Fixed-combination therapies in hypertension

Drug Profile

Fixed-combination therapies in hypertension management: focus on enalapril/lercanidipine Expert Rev. Cardiovasc. Ther. 7(2), 115–123 (2009)

Giuliano Tocci, Francesca Palano, Erika Pagannone, Diana Chin, Andrea Ferrucci and Massimo Volpe† † Author for correspondence II Faculty of Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Via di Grottarossa, 1035-1039, 00189 Rome, Italy Tel.: +39 063 377 5654 Fax: +39 063 377 5061 [email protected]

Recent hypertension guidelines have highlighted the need to achieve blood pressure control in order to effectively reduce cardiovascular and renal morbidity and mortality. However, blood pressure control remains poorly achieved in the general population, particularly in high- or very-high-risk hypertensive patients. In view of the growing need to achieve better blood pressure control and provide adequate cardiovascular and renal protection in hypertensive patients, the implementation of combination therapies – especially fixed-dose combinations – is currently recommended. A greater use of fixed-combination therapies, based on a single daily administration of two drugs, in fact, may favor better compliance and adherence to prescribed antihypertensive medications. Among the possible fixed-dose combinations, the one based on angiotensinconverting enzyme inhibitors and calcium-channel blockers, may be considered an effective, safe and well-tolerated approach and may provide a beneficial impact on cardiovascular risk. This article reviews the potential role of fixed-combination therapy in the treatment of hypertension with a specific focus on an emerging calcium-channel blocker angiotensin-converting enzyme inhibitor fixed-dose combination based on a new-generation dihiidropiridinic calcium-channel blocker (lercanidipine) and the prototype angiotensin-converting enzyme inhibitor (enalapril). Keywords : cardiovascular risk • enalapril • fixed-combination therapy • hypertension • lercanidipine

Blood pressure (BP) control represents a key priority in any prevention strategy for reducing the incidence of major cardiovascular (CV) and renal outcomes [1–3] . Worldwide BP control in the general hypertensive population, however, continues to be far from optimal, probably due to the poor adherence to lifestyle recommendations and relatively low implementation of effective antihypertensive drug therapies [4–6] . The frequent concomitant presence of CV risk factors, diabetes mellitus and markers of organ damage is also poorly recognized and managed, thus resulting in a progressive increase in global CV risk in hypertensive patients [7,8] . Over the last few decades, evidence derived from international clinical trials, mostly performed with the ‘newer’ classes of antihypertensive agents, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers and calcium-channel blockers (CCBs), have consistently demonstrated that it is frequently necessary to use combination therapy of different classes of antihypertensive drugs, in order to achieve the recommended BP targets in a large proportion of hypertensive patients [9–18] . The results of these www.expert-reviews.com

10.1586/14779072.7.2.115

clinical trials also demonstrated that such a therapeutic strategy may represent a powerful tool for improving BP control in hypertensive patients with different levels of CV risk [9–18] . In this latter regard, the recent availability of several fixed-combination therapies may represent an attractive tool in order to achieve better adherence to treatment and more effective BP control. Indeed, the use of fixed-combination therapies has been recommended by the latest set of European Society of Hypertension and European Society of Cardiology hypertension guidelines [1] , and also as a first treatment step, especially in patients with grade 2–3 hyper tension, high or very-high CV risk or when the achievement of lower BP targets is required. This article reviews the potential clinical benefits derived from the use of combination therapies based on those pharmacological agents that counteract the renin–angiotensin system (RAS), with a specific focus on an emerging CCB/ACE inhibitor fixed-dose combination based on a new-generation dihydropiridinic CCB (lercanidipine) and the prototype ACE inhibitor (enalapril).

© 2009 Expert Reviews Ltd

ISSN 1477-9072

115

Drug Profile

Tocci, Palano, Pagannone, Chin, Ferrucci & Volpe

Blood pressure control & cardiovascular risk

Clinical trials [9–18] and meta-analyses [19–22] have demonstrated that the benefits in terms of reduced incidence of major CV events – mostly stroke – are strictly related to the degree of BP reduction. Epidemiological surveys, however, have repeatedly demonstrated that a relatively small proportion of treated hypertensive patients achieve satisfactory BP control, with the remaining larger proportion of hypertensive patients substantially uncontrolled [4–6,23] . Even in the ideal conditions represented by the setting of interventional clinical trials, adequate BP control (mostly systolic BP levels) was achieved in a very low percentage of clinical trials on hypertension and in none of the trials performed in diabetic patients [23] . These observations substantially confirm that effective BP control is quite difficult to achieve in the clinical practice of hypertension, especially in high- or very-high-risk hypertensive patients [4–6] , and that uncontrolled hypertension may consequently promote the development of hypertension-related organ damage, with the classical evolution towards vascular events, heart failure and end-stage renal disease [24] . They may also imply that part of the failure in reaching the recommended BP goals may be linked to current therapeutic habits, such as a persistently high use of monotherapy [25,26] . Although still largely underused and generally viewed as a second step in the clinical practice of hypertension and high-risk patients, combination therapy may represent an interesting treatment option, as has been suggested by several recent interventional clinical trials [15,16,18] . In the Anglo–Scandinavian Cardiac Outcomes Trial– Blood Pressure Lowering Arm (ASCOT–BPLA) trial [15] , in which the vast majority (70%) of high-risk hypertensive patients were on combination therapy, after a median follow-up of 5.5 years, 60% of the nondiabetic population reached the target BP levels, and 32% of the diabetic population achieved the more ambitious target BP levels of 130/85 mmHg or below. In the Felodipine Event Reduction (FEVER) study [16] , which compared incidence of fatal and nonfatal stroke in hypertensive patients treated with combination therapy based on low-dose thiazide diuretic and a CCB versus diuretic monotherapy, a small difference (approximately 4 mmHg) in systolic BP levels was associated with a significant reduction in the primary end point, as well as in other prespecified variables, including coronary events, all cardiac events, all CV events, CV deaths and all causes of death. More recently, in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial [18] , patients whose BP levels were routinely controlled only in 37.5% of the cases on the study-entry therapy, achieved a high percentage of BP control (78.5 and 81.7%, respectively), when they were steadily maintained on a combination regimen based on ACE inhibitors and thiazide diuretics or CCBs. Overall, these observations may suggest that it is possible, to normalize BP levels and keep them in the normal range for years in hypertensive patients, even in those with a high or veryhigh CV-risk profile [9–18] . They also indicate that combination therapy is often necessary in most patients to achieve and maintain effective BP control. An analysis performed by Law has, in fact, demonstrated that low-dose combination antihypertensive 116

treatment increases BP lowering efficacy and reduces the incidence of adverse effects [27] . In that analysis, from the average BP levels observed at baseline, three drugs at half standard dose are estimated to lower BP by 20/11 mmHg systolic and diastolic BP levels, and thereby reduce the risk of stroke by 63% and coronary artery events by 46% at age 60–69 years as compared with high-dose monotherapy [27] . Rationale for combination therapy in hypertension

Multifactorial intervention for achieving tight BP control mostly through combination therapies confers sustained beneficial effects and significantly reduces CV morbidity and mortality in highrisk diabetic patients [28,29] . In particular, the importance of BP control in patients with hypertension at high CV risk or diabetes mellitus has also been highlighted by the recent results of the ACCOMPLISH trial [18] and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial [30] , respectively. Concomitant administration of two drugs that lower BP levels by different pharmacokinetic and pharmacodynamic mechanisms, may allow a substantial gain in BP reduction, and often a reduction of the side effects of higher doses of a single drug is observed [31–34] . In this view, simultaneous and synergistic interferences with different BP regulatory mechanisms may largely account for the additive BP-lowering effects provided by combination therapies as compared with either monotherapy [31–34] . In addition, the combination of two drugs that mutually and reciprocally interfere with the counter-regulatory responses may further increase the rate of BP control [31–34] . Notably, the doses needed when two agents are combined are generally lower than those required when the components are used as single agents. As previously mentioned, in a meta-analysis of 354 randomized, double-blind, placebo-controlled trials involving thiazide diuretics, β-blockers, CCBs, ACE inhibitors and angiotensin II receptor blockers, on the average placebo-controlled fall in BP levels observed in 119 trials, the ‘first’ and the ‘second’ drug given alone lowered BP levels by 7.0/4.1 and 8.1/4.6 mmHg, respectively, compared with 14.6/ 8.6 mmHg when given together [27] . On the basis of these considerations, an ideal combination of antihypertensive drugs for a modern clinical approach to hypertension should be characterized by: • Antihypertensive efficacy greater than that provided by the individual monotherapy, due to different, but pharmacological mechanisms acting synergically to reduce BP levels; • Improved safety and tolerability profile, due to contraregulatory mechanisms that may reciprocally reduce dose-related side effects; • Long-term CV protection, not only due to a tighter BP control, but also due to the specific tissue or organ protective properties of the individual agents. Beyond their BP-lowering efficacy, some combination therapies are based on agents that have documented beneficial effects in terms of effective CV prevention. This is the case for combination Expert Rev. Cardiovasc. Ther. 7(2), (2009)

Enalapril/lercanidipine in hypertension management

therapies based on ACE inhibitors and CCBs, which may provide a favorable impact on major CV events, as compared with conventional antihypertensive therapy [15,18] . Combination therapies based on ACE inhibitors & CCBs

On the basis of the available data, guidelines recommend starting antihypertensive treatment according to BP levels and CV risk profile, using combination therapies of two drugs or adding a third drug if goal BP is not achieved or in the presence of high or veryhigh CV risk [1] . Although different rational combinations of antihypertensive drug classes are available, as listed in Box 1, it should be highlighted that they are not really interchangeable, particularly as they do not share the same safety and tolerability profile. In addition, they are not uniformly available across Europe and worldwide. Nowadays, evidence is available for combining ACE inhibitors and CCBs in a number of clinical conditions, such as patients with grade 2 or 3 hypertension, diabetes mellitus, history of myocardial infarction, stroke or nephropathies [31–34] . From a pharmacological point of view, dihydropiridinic CCBs may induce relevant peripheral vasodilatation by selective blockade of the calcium channels localized at the precapillary arteriolar level [35] . This may result in an increased intracapillary pressure and in a conspicuous amount of fluids moving from the vessels to the tissues, determining the so-called ankle edema, which is one of the most frequent and troublesome CCB-related side effects [35] . The coadministration of ACE inhibitors significantly counterbalances this adverse triggered mechanism, acting on two different pathways [36,37] , as shown in Figure 1 ; first, by inhibiting the sympathetic nervous system and RAS activation that can be induced by CCB; and second, by relaxing the postcapillary small vessels (venules), thus reducing the increased intracapillary pressure, associated to administration of CCB, and even the incidence of ankle edema. Besides the results of large, international clinical trials on hypertension, in which combination therapy based on R AS blocking agents and CCBs was often applied in order to achieve the recommended BP targets [15,18] , over the last few years the results of a growing number of relatively small clinical trials have progressively become available, providing the efficacy, tolerability and safety of such a combination therapy in the clinical management of hypertension [38–42] . In 2007, a preliminary report of the results of the ACCOMPLISH trial has demonstrated that in a large population of hypertensive patients with a high prevalence of diabetes and obesity, for similar BP reductions, the fixed-combination therapy with an ACE inhibitor, benazepril, and CCB, amlodipine, reduced the cumulative incidence of the primary end point by 20% compared with the fixed combination based on the same ACE inhibitor and hydrochlorothiazide [18] . Fixed-combination therapy: focus on enalapril/lercanidipine

Currently, among the numerous available dihydropyridinic CCBs, lercanidipine represents a widely studied molecule, characterized by specific properties, typical of the last-generation CCBs. Lercanidipine www.expert-reviews.com

Drug Profile

Box 1. Possible fixed-combination therapies for the clinical management of hypertension. Possible fixed-combination therapy in hypertension management • β -blockers + thiazide diuretics • Aldactone + thiazide diuretics ACE inhibitors or angiotensin II receptor blockers plus diuretics • ACE inhibitors + thiazide diuretics • ACE inhibitors + indapamide • Angiotensin II receptor blockers + thiazide diuretics ACE inhibitors plus calcium-channel blockers • Benazepril/amlodipine • Enalapril/diltiazem • Enalapril/felodipine • Enalapril/lercanidipine • Trandolapril/verapamil • Ramipril/felodipine Angiotensin II receptor blockers plus calcium-channel blockers • Valsartan/amlodipine • Olmesartan/amlodipine Direct renin inhibitors plus: • ACE inhibitors • Angiotensin II receptor blockers • Calcium-channel blockers ACE: Angiotensin-converting enzyme.

is, in fact, a vasoselective dihydropyridinic CCB, which induces systemic vasodilation by blocking the influx of calcium ions through l-type calcium channels in cell membranes [43–46] . It is a highly lipophilic drug, and as such has many theoretical and practical clinical advantages due to its long permanence at the cell membrane level [43–46] . These favorable membrane-controlled kinetics are most likely involved in the gradual onset of the vasodilatation and the long duration of antihypertensive action. Thus, lercanidipine administration is associated with an effective and persistent BP-lowering effect over the 24-h period, as compared with that observed with other dihydropyridines [43–46] . These pharmacological characteristics may have potentially favorable clinical implications, since hypertensionrelated organ damage has been closely linked to 24-h BP levels [47] . The administration of lercanidipine may also minimize the expected sympathetic activation and the consequent enhanced BP variability and tachycardia, related to early hypotension frequently observed with first-generation dihydropyridines [43–46] . In addition, clinical and experimental studies have suggested that this drug may reduce extension and progression of atherosclerotic lesions in blood vessels through a reduction of the expression and activity of metalloproteinases and of oxidative stress [48] . The characteristics of lercanidipine are, thus, suitable for use in a combination therapy aimed at reducing BP levels and CV risk. In this latter regard, the fixed-combination therapy of lercanidipine and enalapril has been developed, and it may, indeed, fulfil these purposes. The development of such a fixed‑combination 117

Drug Profile

CCBs


Vasodilation

Arteriolar vasodilation Intracapillary vasoconstriction

Fluid exudation from the intracapillary space into the interstitium

Stimulation

Reflex activation of SNS and RAAS ACE inhibitors Post-capillary vasodilation

Edema

Inhibition

Figure 1. Beneficial effects of combination therapy in the clinical management of arterial hypertension. ACE: Angiotensin-converting enzyme; CCB: Calcium-channel blocker; RAAS: Renin–angiotensin–aldosterone system; SNS: Sympathetic nervous system.

therapy appears, in fact, rational for the clinical management of hypertension with different levels of CV risk, since enalapril is a well-known ACE inhibitor, which has been shown to significantly and safely reduce BP levels in hypertensive patients, as well as to reduce the incidence of CV and renal outcomes in patients with post-myocardial infarction cardiomyopathy, left ventricular dysfunction and congestive heart failure [49,50] . It has also been shown to significantly reduce progression of diabetic nephropathy, to promote regression of left ventricular hypertrophy, and to prevent recurrence of atrial fibrillation [49,50] . At present, a fixed-dose tablet formulation of enalapril/ lercanidipine is approved in some European countries for treating hypertension, including mild-to-moderate hypertension, severe hypertension, isolated systolic hypertension, elderly patients and patients not responding to monotherapy [51] . Efficacy

For clinical indications, the appropriate daily dose of enalapril/lercanidipine was established by testing various combinations of lercanidipine (5, 10 or 20 mg) and enalapril (5 or 10 mg) in randomized, controlled clinical trials, performed in hypertensive patients with different CV risk profiles [51] . In these trials, the primary efficacy end point was defined as sitting diastolic BP level changes between baseline and after 12-weeks’, double-blind treatment, while the secondary end points included: • Sitting systolic BP level changes between baseline and after 12-weeks’, double-blind treatment; • Percentage of patients achieving systolic, diastolic or systolic/ diastolic BP control after 12 weeks; 118

• BP responder rate (percentage of patients achieving systolic BP control or reduction in sitting systolic BP levels from baseline by more than 20 mmHg; percentage of patients achieving diastolic BP control or reduction in sitting diastolic BP levels from baseline by more than 10 mmHg). In an 8-week clinical trial, the BP response was significantly greater in patients treated with enalapril/lercanidipine 10/10 mg once daily (-10.4 mmHg; 95% confidence interval [CI]: -11.4 to -9.5 mmHg) as compared with that recorded in patients treated either with lercanidipine 10 mg once daily (-8.2 mmHg; 95% CI: -9.2 to -7.3 mmHg) or lercanidipine 20 mg once daily (-9.9 mmHg; 95% CI: -11.2 to -8.6 mmHg) [51] . In addition, monotherapy with once-daily lercanidipine 10–20 mg or enalapril 10 mg provided significantly better antihypertensive efficacy than that observed with placebo, and there were no differences for 5 mg doses of lercanidipine or enalapril versus placebo [46] . On the basis of these results, enalapril/lercanidipine 10/10 mg was considered the optimal once-daily fixed-dose therapeutic regimen [51] . In a 12-week, randomized, double-blind clinical trial, the administration of once-daily enalapril/lercanidipine 10/10 mg significantly reduced sitting systolic and diastolic BP as compared with that observed in patients treated with once daily lercanidipine 10 mg, in patients with mild-to-moderate hypertension, who had previously not responded to 4-weeks’ treatment with lercanidipine, as shown in Figure 2 [51] . In another 12-week, randomized, double-blind trial, once daily enalapril/lercanidipine 20/10 mg was significantly more effective than enalapril 20 mg once daily in hypertensive patients who had previously not responded to enalapril monotherapy, as shown in Figure 3 [51] . In lercanidipine nonresponder patients, after 12-week treatment, a significantly greater proportion of patients receiving the fixed-dose combination achieved systolic BP control (39 vs 22%), diastolic BP control (29 vs 19%) and/or systolic/ diastolic BP control (22 vs 12%) than that observed in patients receiving lercanidipine monotherapy [51] . Similarly, in enalapril nonresponder patients, after 12-week treatment, a greater, but not significant proportion of patients receiving the fixed-dose combination achieved systolic BP control (33 vs 28%), diastolic BP control (48 vs 37%) and/or systolic/diastolic BP control (24 vs 17%) than that observed in patients receiving enalapril monotherapy [51] . The combination therapy based on enalapril/lercanidipine has also been shown to significantly and persistently reduce BP levels through 24-h ambulatory BP monitoring in a double-blind, placebo-controlled, crossover clinical study on elderly hypertensive patients, aged 60–85 years, with mean office sitting systolic BP of 160–179 mmHg and daytime systolic BP of more than 135 mmHg [52] . After a 2-week run-in period, during which previous antihypertensive medications were discontinued, patients were randomized to receive the following four treatments in a randomized order for 4 weeks: • Group A, lercanidipine 10 mg; • Group B, enalapril 20 mg; • Group C, lercanidipine 10 mg plus enalapril 20 mg; • Placebo. Expert Rev. Cardiovasc. Ther. 7(2), (2009)


Mean BP reduction (mmHg)

sSBP

sDBP

0 -2 -2.3 -4 -4.3 -6 -8 -10

-7.7 p < 0.001

-7.1 p < 0.001

Lercanidipine 10 mg Enalapril/lercanidipine 10/10 mg

Figure 2. Mean BP reduction with lercanidipine 10 mg versus enalapril/lercanidipine 10/10 mg. In a 12-week, randomized, double-blind trial, the administration of once-daily enalapril/lercanidipine 10/10 mg significantly reduced sitting systolic and diastolic blood pressure levels compared with that observed in patients treated with once-daily lercanidipine 10 mg, in patients with mild-to-moderate hypertension, who had previously not responded to 4 weeks of treatment with lercanidipine 10 mg. BP: Blood pressure; sDBP: Seated diastolic blood pressure; sSBP: Seated systolic blood pressure. Data from [53] .

www.expert-reviews.com

sSBP Mean BP reduction (mmHg)

The administration of monotherapy based on placebo, lercanidipine 10 mg or enalapril 20 mg and the fixed combination based on enalapril/lercanidipine 20/10 mg was associated with a progressive, significant reduction in 24-h systolic BP levels by 144, 137, 133 and 127 mmHg, respectively [52] . All active treatments significantly reduced 24-h systolic BP levels as compared with placebo, but enalapril/lercanidipine 20/10 mg was significantly more effective than monotherapy based on either lercanidipine 10 mg or enalapril 20 mg [52] . Similarly, enalapril/lercanidipine 20/10 mg significantly reduced clinical systolic BP levels (-16.9 mmHg) as compared with that observed with monotherapy based either on lercanidipine 10 mg (-5.0 mmHg) or on enalapril 20 mg (-5.9 mmHg) [52] . Finally, the responder rate, as defined by 24-h BP levels less than 140/90 mmHg, was significantly higher in patients randomized to receive combination therapy compared with those randomized to receive monotherapy based on either lercanidipine 10 mg or enalapril 20 mg: 45% of patients with enalapril/lercanidipine 20/10 mg, 18% of patients with lercanidipine 10 mg, and 19% with enalapril 20 mg, respectively [52] . A recent clinical study investigated the BP-lowering effects of the CCB lercanidipine versus hydrochlorothiazide as add-on therapy in diabetic patients with uncontrolled hypertension on enalapril monotherapy [53] . In this study, 174 patients aged 18–80 years with mild-to-moderate hypertension and Type 1 or 2 diabetes were included in a 2-week placebo run-in followed by 4 weeks on enalapril 20 mg. Subsequently, 135 nonresponders

Drug Profile

sDBP

0 -2 -4 -6 -8 -10 -12

-6.7 -9.8 p = 0.015

-7.5 -9.2 p = 0.013

Enalapril 20 mg Enalapril/lercanidipine 10/10 mg

Figure 3. Mean BP reduction with enalapril 20 mg versus enalapril/lercanidipine 10/10 mg. In a 12-week, randomized, double-blind trial, the administration of once-daily enalapril/ lercanidipine 10/10 mg significantly reduced sitting systolic and diastolic BP levels compared with that observed in patients treated with once-daily enalapril 20 mg, in patients with mild-to-moderate hypertension, who had previously not responded to 4 weeks of treatment with enalapril 20 mg. BP: Blood pressure; sDBP: Seated diastolic blood pressure; sSBP: Seated systolic blood pressure. Data from [53] .

(as defined by diastolic BP levels more than 90 mmHg and/or mean sitting diastolic BP less than 109 mmHg) were randomized to receive 20 weeks of double-blind add-on therapy to enalapril with either lercanidipine 10 mg (n = 69) or hydrochlorothiazide 12.5 mg (n = 66). The primary aim of the study was to prove noninferiority of lercanidipine add-on versus hydrochlorot hiazide add-on in reducing sitting diastolic BP levels; response rates and tolerability data were also observed. At the end of the follow-up, both the add-on treatments significantly reduced diastolic BP levels to a greater extent than enalapril monotherapy [53] . As shown in Figure 4 , mean changes in diastolic BP levels were -9.3 mmHg in patients randomized to receive lercanidipine 10 mg and -7.4 mmHg in patients randomized to hydrochlorothiazide 12.5 mg [53] . The BP response rates were significantly greater in patients randomized to receive enalapril/lercanidipine 10/10 mg as compared with that observed in patients randomized to receive enalapril/hydrochlorothiazide 20/12.5 mg (69.6 vs 53.6%). In addition, more ambitious target BP levels of 130/85 mmHg or less, as recommended by current hypertension guidelines [1–3] , were achieved in 30.4% of diabetic hypertensive patients randomized to receive enalapril/ lercanidipine 20/10 mg and in 23.2% of those randomized to receive enalapril/hydrochlorothiazide 20/12.5 mg (p > 0.05). Tolerability

Clinical studies have demonstrated that lercanidipine monotherapy is generally well-tolerated [54–57] . In the Lercanidipine Challenge Trial [54] , an open-label clinical study aimed at comparing the tolerability of lercanidipine, patients already taking 119

Drug Profile


Mean BP reduction (mmHg)

sSBP

sDBP

0 -2 -4 -6

-6

-8 -10

-7.4 -9.6

-9.3

-12 Enalapril/HCTZ 20/12.5 mg Enalapril/lercanidipine 10/10 mg

edema and flush were most likely due to lercanidipine-induced peripheral vasodilation. Dizziness and vertigo were considered to be possibly linked to the BP-lowering effect of the combination. During a 9-month extension phase clinical trial, which was aimed at evaluating long-term efficacy and tolerability of a fixed combination of enalapril/lercanidipine, 221 nonresponders to lercanidipine monotherapy and 186 nonresponders to enalapril monotherapy were selected to receive enalapril/lercanidipine 10/10 mg once daily, with a possible titration to enalapril/lercanidipine 20/10 mg once daily, if needed [51] . Among lercanidipine monotherapy nonresponders, about half of the patients achieved target systolic and diastolic BP levels (52 and 46%, respectively), while among nonresponders to enalapril monotherapy, approximately 40% of patients achieved systolic BP control and 60% of patients achieved diastolic BP control [51] . Conclusion

Figure 4. Mean BP reduction with enalapril/HCTZ 20/12.5 mg versus enalapril/lercanidipine 10/10 mg. In a 24-week, randomized, double-blind trial, the administration of once-daily enalapril/lercanidipine 10/10 mg significantly reduced sitting systolic and diastolic BP levels as compared with that observed in patients treated with once daily enalapril/HCTZ 20/12.5 mg, in patients with mild‑to‑moderate hypertension, who had previously not responded to 8 weeks’ treatment with enalapril 20 mg. BP: Blood pressure; HCTZ: Hydrochlorothiazide; sDBP: Seated diastolic blood pressure; sSBP: Seated systolic blood pressure. Data from [53] .

amlodipine, felodipine, nifedipine gastrointestinal therapeutic system or nitrendipine and experiencing CCB-specific adverse effects were switched to lercanidipine for 4 weeks and then rechallenged with their initial treatment for the remaining 4 weeks. In the presence of comparable BP levels, lercanidipine was associated with a significantly lower incidence of ankle edema, flushing, rash, headache and dizziness compared with other CCBs. In the Tolerabilidad de Lercanidipino 20 mg Frente a Amlodipino y Nifedipino en Condiciones (TOLERANCE) [56] , an observational, transversal, multicenter study performed in a primary care setting and aimed at comparing the tolerability of high doses of lercanidipine (20 mg) with that of amlodipine 10 mg or nifedipine GITS 60 demonstrated that incidence of vasodilation-related signs and symptoms were significantly higher in the amlodipine or in the nifedipine GITS group (76.8%) than that in lercanidipine group (60.8%,), in the presence of similar BP levels and compliance rates in both groups. As expected, fixed-dose enalapril/lercanidipine was generally well-tolerated, to a degree that was comparable to that of either of the individual monotherapy or placebo [51] . Treatment discontinuation because of an adverse event occurred with a similar frequency in both combination and monotherapy groups, with the incidence in enalapril/lercanidipine 10/10 mg and 20/10 mg groups being 4.6 and 4.4%, respectively [51] . Cough and dizziness were two of the most common treatment-emergent adverse events that occurred with both enalapril/lercanidipine dosages. In particular, cough was attributed to enalapril, whereas peripheral 120

Fixed antihypertensive combination therapy based on ACE inhibitors and CCBs, including enalapril/lercanidipine, appears to be rational for a number of pharmacological, clinical and therapeutic reasons. First, this combination is based on the concomitant use of two well-documented antihypertensive agents. Second, clinical trials have largely supported the beneficial effects of this combination strategy in terms of BP-lowering efficacy. Third, this combination therapy is substantially neutral from the metabolic point of view and, thus, may provide consistent advantages in terms of newonset diabetes mellitus, when compared with other conventional antihypertensive strategies. Finally, this combination has important clinical advantages, beyond BP-lowering effect, in terms of tolerability, allowing a significant reduced incidence of side effects of one component (e.g., ankle edema favored by CCBs) through the counter-regulatory peripheral vascular actions of the other one (e.g., post-capillary vasodilation promoted by ACE inhibitors). On the basis of the available evidence, enalapril/lercanidipine may be considered effective and safe and may provide additional advantages in terms of patients’ compliance when compared with the separate administration of the two drugs, by preserving at the same time the efficacy on BP control and CV and renal protection. Expert commentary

The rational of any combination therapy of two different compounds is based on increased efficacy in lowering BP levels and antagonism of the contraregulatory mechanisms, leading to a reduction of dose-dependent incidence of side effects, as compared with that observed with individual monotherapy. An ideal combination therapy for modern clinical management of hypertension should be characterized by: • Antihypertensive efficacy greater than that shown by monotherapy • Improved safety and tolerability profile • Long-term CV and renal protection Currently, there is a preference for combination therapies based on ACE inhibitors and CCBs in a number of clinical conditions, such as patients with grade 2 or 3 hypertension, patients with Expert Rev. Cardiovasc. Ther. 7(2), (2009)


obesity, metabolic syndrome or diabetes mellitus, patients with a history of previous myocardial infarction or stroke and patients with nephropathies. Five-year view

Blood pressure control remains largely unsatisfactory in the general population of hypertensive patients, especially in those with a high or very-high CV risk profile. If not adequately addressed, uncontrolled BP levels, frequent concomitant presence of additional risk factors, signs of organ damage and associated clinical conditions, will further increase the hypertension-related global burden of disease in the next future. In view of the need to achieve more effective and persistent BP control in the general hypertensive population, and of reducing the global CV-risk profile in the individual hypertensive patients,

Drug Profile

the use of combination therapy may represent a useful and powerful tool in the daily clinical practice of hypertension. In this regard, the use of fixed-combination therapies, especially those based on ACE inhibitors and CCBs, has shown to provide additional benefits, beyond BP control. Such combinations may favor a new, positive trend in terms of BP control and, hence, in CV prevention. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Blood pressure (BP) control is largely unsatisfactory in the general population of hypertensive patients, especially those at high or very-high cardiovascular (CV) risk profile. • Evidence derived from clinical trials demonstrate that combination therapy allows an increased antihypertensive efficacy for patients whose BP levels are harder to control, or in hypertensive patients at high or very-high CV risk profile. • In view of the growing need of using combination therapy to achieve effective BP control in hypertensive patients, and to provide adequate CV and renal protection, those combination therapies based on angiotensin-converting enzyme inhibitors and calciumchannel blockers are now considered more effective and safer than conventional antihypertensive strategies, based on β-blockers and low-dose thiazide diuretics. • Fixed-dose combination therapies based on a new-generation dihydropiridinic calcium-channel blocker (lercanidipine) and the prototype angiotensin-converting enzyme inhibitor (enalapril), may provide additional benefits in the daily clinical management of hypertension, in terms of adherence to antihypertensive therapy, BP control, tolerability, organ damage protect and possibly cardiorenal prevention.

References 1

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Drug Profile

Affiliations •

Giuliano Tocci, MD Division of Cardiology, II Faculty of Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Via di Grottarossa, 1035-1039, 00189 Rome, Italy [email protected]

Francesca Palano, MD Division of Cardiology, II Faculty of Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Via di Grottarossa, 1035-1039, 00189 Rome, Italy Erika Pagannone, MD Division of Cardiology, II Faculty of Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Via di Grottarossa, 1035-1039, 00189 Rome, Italy Diana Chin Division of Cardiology, II Faculty of Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Via di Grottarossa, 1035-1039, 00189 Rome, Italy Andrea Ferrucci, MD Division of Cardiology, II Faculty of Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Via di Grottarossa, 1035-1039, 00189 Rome, Italy Massimo Volpe, MD, FAHA, FESC Chair, Division of Cardiology, II Faculty of Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Via di Grottarossa, 1035-1039, 00189 Rome, Italy Tel.: +39 063 377 5654 Fax: +39 063 377 5061 [email protected]

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