Servier’s contribution to the advancement of antihypertensive therapy in the 21st century

Servier International – FRANCE

Servier’s contribution to the advancement of antihypertensive therapy in the 21st century

by V. Vandzhura, France

Hypertension guidelines emphasize that mortality reduction continues to be the ultimate goal of antihypertensive therapy. However, despite substantial achievements in preventivemedicine, hypertension remains the leading cause of death. Among the recent hypertension trials, further survival benefits have been demonstrated with perindopril regimens in ASCOTBPLA (Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and HYVET (HYpertension in the Very Elderly Trial). These findings, across a broad range of patients, had a large impact on the recent reappraisal of the European Society of Hypertension (ESH) guidelines (2009) and British hypertension guidelines (2011), which both support earlier use of proven antihypertensive combinations, and particularly of an angiotensin-converting enzyme (ACE) inhibitor combined with a calcium channel blocker (CCB) or a diuretic (and particularly a thiazide-like diuretic like indapamide). Lessons from ASCOT, ADVANCE, and HYVET also contributed to advancements in hypertension and provided clinical confirmation of the relationship between reduction in key blood pressure (BP) parameters (brachial BP, BP variability, 24-hour/night BP, and central BP), target-organ damage, and improved survival. Systematic evidence of mortality reduction achieved with perindopril and indapamide, reinforced by the recent meta-analysis of mortality reduction in hypertension trials, reward 40 years of Servier’s research in hypertension. Recently, directly derived from the ASCOT trial, Servier has developed a new combination of perindopril and amlodipine to benefit a large number of hypertensive patients.

Medicographia. 2012;34:85-94 (see French abstract on page 94)

“Chance favors only the prepared mind.”

The history of medicine confirms that human commitment, innovative approach, and years of persistent research are unconditional components of real scientific achievements. Evidence of mortality reduction in renin-angiotensin-aldosterone system (RAAS) inhibitor hypertension trials during the last decade—systematically demonstrated with perindopril (combined with amlodipine or indapamide) in ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm),1 ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation),2 and HYVET (HYpertension in the Very Elderly Trial)3—reward more than 40 years of Servier research in hypertension. Perindopril (Coversyl) and indapamide (Natrilix SR) were discovered and developed by Servier, which since its creation has been particularly committed to the fight against hypertension. Presently, more than 8 million patients are treated every day with Coversyl, Coveram (perindopril/amlodipine fixed combination), Preterax (perindopril/indapamide fixed combination), or Natrilix SR (indapamide SR).

Indeed, evidence-based medicine from the last decade has significantly enriched our knowledge and showcased examples for upgrading the management of arterial hypertension. Nevertheless, theWorld Health Organization (WHO) still ranks elevated blood pressure (BP) as the leading cause of premature death worldwide4 and European hypertension guidelines emphasize that reducing mortality remains the ultimate goal of antihypertensive treatment.5 To achieve this goal, reduction of elevated BP is an indispensible step. In 1991, STOP-Hypertension (Swedish Trial in Old Patients with Hypertension) showed unsurprisingly higher rates of cardiovascular (CV) events and mortality among patients receiving “pure placebo” (whose mean BP remained 193/95 mm Hg until the end of the study) versus those achieving a mean BP of 166/ 85 mm Hg with atenolol/hydrochlorothiazide (HCTZ).6 Since that time, BP goals and ethical requirements for the study design have been tightened. Nowadays, the actual question is which of the various BP-lowering treatments is the most beneficial in achieving further mortality reduction among hypertensive patients receiving contemporary preventive therapy? Indeed, in later trials, a systematic link between the magnitude of BP reduction and mortality could not always be observed.

Better BP reduction achieved with angiotensin receptor blockers (ARBs) in SCOPE (Study on COgnition and Prognosis in the Elderly [mean ΔSBP, 3.2 mm Hg]),7 TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease [mean ΔSBP, 4 mm Hg]),8 and PRoFESS (PRevention regimen For Effectively avoiding Second Strokes [mean ΔSBP, 3.8 mm Hg])9 did not translate into better reduction in the risk of CV outcomes and mortality versus placebo.

On the other hand, in another study, the reverse was true. In ASCOT-BPLA, CV risk reduction was greater than expected given the achieved difference in mean BP with the two treatments. Indeed, a statistical adjustment analysis showed that the difference in brachial BP (mean ΔSBP, 2.7 mm Hg) could only partially account for the superiority of amlodipine ± perindopril versus atenolol ± bendroflumethiazide in reducing CV events and mortality.1,10

Experts are therefore talking about a new era in hypertension management, in which traditional beliefs about the accuracy of “usual” brachial BP to predict the risk of CV events are being challenged, in particular by the use of other “new” key BP parameters, such as central BP and BP variability.11-13

In 2009, the reappraisal of the European guidelines on hypertension management critically assessed results from recent clinical trials. The guidelines prompted physicians to focus treatment strategy on optimizing BP control and survival among patients.14 Among the major clinical trials that have influenced the guidelines, ASCOT-BPLA,1 ADVANCE,2 and HYVET3 are acknowledged for having demonstrated additional benefits in different clinical situations.

The guidelines supported the earlier use of proven antihypertensive combinations, and particularly combinations of an angiotensin- converting enzyme (ACE) inhibitor with a calcium channel blocker (CCB) or a diuretic, and, according to the recent British 2011 hypertension guidelines, the only recommended combination for step 2 treatment of hypertension (after initial treatment as monotherapy) is that of a renin-angiotensin- aldosterone system (RAAS) inhibitor and a CCB, followed, if need be by addition of a diuretic (step 3), in particular a thiazide-like diuretic such as indapamide, while HCTZ is not advised.15

ASCOT-BPLA, ADVANCE and HYVET, despite featuring different hypertensive populations, have at least three major points in common. Firstly, these trials were initiated and designed independently by their respective investigators, in order to answer unresolved clinical questions. Secondly, all three demonstrated significant reduction in all-cause mortality with active treatment. For that reason, ASCOT-BPLA and HYVET were prematurely terminated. Finally, these three trials investigated the efficacy of the ACE inhibitor perindopril, in combination with either amlodipine or indapamide, and were supported totally or partially by Servier.

This article reviews the key lessons from ASCOT, ADVANCE, and HYVET, and examines how they were instrumental in making it possible to achieve further reduction in CV complications and mortality in hypertensive patients.

Rationale for ACE inhibition with perindopril (Coversyl) in patients with arterial hypertension

In the early 1980s, perindopril, a third-generation lipophilic tissue-ACE inhibitor, was developed by Servier with the aim of providing all the benefits of ACE inhibition in hypertension with an effective 24-hour efficacy after once-daily dosing. From that time, perindopril (Coversyl) has been extensively studied in more than 1500 preclinical and clinical studies.

_ Dose-dependent antihypertensive efficacy
A growing body of clinical evidence has specified the relationship between the dose and the 24-hour efficacy of perindopril and showed that trough effects were about 75% to 100% of peak effects.16-18 Large, practice-based trials with participation of more than 76 000 hypertensive patients have demonstrated that BP can be significantly reduced with perindopril on both short-term and long-term use.19-22

The dose-dependent antihypertensive efficacy and safety of perindopril were assessed in a recent observational, multicenter trial in 8300 patients with hypertension.23 The initial dosage of perindopril corresponded to 5 mg of the arginine salt and was titrated up to 10 mg as required for BP control. Mean BP was reduced by 19/10 mm Hg versus baseline (152/89 mm Hg), and, in a separate group of severely hypertensive patients, mean BP was reduced by 36/15 mm Hg. Perindopril dose uptitration to 10 mg resulted in an additional decrease in mean BP of 10/5 mm Hg in the total population and of 15/6 mm Hg in patients with severe hypertension.

_ Vascular protection benefits of ACE inhibition with perindopril
Arterial hypertension is a vascular disease, in which hyperactivity of the RAAS is the leading pathophysiological mechanism. ACE, which is present in the endothelium and smooth muscle, is primarily a tissue enzyme (80%-90%). Chronic overexpression of tissue ACE disrupts the angiotensin II/ bradykinin balance, leading to a host of negative vascular effects, including vasoconstriction, early vascular aging, and atherosclerosis. Perindopril, due to its strong affinity for ACE— and tissue ACE in particular 24—together with its long duration of action,16-18 differs substantially from other ACE inhibitors.

Perindopril’s favorable pharmacokinetic profile increases the potency of ACE inhibition, leading to greater reduction in angiotensin II production and greater prevention of vasoconstriction and release of adhesion molecules and growth factors, and decrease in oxidative stress. In addition, perindopril is known to have high selectivity for bradykinin binding sites and effectively decreases degradation of bradykinin. Perindopril induces a marked increase in bradykinin level, resulting in vasodilator, antioxidant, antiremodeling, profibrinolytic, and antiapoptotic effects, as well as opposing the negative actions of angiotensin II.25-27

The clinical evidence for the mode of action of ACE inhibitors in patients with chronic vascular disease was largely enriched by the results of EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease)28 and its substudies. The effect of perindopril on endothelial function in stable coronary artery disease (CAD) was determined by PERTINENT (PERindopril-Thrombosis InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial),29 a substudy of EUROPA. These trials showed that perindopril improved the markers of endothelial function by increasing endothelial nitric oxide synthase (eNOS), decreasing the level of von Willebrand factor (vWf), normalizing the angiotensin II:bradykinin balance, and reducing inflammation and rate of endothelial cell apoptosis.

Figure 1
Figure 1. Reduction in mortality and cardiovascular events in 29 463 patients receiving perindopril (Coversyl)-based therapy.

The consistency of the treatment effect of a perindoprilbased treatment regimen in patients with vascular disease or high risk of vascular disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials.
Adapted from reference 38: Brugts et al. Eur Heart J. 2009; 30:1385-1394. Published on behalf of the European Society of Cardiology by Oxford University Press. © 2009, The Author.

Reduction in apoptosis appears to be one explanation for how perindopril may be able to reverse new atherosclerotic plaque formation when it occurs. A post hoc analysis30 of the PERSPECTIVE substudy (PERindopril’s proSPective Effect on Coronary aTherosclerosis by IntraVascular ultrasound Evaluation) of EUROPA found that perindopril was able to regress the size of “young,” noncalcified plaques, as compared with placebo. Finally, perindopril appears to correct the damage of pathologically augmented apoptosis by increasing the production and incorporation of endothelial progenitor cells. Recent clinical data about acute coronary syndrome also suggest that perindopril decreases the rate of endothelial apoptosis, and increases endothelial renewal by stimulating production of endothelial progenitor cells in bone marrow. In contrast, the ARB valsartan does not increase endothelial renewal, nor does it counter serum-induced proapoptosis.31

_ Cardiovascular event prevention with perindopril in patients with established vascular diseases
EUROPA28 evidenced a significant 20% reduction in risk of CV death, acute myocardial infarction (MI), and resuscitated cardiac arrest in patients with stable CAD treated with perindopril. It also provided further support for the use of ACE inhibitors by showing a prognostic benefit for a target dose corresponding to perindopril arginine 10 mg in patients with stable CAD.32

Furthermore, the fact that other ACE inhibitors—quinapril in QUIET (QUinapril Ischemic Event Trial)33 and trandolapril in the PEACE study (Prevention of Events with Angiotensin-Converting Enzyme inhibition)34—failed to demonstrate morbidity-mortality benefits in stable CAD suggests that differences in the clinical effects of ACE inhibitors may be related to tissue-ACE affinity24 (the ability to penetrate into atherosclerotic plaques) and affinity for bradykinin binding sites.27 Finally, the BPLTTC trial (Blood Pressure Lowering Treatment Trialists’ Collaboration)35,36 demonstrated that the BP-independent effects of ACE inhibitors indeed contribute to the better reduction in coronary events. Today, use of ACE inhibitors with proven efficacy and at proven dosages is recommended in stable CAD patients.37

The effect of an ACE inhibitor–based regimen in a broader spectrum of patients with, or at risk of, vascular disease was analyzed using individual patient data from ADVANCE, EUROPA, and PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study).38 Findings from these trials involving 29 000 patients showed that the perindopril-based regimen was associated with a significant reduction in all-cause mortality, CV mortality, nonfatal MI, stroke, and heart failure (Figure 1).38 Notably, these results were consistent in subgroups with different clinical characteristics and across all strata of baseline and final BP. This consistent and distinguishing lifesaving evidence in support of a Coversyl regimen—demonstrated in a broad spectrum of patients with vascular diseases— together with its well-demonstrated 24-hour BP-lowering efficacy, encourages investigators to choose Coversyl for new trials in patients with broader clinical profiles.

ASCOT-BPLA: a breakthrough in hypertension

ASCOT was initiated to resolve clinical questions after new BP targets (<140/90 mm Hg) were for the first time established by the US39 (1997) and UK40 (1999) hypertension guidelines. In 2001, Peter Sever (UK), the principal ASCOT investigator, wrote: “If recently recommended BP targets are to be reached, the majority of patients will require at least two drugs. So far, no trials have evaluated or compared the efficacy of prespecified drug combinations for hypertensive patients.”41 ASCOT investigators decided to study the hypothesis that combining newer, but already well-established antihypertensive treatments (amlodipine and perindopril) might provide additional benefits versus an older combination (β-blocker/thiazide diuretic) in patients with hypertension, yet free of CAD.

In 2005, ASCOT-BPLA results1 were considered a breakthrough, as they showed that antihypertensive strategies could differ in CV outcomes, despite producing comparable brachial BP decreases. 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 amlodipine ± perindopril, as required, with atenolol ± bendroflumethiazide, as required, to reach BP targets. ASCOT-BPLA was stopped early due to an 11% difference in all-cause mortality in favor of the amlodipine ± perindopril group (P=0.0247) after a median of 5.5 years. Regarding secondary end points, there was a 24% difference in CV mortality (P=0.001), a 13% difference in all coronary events (P=0.007), and a 23% difference in fatal and nonfatal stroke (P=0.0003). Notably, the rates of CV death in the two treatment arms began to split at the very point where the majority of patients (78%) were already receiving perindopril in addition to amlodipine (Figure 2).42

_ Importance of key BP parameters in assessment and management of arterial hypertension: lessons from ASCOT-BPLA
ASCOT substudies have provided clinical proof that reduction in BP variability, 24-hour/night BP, and central BP with an amlodipine/perindopril regimen is directly associated with prognostic benefits, additional to those achieved due to better reduction in brachial BP.

_ In ASCOT, mean brachial BP reduction versus baseline was 27.5/17.7 mm Hg with amlodipine/perindopril and 25.7/ 15.6 mm Hg with β-blocker/diuretic with a mean difference of 2.7 mm Hg in systolic blood pressure (SBP). Yet, in 2005, the ASCOT investigators demonstrated that the adjustment for this BP difference only explained about half of the differences in coronary and stroke events.43

Figure 2
Figure 2. Reduction in cardiovascular mortality in
patients treated with amlodipine/perindopril (Preterax)
versus atenolol/thiazide diuretic.

Comparison of the proportion of patients receiving perindopril
and amlodipine with the proportion receiving amlodipine without
perindopril in the ASCOT-BPLA study (Anglo-Scandinavian
Cardiac Outcomes Trial–Blood Pressure Lowering Arm), and the
relationship to cardiovascular mortality risk over time. Note the
divergence of risk profiles at two years as the proportion of patients
receiving perindopril in addition to amlodipine exceeds 50%.
Abbreviations: CV, cardiovascular; HR, heart rate; RRR,
relative risk reduction.
After reference 42: Meurin. Am J Cardiovasc Drugs. 2006;6(5):
327-334. © 2006, Adis Data Information BV.

_ Recently, variability in SBP in patients with arterial hypertension has been shown to be a powerful predictor of stroke and coronary events independent of mean SBP.44 Whether antihypertensive treatment can affect this variability was the subject of a complementary analysis of ASCOT. In this study, amlodipine ± perindopril reduced BP variability and stabilized BP better than atenolol ± bendroflumethiazide.45 This applied both to short-term BP variability (consecutive BP measurements in the doctor’s surgery or 24-hour ambulatory BPmonitoring) as well as to long-term BP variability, between visits. As demonstrated by the statistical adjustment analysis, the reduction in BP variability contributed to the better CV event prevention seen with amlodipine ± perindopril treatment in ASCOT. In the wake of these findings, the updated British 2011 guidelines were the first hypertension guidelines to recognize BP variability as an independent CV risk factor for cardiovascular events and to recommend using “the best available evidence- based treatment option to suppress BP variability.”15

_ 24-Hour and night BP are known to be superior to mean clinic BP as predictors of CV outcomes or stroke, and this superiority has been recently recognized by the NICE 2011 guidelines.15,46 The ASCOT-ABP substudy (Anglo- Scandinavian Cardiac Outcomes Trial–Ambulatory Blood Pressure), using ambulatory blood pressure monitoring, demonstrated early and effective reduction in nocturnal BP, which was observed across the entire study follow-up, with a mean difference of 2.2 mm Hg in night SBP in favor of the amlodipine/perindopril regimen. The study concluded that different effects on daytime and night ambulatory BP may have contributed to the lower rates of events in patients treated with amlodipine/perindopril.47

_ CAFE48 (Conduit Artery Function Evaluation), a substudy of ASCOT, was the largest prospective evaluation of the effects of CV drugs on derived central aortic pressures and hemodynam- ics, and showed that central aortic pulse pressure may be a factor affecting clinical outcomes. The CAFE substudy was designed to be initiated 1 year after randomization into ASCOT, when all treatments were uptitrated in order to reach target brachial BP. The study found that despite minimal difference (ΔBP, 0.7 mm Hg; P=0.2) in brachial SBP between the groups, the differences between the central aortic pressures were substantial and in favor of the amlodipine ± perindopril group (Δ central aortic SBP, 4.3 mm Hg; P<0.0001; Δ central aortic pulse pressure, 3.0 mm Hg; P<0.0001). The investigators concluded that the different effect on central BP between the two treatment arms of ASCOT may offer a potential explanation for the different clinical outcomes observed. Figure 3
Figure 3. Further reduction in blood pressure and cardiovascular events with
perindopril/indapamide (Preterax) in the ADVANCE trial.

Reduction in blood pressure with perindopril/indapamide (Preterax) in ADVANCE in the context
of UKPDS. Blood pressure levels of ADVANCE patients at the study entry were at the level of
blood pressure achieved among diabetic patients in UKPDS.
Abbreviations: ADVANCE, (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation); SBP, systolic blood pressure; UKPDS, UK Prospective Diabetes Study.
Based on references 2, 50, and 51.

In conclusion: Following and derived from the ASCOT trial findings, Coveram was developed as a fixed combination of amlodipine/perindopril, the only evidence-based combination shown to provide hypertensive patients with the expected lifesaving benefits demonstrated with amlodipine/perindopril in ASCOT patients. Coveram provides rapid and effective brachial BP reduction in a broad range of hypertensive patients and acts synergistically on all the components cited above as having been shown by the ASCOT substudies to be associated with prognostic benefits: brachial BP, central BP, 24-hour/night BP, and BP variability. Thus Coveram, indicated in both hypertension and CAD, stands out among currently available combinations of RAAS inhibitors and CCBs in having proven efficacy in decreasing the risk of death and CV events.49

ADVANCE: a step forward in the management of hypertensive diabetic patients

Like ASCOT, ADVANCE was an investigator-initiated trial. The group of trialists, led by John Chalmers (Australia), sought to identify what BP levels would be associated with the greatest benefit in patients with diabetes mellitus. It was a factorial randomized controlled trial evaluating the effects of BP lowering and intensive blood glucose control on vascular outcomes. The primary hypothesis of ADVANCE was that further reduction in BP values below the 145 mm Hg SBP achieved in the hypertensive diabetic patients of UKPDS (United Kingdom Prospective Diabetes Study), would provide even more benefits in this high-risk population.2

Patients were potentially eligible if they had been diagnosed with type 2 diabetes at the age of 30 years or older, were 55 years of age or older at study entry, and had evidence of elevated risk of CV disease. The study comprised 11 000 patients with a mean entry BP of 145/81 mm Hg, who were subsequently randomized to perindopril/indapamide (2 mg/0.625 mg) or matching placebo. The doses were doubled after 3 months, so that participants were receiving either perindopril/indapamide 4 mg/1.25 mg or matching placebo on top of preventive therapy. BP levels of ADVANCE patients at study entry were the levels achieved in diabetic patients in UKPDS (Figure 3).2,50,51 In ADVANCE, treatment with perindopril/indapamide resulted in further BP reduction of 5.6/2.2 mm Hg. This significantly greater antihypertensive effect of perindopril/indapamide in addition to current therapy in patients with diabetes and hypertension was associated with significant improvement in morbidity and mortality, compared with standard therapy alone: perindopril/indapamide reduced the relative risk of CV disease by 18%, all-causemortality by 14%, total coronary events by 14% and new microalbuminuria by 21% (Figure 4).2

_ Importance of reduction in microcirculatory disorders and target-organ damage in improving survival and CV outcomes among hypertensive patients
_ In addition to the further BP reduction and significant survival benefits achieved with perindopril/indapamide, the ADVANCE trial provided the first clinical evidence that reduction in microalbuminuria correlates with morbidity-mortality benefits. Further analysis of clinical trials has shown that, in mostantihypertensive treatment trials in patients with type 2 diabetes, reduction in microalbuminuria was associated with evidence of renal protection. ADVANCE was the first and only trial to provide evidence of parallel reduction in microalbuminuria, and CV and all-cause mortality.52 Indeed, in the recent ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention Study), a 20% reduction in microalbuminuria with olmesartan was not associated with outcomes reduction, but rather with a significant increase in mortality rates.53

Figure 4
Figure 4. Reduction in all-cause and cardiovascular mortality with perindopril/indapamide (Preterax). Results of ADVANCE.
Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; RRR, relative risk reduction.
Based on data from reference 2.

_ The effect of perindopril/indapamide on target-organ damage prevention shows that reversal and prevention of microvascular damage is a potentially important clinical goal in hypertension.

Robust evidence suggests that, in hypertensive patients, there are severe alterations in microvascular structure and function, mainly characterized by capillary rarefaction, endothelial dysfunction, and decreased vasodilator reserve. Abnormal microcirculation contributes to impairment of tissue perfusion and thus to end-organ damage.

A recent study showed that capillary density and endothelial response were improved only in controlled hypertensive patients receiving perindopril/indapamide, and not in those receiving agents other than ACE inhibitors or diuretics.54

_ Further analysis of the ADVANCE trial assessed the effects of the fixed combination of perindopril/indapamide on renal and CV outcomes in patients with type 2 diabetes and concomitant chronic kidney disease (CKD). Among the 10 640 participants for whom CKD status was known, 6125 did not have CKD, 2482 were classified as CKD stage 1 or 2, and 2033 as CKD stage ≥3. Treatment benefits of routine administration of a fixed combination of perindopril/indapamide, in terms of renal and CV outcomes in patients with type 2 diabetes, were consistent across all stages of CKD, with no heterogeneity in the magnitude of effects for any outcome. In contrast, the absolute treatment effects approximately doubled in those with CKD stage ≥3 versus those with no CKD.55

HYVET: solving the hypertension management dilemma in elderly patients

Until recently, benefits of BP reduction in elderly hypertensives were largely unclear. In 2003, Christopher Bulpitt (UK) and his team published results of the pilot study for HYVET,56 in which treatment for hypertension (lisinopril and HCTZ), despite being associated with reduction in stroke, was also associated with increase in all-cause mortality versus placebo. Concerning the design of the main HYVET trial, Professor Bulpitt wrote: “In the main HYVET study, we aimed to resolve persistent areas of clinical uncertainty about the relative benefits and risks of antihypertensive treatment in patients 80 years of age or older.”3

HYVET provided the first definite demonstration of the benefits of effective reduction in BP and CV outcomes with indapamide (in combination with perindopril in the majority of patients) in very elderly hypertensive patients. HYVET showed that, even in patients 80 years of age or older, antihypertensive treatment not only prevents CV events, but contributes to prolong life. The study results demonstrated 39% reduction in fatal stroke (P=0.046), 21% reduction in all-cause mortality (P=0.02), 23% reduction in CV mortality (P=0.06), and 64% reduction in the incidence of fatal or nonfatal heart failure (P=0.001).3

This unique study thus shows that it is worthwhile, even in a very old population, to start treatment for hypertension, and that the perindopril/indapamide combination is an evidencebased way to do so.

Figure 5
Figure 5. Perindopril (Coversyl) regimens demonstrate further significant mortality reduction among hypertensive patients.

Treatment effect of different angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) on all-cause mortality. Preliminary results from
the meta-analysis of randomized controlled hypertension trials conducted in the 21st century.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CI, confidence interval; HR, hazard ratio.
Reproduced from reference 56: Bertrand et al. Eur Heart J Suppl. 2011;32:13. Abstract. Published on behalf of the European Society of Cardiology by Oxford University
Press .© 2011, The Author.

Finally, HYVET and ADVANCE trials both provided evidence of high antihypertensive efficacy and metabolic neutrality of therapeutic strategies including indapamide. British 2011 hypertension guidelines critically reviewed evidence from the latest trials on diuretic use in hypertension management. Guidelines recommend that thiazide-like diuretics (chlorthalidone or indapamide) are used in preference to a conventional thiazide diuretic, such as bendroflumethiazide or hydrochlorothiazide.15

Coversyl—solid evidence of efficacy in further improving survival in hypertensive patients

During the last decade, when treatment BP goals <140/90 mm Hg and <130/85 in diabetes and high-risk patients39,40 and preventive medicine were implemented in clinical practice, objectives for, and approaches to, the management of hypertension substantially evolved. RAAS inhibitors are the most recent class to have been developed over the last 20 years for the treatment of hypertension. Paradoxically, despite evidence that BP reduction with RAAS inhibitors is associated with lower risk of stroke and CV events, their efficacy in reducing mortality (the ultimate guideline-recommended goal of antihypertensive therapy) has remained uncertain until now.

A recent meta-analysis by Bertrand et al looked at randomized controlled RAAS-inhibitor trials conducted in the majority of hypertensive patients (>2/3 of study population) during the last decade and evaluated the impact of RAAS inhibitors on further mortality reduction for their main indication, hypertension. It revealed that only Coversyl regimens significantly reduce mortality among hypertensive patients.56 This metaanalysis included 19 trials in 165 971 patients, of whom 92% were hypertensive. Trials in heart failure, acute MI or stroke, post-cardiac surgery, and acute atrial fibrillation were excluded due to expected benefits from RAAS inhibition other than BP lowering. The pooled results of ACE-inhibitor trials in 88 860 patients demonstrated a significant 6% reduction in all-cause death (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90-0.98; P=0.007). Among ACE-inhibitor trials, only perindopril-based regimens—investigated in ASCOTBPLA, ADVANCE, and HYVET in 34 242 patients—demonstrated significant reduction in all-cause mortality (HR, 0.87; 95% CI, 0.81-0.94; P<0.0001). No significant reduction in allcause mortality was demonstrated with ARBs in 12 trials totaling 77 111 patients (HR, 0.99; 95% CI, 0.95-1.04; P=0.75).

The investigators’ conclusion was that because of the high prevalence of hypertension, treatments with proven efficacy such as Coversyl-based regimens may result in a considerable number of lives saved (Figure 5).56


Since its creation, Servier has been persistent in its commitment to therapeutic advancements in cardiology. Today, results of more than 40 years of research and development of evidence-based antihypertensive treatments have contributed to significant improvement in the knowledge of hypertensive disease and its management. Indeed, striking lifesaving benefits of treatment with perindopril (Coversyl), either alone or in combination with amlodipine or indapamide, have been extensively demonstrated in trials such as ASCOT-BPLA, ADVANCE, and HYVET.

Furthermore, these trials with Coversyl-based regimens have provided the first clinical demonstration that reduction in all key BP parameters (brachial BP, 24-hour/night BP, central BP, and BP variability), as well as in microcirculatory disorders and target-organ damage, can contribute to better reduction in CV complications and mortality among contemporary hypertensive patients.

Finally, a preliminary report of the meta-analysis of clinical trials in hypertension indicates that strategies that include Coversyl significantly reduce all-causemortality by 13% among patients with arterial hypertension, thus providing convincing demonstration of the benefit of achieving guideline-recommended goals for hypertensive patients in the 21st century. _

1. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906.
2. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
3. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. Engl J Med. 2008;358:1887-1898.
4. Mathers C, Stevens G, Mascarenhas M. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva, Switzerland: World Health Organization; 2009.
5. Mancia G, De Backer G, Dominiczak A, et al; The task force for the management of arterial hypertension of the European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007;28(12): 1462-1536.
6. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekborm T, Wester PO. Morbidity andmortality in the Swedish Trial in Old Patients with Hypertension (STOPHypertension). Lancet. 1991;338:1281-1285.
7. Lithell H, Hansson L, Skoog I, et al; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875-886.
8. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators; Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. Lancet. 2008;372:1174-1183.
9. Yusuf S, Diener HC, Sacco RL, et al; PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359: 1225-1237.
10. Poulter NR, Wedel H, Dahlöf B, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet. 2005;366:907-913.
11. Oparil S. Hypertension in 2010: new challenges in blood pressure goals and assessment. Nat Rev Cardiol. 2011;8:73-75.
Benetos A, Salvi P, Lacolley P. Blood pressure regulations during the aging process: the end of the “hypertension era”? J Hypertens. 2011;29:646-652.
13. Dresser GK, Feldman R. New trends in hypertension management: of salt, going solo and single pill combos. Curr Opin Cardiol. 2010; 25:342-349.
14. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
15. National Institute for Health and Clinical Excellence. Hypertension. Clinical management of primary hypertension in adults. NICE clinical guideline 127; August 2011. Available from: 56008.pdf. Last accessed January 2012.
16. Myers MG. A dose-response study of perindopril in hypertension: effects of blood pressure 6 and 24 h after dosing. Perindopril Multicentre Dose-Response Study Group. Can J Cardiol. 1996;12:1191-1196.
17. Morgan T, Anderson A. How important is 24-hour control of blood pressure? Drug safety. 1996;15:243-248.
18. Morgan T. Twenty four hour BP control—which is best, trough:peak ratios or ABPM? Br J Cardiol. 1995;Suppl.1:57-59.
19. Julius S, Cohn JN, Neutel J, et al. Antihypertensive utility of perindopril in a large, general practice-based clinical trial. J Clin Hypertens (Greenwich). 2004;6:10-17.
20. Poggi L, Renucci JF, Denolle T. Treatment of essential hypertension in general practice: an open-label study of 47 351 French hypertensive patients treated for one year with perindopril. Can J Cardiol. 1994;10(suppl D):21D-24D.
21. Speirs C,Wagniart F, Poggi L.Perindopril post-marketing surveillance: a12month study in 14 351 hypertensive patients. Br J Clin Pharmacol. 1998;46:63-70.
22. Ionescu DD; PREFER investigators. Antihypertensive efficacy of perindopril 5- 10 mg in primary health care. Clin Drug Investig. 2009;29:767-776.
23. Tsoukas G, Anand S, Yang K; CONFIDENCE Investigators. Dose-dependent antihypertensive efficacy and tolerability of perindopril in a large, observational, 12- week, general practice-based study. Am J Cardiovasc Drugs. 2011;11(1):45-55.
24. Ferrari R. Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril. Expert Rev Cardiovasc Ther. 2005;3(1):15-29. 25. Nilsson MP, Lurbe E, Laurent S. The early life origins of vascular ageing and cardiovascular risk: the EVA syndrome. J Hypertens. 2008;26:1049-1054.
26. Dzau V. The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens Suppl. 2005;23:S9-S17.
27. Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T, Ferrari R. Angiotensinconverting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol. 2007;577:1-6.
28. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebocontrolled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.
29. Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with perindopril and endothelial dysfunction. Results of a susbstudy of the EUROPA study: PERTINENT. Cardiovasc Res. 2007;73:237-246.
30. Bruining N, de Winter S, Roelandt JR, et al; EUROPA/PERSPECTIVE Investigators. Coronary calcium significantly affects quantitative analysis of coronary ultrasound: importance for atherosclerosis progression/regression studies. Coron Artery Dis. 2009;20:409-414.
31. Cangiano E, Cavazza C, Campo G, et al. ACE inhibition modulation of endothelial apoptosis and renewal via endothelial progenitor cells in patients with acute coronary syndromes. Am J Cardiovasc Drugs. 2011;11(3):189-198.
32. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342: 145-153.
33. Pitt B, O’Neill B, Feldman R, et al. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:1058-1063.
34. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058- 2068.
35. Blood Pressure Lowering Treatment Trialists’ Collaboration; Turnbull F, Neal B, Pfeffer M, et al. Blood pressure dependent and independent effects of agents that inhibit renin-angiotensin system. J Hypertens. 2007;25:951-958.
36. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ. 2008;336:1121-1123.
37. Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive summary. The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J. 2006;27:1341-1381.
38. Brugts JJ, Ninomiya T, Boersma E, et al. The consistency of the treatment effect of an ACE inhibitor-based treatment regimen in patients with vascular disease or high risk of vascular disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials. Eur Heart J. 2009;30:1385-1394.
39. The Sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. Arch Intern Med. 1997;157:2413- 2446.
40. Ramsay LE, Williams B, Johnston GD, et al. British Hypertension Society guidelines for hypertension management 1999: summary. BMJ. 1999;319:630-635.
41. Sever PS, Dahlo EB, Poulter NR, et al; ASCOT investigators. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. J Hypertens. 2001;19:1139-1147.
42. Meurin P. The ASCOT Trial. Clarifying the Role of ACE Inhibition in the Reduction of Cardiovascular events in patients with hypertension. Am J Cardiovasc Drugs. 2006;6(5):327-334.
43. Poulter NR, Wedel H, Dahlöf B, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet. 2005;366:907-913.
44. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-tovisit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375:895-905.
45. Rothwell PM, Howard SC, Dolan E, et al; ASCOT-BPLA and MRC Trial Investigators. Effects of -blockers and calcium channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol. 2010;9(5): 469-480.
46. Dolan E, Stanton A, Thijs L, et al. Superiority of ambulatory over clinic blood pressure measurement in prediction mortality: the Dublin Outcome Study. Hypertension. 2005;46:156-161.
47. Dolan E, Stanton AV, Thom S, et al. Ambulatory blood pressure monitoring predicts cardiovascular events in treated hypertensive patients–an Anglo-Scandinavian cardiac outcomes trial substudy. J Hypertens. 2009;27:876-885.
48. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure– lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006; 113:1213-1225.
49. Bertrand M, Ferrari R, Remme WJ, Simoons ML, Deckers JW, Fox KM; EUROPA Investigators. Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study. Am Heart J. 2010;159: 795-802.
50. Adler AI, Stratton IM, Andrew H, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419.
51. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713.
52. García-Donaire JA, Segura J, Ruilope LM. A review of renal, cardiovascular and mortality endpoints in antihypertensive trials in diabetic patients. Blood press. 2011;20(6):322-334.
53. Haller H, Ito S, Izzo JL, et al. Olmesartan for delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364:907-917.
54. Debbabi H, Bonnin P, Levy B. Effects of blood pressure control with perindopril/ indapamide on the microcirculation in hypertensive patients. Am J Hypertens. 2010;23:1136-1143.
55. Heerspink L, Ninomiya T, Perkovic V, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide in patients with type 2 diabetes and chronic kidney disease. Eur Heart J. 2010;31(23):2888- 2896.
56. Bertrand ME, Mourad JJ, Fox K, Boersma E, Van Vark L. Impact of ACE inhibitors and angiotensin II receptor blockers on all-cause mortality in hypertension trials. Eur Hear J Suppl. 2011;32:13. Abstract.

Keywords: antihypertensive therapy; angiotensin-converting enzyme inhibitor; combination therapy; efficacy; indapamide; morbidity; mortality; perindopril; perindopril/amlodipine; perindopril/indapamide