Direct Renin Inhibition with Focus on Aliskiren and Cardiovascular Outcome Studies

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Citation
European Cardiovascular Disease 2006 - Issue 2;2006:2(2):17-19
DOI
http://dx.doi.org/10.15420/ecr.2006.0.2.17

Hypertension affects approximately 26% of adults globally and is a leading risk factor for cardiovascular disease and death. The renin system is central to blood pressure (BP) control, and chronic activation of the system, as occurs in pathological conditions, leads to damage to organs (such as the heart and kidneys), as well as perpetuating elevated BP. Identification of the pivotal role played by the renin system in the pathophysiology of hypertension has led to the development of agents that specifically target the system, namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Inhibition of the renin system with these agents reduces BP and provides significant protection in patients with chronic heart failure and diabetic nephropathy.

ACE inhibitors and ARBs mediate their effects on the renin system by blocking the synthesis and actions of angiotensin (Ang) II (the major effector molecule of the system), respectively. Renin cleaves angiotensinogen to Ang I, which is in turn converted to Ang II by ACE. The renin system can be considered as a feedback loop in which Ang II regulates renin release from the kidney. Both ARBs and ACE inhibitors interrupt this feedback inhibition of renin secretion, resulting in elevated renin concentrations and an increased capacity to generate Ang I, as measured by plasma renin activity (PRA). Therefore, neither ACE inhibitors nor ARBs provide complete suppression of the renin system. In the case of ACE inhibitors, Ang II generation can occur through ACE-independent mechanisms, and studies have shown that this escape from ACE inhibition is associated with poorer outcomes.

Other antihypertensive agents, such as calcium channel blockers (CCBs) and diuretics, do not directly target the renin system, but act through other regulatory mechanisms that impact on renin system activity, causing an increase in renin concentration and PRA. A clear rationale therefore exists for the development of antihypertensive therapies that can provide more comprehensive suppression of the renin system.

Development of Direct Renin Inhibitors

It has long been proposed that the optimal way of inhibiting the renin system is by targeting the renin enzyme, thereby suppressing the system at its point of activation. Renin has high specificity for its only naturally occurring substrate, angiotensinogen, and therefore direct renin inhibition is expected to be associated with a low risk of adverse events. Early attempts to develop direct renin inhibitors (DRIs) for the treatment of hypertension and associated cardiovascular disorders were hampered by poor oral bioavailability, lack of clinical efficacy, short plasma half-lives and high cost of synthesis.

However, a combination of molecular modelling techniques and crystal structure elucidation led to the development of aliskiren, which will be the first orally effective DRI for the treatment of hypertension. Aliskiren is a highly specific inhibitor of human renin in vitro. Like ACE inhibitors and ARBs, aliskiren causes a reactive rise in renin concentration due to interruption of the normal feedback inhibition of renin release by Ang II but, unlike these agents, aliskiren inhibits PRA and therefore provides suppression of the entire renin system. Indeed, aliskiren provided dose-dependent reductions in PRA and Ang I and II levels in healthy human volunteers, and neutralised the compensatory rise in PRA, when given in combination with other antihypertensive agents that strongly stimulate renin secretion.

Pharmacokinetics of Aliskiren

Studies in healthy human volunteers have demonstrated that aliskiren is rapidly absorbed (tmax one to three hours) and exhibits a plasma half-life of approximately 40 hours, making is suitable for once-daily dosing. Metabolism plays a minimal role in the elimination of aliskiren, and the majority of the absorbed drug is eliminated unchanged by the hepatobiliary route (Novartis, data on file). The pharmacokinetic interaction profile of aliskiren has been extensively studied. Aliskiren shows no clinically relevant pharmacokinetic interactions with warfarin, lovastatin, atenolol, celecoxib, cimetidine or digoxin in healthy volunteers. Furthermore, there are no clinically relevant interactions between aliskiren and the CCB amlodipine, the ACE inhibitor ramipril, the ARB valsartan or the diuretic hydrochlorothiazide (HCTZ). Pharmacokinetic studies in the elderly and in patients with hepatic or renal impairment indicate that no initial dosage adjustment of aliskiren is required in these patient populations.

Antihypertensive Efficacy of Aliskiren

To date, the safety and efficacy of aliskiren in lowering BP has been demonstrated in more than 8,000 patients with mild-to-moderate hypertension, over treatment durations of six to 52 weeks. Aliskiren monotherapy at once-daily doses of 75-600mg demonstrates comparable efficacy in men and women, in elderly (65 years) and younger individuals (<65 years) and lowers BP effectively across all racial and ethnic subgroups. Furthermore, aliskiren has a placebo-like tolerability profile at doses up to 300mg across a broad range of patients. In an eight-week study in 1,123 patients with mild-to-moderate hypertension, aliskiren 75-300mg lowered clinic BP as effectively as valsartan 80-320mg. Aliskiren at once-daily doses of 150mg demonstrated antihypertensive efficacy comparable to irbesartan 150mg in an eight-week study in 652 patients with mild-to-moderate hypertension. Moreover, aliskiren 300mg was superior to the ACE inhibitor ramipril 10mg in lowering systolic BP in an eight-week trial in 837 patients with diabetes and hypertension.

In ambulatory BP monitoring (ABPM) studies, aliskiren provided sustained BP lowering throughout the 24-hour dosing period, with trough-to-peak ratios for diastolic response up to 98% for the 300mg dose, indicative of good BP control even at the end of the 24-hour dosing interval. Maintaining BP control over 24 hours is important for preventing end-organ damage and cardiovascular events in patients with hypertension. Meta-analyses have demonstrated that the risk of myocardial infarction (MI) and stroke is highest between 6 am and 12 noon and, as most patients take their antihypertensive medication in the morning, the period of greatest cardiovascular risk coincides with trough plasma drug levels. Long-acting antihypertensive medications are therefore of considerable clinical importance.

Finally, a long-term study has shown that aliskiren-based treatment (with optional addition of a diuretic in patients with BP 140/90mmHg) provides antihypertensive efficacy that is sustained over 12 months, with no evidence of rebound hypertension upon drug withdrawal. Aliskiren-based treatment was well tolerated, with no evidence of dose-dependent adverse events with aliskiren alone or in combination with HCTZ. As antihypertensive therapy is often life-long, it is important that treatments have good long-term tolerability in order to maximise patient compliance and, thereby, treatment success.

Aliskiren Combination Therapy

Aliskiren has demonstrated additional BP lowering when given in combination with other inhibitors of the renin system. The antihypertensive efficacy of aliskiren 300mg administered in combination with ramipril 10mg was superior to monotherapy with ramipril 10mg in an eight-week study in patients with diabetes and hypertension. Interestingly, the incidence of cough was lower in patients receiving aliskiren in combination with ramipril than in those individuals receiving ramipril monotherapy. Treatment for eight weeks with aliskiren/valsartan in combination at once-daily doses of 75/80mg, 150/160mg or 300/ 320mg lowered BP more effectively than the component monotherapies in patients with mildto- moderate hypertension.

Combination therapy with aliskiren and the diuretic HCTZ provided greater reductions in BP than the component monotherapies in patients with mild-to-moderate hypertension. Co-administration of aliskiren 150mg with amlodipine 5mg in patients with an inadequate response to amlodipine 5mg provided significant additional BP lowering. Furthermore, the antihypertensive efficacy was similar to that achieved by doubling the dose of amlodipine, but with better tolerability. Indeed, the overall incidence of AEs was similar across treatment groups; however, the incidence of oedema was lower with aliskiren/amlodipine combination therapy than with amlodipine 10mg monotherapy.

In all these studies, there was no evidence for an increase in the number or type of adverse events with combination therapy compared with the component monotherapies. As the majority of patients require more than one antihypertensive agent in order to achieve BP control, aliskiren is likely to be a useful adjunct to other antihypertensive treatments to improve renin system suppression.

Future and On-going Studies with Aliskiren

Clinical investigation of the DRI aliskiren is ongoing, and an extensive trial programme will generate new data on the BP-lowering and organ protection benefits of the drug. The Aspire Higher clinical trial programme has been designed to assess the effect of aliskiren on organ damage, with a particular focus on patients with diabetic nephropathy or obesity.

Three outcomes studies to investigate the effect of direct renin inhibition with aliskiren on morbidity and mortality are currently planned to begin in 2007 and 2008. These are in

  • patients with pre-hypertension (systolic BP 120-140mmHg) and moderate cardiovascular (CV) risk to evaluate improvement in CV and metabolic outcomes (AVIATOR);
  • type 2 diabetes patients at high risk of CV and renal events to evaluate improvement in renal function and CV outcomes (ALTITUDE); and
  • post-MI patients with renal dysfunction to evaluate reduction of cardiac remodelling (ASPIRE).

In addition to the above outcome trials, three ongoing key studies will assess the effects of aliskiren on surrogate markers of organ damage. In the Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) study, 496 patients with hypertension, type 2 diabetes and proteinuria will receive aliskiren or placebo added to losartan treatment to assess the effect on microalbuminuria (urinary albumin-to-creatinine ratio). The ALiskiren Observation of heart Failure Treatment (ALOFT) is a 12-week study of aliskiren versus placebo added to standard therapy in 280 patients with hypertension and stable heart failure. End-points will include change in B-type natriuretic peptide and aldosterone levels, cardiac ultrasound and markers of glucose metabolism. The study will also assess the safety and tolerability of aliskiren. Finally, in the ALiskiren Left ventricular Assessment of hypertrophY (ALLAY) study, overweight patients (body mass index >25kg/m2) with hypertension and left ventricular hypertrophy will receive aliskiren, losartan or the combination. The study will run for 36 weeks; the primary end-point will be the change from baseline to study end in echocardiographic measures including left ventricular wall thickness, left ventricular mass index and left ventricular ejection fraction (LVEF).

Summary

Numerous clinical trials have demonstrated the clear benefit of renin system inhibition on lowering BP and reducing cardiovascular morbidity and mortality. However, ACE inhibitors and ARBs do not provide comprehensive suppression of the renin system. Direct inhibition of the renin enzyme has long been recognised as the optimal method of inhibiting the renin system, but previous attempts to develop such inhibitors have been thwarted by poor bioavailability and efficacy and high synthesis costs. Aliskiren will be the first orally active DRI, and is currently under evaluation by the US Food and Drug Administration (FDA) for the treatment of hypertension. Aliskiren demonstrates dose-dependent BP lowering up to 300mg with placebo-like tolerability, is effective across a broad range of patients with mild-to-moderate hypertension, and provides additional BP lowering when used in combination with other antihypertensive agents. Furthermore, aliskiren provides 24-hour BP control with no evidence of rebound hypertension upon drug withdrawal. The ASPIRE HIGHER trial programme will determine the potential benefits of aliskiren treatment on morbidity and mortality, but clinical trials conducted to date suggest that DRIs are likely to be an important therapeutic option in the treatment of hypertension.

Acknowledgements:

The author is a member of the AVIATOR Executive Committee. Mohammed Atif Ali and Dave Anderson of Novartis Pharma, East Hanover, NJ, are acknowledged for providing detailed information on other on-going and future studies.

A version of this article containing references can be found in the Reference Section on the website supporting this briefing (www.touchcardiology.com).