Coveram: Optimizing combination therapy for cardiovascular protection: evidence from landmark trials





84
Nicolas CLAVREUL,PhD
Servier International
Suresnes, FRANCE

Optimizing combination therapy for cardiovascular protection: evidence from landmark trials


by N. Clavreul, France



Advances in the field of cardioprotection have established the value of combination therapy for hypertensive patients. If lowering blood pressure remains the primary goal of antihypertensive treatment, decreasing cardiovascular morbidity and mortality has emerged as the true objective of hypertension management. Combining drugs with complementary modes of action in a single pill offers a real advantage in terms of efficacy and rapidity of action. Patient adherence and tolerance to treatment are also enhanced, ultimately resulting in greater cardiovascular protection. Major landmark trials in hypertension such as ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), or HYVET (HYpertension in the Very Elderly Trial) have demonstrated the clear advantage of combining the leading drugs in their respective class—the angiotensin-converting enzyme inhibitor perindopril, the thiazide-like diuretic indapamide, and the calcium channel blocker amlodipine—in reducing mortality. Recent meta-analyses have confirmed not only that treatment with perindopril-based combinations results in a 13% reduction in all-cause mortality and a 22% reduction in cardiovascular mortality in hypertensive patients, but also that these combinations are the cornerstone of cardiovascular prevention in high-risk patients and diabetic patients. Additional therapeutic needs should be fulfilled in the near future, when new fixed combinations of these three drugs become available.

Medicographia. 2013;35:455-463 (see French abstract on page 463)



Current guidelines in hypertension support the view that, whatever the drug used, monotherapy will only control the blood pressure in a limited number of patients in the long term.1 Of course, treatment initiation with monotherapy with consecutive uptitration at full-dose remains the most widely applicable strategy for hypertensive patients. However, a recent meta-analysis of 42 studies has shown that in most cases, the blood pressure reduction obtained by combining two agents from any two classes of antihypertensive drugs is five times that obtained with doubling the dose of one agent.2 This observation is supported by the obvious advantage of combining the complementary pharmacological mode of actions of two or more drug classes. Not only are blood pressure reduction and cardiovascular protection enhanced, but tolerance is also improved by initially lowering the dose of each component and offsetting their potential side effects. In addition, it is unlikely that patients would be willing to try all the various monotherapies at fulldose prior to upgrading to combination therapy, which would ultimately be counter- productive when trying to reach the target objective of treating hypertension: to lower cardiovascular morbidity and increase life expectancy. Indeed, patients tend to be less reluctant to follow their treatment when they reach blood pressure targets with their initial treatment as opposed to having to go through multiple switches from one monotherapy to another.

Several recent studies have demonstrated the need to achieve rapid blood pressure control in order to obtain better outcomes. It was already apparent in a post-hoc analysis of the VALUE study (Valsartan Antihypertensive Long-term Use Evaluation) that, independently of the treatment, the rate of cardiovascular events was lower during the whole study for patients who initially reached blood pressure control within the first month.3 This observation was reinforced further in a recent Italian cohort study in more than 200 000 patients who were newly treated with antihypertensive drugs. Initiation with a combination treatment resulted in a significantly better protection over the 6 years of follow-up, with a lower rate of coronary and cerebrovascular events.4 It seems reasonable to suggest that the more rapid and sustained reduction in blood pressure afforded by combination treatment accounts for these results. Newer single-pill formulations for combination therapy also contribute greatly to helping patients attain controlled blood pressure by improving compliance. A 1-year study in more than 100 000 patients showed that patients whose antihypertensive treatment was initiated with a singlepill combination reached blood pressure targets more rapidly than their counterparts who were treated with either monotherapy or free combinations.5 Single-pill combinations are, therefore, expected to improve not only the rapidity of blood pressure control, but also the survival rate.







How combining perindopril and indapamide
in a single pill contributed to better hypertension
management

Investigations aiming to demonstrate the potential benefit of combination therapy in cardiovascular protection began early on. Based on the assumption that combining a long-acting angiotensin-converting enzyme (ACE) inhibitor, perindopril, with a metabolically neutral diuretic, indapamide, as first-line treatment would be more effective than a classic monotherapy strategy, the STRATHE trial (STRAtegies of Treatment in Hypertension: Evaluation) compared treatment initiation with Preterax (perindopril/indapamide) with a sequential strategy (starting with a β-blocker and then adding an angiotensin receptor blocker [ARB] and a calcium channel blocker [CCB]), or a step-by-step strategy (uptitration of an ARB and addition of a thiazide diuretic) in grade 2 hypertensives.6 Preterax was shown to rapidly control a greater number of patients than the other strategies, paving the way for the first recognition of combination therapy as an option for treatment initiation in patients with marked hypertension or at high cardiovascular risk.1 Preterax was also shown to be superior to enalapril or atenolol in reducing blood pressure in hypertensive patients with left ventricular dysfunction or diabetes.7-9 Preterax’s ability to preserve and regenerate the microcirculation to improve targetorgan function was observed in the PICXEL study (Perindopril/ Indapamide in a double-blind Controlled study versus Enalapril in Left ventricular hypertrophy),8 in which it achieved a greater reduction in left ventricular hypertrophy than enalapril. In the PREMIER study (PREterax in albuMInuria rEgRession),9 there was also a significantly greater reduction in albumin secretion with Preterax than with enalapril, which led to fewer major cardiovascular outcomes.

Although blood pressure was recognized as an important determinant of the risk of initial stroke in both normotensive and hypertensive patients, and a linear correlation between blood pressure levels and occurrence of ischemic stroke and cerebral hemorrhage was established,10 clinical uncertainty remained about the efficacy and safety of routine administration of a blood-pressure-lowering regimen in this population. In the PROGRESS study (Perindopril pROtection aGainst REcurrent Stroke Study), 6105 patients with a history of stroke or transient ischemic attack, half of them hypertensive, were randomized to placebo or perindopril with addition of indapamide, as required, on top of their current standard treatment.11 In patients assigned to the active treatment, blood pressure was lowered by an average of 9 mm Hg for systolic blood pressure (SBP) and 4 mm Hg for diastolic blood pressure (DBP). In patients who had received the combination of perindopril and indapamide since randomization, the reduction in SBP/DBP was even greater (–12.3/–5 mm Hg). This was associated with a 43% relative reduction in the risk of stroke and a 42% reduction in all major vascular events (Table I). Interestingly, the protection afforded by combination therapy was similar whether patients were hypertensive or not.

Later on, these encouraging effects of Preterax on microvascular and macrovascular events spurred the launch of the ADVANCE trial (Action in Diabetes and Vascular disease: Preter- Ax and DiamicroN MR Controlled Evaluation), which evaluated the benefit of tight blood pressure control with Preterax in patients with diabetes, irrespective of whether they were hypertensive or not.12 The primary hypothesis was that a further reduction in SBP below the 145 mm Hg achieved in the hypertensive diabetic patients of UKPDS (United Kingdom Prospective Diabetes Study) would provide even greater protection in this high-risk population.13 A total of 11 140 patients in 20 countries were enrolled in ADVANCE. To be eligible, patients had to have been diagnosed with type 2 diabetes at the age of 30 years old or older, be 55 years old or older at study entry, and show evidence of elevated cardiovascular risk. Patients were randomized to perindopril/indapamide or matching placebo, on top of their previous standard therapy, with progressive uptitration. Baseline blood pressure was 145/81 mm Hg on average, and active treatment led to a further 5.6/ 2.2-mm Hg decrease in blood pressure. In these conditions, perindopril/indapamide treatment was associated with a significant improvement in cardiovascular morbidity and mortality compared with standard therapy alone. As well as a significant 9% (P=0.04) reduction in the primary end point, a composite of major macrovascular events (cardiovascular death, nonfatal stroke, and nonfatal MI) and microvascular events (new or worsening renal or diabetic eye disease), there were also significant reductions in cardiovascular death and all-cause death, of 18% (P=0.04) and 14% (P=0.04), respectively (Table I).12

The positive impact of perindopril/indapamide on the microcirculation was illustrated by a 21% reduction in the relative risk of renal events, which was driven by a marked reduction in microalbuminuria. A subsequent subanalysis of renal events in ADVANCE revealed a consistent beneficial effect on kidney function, independently of the blood pressure level achieved, with no threshold effect.14 Similarly, analysis of the 10 640 patients with chronic kidney disease revealed a consistent benefit in terms of renal and cardiovascular outcomes across all stages of chronic kidney disease.15


Table I
Table I. Landmark trials with perindopril/indapamide: main results.

Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR
Controlled Evaluation; CI, confidence interval; HYVET, HYpertension in the Very Elderly Trial. MI,
myocardial infarction; NA, not applicable; PROGRESS, Perindopril pROtection aGainst REcurrent
Stroke Study.
Based on data from reference 11: PROGRESS Collaborative Group. Lancet. 2001;358:1033-1041;
reference 12: ADVANCE Collaborative Group. Lancet. 2007;370:829-840; and reference 20:
Beckett NS et al. N Engl J Med. 2008;358:1887-1898.



In addition to increased survival with perindopril/indapamide in diabetic patients, ADVANCE was the first and only trial to provide evidence of parallel reductions in microalbuminuria and cardiovascular and all-cause mortality. In contrast, in the recent ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention Study), the 20% reduction in microalbuminuria obtained with olmesartan treatment was not associated with a reduction in cardiovascular outcome.16 A recent meta-analysis in diabetic patients confirmed that only ACE inhibitors, and not ARBs as a class, were associated with a significant improvement in renal protection, with a 29% reduction in micro/macroalbuminuria that was mostly driven by the results of ADVANCE.17 This effect resulted in a 16% reduction in all-cause mortality in the trials including ACE inhibitors, while there was no effect with ARBs. For all these reasons, the SBP target for diabetics was based on the results of ADVANCE and set at 135 mm Hg. This threshold has not been modified since then, not even following more recent trials.18

The most recent demonstration of the cardiovascular protective effect of Preterax has come from an as-yet poorly documented fringe of the hypertensive population: very elderly hypertensive patients. The pilot study for HYVET (HYpertension in the Very Elderly Trial) in 2003 did not do much to clarify the situation, with the observation that an antihypertensive strategy based on lisinopril and hydrochlorothiazide was associated with an increase in all-cause mortality, despite a significant reduction in stroke.19 In the main HYVET trial, which included hypertensive patients aged 80 years or older, the combination of perindopril and indapamide was clearly shown to have effective blood pressure–lowering benefits in the very elderly.20 The study results showed a 39% reduction in fatal stroke (P=0.046), a 21% reduction in all-cause mortality (P=0.02), a 23% reduction in cardiovascular mortality (P=0.06), and a 64% reduction in the incidence of fatal or nonfatal heart failure (P=0.001) (Table I). The one-year extension of the trial also confirmed the need for early treatment initiation in this population.21

The recently published ambulatory blood pressure monitoring (ABPM) data of the HYVET study confirmed that blood pressure reduction with the perindopril/indapamide combination, which averaged 8/5 mm Hg over 24 hours, was the main explanation for the difference in outcome.22 Interestingly, this substudy revealed that, on account of their 24h-blood pressure, half of the HYVET population could be considered to have “white-coat hypertension” and that, therefore, treatment with perindopril/indapamide would have been beneficial for them as well. In the absence of clear recommendations for these patients in the guidelines, this study could help to improve prevention in this group of patients.

HYVET and ADVANCE also both provided evidence of the antihypertensive efficacy and metabolic neutrality of therapeutic strategies including indapamide. The 2011 British guidelines for hypertension management now recommend using thiazide-like diuretics such as indapamide rather than conventional thiazide-type diuretics such as hydrochlorothiazide.23

Why a fixed-drug combination of perindopril
and amlodipine made sense

Coveram was launched as a fixed-combination of amlodipine and perindopril after the publication of the results of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial), which was considered to be a breakthrough in the management of hypertension.24 Indeed, in order to reach the newly recommended blood pressure levels of 140/90 mm Hg set by both the American and British guidelines,25,26 the need for combination therapy had become more acute. However, there was limited comparative data on treatment strategies. The investigators of ASCOT therefore decided to address the question of whether a strategy based on combining newer drugs (amlodipine and perindopril) might provide additional benefits over the popular drugs used at the time (atenolol and a thiazide diuretic). A total of 19 257 hypertensive patients (baseline blood pressure, 164/95 mm Hg) with at least three risk factors, but who were free of coronary artery disease (CAD) were enrolled in ASCOT. Despite there being only a small difference in brachial blood pressure reduction, the reduction in all-cause mortality was significantly greater in the perindopril/ amlodipine arm (relative risk reduction, 11%; P=0.0247), and this motivated the decision to stop the trial early, after 5.5 years. In addition, cardiovascular mortality was reduced by 24% (P=0.001), coronary events by 13% (P=0.007), and strokes by 23% (P=0.0003), all in favor of the perindopril/amlodipine combination (Table II and Figure 1). In particular, the rates of cardiovascular death in the two treatment arms diverged at the very point where the majority of patients (78%) were treated with perindopril in addition to amlodipine rather than by amlodipine alone (indicated by a red arrow on Figure 1).27


Figure 1
Figure 1. ASCOT: Reduction in cardiovascular mortality in patients treated with
amlodipine/perindopril versus atenolol/thiazide diuretic .

Abbreviations: ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; CV, cardiovascular; HR, hazard
ratio; RRR, relative risk reduction.
After reference 27: Meurin. Am J Cardiovasc Drugs. 2006;6:327-334. © 2006, Adis Data Information

BV.


Substudies of ASCOT have provided clinical proof that reduction in brachial blood pressure alone cannot predict prognostic benefits. Indeed, since then, the importance of key blood pressure parameters such as blood pressure variability, 24-hour blood pressure control, and central blood pressure has emerged following the demonstration that the 2.7 mm Hg difference in SBP reduction in favor of the amlodipine/ perindopril group could only account for half of the differences in coronary and stroke events.28

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.29 In ASCOT, perindopril/ amlodipine was more effective in controlling intra-visit blood pressure variability (variability between repeated measures in a single medical visit) and between-visit blood pressure variability, a parameter considered to be a predictive indicator of long-term prognosis in guidelines. Statistical adjustment confirmed that this reduction in blood pressure variability contributed to the better cardioprotection afforded by perindopril/ amlodipine, a combination that the UK’s National Institute for Health and Clinical Excellence (NICE) declared to be “the best available evidence-based treatment option to suppress blood pressure variability.”23

In the ASCOT-ABP substudy (Anglo-Scandinavian Cardiac Outcomes Trial–Ambulatory Blood Pressure), ABPM demonstrated an early and effective reduction in nocturnal blood pressure, which was observed during the entire follow-up, with a mean difference of 2.2 mm Hg in nighttime SBP in favor of the perindopril/amlodipine regimen.30 In addition, the CAFÉ study (Conduit Artery Function Evaluation), which was initiated one year after randomization—when all treatments were already uptitrated in order to reach the blood pressure targets—evaluated central aortic pressures and hemodynamic indexes in a subset of patients.31 Despite a minimal and nonsignificant difference in brachial blood pressure between the two arms (ΔBP, 0.7 mm Hg; P=0.2), the difference in central blood pressure was largely in favor of the perindopril/amlodipine group (Δ central aortic SBP, 4.3 mm Hg; Δ central aortic pulse pressure, 3 mm Hg; P<0.0001 for both). This discovery offered a potential additional explanation to the better outcome observed with this combination. The clinical complementarity and synergy of perindopril and amlodipine used in combination was further demonstrated in a recent subanalysis of the EUROPA trial (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease).32 The purpose of this substudy was to determine the effect on cardiac outcomes of adding perindopril to long-term treatment with a CCB in the CAD patients of EUROPA. This substudy, therefore, focused on patients who received a CCB for the whole duration of the trial, including those who were randomized to the perindopril group or the placebo group. The two populations had exactly the same baseline characteristics and the addition of perindopril to a CCB was shown to result in a 46% reduction (P<0.01) in allcause mortality and in a 35% reduction (P<0.05) in the primary end point, a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), and resuscitated cardiac arrest. Interestingly, when compared with the population who received placebo without a CCB, the benefit provided by the perindopril/ CCB combination reached a 69% reduction in all-cause mortality and a 71% reduction in cardiovascular death! Thus, Coveram, which is indicated in both hypertension and CAD, stands out among the currently available combinations of renin-angiotensin-aldosterone system (RAAS) inhibitors and CCBs in having proven efficacy in decreasing the risk of death and cardiovascular events.

Figure 2
Figure 2. Perindopril-based combinations and mortality reduction in hypertension trials.

Abbreviations: ACE, angiotensin-converting enzyme; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; ALLHAT, Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial; ANBP-2, Second Australian National Blood Pressure (study); ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; CV, cardiovascular; HR, hazard ratio; HYVET, HYpertension in the Very Elderly Trial; JMIC-B, Japan Multicenter Investigation for Cardiovascular diseases B.
After reference 35: Ferrari and Boersma. Expert Rev Cardiovasc Ther. 2013;11:705-717. © 2013, Expert Reviews Ltd.



A recent meta-analysis by van Vark et al, which considered 20 trials evaluating RAAS inhibitors in hypertension and included 158 998 patients, reported that only in three trials was the active treatment significantly better at reducing mortality than the comparator: ASCOT, ADVANCE, and HYVET.33 These three trials all had perindopril as part of their active treatment, combined with amlodipine in ASCOT, and with indapamide for ADVANCEand HYVET. Treatment with perindopril-based combinations resulted in a 13% reduction in all-cause mortality and a 22% reduction in cardiovascular mortality (Figure 2, page 459).34,35 In contrast, none of the ARB trials showed any further decrease in mortality. The results of this study were echoed in a very recent new meta-analysis including 108 212 high-risk patients without heart failure where ACE inhibitors and ARBs were compared with placebo, and ACE inhibitors were shown to reduce all-cause death by 8.3% while ARBs had not such effect.36 In PROGRESS and EUROPA, perindopril-based regimens were once again the only ones to reduce both the primary outcome (cardiovascular death, MI, and stroke) and MI (Figure 3).

The consistent evidence showing the ability of ACE inhibitors to further reduce morbidity and mortality in hypertensive and high-risk patients is now acknowledged not only in the literature, but also in guidelines,37 and even by some health authorities,38 who recommend ACE inhibitors for first-line use and reserve ARBs for patients who are intolerant to ACE inhibitors.

New combinations… for unsatisfied medical needs

New complementary combinations aiming to fulfill the needs of all patients are on the horizon: Natrixam, the first and only combination of amlodipine and indapamide, which specifically addresses the issue of uncontrolled systolic hypertension, and Triplixam, the triple combination of perindopril, amlodipine, and indapamide.

The 2009 reappraisal of the European guidelines on Hypertension Management acknowledged the protection afforded by CCB/diuretic single-pill combinations against stroke and cardiac outcomes, and gave this combination preferred status based on promising results from randomized controlled trials, including VALUE.39 Indeed, in this high-risk population, the amlodipine/diuretic combination protected patients against MI (–19%) significantly better than the valsartan/diuretic strategy and showed a positive trend on stroke as well.

Diuretic/CCB combinations have also been shown to successfully reduce outcomes in patients with hypertension in other trials.40,41 In van Vark’s recent meta-analysis of mortality in hypertension trials, amlodipine and indapamide were also found to be among the only three antihypertensive drugs to significantly reduce mortality.33

Indapamide SR directly lowers peripheral resistance and has a direct vasorelaxant effect on blood vessels which complements the vasodilation produced by amlodipine and enhances the overall blood pressure reduction (Figure 4). Both drugs control blood pressure over 24 hours, have been shown to reduce SBP variability,42 and share the common advantage of being the most effective in lowering central blood pressure.43 In particular, a meta-analysis has shown that indapamide is more effective than hydrochlorothiazide in reducing blood pressure.44 Moreover, its neutral metabolic profile has led NICE to recommend that, when a diuretic is needed, a thiazide-like diuretic such as indapamide be preferred to hydrochlorothiazide.23

The complementary action of these two strongly active drugs appears to be particularly effective in lowering SBP, a parameter for which there remains a critical clinical need. A recent publication confirmed that, while DBP is frequently controlled in clinical practice, SBP is rarely, if ever, controlled.45 In addition, a low active RAAS is found in approximately 25% to 30% of hypertensive patients; as a result, a combination of RAAS blockers will not be of much benefit in these patients. The new amlodipine/indapamide combination will, therefore, be a welcome addition to the range of therapeutic strategies available to physicians.


Figure 3
Figure 3. Mortality reduction in major meta-analyses including perindoprilbased
combinations.

All-cause mortality reduction with ACE inhibitors and ARBs in different types of population:
at-risk patients, hypertensive patients, and diabetic patients.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker;
NS, not significant.
Based on data from reference 17: Lv et al. Cochrane Database of Syst Rev. 2012;12:CD004136.
doi:10.1002/14651858.CD004136.pub3; reference 33: van Vark et al. Eur Heart J. 2012;33,
2088-2097; and reference 36: Savarese et al. J Am Coll Cardiol. 2013;61:131-142.



Indeed, there is still a great need for better blood pressure control. Despite improvements in the treatment of hypertension, blood pressure remains uncontrolled in 60% of patients treated with a twodrug therapy,46 as demonstrated in a large pool of patients (11 182 patients), whatever their sex or the initial twodrug therapy used. Triple therapy is more effective than two drug therapy and monotherapy in reducing both SBP and DBP. This superiority in blood pressure lowering ultimately results in organ protection, with a superior reduction in stroke and ischemic heart disease.47 This was shown in a subanalysis of ADVANCE focusing on the patients who received a CCB at baseline and all through the trial.48 There was a significant 28% reduction in total mortality and an almost significant 24% reduction in cardiovascular mortality in the patients who received the perindopril/indapamide/CCB triple combination compared with the patients who received placebo in addition to CCB. In addition, a prospective, multicenter, observational study in 12 064 patients with stage 1 or stage 2 primary hypertension reported a further reduction of 30 mm Hg in SBP with perindopril/amlodipine/indapamide combination after 4 months of treatment.49 This efficacy was maintained over 24 hours, as demonstrated in an ABPM subanalysis, and was clinically significant on account of the fact that 70% of patients with uncontrolled hypertension at inclusion were already receiving treatment with ACE inhibitors/ ARBs ±hydrochlorothiazide.


Figure 4
Figure 4.
Complementary
modes of action
of perindopril,
amlodipine, and
indapamide as
a basis to fixeddose
combination.

Abbreviations:
ACE, angiotensinconverting
enzyme;
ANG II, angiotensin
II; BK, bradykinin,
NO, nitric oxide;
PGE2, prostaglandin
E2; PGI2,
prostacyclin
(prostaglandin I2).


Conclusion

Over the years, therapeutic advances in the management of hypertension have emerged as a result of landmark trials which have contributed to the recognition by all guidelines that the purpose of treating hypertension is, above all, to reduce cardiovascular morbidity and mortality. Modern trials with combination therapy were true breakthroughs and have erected evidence-based medicine as the gold standard.

Indeed, not only have they demonstrated the lifesaving benefits of perindopril-based combinations such as Coveramor Preterax in a wide range of populations, from hypertensive patients to CAD or diabetic patients, but they have also provided the first clinical demonstrations that a reduction in all key blood pressure parameters (brachial blood pressure, 24-hour blood pressure, central blood pressure, and blood pressure variability), as well as microcirculatory disorders and target organ damage, can contribute to a greater reduction in cardiovascular complications. This successful combination of some of the most active drugs will be expanded by the arrival of new fixed-dose combinations, for the benefit of both doctors and patients. ■


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Keywords: blood pressure; cardiovascular protection; combination therapy; hypertension management