Perindopril was chosen to be added to amlodipine as required in order to provide better target BP achievement. Target BP was < 140/90 mm Hg, or < 130/80 mm Hg in patients with diabetes mellitus. ASCOT was stopped early because of an 11% difference in all-cause mortality in favour of the amlodipine ± perindopril group (P = 0.0247) after a median of 5.5 years. With regard to secondary end points, there was a 24% difference in CV mortality (P = 0.001) (Figure 2), a 13% difference in all coronary events (P = 0.007), and a 23% difference in fatal and non-fatal stroke (P = 0.0003). At the end of the study, 78% of the population were receiving combination therapy, and only 15% of the subjects in the amlodipine arm were receiving monotherapy. Interestingly, the rates of CV death in the two treatment arms began to split at the very point where the majority of patients were receiving perindopril in addition to amlodipine (Figure 2).43 Efficacy on All Key BP Parameters Brachial BP The brachial BP reduction seen with amlodipine ± perindopril in ASCOT compares favourably with that obtained using other antihypertensive combinations. Brachial BP fell markedly in the amlodipine ± perindopril group in ASCOT, from a mean of 163.6/95.1 mm Hg at baseline to 136.1/77.4 mm Hg at the end of the study (Δ SBP/DBP, -27.5/-17.7 mm Hg) after a median follow-up of 5.5 years. For comparison, brachial BP in the amlodipine ± hydrochlorothiazide group of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial44 fell from a mean of 154.8/87.6 mm Hg at baseline to 137.5/77.7 mm Hg at the end of the study (Δ SBP/DBP, -17.3/-9.9 mm Hg) after a mean follow-up of 4.2 years. Demonstrations of the antihypertensive efficacy of fixed-combination perindopril/amlodipine come from the STRONG (Safety and Efficacy Analysis of Coversyl Amlodipine in Uncontrolled and Newly Diagnosed Hypertension)45 and SYMBIO (Study of Optimized Blood Pressure Lowering Therapy With Fixed Combination Perindopril/Amlodipine) studies.46 In STRONG, a prospective, observational multicentre trial in 1,250 hypertensive adults aged 40–70 years old, 33% of patients had newly diagnosed/untreated stage 2 hypertension (BP ≥ 160/100 mm Hg), 41% had hypertension (BP > 140/90 mm Hg) uncontrolled with monotherapy, and 27% had hypertension that was inadequately controlled with another combination therapy. After 60 days, mean SBP/DBP had fallen significantly by 42 ± 35/23 ± 22 mm Hg (P < 0.0001) from baseline levels of 167 ± 15/101 ± 9 mm Hg, and twothirds of patients (66%) had attained target BP. It was also well tolerated, with most participants (94%; n = 1,175) completing the trial. SYMBIO, a longitudinal cohort study, found that fixed-combination perindopril/ amlodipine was effective at lowering BP to recommended target levels in ambulatory patients with treatedbut- uncontrolled essential arterial hypertension in real-life clinical practice. Within 3 months of treatment initiation, the BP of three-quarters of patients had been controlled. Both studies add further support to the ASCOT results. New ASCOT data show that amlodipine ± perindopril reduces the relative risk of CV events more effectively than β-blocker ± diuretic, regardless of the patient’s age. A new substudy shows that amlodipine ± perindopril reduced the relative risk of CV events more effectively than β-blocker ± diuretic in both older (≥ 65 years) and younger patients (< 65 years), although the absolute benefits were greater for older patients owing to the higher event rates.47 With the amlodipine- based regimen, mean brachial BP fell by 32/19 mm Hg in the older group and by 26/17 mm Hg in the younger group. There also appeared to be advantages in terms of safety in ASCOT: there was a significant difference in favour of the amlodipine ± perindopril group in the number of dropouts because of serious adverse events (2% for amlodipine ± perindopril vs 3% for β-blocker ± diuretic; P < 0.0001). The difference in brachial BP between the two arms of ASCOT, which was similar (an average difference of 2.7/1.9 mm Hg between the regimens over the duration of the study [P < 0.0001]), cannot entirely explain the advantage of the amlodipine ± perindopril regimen in terms of reduction in coronary and stroke events,10 implying that mechanisms other than brachial BP lowering may be at work. Further support for this idea comes from two trials with significantly different BP-lowering results, the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT)48 and VALUE.44 They showed no major differences in CV outcomes between the monotherapy treatment arms in each trial. Moreover, the ASCOT results may not be due to a class effect because in INVEST,36 which compared a verapamil/trandolapril combination with atenolol/hydrochlorothiazide in 22,576 hypertensive patients with CAD, there were no additional benefits with the CCB/ACE inhibitor combination versus β-blocker/diuretic. The clinical importance of ASCOT is that it shows that peripheral BP reduction is not the full story with regard to mortality reduction. Back in 2005, the ASCOT investigators stated that peripheral BP reduction alone could not account for the magnitude of reduction in all-cause mortality observed in the Blood Pressure– Lowering Arm of the ASCOT study (ASCOT-BPLA).10 Today, the view that antihypertensive efficacy should be judged purely on the basis of how much brachial BP is lowered appears outdated. The way BP is viewed has evolved with the discovery of how different BP parameters are associated with CV risk and mortality; these include BP variability, central BP, pressure wave reflection, nighttime/ 24-hour BP, and brachial BP. Accordingly, our concept of what constitutes a ‘good’ antihypertensive medication should perhaps change to reflect this shift away from a purely brachial model of BP. A ‘good’ antihypertensive medication should be able to reduce as many of the above parameters as possible, if not all of them. Central Blood Pressure CAFE (Conduit Artery Function Evaluation),49 a substudy of ASCOT, showed that brachial BP is not always a good surrogate for evaluating the effect of BP-lowering drugs on arterial haemodynamics and that BP-lowering drugs that give similar reductions in brachial BP can have substantially different effects on central aortic pressures and haemodynamics, which in turn can have an impact on clinical outcomes. The substudy, which was the largest prospective evaluation of the effects of CV drugs on derived central aortic pressures and haemodynamics, indicated that central aortic pulse pressure may be a factor affecting clinical outcomes, while the differences between the two BP treatment arms of ASCOT may offer a potential explanation for the different clinical outcomes observed. The study, which was conducted in 2,199 patients to determine the effects of two different BP-lowering regimens with similar brachial BP reduction (atenolol ± thiazide vs amlodipine ± perindopril) on central aortic pressures and haemodynamics found that despite similar levels of brachial BP reduction between the treatment groups (Δ BP, 0.7 mm Hg; 95% confidence interval [CI], -0.4 to 1.7; P = 0.2), the differences between the central aortic pressures of the two groups were substantial and in favour of the amlodipine ± perindopril group (Δ central aortic SBP, 4.3 mm Hg; 95% CI, 3.3–5.4; P < 0.0001; Δ central aortic pulse pressure, 3.0 mm Hg; 95% CI, 2.1–3.9; P < 0.0001). Furthermore, reduction in central aortic pulse pressure significantly correlated with a post hoc composite outcome of total CV events/procedures and development of renal impairment in the CAFE cohort (unadjusted P < 0.0001; adjusted for baseline variables, P < 0.05). Pressure Wave Reflection The CAFE researchers attributed the higher central aortic systolic and pulse pressures with the atenolol ± thiazide regimen to an increase in pressure wave reflection from distal reflection sites, and suggested that the principal mechanism for explaining the differences in aortic systolic pressure wave reflections between the two treatment arms was differences in timing of systolic ejection.49 This was thought to be a function of the slower heart rate obtained with an atenolol ± thiazide regimen; however, this may not be the sole explanation. Pressure wave reflection is capable of predicting future CV events independent of conventional risk factors in patients treated for hypertension, and its reduction is a valuable goal in hypertension.50 Elevated wave reflection is associated with elevated ventricular workload and increased risk of CV events in patients with well-controlled hypertension, independent of other risk factors. A wave reflection substudy of ASCOT showed that randomization to the ASCOT amlodipine-based regimen was associated with reduced magnitude of wave reflection as well as lower carotid SBP, a direct measure of central SBP, compared with the atenolol-based regimen.51 BP and flow velocity were measured in the right carotid arteries of 259 patients, and wave intensity analysis was used to separate and quantify the forward and backward waves. Several haemodynamic parameters differed between the different treatment groups, even though brachial BP did not differ significantly. Carotid SBP (127 ± 12 mm Hg vs 133 ± 15 mm Hg; P < 0.001), ratio of backward to forward pressure (0.48 ± 0.17 vs 0.53 ± 0.19; P = 0.01), and wave reflection index (20% ± 11% vs 23% ± 13%; P = 0.02) were all significantly lower in the amlodipine regimen–treated patients. In addition, LV mass index, an established independent predictor of CV events, was lower in this group. In conclusion, reduced wave reflection with amlodipine-based therapy may be due to the improvement of impedance mismatching in hypertensive patients via vasodilation, which is consistent with the observation that subjects randomized to the atenolol-based therapy group had higher peripheral resistance. 24-Hour and Night-time Blood Pressures In the 5.5-year ASCOT Ambulatory Blood Pressure (ASCOT-ABP) substudy in 1,905 patients,52 amlodipine ± perindopril reduced night-time SBP over the long term by an average of 2.2 mm Hg versus atenolol ± bendroflumethiazide. As in the general ASCOT population, clinic BP values were lower in ASCOT-ABP amlodipine ± perindopril- treated patients than in atenolol ± bendroflumethiazide-treated patients (inter-regimen Δ SBP, -1.5; 95% CI, -2.4 to -0.5 mm Hg; inter-regimen Δ DBP, -1.2; 95% CI, -1.8 to 0.5 mm Hg). Night-time SBP but not DBP was lower in patients treated with amlodipine ± perindopril therapy (SBP, -2.2; 95% CI, -3.4 to 0.9 mm Hg; DBP, +0.8; 95% CI, 0.0–1.6 mm Hg), while daytime BP during follow-up was higher (SBP, +1.1; 95% CI, 0.1–2.1 mm Hg; DBP, +1.6; 95% CI, 0.8–2.3 mm Hg). This is clinically relevant since night-time SBP is a predictor of CV outcomes and stroke. This may be rationalized as being due to the relatively high trough-to-peak ratios of perindopril and amlodipine (75–100% and 87%, respectively), which confer 24-hour antihypertensive efficacy. This ensures that patients taking these medications are protected from adverse CV events, such as stroke, in the early morning, the time of greatest risk for such events. Chronotherapy has been proposed as a possible solution for controlling nocturnal BP profiles in certain groups of patients, such as those with obstructive sleep apnoea.53 Blood Pressure Variability SBP visit-to-visit variability has been shown to be a powerful predictor of stroke and coronary events independent of mean SBP.54 Furthermore, hypertensive patients with residual SBP variability following antihypertensive treatment have a poor prognosis, while those with episodic hypertension have a worse prognosis than those with stable hypertension. BP is a naturally variable parameter, and in healthy individuals the sympathetic nervous system and baroreceptors regulate BP resulting in physiological adaptation to physical or emotional stimuli. However, in patients with arterial hypertension, this physiological adaptation is impaired by arterial remodelling and increased arterial stiffness, which lead to decreased arterial elasticity, loss of arterial buffering capacity, and ultimately greater BP variability. High BP variability in hypertensive individuals causes impaired organ perfusion and is associated with a higher risk of stroke and CV events. Whether antihypertensive treatment can affect this variability was the subject of a complementary analysis of ASCOT. In this study,10 not only did amlodipine ± perindopril reduce BP variability better than atenolol ± bendroflumethiazide, but amlodipine ± perindopril also stabilized BP better. This applied both to short-term BP variability (consecutive BP measurements in the doctor’s surgery or 24-hour ambulatory BP monitoring) as well as to long-term BP variability, between visits. The reduction in BP variability with amlodipine ± perindopril is a possible explanation for the CV event prevention seen with amlodipine ± perindopril treatment in ASCOT, as statistical adjustment analysis showed that the difference in brachial BP (mean Δ SBP, 2.7 mm Hg in favour of amlodipine ± perindopril) between the ASCOT treatment arms could only partially account for the ASCOT results. There was still a significant residual difference in events, which was totally accounted for after the results were further adjusted for BP variability. Fixed-combination perindopril/ amlodipine therefore appears to be a useful way of achieving the aim of lowering both mean BP and BP variability in clinical practice.55 Clinical Evidence for Fixed combination Perindopril/ Amlodipine in CAD A recent EUROPA analysis of the effects on cardiac outcomes of the addition of perindopril to long-term continuous treatment with CCB in a stable CAD population found that there was a significant supplementary reduction in cardiac outcomes and mortality.56 By identifying study participants who received CCB at every visit in the perindopril and placebo arms of EUROPA (perindopril/CCB, n = 1,022; placebo/ CCB, n = 1,100), the researchers found that total mortality was reduced by 46% (P < 0.01 vs placebo) and that the primary end point (a composite of CV mortality, non-fatal MI, and resuscitated cardiac arrest) was reduced by 35% (P < 0.05 vs placebo) with perindopril/ CCB (Figure 3). Furthermore, analysis of the hazard ratios pointed toward a greater total effect than the sum of the individual effects of each component, suggesting clinical synergy. The source of the synergy has yet to be conclusively determined, but it has been postulated that it might be due to enhanced reduction of central aortic BP or to an enhanced anti-atherosclerotic effect. Although the researchers were unable to determine the CCBs used, it was speculated that they were likely to be dihydropyridine CCBs.56 A substantial proportion of the population should have been receiving dihydropyridine CCBs because half the study population was on β-blockers, which theoretically rules out the coprescription of non-dihydropyridine CCBs such as verapamil and diltiazem. More specifically, there are indications that adding the CCB amlodipine to treatment with perindopril has a particularly beneficial effect in CAD populations. Although stable angina was a criterion for exclusion from ASCOT and thus impeded the assessment of the effects of the combinations on the symptoms and prognosis of stable CAD, two results indicate that amlodipine ± perindopril has a beneficial effect in CAD populations: (1) a 13% reduction in coronary events; and (2) a 32% difference in the tertiary end point of unstable angina (P = 0.01).10 Both perindopril and amlodipine have already shown their worth as monotherapy in CAD. The value of ACE inhibition with perindopril in preventing CV events in stable CAD was initially determined in EUROPA. In this trial, the primary end point of CV mortality, non-fatal MI, and resuscitated cardiac arrest was reduced by 20% versus placebo over 4 years (P < 0.0003) with high-dose perindopril.17 Similarly positive results were obtained in the HOPE (Heart Outcomes Prevention Evaluation) trial with ramipril.57 The efficacy of amlodipine was demonstrated in the CAMELOT (Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis) study,58 which showed that amlodipine significantly reduced hospitalization for angina and the need for revascularization over a 2-year follow-up versus placebo.4 Furthermore, in the VALUE study,44 which was designed to compare the effect of valsartan and amlodipine treatment on blood pressure control in hypertensive patients at high CV risk, amlodipine reduced the risk of MI by 19% (P = 0.02) versus valsartan, although cardiac morbidity and mortality did not differ between the treatments. Amlodipine ± perindopril may also improve cardiac perfusion in CAD patients by enhancing LV diastolic function. In the HACVD59(Hypertension Associated Cardiovascular Disease) substudy of ASCOT, patients who received the amlodipine-based regimen had better diastolic function than those treated with the atenolol-based regimen. Assessment of CV phenotypic data took place in 1,006 participants 1 year after randomization to either an atenolol-based or amlodipine-based regimen. Although the BP of both groups on treatment was similar (137 ± 17/82 ± 9 mm Hg with the atenolol- based regimen vs 136 ± 15/80 ± 9 mm Hg with the amlodipine-based regimen) and ejection fraction did not differ, early mitral annular velocity (E′), a measure of diastolic relaxation, was lower in patients on the atenololbased regimen (7.9 ± 1.8 cm/s vs 8.8 ± 2.0 cm/s).59 B-type natriuretic peptide (BNP) levels and a marker of LV filling pressure, E/E′, were significantly lower in patients on the amlodipine ± perindopril, and differences in E’, E/E’, and BNP remained significant after adjustment for age and sex. Further adjustment for SBP, LV mass index and heart rate had no effect on the differences in mean E’ or BNP, but attenuated the difference in E/E’. This study indicates that treatment with amlodipine ± perindopril may be associated with improved diastolic function independent of BP reduction. For the reasons detailed above, ESC guidelines6 consider pharmacological therapy alone suitable for the majority of stable angina patients. Pharmacological therapy also has the advantage of being associated with a lower risk of complications than either surgery or percutaneous coronary intervention. Conclusion This review indicates that fixed-combination perindopril/amlodipine may provide physicians with the opportunity to replicate the CV mortality and morbidity reduction seen in ASCOT in daily clinical practice. As well as reducing CV risk, the combination also appears to reduce the risks of CAD and heart failure via perindopril, and the risk of stroke via amlodipine. Furthermore, it has a positive effect on all parameters associated with the measurement of BP. A preliminary report of a meta-analysis of clinical trials in hypertension indicates that the inclusion of perindopril and amlodipine in antihypertensive treatment strategies may lead to a reduction in all-cause mortality.60 This metaanalysis looked at 18 randomized controlled morbidity-mortality trials with 210,000 patients. Of the 18 trials examined, only three trials—ASCOT,10 ADVANCE,12 and HYVET13—in 34,242 patients demonstrated significant reductions in all-cause mortality (13% when pooled; 95% CI, 0.81–0.93; P < 0.0001). When these three trials were excluded, the treatment effect of the remaining 15 trials in 176,190 patients became neutral (odds ratio, 0.98; 95% CI, 0.95–1.01; P = 0.21).60 All three trials with significant all-cause mortality reductions had treatment strategies that included perindopril, while amlodipine was used in two trials and indapamide in one. Neither the level of patient risk nor the trial duration could explain the results. A fixed combination of perindopril arginine and amlodipine besylate, Coveram®, exists and is available in four dosages: 5/5 mg, 5/10 mg, 10/5 mg, and 10/10 mg. As well as being endorsed by ESH guidelines,6 the clinical evidence for fixed-combination perindopril/amlodipine indicates it is a suitable combination to optimize the management of hypertension with or without stable CAD. Fixed-combination perindopril/amlodipine combines symptomatic and prognostic management of stable CAD. In hypertension, it optimizes management via complementary mechanisms of action working in potential synergy, leading to more efficient BP lowering, better tolerability, and improved CV prognosis. Declaration of Interests Professor Ferrari and Dr Ceconi have received consultancy fees, research grants, and payment for services from Servier International.