A new first-line treatment in hypertension



by H. Lhoste, France

Harpreet LHOSTE, MD
Medical Project Manager
in Hypertension
Servier International
Suresnes, FRANCE




Hypertension remains undertreated and poorly controlled worldwide. An unmet need in the management of hypertension is for simpler treatment regimens that effectively control blood pressure (BP) and that are used by patients in the long term because of good tolerability. Rapid and effective BP lowering with first-line combination therapy remains underutilized. Perindopril and amlodipine have an established history of clinical use, are well tolerated, have complementary mechanisms of action (and thus reduce BP in an additive fashion), and have reduced end points in long-term clinical trials. Adapted-dose perindopril/amlodipine 3.5/2.5 mg has been developed for first-line use to provide hypertensive patients with a combination option that possesses optimal efficacy with the best tolerability. The efficacy of first-line treatment with this adapted-dose strategy versus a monotherapy stepped-care strategy has been compared in three large randomized controlled trials. Perindopril/amlodipine 3.5/2.5 mg was shown to provide superior or noninferior BP reduction, with benefits observed from the first month of treatment. A combined analysis in patients with mild-to-moderate hypertension confirmed the superior efficacy of perindopril/amlodipine 3.5/2.5 mg versus monotherapy. The tolerability of perindopril/amlodipine 3.5/2.5 mg was better than that of the lowest approved doses of its components. Trial results with perindopril/amlodipine 3.5/2.5 mg provide support for broadening the recommendation for this adapted-dose strategy in future hypertension guidelines to include newly diagnosed patients.


Hypertension remains the single largest contributor to the global burden of disease and to global mortality,1 with an estimated 1.13 billion hypertensive people worldwide in 2015.2 Its prevalence is increasing with an estimated 23.5 million newly diagnosed patients per year.3 With recent evidence showing that delays in controlling blood pressure (BP) significantly increase cardiovascular morbidity and mortality,4 the identification, treatment, and control of hypertension should be a top public health priority. However, despite its importance, BP control remains poor worldwide, with only one-third of treated patients reaching BP targets of <140/90 mm Hg.5

A number of factors are implicated in poor BP control, including poor adherence to treatment, therapeutic inertia, and inequalities in health-care services.6 Mancia et al recently proposed a fourth important factor: the reluctance to adopt drug treatment strategies that reduce elevated BP more effectively.7 A stepped-care approach—in which a single agent is initiated and titrated to its maximum tolerated dose before the addition of a second therapy is considered—has long been the preferred strategy for the management of hypertension. The rationale for this approach is based on the often unfounded assumptions that monotherapy is more convenient than combination therapy, is associated with fewer side effects, allows easier identification of which drug is causing an adverse event if it occurs, and is less expensive. In reality, the vast majority of patients with hypertension require at least two agents to reach target BP,8-10 with a large international study demonstrating that only 30% of hypertensive patients were treated satisfactorily with a single antihypertensive drug.11 A stepped care approach is also more likely to increase the risk of side effects due to higher drug doses and lead to problems with medication adherence. Furthermore, delays in drug titration can lead to patients’ BP remaining uncontrolled for long periods of time. Recent evidence shows that inaction—waiting until SBP is >150 mm Hg before initiation or uptitration of antihypertensive treatment, delays >1.4 months in the initiation or uptitration of treatment after SBP elevation, or delays >2.7 months before follow-up of BP following medication intensification— significantly increased the risk of an acute cardiovascular event or death.4 A separate study reported that BP control was nearly a fifth (18.5%) faster with combination therapy versus monotherapy, which led to a 34% reduction in risk of cardiovascular events and death.12

Despite substantial evidence that the use of single-pill, optimized- dose combination therapy as first-line treatment represents a more effective alternative to add-on therapy or sequential monotherapies, current guidelines only recommend first-line combination therapy in high-risk patients who require rapid BP control.6,8-10 As things stand, the majority of untreated hypertensive patients have grade 1 hypertension (62%), defined as a systolic blood pressure (SBP)/diastolic blood pressure (DBP) of 140-159/90-99 mm Hg, and therefore by following guideline recommendations would be treated with monotherapy.13 With data showing that at least 75% of patients require combination therapy to achieve BP targets,12 these patients may endure months of suboptimal treatment before their BP is controlled, exposing them to unnecessarily increased cardiovascular risk.





Whether treating patients with grade 1 hypertension is beneficial in terms of cardiovascular outcomes has been debated. Due to a lack of specific trials, meta-analyses have been used to examine this issue. When limited to trials of individuals with mild hypertension, some have suggested limited benefits14 and others more substantial effects.15 Another, different meta-analytical approach—one that allowed a large number of trials to be analyzed, avoided selection bias, and increased statistical power—has also been tried.16 This type of meta-analysis allowed the inclusion of all BP-lowering trials, provided that no antihypertensive treatment was present at randomization, which allowed average baseline SBP/DBP values to be used for classifying each trial in a given hypertension grade.16 With this approach, BP lowering in low-to-moderate risk patients with grade 1 hypertension was associated with significant relative risk reductions for stroke, coronary heart disease, the composite of stroke and coronary heart disease, cardiovascular mortality, and all-cause mortality.17 Only a marked reduction in the risk of heart failure did not reach statistical significance.

With evidence in favor of more rapid achievement of BP control and treating newly diagnosed patients with mild hypertension to reduce cardiovascular outcomes, it is perhaps time to challenge our current way of management and begin using treatment strategies that guarantee the highest rate of success from the start. With this in mind, a new first-line treatment in hypertension containing adapted doses of perindopril (3.5 mg) and amlodipine (2.5 mg), Viacoram®, has been developed. The aim of this review is to summarize the evidence in support of single-pill perindopril/amlodipine 3.5/2.5 mg as a new first-line treatment in hypertension.

Benefits of first-line combination antihypertensive treatment

◆ More rapid control, fewer side effects, and earlier cardioprotection
It is common clinical practice to reserve combination therapy as a second-line treatment in the management of hypertension, after first-line monotherapy.18,19 However, there are a number of potential benefits of first-line combination antihypertensive therapy versus high-dose monotherapy, which result from the activation of multiple BP-regulating mechanisms and the avoidance of effect blunting by compensatory mechanisms. Wald et al have shown that combining two drugs from different classes is five times more effective at reducing BP than doubling the dose of a monotherapy.20 A number of other studies have shown that combination therapy achieves more rapid and greater reductions in BP.21-24 The use of antihypertensive combinations containing adapted doses—developed to provide optimal efficacy with the best tolerability for first-line use—provides greater BP reductions than full doses of the monotherapy components. Thus, in the STITCH (Simplified Treatment Intervention To Control Hypertension) trial, superior BP-lowering efficacy was demonstrated in practices assigned to use an algorithm in which initial combination therapy with half-standard doses of each therapeutic class was the first step compared with guideline-based recommendations for the management of hypertension, ie, monotherapy.25 In addition, a meta-analysis of BP cohort studies and of trials determining the BP-lowering effects of drugs according to dose showed that in 60-to-69-year-old patients with mild hypertension (DBP before treatment of 90 mm Hg), three drugs at half-standard dose in combination reduced the risk of coronary heart disease and stroke by an estimated 46% and 62%, whereas the risk reductions for one drug at standard dose were 24% and 35%, respectively, and for two drugs at standard dose, 40% and 56%.26 The use of lower doses of individual components in a combination treatment is also associated with fewer side effects.8

A case control study published by Corrao et al in 2011 analyzed data from 10 688 patients who were newly treated with antihypertensive drugs and who were hospitalized for cardiovascular disease in the 7 years following their initial prescription.18 They found that patients initiated on combination therapy had 11% less risk compared with those initiated on monotherapy. A comparison of patients who persisted with either monotherapy or combination therapy for the full follow up period showed that combination therapy was associated with a 26% reduction in cardiovascular risk. Interestingly, patients who were switched from monotherapy to combination therapy did not show a significant difference in cardiovascular event rates compared to patients who received long-term monotherapy.18

The findings of Corrao et al are supported by a more recent matched cohort analysis of 1762 adult patients with hypertension, who were either prescribed initial combination therapy or initial monotherapy and later switched to combination therapy.12 Initiation with combination therapy versus monotherapy not only led to faster achievement of BP target (9.7 versus 11.9 months) and more effective BP control (40.3% versus 32.6%), but it was also linked to a 34% reduction in cardiovascular events or death. The authors noted that the lag time to uptitration in the monotherapy arm (13.5 months after treatment initiation) may have reflected therapeutic inertia, a factor that is known to contribute to poor BP control.

◆ Improved adherence and reduced therapeutic inertia
The use of single-pill combinations in the treatment of cardiovascular disease has been shown to markedly improve patient adherence,27-31 and improved adherence is associated with greater BP control32,33 and reduced cardiovascular events.34-36 Patients’ perceptions of adverse effects contribute significantly to decisions regarding medication adherence and are frequently listed as the most common concern among patients who are nonadherent to their antihypertensive medication.37 The potential to use lower doses in combination therapy than in monotherapy may help to reduce adverse events and increase adherence to medication regimens.

Physicians, like patients, may also adopt the standpoint that it is better to avoid the risk of developing side effects and leave things as they are than to intensify antihypertensive treatment. Such therapeutic inertia, or failure to initiate or intensify therapy despite an inadequate treatment response, has multiple causes (relating to physicians, patients, and health-care systems). Inertia can, however, be dispelled by improving efficacy and tolerability at the same time as reducing dosing complexity, which can be done with single-pill combination regimens.38-40

Viacoram®, a new first-line treatment in hypertension

◆ What is Viacoram®?
Viacoram® is a new first-line antihypertensive treatment containing perindopril and amlodipine in a single pill at dosages adapted for initiation of antihypertensive treatment (3.5/2.5 mg). It is currently marketed in approximately 10 countries worldwide, and it is available in doses of 3.5/2.5 mg and 7/5 mg (plus 14/10 mg in certain countries).

◆ Why perindopril and why amlodipine?
An angiotensin-converting enzyme (ACE) inhibitor plus calcium channel blocker (CCB) is one of the preferred combinations of antihypertensive drugs recommended by medical practice guidelines as being safe and effective for the management of hypertension.6 The two classes of agent also have a number of complementary effects.41 CCBs stimulate the sympathetic nervous system and, indirectly, the renin-angiotensin system (RAS), whereas ACE inhibitors have the opposite effects. These complementary effects also have a positive impact on adverse events. For example, combining an ACE inhibitor with a dihydropyridine CCB reduces the adverse dose-dependent vasodilatory effects of the CCB, with an estimated 54% decrease in the occurrence of leg edema.42 CCBs reduce ACE inhibitor– related cough by decreasing prostaglandin synthesis induced by bradykinin.43

The rationale for the treatment of hypertension with a combination of perindopril and amlodipine is multifaceted. Both perindopril and amlodipine have individually demonstrated efficacy and safety in the management of essential hypertension in a wide range of patients,44-48 have a long history of clinical use, and are registered in all European countries.49 The two drugs have been frequently prescribed in free combination since the publication of the ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm) trial, which demonstrated highly significant benefits of an amlodipine ± perindopril regimen in reducing major cardiovascular events and all-cause mortality compared with an atenolol ± bendroflumethiazide regimen.50 Evidence for synergy between perindopril and a CCB was suggested by a subanalysis of the EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) trial in patients with stable coronary artery disease, which demonstrated a significantly greater reduction in the primary end point of cardiovascular death, myocardial infarction, or cardiac arrest in patients receiving perindopril and a CCB compared with those receiving perindopril alone or CCB alone.51 The difference in outcomes was greater than would have been predicted by the simple addition of their individual effects.51


Figure 1. Blood-pressure lowering efficacy of perindopril/amlodipine
3.5/2.5 mg compared with the lowest approved doses of its
monotherapy components. Based on data from reference 52.




◆ Efficacy versus monotherapy
Four trials have compared the efficacy of Viacoram® versus a range of monotherapy strategies: three evaluated strategies based on perindopril/amlodipine 3.5 mg/2.5 mg52-54 and one evaluated the dose of perindopril/amlodipine 14/10 mg.55

In the first study in 1581 patients with mild-to-moderate hypertension, combination therapy with perindopril/amlodipine 3.5/2.5 mg was compared with perindopril or amlodipine monotherapy at the same dose, the lowest approved doses of the two agents (5 mg), and placebo.52 The primary efficacy end point was the change from baseline in mean supine DBP at the end of the 8-week study period. Secondary end points included change from baseline in mean supine SBP and the proportion of patients with normalization of BP at the end of the treatment period.

Perindopril/amlodipine 3.5/2.5 mg produced significant and clinically relevant decreases in BP compared with placebo (between- group differences: SBP, –7.22 mm Hg; DBP, –4.12mm Hg; P<0.001 for both). The efficacy of the combination was better than either monotherapy at the same dose, and it was also superior to perindopril and noninferior to amlodipine at their lowest approved doses of 5 mg in terms of BP-lowering efficacy (Figure 1). There were significantly more patients with normalized BP at the end of treatment in the combination group than the placebo group (43.5% versus 26.6%; intergroup difference, 16.9% [P<0.001]). A numerical difference quickly became apparent (30.6% versus 16.2% after 2 weeks), and this difference was confirmed by a subanalysis showing that efficacy was significantly better with perindopril/amlodipine 3.5/2.5 mg after 1 month.56


Figure 2. A. Proportion of patients with controlled blood pressure
(<140/90 mm Hg) with the adapted-dose first-line strategy (initiation
with perindopril/amlodipine 3.5/2.5 mg) compared with the initial
monotherapy (valsartan 80 mg) followed by stepped-care strategy.
B. Time required to achieve blood pressure control with the adapteddose
first-line strategy compared with the initial monotherapy
stepped-care strategy.
Abbreviations: amlo, amlodipine; BP, blood pressure; per, perindopril; RCT,
randomized controlled trial; val, valsartan.
Modified from reference 7: Mancia et al. J Hypertens. 2017;35:225-233. © 2017,
Wolters Kluwer Health, Inc.




In a separate trial with a stepped-care design, Mancia and colleagues randomized 1774 patients to perindopril/amlodipine 3.5/2.5 mg or valsartan 80 mg.53 Patients could be uptitrated at 1, 2, and 3 months if their BP remained uncontrolled (≥140/90 mm Hg). This involved two dose-doubling phases for perindopril plus amlodipine, with the later addition of indapamide slow release 1.5 mg. Similarly, for the valsartan arm, treatment was initially doubled and then included amlodipine 5 mg and then 10 mg. Treatment with perindopril/amlodipine initiated at a dose of 3.5/2.5 mg was associated with significantly better rates of BP control than the valsartan stepped care strategy, with a 23% greater number of patients controlled at 1 month, and 27% greater number of patients controlled at 2 months compared with the valsartan monotherapies at different doses. Importantly, the initiation of first-line therapy with adapted-dose perindopril/amlodipine (3.5/2.5 mg) reduced the time required to achieve BP control by 20% compared with the valsartan stepped-care strategy (74 versus 93 days) (Figure 2).7 Although cardiovascular outcomes were not assessed in this study, a similar improvement in the time to BP control was demonstrated in a large retrospective cohort study by Gradman et al, which assessed the impact of initial versus delayed combination therapy on the risk of developing a cardiovascular event.12 In the Gradman et al analysis, initial treatment with a drug combination was associated with a 34% reduction in the risk of cardiovascular events or death. Faster achievement of target BP was found to be the main contributor to the estimated risk reduction.

In a similarly designed stepped-care trial, Poulter et al randomized 3270 patients, 37.5% of whom had grade 1 hypertension, to initial therapy with perindopril/amlodipine 3.5/2.5 mg or irbesartan 150 mg.54 Perindopril/amlodipine was uptitrated from 3.5/2.5 mg to 7/5 mg, 14/5 mg, and then 14/10 mg. In the other arm, patients went from irbesartan 150 mg to irbesartan±hydrochlorothiazide 150/12.5 mg, 300/12.5 mg, and finally 300/25 mg. BP control increased at each evaluation with the first-line combination strategy up to 6 months (primary end point): 21%, 30% (P<0.001), 37% (P<0.001), and 42% (P=0.003) at 1, 2, 3, and 6 months, respectively. Over the next 3 months, up until 9 months, the percentage of patients with BP control remained largely unchanged.

Figure 3. Decrease in systolic blood pressure and diastolic blood
pressure achieved with perindopril 3.5 mg/amlodipine 2.5 mg
compared with renin-angiotensin system blocker monotherapies
after 1 month of treatment. Based on data from reference 57.
Abbreviations: aml, amlodipine; per, perindopril.




A combined-analysis of data from the Laurent et al,52 Mancia et al,53 and Poulter et al54 trials compared the BP-lowering efficacy of 1-month treatment with perindopril/amlodipine 3.5/ 2.5 mg versus monotherapy with a RAS inhibitor.57 The analysis included 5507 patients with mild-to-moderate hypertension and similar baseline BP levels. The decrease in SBP/DBP achieved with perindopril/amlodipine 3.5/2.5 mg was superior to the decrease achieved with each RAS blocker monotherapy after only 1 month of treatment, with an overall significant difference in SBP and DBP reduction of 2.4 mm Hg (P=0.002) and 1.3 mm Hg (P=0.005) in favor of perindopril/amlodipine 3.5/2.5 mg (Figure 3).

◆ Tolerability versus monotherapy
European hypertension guidelines stress that efforts should be made to limit drug-related side effects, in part, because adverse events are the most important causes of treatment nonadherence.6 Perindopril/amlodipine 3.5/2.5 mg has been demonstrated to have better tolerability than the lowest ap- proved doses of its components as monotherapy.52 The single- pill combination and its components had similar incidences of all emergent adverse events: 18.9% for perindopril/amlodipine 3.5/2.5 mg versus 18.7% for perindopril 3.5 mg and 18.6% for amlodipine 2.5 mg. For comparison, the incidence with placebo was 15.9%, while the highest rate of emergent adverse events was observed in another comparator group, the amlodipine 5 mg group (21.6%). The number of patients reporting lower limb edema was greater in the amlodipine 5 mg group than the combination group (14 [5.3%] versus 4 [1.6%]; intergroup difference, –3.7 [95% confidence interval, –6.8 to –0.6]). With perindopril/amlodipine 3.5/2.5 mg, the incidences of headache (1.2%) and cough (0.8%) were low and no different to those observed in the perindopril 5 mg and amlodipine 5 mg groups.

In the Mancia et al53 and Poulter et al studies,54 the pattern of specific emergent adverse events was consistent with the known safety profile of the individual components, and no safety concerns were raised. Perindopril/amlodipine 14/10 mg was associated with a 42% reduction in the incidence of peripheral edema versus amlodipine (7.2% [20/279] versus12.5% [35/280]) in the three-arm trial, in which it was compared with perindopril erbumine and amlodipine.55 Finally, a meta-analysis of the perindopril/amlodipine 3.5/2.5 mg trials showed that tolerability was similar in all groups with an incidence of emergent adverse events of 28.4% for perindopril/amlodipine 3.5/2.5 mg versus 28.2% for monotherapy comparators (P=0.929).57

Cough was more frequent in the perindopril/amlodipine 3.5/ 2.5 mg group (4.5%), while headache (3%) and diarrhea (0.8%) were more frequent in the RAS blocker group. None of the trials reported any serious treatment-related adverse events or detected any clinically relevant changes or differences between treatment groups in blood biochemistry or hematology in laboratory analyses.

Discussion

There is unequivocal evidence that hypertension is a major cardiovascular risk factor and that BP-lowering strategies substantially reduce this risk. It is also clear that target BP levels are not achieved in a high proportion of patients. There is therefore a strong need to detect and treat more hypertensive patients as well as to improve the efficacy of ongoing treatment.

Three main causes of the low rate of BP control in real life have been described: (i) physicians’ therapeutic inertia; (ii) low adherence to a prescribed treatment regimen by patients; and (iii) deficiencies of health-care systems in their approach to chronic diseases.6 A fourth factor has also recently been put forward as important: the reluctance to adopt drug treatment strategies that reduce elevated BP more effectively.7

According to the latest European hypertension management guidelines, the first-line use of antihypertensive drug combinations should be reserved for high-risk patients or patients with particularly elevated baseline BP.6 By implication, treatment with monotherapy should be initiated in patients with less risk and less elevated baseline BP. The problem with the monotherapeutic approach to the control of BP is that it works in so few hypertensive patients; most will need more than one antihypertensive agent to control BP.10 Given this undisputed fact, one could legitimately argue that we are approaching this treatment dilemma from the wrong direction. Perhaps we ought to be asking whether the initiation of antihypertensive treatment with combination therapy should be preceded by monotherapy.6

In the treatment of patients with mild-to-moderate (grade 1) hypertension, there is increasing evidence that combinations containing adapted doses (developed to provide optimal efficacy with the best tolerability for first-line use) are particularly beneficial. BP has multiple regulatory pathways, and combining agents from different antihypertensive drug classes has positive effects on BP control—allowing earlier, larger, and more sustained reductions in BP than uptitration of monotherapy and a sequential add-on regimen—leading to earlier cardioprotection.12,20 By simplifying the dosing regimen and improving tolerability, combination therapy can also improve medication adherence and reduce therapeutic inertia.22

Conclusion

Initial combination therapy could lessen the long-term impact of hypertension on cardiovascular disease and mortality, and the findings outlined in this paper support the case for the first-line use of adapted-dose antihypertensive combinations in future hypertension guidelines. A large-scale dossier of development studies shows clinically significant reductions in BP with adapted-dose perindopril/amlodipine 3.5/2.5 mg that were superior or noninferior to perindopril and amlodipine monotherapies at their lowest approved doses, with BP lowering efficacy seen as early as 4 weeks after the start of treatment. Adapted-dose perindopril/amlodipine 3.5/2.5 mg was well tolerated and reduced the time required to achieve BP control compared with stepped-care strategies. In short, the data presented in this review strongly support the use of adapted-dose perindopril/amlodipine 3.5/2.5 mg as a first line treatment of hypertension in a wide range of patients, including those with mild-to-moderate hypertension.


Keywords: adapted-dose strategy; hypertension; antihypertensive treatment; Viacoram; first-line; newly diagnosed; perindopril/ amlodipine


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