Coveram in the management of hypertension: improving each and every component of antihypertensive efficacy for lifesaving benefits

Servier International
Suresnes, FRANCE

by V. Vandzhura, France

The ultimate goal of antihypertensive therapy is to minimize the risk of hypertension- related death and morbidity. Reappraisal of European guidelines on hypertension has underlined the importance of blood pressure (BP) reduction per se, and highlighted the fact that systolic pressure, 24-hour BP profile, and central BP are strong predictors of cardiovascular events. Guidelines now recommend tailored management of hypertension adapted to each individual patient’s needs, and to initiate treatment with combination antihypertensive therapy. Based on recent evidence from the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm(ASCOT-BPLA), the combination of an angiotensin-converting enzyme inhibitor with a calciumchannel blocker (CCB) is one of the preferred therapeutic options. ASCOTBPLA was a breakthrough as it showed that antihypertensive strategies could differ in cardiovascular outcomes despite producing comparable brachial BP decreases. The amlodipine/perindopril regimen was more effective than atenolol/bendroflumethiazide in preventing death and major cardiovascular events. More efficient control of central BP, BP variability, and nocturnal hypertension with amlodipine/perindopril contributed to the difference in outcomes. Following the ASCOT trial results, Coveram was developed as a fixed combination of perindopril and amlodipine, and has already received consistent evidence-based support. Coveram provides rapid and effective brachial BP reduction in a broad range of hypertensive patients and acts synergistically on each and every component of antihypertensive efficacy: central BP, 24-hour BP, BP variability, and nocturnal hypertension. Coveram, indicated for both hypertension and coronary artery disease, stands out among currently available combinations of renin-angiotensin system inhibitors and CCBs, as it has been shown to decrease the risk of death and cardiovascular events.

Medicographia. 2010;32:281-289 (see French abstract on page 289)

Hypertension is the leading risk factor for premature death, responsible for 12.8% (7.5 million) of deaths worldwide, as well as causing up to 54% of cardiovascular deaths, according to a report from the World Health Organization published in 2010.1 At the same time, a so-called hypertension paradox was described, consisting of an increase in the number of uncontrolled hypertensive patients, despite therapeutic advances.2 More than two thirds of hypertensive adults in the United States fail to reach the blood pressure (BP) goal of <140/90 mm Hg, and over 80% of patients in Canada and Europe show suboptimal BP control.3,4

However, hypertension, as a disease whose defining feature is elevated blood pressure, has as many faces as the patients it impacts. In practice, physicians have to treat patients with systolic and/or diastolic hypertension, those whose BP increases in the evening or at night, and BP that “jumps” several times a day. Thus, a patient’s specific BP profile as well as concomitant risk factors and diseases determine each patient’s risk.

To improve the management of hypertension, the Reappraisal of European Guidelines on Hypertension Management: A European Society of Hypertension Task Force Document5 emphasizes the need for overall cardiovascular risk evaluation and the importance of BP reduction per se. Furthermore, guidelines recognize that central blood pressure and 24-hour BP profile are more informative than clinic (brachial) BP in determining cardiovascular risk as well as the treatment decision.

Based on evidence from clinical trials, use of antihypertensive drug combinations for treatment initiation, “particularly in patients at high cardiovascular risk in which early blood pressure control may be desirable” is recommended.5 The combination of an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel blocker (CCB) is one of the regimens preferentially recommended, as the guidelines point out. Data on morbidity-mortality for angiotensin receptor blocker (ARB)/ CCB combinations are lacking.5

The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure– Lowering Arm (ASCOT-BPLA) was the first, and is still the only, clinical trial to demonstrate effective reduction in mortality among hypertensive patients treated with a CCB in combination with a renin-angiotensin system (RAS) inhibitor. A significant decrease of 11% in deaths from all causes and of 24% in cardiovascular mortality was achieved with an amlodipine/ perindopril regimen, despite almost comparable lowering of brachial BP with a β-blocker/diuretic combination. In addition, ASCOT substudies have demonstrated that a better prognosis is directly associated with more effective reduction in central aortic and central carotid BP as well as BP variability and true 24-h efficacy with nighttime hypertension reduction by the amlodipine/perindopril regimen.

Furthermore, the recent subanalysis of the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) provided evidence that patients receiving perindopril (Coversyl) together with a CCB benefited from a markedly greater decrease in the risk of cardiovascular mortality and morbidity.6

Following the results of the ASCOT and EUROPA trials, Coveram, a fixed-dose combination of Coversyl (perindopril) and amlodipine, was developed. Coveram is the focus of this review. Representing a type of exception among antihypertensive treatments, Coveram:
_ Was introduced into clinical practice as a consequence of evidence-based support in clinical trials (ASCOT, EUROPA).
_ Decreases elevated BP rapidly and markedly (SafeTy and efficacy analysis of coveRsyl amlodipine in uncOntrolled and Newly diaGnosed hypertension [STRONG], StudY of opti- Mized Blood pressure lowerIng therapy with fixed cOmbination perindopril/amlodipine [SYMBIO]); and
_ On top of its superior BP reduction, Coveram improves central and nocturnal BP control and BP variability, thus providing lifesaving benefits for a broad range of patients with hypertension.

Evidence for Coveram in mortality and cardiovascular morbidity prevention: a primary objective of antihypertensive treatment


ASCOT-BPLA was a landmark multicenter prospective randomized controlled trial in 19 257 patients with hypertension (mean BP at baseline was roughly 164/94 mm Hg), 40 to 79 years of age, and who had at least three other cardiovascular risk factors, but were still free from coronary artery disease (CAD). Patients were assigned either to amlodipine plus perindopril as required to achieve target BP or atenolol plus bendroflumethiazide as required.

The rationale for the ASCOT study was the lack of morbidity or mortality evidence on optimum combinations of antihypertensive agents. In addition, for a given reduction in blood pressure, some authors suggested that newer agents such as amlodipine with perindopril (Coversyl) would confer advantages over the traditional approach of diuretics and β-blockers. The study was discontinued prematurely because of a significant reduction in cardiovascular mortality (RRR,–24%; P=0.001), all-cause mortality (RRR,–11%; P=0.02), and in stroke (RRR, –23%; P=0.0003) in favor of the amlodipine/ perindopril group, even though the necessary number of primary end point events was not reached due to early termination. The amlodipine/perindopril group also had a significantly lower incidence of new-onset diabetes (RRR-31%; P<0.0001) as well as fatal and nonfatal stroke, total cardiovascular events, and renal impairment (Figure 1).7

Figure 1
Figure 1. The ASCOT-BPLA study results.

Evidence of a consistent reduction in morbidity and mortality among patients treated with amlodipine-Coversyl compared with those treated with atenolol-bendroflumethiazide.
Abbreviation: ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm.
Adapted from reference 7: Dahlöf et al. Lancet. 2005;366:895-906. © 2005, Elsevier, Ltd.

Mean brachial BP reduction vs baseline was 27.5/17.7 mm Hg with the amlodipine/perindopril regimen 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). Based on long-term observational data,8 this systolic difference should translate into a difference in the rate of coronary events of about 8% and in the rate of stroke of about 11%, while the actual differences in coronary and stroke events reported in ASCOT-BPLA were 14% and 23%, respectively.7 Yet, in 2005, the ASCOT investigators demonstrated that the adjustment for BP difference only explained about half of the differences in coronary and stroke events. They suggested, that some of the benefits of the amlodipine/Coversyl regimen might relate to differences in other variables on blood pressure, such as blood pressure variability or central blood pressure, or to other treatment benefits not related to blood pressure.9 This hypothesis has been recently confirmed by additional results of ASCOT-BPLA substudies, detailed here below.

_ The EUROPA study

The clinical synergy of Coversyl and a CCB in the prevention of cardiac events and mortality in CAD patients was investigated to determine the effects of addition of Coversyl to longterm continuous treatment with a CCB on cardiac outcomes in the stable CAD population of the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA),10 and explore the presence of synergy between Coversyl and CCB in secondary prevention. Patients receiving a CCB at every visit during the 4.2-year followup were identified and the effect of adding perindopril was analyzed (n=1022 perindopril/ CCB versus n=1100 placebo/CCB). Addition of Coversyl to CCB significantly reduced total mortality by 46% (P<0.01 versus placebo+CCB) and the primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P<0.05 versus placebo+CCB). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively (Figure 2, page 284).6 The magnitude of benefits suggests the existence of a clinical synergy between perindopril and CCB. The synergy of Coversyl with CCB was observed independently of baseline BP. It must therefore be related to other “beyond BP” mechanisms, similar to those observed with perindopril in the overall EUROPA population.6

It was concluded that the addition of Coversyl to a CCB in patients with stable CAD had a significant additional impact on decreasing the risk of cardiovascular mortality and other cardiovascular complications, suggesting the potential for lifesaving benefits as well for the use of the perindopril/amlodipine fixed-dose combination (Coveram) in hypertensive coronary patients.

Synergy is one of the most widely mentioned properties of combinations of two different drug classes, particularly in the field of hypertension. The additive efficacy of an ACE inhibitor and a CCB in terms of vasorelaxation and BP lowering is well known.11-13 One possible mechanism is the potentiation of each drug’s efficacy on reduction of central aortic BP. A preferential reduction in central aortic BP was postulated as a source of benefit on cardiac outcomes with amlodipine/perindopril vs the β-blocker/thiazide diuretic in ASCOT.7 Other mechanisms exist underlying the pharmacodynamic synergy between Coversyl and CCB, where one component counteracts effects of the other. For example, CCBs stimulate the sympathetic nervous system and, indirectly, the RAS, whereas ACE inhibition with perindopril has the opposite effect. We could also summarize the synergy of perindopril and CCB on atherosclerosis. In this context, the positive impact of perindopril on endothelial function was demonstrated in the EUROPA population,14,15 together with a reduction in the size of early noncalcified plaque.16 A trend has been detected toward reduced progression of atherosclerosis with amlodipine versus placebo in the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial.17

Figure 2
Figure 2. Results of a post hoc subanalysis of the EUropean trial on Reduction Of
cardiac events with Perindopril in stable coronary Artery disease (EUROPA) study.

Clinical synergy of a therapeutic regimen including Coversyl and calcium channel blocker( CCB) showing greater magnitude of morbidity-mortality benefits vs placebo + CCB.
Adapted from reference 6: Bertrand et al. Am Heart J. 2010;159:795-802. © 2010, Elsevier, Inc.

Synergistic effects also have a positive impact on side effects. ACE inhibitors reduce lower-limb edema associated with use of CCBs. Clinical synergy may also be expected given the combination of the cardioprotective properties of Coversyl with the anti-ischemic and antianginal activity of amlodipine.13

Evidence for Coveram in blood pressure lowering: an early clinical criterion of antihypertensive therapy

_ Blood pressure–lowering efficacy of Coveram simply assessed by brachial tonometry
The pronounced antihypertensive efficacy of Coveram was demonstrated in the STRONG study. STRONG, a multicenter observational study, evaluated the efficacy and safety of Coveram at a dose equivalent to that of perindopril arginine/ amlodipine 5 mg/5 mg in 1250 patients with stage 2 hypertension (newly diagnosed or untreated at baseline, patients uncontrolled on monotherapy, those inadequately managed on another free- or fixed-combination therapy) in a real-world clinical practice setting.18

No additional antihypertensive drugs were permitted throughout the 2-month study period. Coveram decreased BP rapidly and progressively during the study with a significant reduction of mean SBP/DBP from 167.4±15.2/101.4±9.1 mm Hg to 125.4± 33.1/78.2±20.3 mm Hg (both P<0.0001 vs baseline), representing a decrease of 25.0% and 22.9% in SBP and diastolic blood pressure (DBP), respectively.18 Overall, 66.1% of patients reached the BP target of ≤140/ 90 mm Hg (≤130/80 mm Hg in diabetics).18 The combination was well tolerated. During the study, treatment was discontinued by 0.4% of patients because of cough, and by 0.2% because of ankle edema. Treatment- related adverse events not resulting in withdrawal were mild cough (1.1%), ankle edema (0.5%), headache with dizziness (0.3%), and nausea (0.2%).18 A longitudinal StudY of optiMzed Blood pressure lowerIng therapy with fixed cOmbination perindopril/amlodipine (the SYMBIO study) evaluated efficacy of Coveram in 2132 patients (age 60.8±11.9 years, 49% female, BMI 29.7±5.1) with treated but uncontrolled hypertension (ie, SBP/DBP ≥140/90 mm Hg or ≥130/ 80 mm Hg in the presence of high cardiovascular risk) from 223 healthcare centers. At study inclusion, patients receiving an angiotensin-converting enzyme inhibitor (77% of patients) and/or CCBs (59%), either as individual drugs or in combination, were switched to treatment with Coveram (5/5 mg, 5/ 10 mg, 10/5 mg, or 10/10 mg). Dosages were determined at the discretion of the treating physician and were titrated to optimize management of hypertension. Other antihypertensive treatments remained unchanged.19

At baseline, SBP and DBP values were 158.5±17.5 mm Hg and 93.6±9.8 mm Hg, respectively. Cardiovascular risk factors included dyslipidemia (70% of patients), smoking (24%), and diabetes (23%). Notable medical histories included coronary heart disease (34%), myocardial infarction (8% of patients), left ventricular hypertrophy (34%), and stroke (8%).

At month 3, BP had decreased to 132.9±10.6 /80.6±6.3 mm Hg (ΔBP = –25.9/-13 mm Hg vs baseline; P<0.00001). Furthermore, 74% of patients achieved recommended target BP levels. According to the grade of hypertension, 84% of patients with previously uncontrolled grade 1 hypertension achieved target BP, and 72% and 52% of those with grade 2 and grade 3 hypertension, respectively. Lower-limb edema was reported in 5.4% of patients.

_ Effective BP normalization: the Coveram solution to the contemporary emphasis on SBP
The rise in SBP is linear throughout life, starting from the age of 30 years, while DBP falls progressively from the age of 50 years. As more than 75% of people with hypertension are over the age of 50, the burden of disease is mainly due to elevated SBP. Moreover, systolic hypertension is a better predictor of stroke, coronary heart disease, heart failure, as well as allcause mortality than DBP.20-22

The clinical advantages of achieving high rates of BP treatment goals with Coveram in a broad range of patients, such as those with newly diagnosed, untreated, or uncontrolled hypertension (the STRONG study), are obvious, as well as additional BP reduction and BP control in patients previously unsuccessfully treated with multiple antihypertensive therapies (the SYMBIO study). Of note, the rates of guideline-recommended BP goals (<140/90 mm Hg and <130/80 mm Hg in patients with diabetes) reported with Coveram (66% to 74%) seem to be the most effective, since results published for other combinations often include add-on therapy with a diuretic as a 3rd antihypertensive agent (Table I).18,19,23-27

Table I
Table I.

Antihypertensive efficacy beyond brachial BP lowering: evidence for Coveram

A large body of clinical evidence suggests that central blood pressure (ie, the pressure exerted at the level of the heart, brain, and kidneys) provides additional information regarding cardiovascular risk beyond that provided by peripheral blood pressure.28 Central aortic BP more accurately reflects the contribution of stiffness of the conduit arteries and peripheral resistance to pulse wave morphology and central hemodynamics.29,30

_ Effective reduction of central aortic blood pressure
The Conduit Artery Function Evaluation (CAFE) substudy examined the effect of the two treatment strategies on central aortic BP and hemodynamics,31 suggesting that the differential effect of amlodipine/perindopril on central aortic pulse pressure may be a factor in the protective efficacy of the treatment strategy.

The CAFE study recruited 2199 patients in 5 ASCOT centers. Most patients received combination therapy throughout the study. Radial artery applanation tonometry and pulse wave analysis were used to determine central aortic blood pressure and hemodynamic indices in repeated clinic visits for up to 4 years. Despite similar brachial SBPs between treatment groups (–0.7 mm Hg; P=0.2), there were substantial reductions in central BP with the amlodipine-Coversyl regimen (central aortic SBP, –4.3 mm Hg; P=0.0001; central aortic pulse pressure, –3.0 mm Hg; P=0.0001) (Figure 3, page 286).31

Additionally, it was observed that central pulse pressure was significantly associated with total cardiovascular events/procedures and development of renal impairment in the CAFE cohort (unadjusted P=0.0001; adjusted for baseline variables, P=0.05), suggesting that a differential effect of amlodipine/ perindopril on central aortic pulse pressure may be a factor in the protective efficacy of the treatment strategy. The investigators concluded that differences in central aortic pressures might be a potential mechanism to explain the different clinical outcomes between the 2 BP treatment arms in ASCOT.

Figure 3
Figure 3. Results of ASCOT/CAFE (Anglo-
Scandinavian Cardiac Outcomes Trial/Conduit Artery Function Evaluation).

Findings highlight the more effective reduction in central
aortic systolic blood pressure (SBP) with the amlodipine/perindopril regimen.
Adapted from reference 31: Williams et al. Circulation. 2006;113:1213-1225. © 2006, American Heart Association.

_ Effective reduction in central carotid blood pressure
Central carotid blood pressure provides information about the arterial pressure in the cerebral arteries. A recent substudy of the ASCOT trial investigated whether directly measured carotid SBP differed between subjects randomized to amlodipine/ Coversyl or atenolol/bendroflumethiazide therapies and whether this is accounted for by differences in wave reflection patterns. Between-treatment differences in the left ventricular mass index were also evaluated. Blood pressure was measured in the right carotid artery of 259 patients. Wave intensity analysis was used to separate and quantify forward and backward waves. All of the measurements were performed between 12 and 18 months after randomization, when study drugs had been fully uptitrated and combined and the brachial BP target had been achieved and was stable.

Figure 4
Figure 4. Results of the Anglo-Scandinavian Cardiac Outcomes Trial substudy on carotid BP.

Findings show the extent of reduction in central carotid blood pressure and lesser magnitude of wave reflection with amlodipine/perindopril regimen vs atenolol/bendroflumethiazide (BFZ).
Adapted from reference 32: Manisty et al. Hypertension. 2009;54:724-730. © 2009, American Heart Association.

Carotid SBP was significantly lower in subjects randomized to amlodipine/perindopril (127 vs 133 mm Hg; P=0.001) compared with atenolol/bendroflumethiazide, despite there being no significant difference in brachial BP. This difference is attributable to a lesser magnitude of wave reflection in patients randomized to the amlodipine/Coversyl regimen. The ratio of backward/forward pressure (0.48 versus 0.53; P=0.01), and wave reflection index (19.8% versus 23.3%; P=0.02) were significantly lower in patients randomized to amlodipine/ perindopril. Similarly, the left ventricular mass index was lower in this group (Figure 4).32 This study demonstrated that directly measured carotid SBP is lower with an amlodipine/perindopril strategy and determined that the differences in central SBP were attributable to a difference in the magnitude of wave reflection, rather than difference in heart rate. The mechanism underlying a better central carotid BP decrease, as suggested by the investigators, is related to the better decrease in peripheral resistance (vasodilatation and antiremodeling effects) with amlodipine/perindopril than with atenolol/bendroflumethiazide.32

_ 24-hour blood pressure control and reduction in nighttime hypertension
The importance of effective 24-h BP management has been established since ambulatory blood pressure monitoring (ABPM) demonstrated that blood pressure behavior over 24 hours is individual to each patient. Nighttime ambulatory BP is known to be superior to daytime ambulatory blood pressure as a predictor of cardiovascular outcomes or stroke.33

For the landmark ASCOT-BPLA trial, Coversyl was chosen among available ACE inhibitors because of its well demonstrated 24-hour antihypertensive efficacy with a once-daily regimen. With the highest trough-to-peak (T/P) ratio of 75% to 100%,Coversyl provided synergistic 24-h efficacy when added to the long-acting CCB amlodipine with its 87% T/P ratio.34 The clinical confirmation of Coveram’s 24-hour efficacy provided by the Anglo-Scandinavian Cardiac Outcomes Trial Ambulatory Blood Pressure (ASCOT-ABP) substudy with ambula- tory blood pressure monitoring (Figure 5),35 which demonstrated early and effective reduction in nocturnal BP, was observed across all the study follow-up with a mean difference of 2.2 mm Hg in nighttime SBP in favor of the amlodipine/ Coversyl regimen. Nighttime DBP was preserved, which is important in light of renewed interest in the J-curve phenomenon for DBP.5 In summary, the study showed that amlodipine/ perindopril and atenolol/thiazide regimens had different effects on daytime and nighttime ambulatory blood pressure, which may have contributed to the lower rates of events in patients treated with amlodipine/Coversyl.

_ Reduction in blood pressure variability
In healthy individuals, physiological adaptation to physical or emotional stimulus results in changes in blood pressure. However, in hypertensive patients the variability (fluctuation with time) of BP values is associated with a higher risk of stroke and cardiovascular events. The recent ASCOT-BPLA substudy36,37 has evaluated the prognostic value of BP variability. It also examined whether the effects of the BP variability of amlodipine/Coversyl versus β-blocker/thiazide could explain the difference in outcomes. SBP variability was measured by three methods:
– Within-visit variability: difference in clinic BP values from 3 consecutive BP measurements during the same visit.
– Visit-to-visit BP variability: difference in clinic BP values between visits.
– Intra-ABPM variability: difference in BP values over a 24- hour period.

_ Results
1. Variability in SBP was found to be a strong predictor of stroke and coronary events in hypertensive patients.
2. BP variability is thought to be linked to arterial stiffness, changes in peripheral vascular resistance, and structural remodeling of arteries.

Figure 5
Figure 5. Results of the Anglo-Scandinavian Cardiac Outcomes
Trial Ambulatory Blood Pressure substudy.

Findings show the decrease in nocturnal systolic blood pressure with the amlodipine/perindopril regimen.
Abbreviations: BP, blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic
blood pressure.
Adapted from reference 35: Dolan et al. J Hypertens. 2009;27:876-885. © 2009,
Lippincott Williams & Wilkins.

3. Amlodipine/Coversyl was more effective in reducing variability in SBP (both clinic and ABPM) than β-blocker/thiazide in hypertensive patients (Figure 6).36
4. Better reduction in BP variability explained the differences in stroke and coronary events between the amlodipine/Coversyl arm and β-blocker/thiazide arm in ASCOT.

The investigators have concluded, that to prevent cardiovascular and cerebrovascular events most effectively, antihypertensive drugs should reduce not only brachial BP, but also BP variability.

Reconsidering and improving hypertension management in clinical practice: the added value of Coveram

Solid clinical evidence suggests that Coveram provides an elegant therapeutic option, tailored to improve the management of hypertension and survival among a broad range of patients:
_ Real-world clinical studies in over 3300 patients have confirmed that Coveram is able to achieve effective BP decrease and the highest rates of BP treatment goals, whether in patients with newly diagnosed hypertension or those uncontrolled on other medications.18,19

Figure 6
Figure 6. Results of the Anglo-Scandinavian Cardiac Outcomes Trial blood pressure variability substudy.

Results show the greater extent of reduction in blood
pressure variability with amlodipine/perindopril vs -blocker and thiazide.
Abbreviations: ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm; CV, cardiovascular; SBP, systolic blood pressure.
Adapted from reference 36: Rothwell et al. Lancet Neurol. 2010;9:448-449.Epub ahead of print 2010 Mar 11. © Elsevier, Ltd.

_ On top of its marked brachial BP-lowering effect, Coveram is the only evidence-based combination to improve all the components of antihypertensive efficacy (central and nighttime BP and BP variability), leading to consistent reduction in mortality and morbidity, as demonstrated by the ASCOTBPLA trial:
– An effective reduction in central aortic blood pressure with Coveram is clinically significant for patients at high cardiovascular risk, and especially at coronary risk.31
– Evidence of central carotid BP reduction with Coveram is important for patients at risk of cerebrovascular events.32
– Effective 24-hour BP control and nighttime hypertension normalization is of added value not only for patients with nocturnal hypertension, but for hypertensives, such as those participating in the ASCOT trial.35
– More stable BP values and fewer incidents of BP “jumps” were seen with amlodipine/perindopril in the ASCOT study. BP variability reduction leads to a lower risk of developing stroke or coronary events in patients with arterial hypertension.36,37

_ The evidence for mortality and morbidity risk reduction with Coveram in a broad range of hypertensive patients still free from CAD is provided by the ASCOT-BPLA trial.7 Furthermore, this combination is beneficial in hypertensive coronary patients, as confirmed by the EUROPA trial, with a markedly greater decrease in the risk of cardiovascular mortality and other cardiovascular complications in patients treated with Coversyl together with a CCB.6 Although combinations of RAS-inhibitor/ CCB are recommended, one must acknowledge that the level of evidence-based findings differ in terms of real lifesaving benefits. As highlighted by the Reappraisal of European Guidelines on Hypertension, data on morbidity-mortality are lacking for all ARB/CCB combinations.5 Furthermore, clinical evidence suggests that lifesaving benefits for ACE inhibitor/CCB combinations are not class-dependent, but rather drug-dependent, benefits. As demonstrated in the INternational VErapamil trandolapril STudy (INVEST), a trandolapril/verapamil combination was not different from an atenolol/diuretic combination in terms of mortality reduction in hypertensive patients with CAD.38 In the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial, more effective reduction in MI did not translate either into reduction of all-cause mortality nor into significant reduction of cardiovascular mortality among patients treated with benazepril/amlodipine compared to those receiving benazepril/hydrochlorothiazide (Table II).39

Table II
Table II. All-cause mortality and cardiovascular mortality in trials with renin-angiotensin-aldosterone system inhibitor plus calcium channel blocker treatment regimens.

Coveram is the only treatment among ACE inhibitor/CCB and ARB/CCB combinations that has demonstrated the achievement of the primary objective of antihypertensive therapy, that is, overall reduction of hypertension-related death and morbidity. By effective BP lowering and synergistic action on each criterion of antihypertensive efficacy, Coveram represents a tailored therapeutic option for a broad range of hypertensive patients with their individual profiles of cardiovascular risk. _

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Keywords: antihypertensive therapy; perindopril/amlodipine fixed combination; arterial hypertension; angiotensin-converting enzyme inhibitor; calcium channel blocker; combination therapy; antihypertensive treatment efficacy; mortality