Article

Aliskiren - Clinical Benefits in the Management of Hypertension

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DOI:https://doi.org/10.15420/ecr.2007.0.2.61

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The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

It is widely acknowledged that effective management of hypertension – even if blood pressure (BP) is reduced by only 2mmHg – can significantly reduce the incidence of stroke, myocardial infarction (MI) and heart failure (HF).1 However, despite the wide range of conventional antihypertensive agents available, approximately 70% of patients fail to achieve adequate BP control.2 Furthermore, although certain antihypertensive agents – such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) – have been shown to provide organ protection beyond BP control, these agents have failed to provide the anticipated great step forwards to improved cardiovascular (CV) morbidity and mortality.3–5 There is still room for improvement in terms of the clinical benefits provided by antihypertensive therapy.

The renin system has a key role in controlling BP.6 Renin, a proteinase enzyme synthesised by the kidney, catalyses the conversion of angiotensinogen to angiotensin I (Ang I). Ang I is then converted by ACE to angiotensin II (Ang II), which regulates BP via its interaction with the AT1 receptor. Binding of Ang II at the AT1 receptor increases BP by stimulating generalised vasoconstriction, promoting re-absorption of sodium and stimulating aldosterone secretion. In hypertension, the renin system can become chronically activated, resulting in a persistently elevated concentration of circulating and/or locally activated renin. Aliskiren is the first orally effective direct renin inhibitor (DRI),7 and has recently been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of hypertension. It inhibits the activity of renin, controlling the renin system at the rate-limiting step. The antihypertensive efficacy of aliskiren as monotherapy has been established, as well that as of aliskiren in combination with other antihypertensive agents.8–12 In addition, the potential organ-protective benefits of aliskiren are being investigated in an extensive, ongoing clinical study programme. The aim of this review is to evaluate the clinical benefits provided by direct renin inhibition, and to explore the wider potential benefits of aliskiren in the management of hypertension.

Control of the Renin System with Direct Renin Inhibition

Hypertension can cause the renin system to become pathologically activated, as indicated by an increase in plasma renin activity (PRA) – a measure of the rate at which Ang I is generated. ACEIs and ARBs lower BP by attenuating the deleterious effects of Ang II. However, neither class of antihypertensive provides complete control of the renin system. By reducing activity at the AT1 receptor, both ACEIs and ARBs stimulate renin release via a negative feedback mechanism, ultimately increasing PRA.5

Aliskiren binds to the active site of renin, inhibiting the enzymatic conversion of angiotensinogen to Ang I and, consequently, reducing the amount of Ang II.13 Aliskiren therapy reduces both Ang I and Ang II. However, in contrast to ACEIs and ARBs aliskiren inhibits the activity of secreted renin, thereby lowering PRA and providing more complete control of the renin system.14,15

Aliskiren – A Novel Monotherapy for the Treatment of Hypertension

A wealth of clinical evidence supports the BP-lowering efficacy of aliskiren monotherapy in patients with mild to moderate hypertension – defined as mean sitting diastolic blood pressure (DBP) ≥95mmHg and <110mmHg. In dose-response studies, the optimal starting dose of aliskiren was 150mg, with optional titration to 300mg if additional BP-lowering efficacy was required.8,16 Analysis of pooled BP efficacy data from over 3,500 patients showed that aliskiren 150mg once daily lowered systolic blood pressure (SBP) by 12.5mmHg and DBP by 10.1mmHg (both p<0.0001 versus placebo). Increasing the dosage of aliskiren to 300mg/day reduced mean SBP by 15.2mmHg and mean DBP by 11.8mmHg (both p<0.0001 versus placebo)9 (see Figure 1). The BP-lowering effect of aliskiren is observed irrespective of age (≤ or ≥65 years), gender or presence of co-morbid diseases (such as obesity and diabetes).9,17,18 Furthermore, no dosage adjustment is necessary in the elderly or in those patients with renal or hepatic impairment.19

The efficacy of aliskiren monotherapy has been compared with hydrochlorothiazide (HCTZ).20 In a long-term study, 1,124 patients were randomised to receive either aliskiren 300mg or HCTZ 25mg. After 12 weeks, ramipril 5mg was added for patients who had not achieved the BP target of <140/90mmHg, increasing to 10mg after a further six weeks if required. Compared with HCTZ 25mg, aliskiren 300mg monotherapy provided significantly greater reductions in DBP and SBP after 12 weeks of treatment (p<0.001 for both comparisons) (see Figure 2). Furthermore, the superior BP-lowering efficacy of aliskiren was maintained after 26 weeks. After 52 weeks of treatment, aliskiren-based therapy was more effective in reducing DBP than HCTZ-based therapy (p<0.05), and at least as effective in reducing SBP (p<0.0001 for non-inferiority of aliskiren).20 The BP-lowering efficacy of aliskiren was compared with ramipril in 842 patients with mild to moderate hypertension.21 Patients received aliskiren 150mg or ramipril 5mg, with optional dose-doubling after six weeks for patients not achieving BP <140/90mmHg. After 12 weeks, HCTZ 12.5mg was added for patients not achieving the target BP, with optional uptitration to 25mg after a further six weeks if required.

Aliskiren 150mg lowered DBP as effectively as ramipril 5mg, and provided greater SBP reductions than ramipril 5mg (12.5mmHg versus 10.9mmHg; p<0.01). After 12 weeks, BP reductions observed with aliskiren were significantly greater than those for ramipril (p<0.01 for SBP and DBP). Furthermore, after 26 weeks aliskiren-based therapy lowered BP more effectively than the corresponding ramipril-based therapy, reducing SBP by 17.9mmHg (versus 15.2mmHg with ramipril; p<0.01) and DBP by 13.2mmHg (versus 12.0mmHg with ramipril; p<0.05).21

Aliskiren in Combination with Other Antihypertensive Agents

Most patients with hypertension require more than one antihypertensive agent to achieve their BP goal.22,23 Several studies have investigated the efficacy of aliskiren in combination with other antihypertensive agents, including a diuretic, a calcium channel blocker (CCB), an ACEI and an ARB.10–12,24 When aliskiren 300mg was combined with HCTZ 25mg, mean SBP was reduced by 21.2mmHg and mean DBP by 14.3mmHg, a significant improvement compared with component monotherapies (p<0.05 versus HCTZ; p<0.05 versus aliskiren)10 (see Figure 3). The efficacy of aliskiren/HCTZ combination therapy has also been investigated in obese patients with hypertension. In a study by Jordan et al.,25 patients with an inadequate response to HCTZ 25mg – defined as DBP ≥90mmHg after four weeks – received aliskiren in addition to continued HCTZ therapy.25 After eight weeks of treatment, aliskiren 300mg in combination with HCTZ 25mg reduced mean SBP/DBP by 21.2/14.3mmHg, a significant improvement compared with continuation of HCTZ 25mg (14.3/9.4mmHg; p<0.0001). In a separate study, 545 patients who failed to respond adequately to amlodipine 5mg – defined as DBP >90mmHg after four weeks – received aliskiren/amlodipine combination therapy (150mg/5mg), high-dose amlodipine (10mg) or continued low-dose amlodipine (5mg) for six weeks.24 Combining aliskiren 150mg with amlodipine 5mg improved BP-lowering efficacy compared with continuation of amlodipine 5mg; combination therapy reduced mean SBP/DBP from baseline by 11.0/8.5mmHg (p<0.0001 versus amlodipine 5mg). High-dose amlodipine monotherapy was similarly effective, reducing mean SBP/DBP by 9.6/8.0mmHg (p=0.002 versus amlodipine 5mg); however, high-dose amlodipine increased the incidence of oedema compared with combination therapy.24 In patients with hypertension and diabetes, aliskiren 300mg in combination with ramipril 10mg provided superior BP-lowering efficacy compared with either of the component monotherapies.11

After eight weeks of treatment, aliskiren/ ramipril combination therapy reduced SBP from baseline by 16.6mmHg (versus 12.0mmHg with ramipril; p<0.05). Combination therapy reduced DBP from baseline by 12.8mmHg compared with reductions of 10.7mmHg with ramipril and 11.3mmHg with aliskiren (both p<0.05 versus combination therapy).11 Furthermore, the BP-lowering effect of combination therapy was significantly greater than that of ramipiril monotherapy irrespective of the degree of glycaemic control (p<0.05).26

The results of a study published recently by Oparil et al.12 have demonstrated the additional BP-lowering effect of aliskiren when combined with valsartan.12 Over 1,700 patients were randomised to receive aliskiren 150mg, valsartan 160mg, aliskiren/valsartan 150mg/160mg combination therapy or placebo. After four weeks, dosages were doubled for the remainder of the study. After eight weeks of treatment, combination therapy with aliskiren and valsartan provided superior BP-lowering efficacy compared with either of the component monotherapies. Aliskiren/valsartan combination therapy reduced mean SBP/DBP from baseline by 17.2/12.2mmHg compared with 12.8/9.7mmHg for valsartan and 13.0/9.0mmHg for aliskiren (p<0.0001 versus placebo for all comparisons)12 (see Figure 4).

Consistency and Duration of Blood-pressure Control with Aliskiren

It is well recognised that organ damage is more closely correlated with ambulatory BP than with office BP measurements.22 Improving control of ambulatory SBP (to <135mmHg) reduces left ventricular hypertrophy (LVH) and reduces the incidence of CV events independent of office BP values.27,28 Consequently, antihypertensive agents that provide 24-hour control of BP with once-daily dosing are preferred in the guidelines.23 Aliskiren has a half-life of approximately 40 hours, and the 300mg dose maintains up to 98% of its peak BP-lowering effect during the trough of the dosing period.16,29 Therefore, aliskiren is well suited to once-daily administration. Ambulatory BP data obtained from more than 700 patients show that aliskiren monotherapy provides sustained 24-hour BP control (see Figure 5). The smoothness index (SI) observed with aliskiren therapy is 0.81; this is close to unity (1.0), indicating the homogeneity of ambulatory BP reductions.30 In combination with valsartan, aliskiren lowers mean 24-hour ambulatory SBP/DBP by 14.4/10.3mmHg, a significantly greater reduction than aliskiren (9.8/7.1mmHg; p<0.0001) or valsartan (10.7/7.1mmHg; p<0.0001).12 Furthermore, aliskiren/valsartan 300/320mg combination therapy improves the SI (1.01) compared with valsartan 320mg (0.72; p=0.019).30

Hypertension is usually asymptomatic, and compliance with antihypertensive medication can be poor. In turn, poor compliance results in poor BP control and, in the long term, increases the risk of morbidity and mortality.31 For this reason, it is important that, wherever possible, antihypertensive therapy should protect patients from the consequences of an occasional missed dose. Several clinical studies have investigated the duration of effect of aliskiren after treatment discontinuation.32–34 The results of these studies suggest that there is no rebound in BP after discontinuation of aliskiren monotherapy. In patients randomised to receive aliskiren 150 or 300mg for eight weeks, DBP remained below baseline levels for up to two weeks after treatment discontinuation.32 Furthermore, BP returned to baseline levels more gradually after discontinuation of aliskiren-based therapy than after discontinuation of ramipril-based therapy.34 In the first week after stopping treatment, DBP increased by 4.6mmHg in patients who had received ramipril compared with 2.4mmHg in patients who had received aliskiren. Further studies will be necessary to determine more precisely the effect on BP after a missed dose of aliskiren.

Benefits Beyond Blood-pressure Control

It has been suggested that improving control of the renin system beyond that provided by ACEIs and ARBs may improve organ protection. The ASPIRE HIGHER clinical study programme is currently under way to evaluate the organ protection potential of aliskiren. The ASPIRE HIGHER studies will assess the effect of aliskiren on intermediate clinical end-points and on rates of morbidity and mortality. Results of the ALiskiren Observation of heart Failure Treatment (ALOFT) study were reported recently at the European Society of Cardiology (ESC) annual congress.35 This study evaluated the cardioprotective effect of aliskiren given with optimal therapy for stable heart failure, which included either an ACEI or an ARB. The results of the ALOFT study, to be published in due course, were supportive of the organ protection potential of aliskiren. Ongoing studies include Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) and ALiskiren in Left ventriculAr hypertrophY (ALLAY). AVOID will investigate the renoprotective effects of aliskiren compared with placebo in patients who have proteinuria despite three months of treatment with losartan 100mg.36 The ALLAY study will compare the effect of aliskiren/losartan 300mg/100mg combination therapy and component monotherapies on LVH regression – assessed by magnetic resonance imaging (MRI) – in overweight patients (body mass index (BMI) >25mg/m2) with mild to moderate hypertension and left ventricular thickening.37

Tolerability

As we have already discussed, good compliance with antihypertensive medication is essential to lowering the risk of hypertension-related morbidity and mortality.31 To help maximise the likelihood of treatment compliance, antihypertensive therapy should be well tolerated. When administered at the approved dosages of 150 or 300mg/day, aliskiren has a placebo-like tolerability profile (see Table 1).38 Furthermore, when used in combination with other antihypertensive agents, aliskiren appears to reduce the incidence of certain treatment-specific adverse events compared with component monotherapies.21,24 Combination therapy with aliskiren and ramipril is associated with a lower incidence of cough than either ramipril monotherapy or aliskiren monotherapy.21 As mentioned previously, in patients failing to respond to amlodipine 5mg monotherapy combining aliskiren with amlodipine reduces the incidence of oedema compared with high-dose (10mg) amlodipine monotherapy.24 Combination of high-dose aliskiren (300mg) with high-dose valsartan (320mg) did not increase the incidence of serum potassium ≥6.0mmol/l (0.5%) compared with component monotherapies (1.0 and 1.1% for aliskiren and valsartan, respectively) and placebo (1.3%). The incidence of serum potassium ≥5.5mmol/l in patients receiving aliskiren/valsartan combination therapy was 4.2% (compared with 2.7, 1.7 and 1.6% for placebo, aliskiren and valsartan, respectively). However, in most cases increases were transient and serum potassium returned to normal levels.12

Aliskiren has no clinically significant interactions with other antihypertensive agents, such as amlodipine, valsartan, ramipril, HCTZ and atenolol, or with warfarin, digoxin, lovastatin, celecoxib and cimetidine.39–43 When aliskiren is administered with furosemide, the area under the curve (AUC) for furosemide is reduced by 28% and the maximum plasma concentration Cmax is reduced by 49%.44 Therefore, the diuretic effect of furosemide should be monitored when initiating and adjusting furosemide therapy.

Conclusion

Aliskiren demonstrates greater antihypertensive efficacy than HCTZ and ramipril when given as monotherapy, and provides additional BP-lowering efficacy when used in combination with HCTZ, ramipril, valsartan or amlodipine in non-responders to amlodipine monotherapy. The tolerability profile of aliskiren monotherapy and combination therapy is similar to that of placebo. In addition, aliskiren provides sustained BP reductions over the 24-hour dosing period. Emerging evidence from the ASPIRE HIGHER clinical study programme is expected to provide support for the potential organ protection benefits of aliskiren. Ôûá

Acknowledgements

The author was assisted in the preparation of this text by a professional medical writer, Claire Cridland. Funding for this support was provided by Novartis Pharma AG.

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