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Direct Renin Inhibition: Upstream blocking of the Renin-Angiotensin System in Hypertension

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

World Congress of Cardiology 2006

Barcelona, Spain / September 2-6, 2006

Reviewed by: Sheldon Tobe, MD, FRCPC

Sunnybrook Health Sciences Centre Chair, CHEP Recommendations Task Force

Associate Professor of Medicine University of Toronto Toronto, Ontario

A survey published in 2004 (Wolf-Maier et al. Hypertension 2004;43:10-7) established that of Canadian and European patients with hypertension, two-thirds to three-quarters were not receiving adequate treatment compared with slightly fewer than half in the US. The same survey found that only 17% of Canadian patients treated for hypertension were achieving blood pressure (BP) goals of <140/90 mm Hg vs. 29% in the US and £10% in European countries. Thus, the majority of patients are not at BP target with existing therapies, according to Dr. Neil Poulter, Professor of Preventive Cardiovascular Medicine, Imperial College, London, UK.

There are many causes of this therapeutic gap, including physician, patient and medication factors. Clinical inertia is one of these factors, particularly when it comes to initiating drug therapy and then adding more agents to achieve BP targets. Physicians need to acknowledge this and should be prepared to prescribe more than one antihypertensive when BP control is not achieved. A research nurse will not accept that some stressor has increased their patient’s BP that day and that the patient can therefore avoid an up-titration or addition of medication until the next visit some months away. Physicians must acknowledge the success of research nurses for chronic disease management and use this knowledge to help patients achieve targets.

Direct Renin Inhibition: An unmet need

As discussed by Dr. Morris Brown, Professor of Clinical Pharmacology, University of Cambridge, UK, the renin system plays a central role in BP regulation. Activation of the renin system occurs with the release of the enzyme renin from the juxtaglomerular apparatus in the kidney. Renin catalyzes the conversion of angiotensinogen to angiotensin I (Ang I), which in turn is converted to angiotensin II (Ang II) by the angiotensin-converting enzyme (ACE). Plasma renin activity (PRA) is the capacity of circulating active renin to cleave angiotensinogen into Ang I.

Antihypertensive agents that target the renin system include ACE inhibitors, the angiotensin receptor blockers (ARBs) and ß-blockers. ß-blockers suppress renin secretion through their action on the renal nerves, though their main effect is through reduced heart rate and cardiac output. While both ACE inhibitors and ARBs act downstream of renin and reduce the level of stimulation of the AT1 receptor, the reduction in stimulation of the AT1 receptor causes a compensatory rise in renin release and in PRA (Figure 1).

Figure 1. Effects of Renin System Inhibitors on the Renin System


The new class of antihypertensive agents, which has been described as direct renin inhibitors (DRIs) and of which aliskiren is the first, blocks the renin system at its rate-limiting step, thereby reducing levels of Ang I, Ang II and PRA. This exciting new class of drug that reduces renin activity should produce a synergistic effect when added to other agents and help achieve BP control.

Profile

Dr. Roland Schmieder, Professor of Medicine, Friedrich Alexander University, Erlangen, Germany, noted that pharmacokinetic (PK) studies demonstrated the half-life of aliskiren to be approximately 40 hours, supporting its use as a once-daily medication. In a long-term study, the agent demonstrated persistency of BP-lowering effect for up to four weeks after withdrawal.

While the bioavailability of aliskiren is relatively low at 2.6%, achieving even this degree was a breakthrough for this class and it is still enough to control BP. The PK profile is not altered in elderly patients, in those with diabetes or in patients with renal impairment. Trial data to date indicate that it does not appear to interact with most widely used drugs so it should be safe to use in patients on multiple medications. This is an intriguing class of drug and one which may have benefits beyond BP lowering. One of its properties—impairing the conversion of inactive to active renin—might be a potentially important advantage, since elevated PRA levels have been identified as a risk factor for myocardial infarction in hypertensive patients in some studies.

Regarding its tolerability and side-effect profile, speakers here concurred that aliskiren has a placebo-like tolerability profile at all doses studied and a comparable adverse-event rate. Thus, preliminary results of the clinical trial program evaluating it either as monotherapy or in combination with other antihypertensive agents are highly encouraging.

Monotherapy Data

Dr. Matthew R. Weir, Professor of Medicine, University of Maryland School of Medicine, Baltimore, noted that there have been seven randomized, double-blind, clinical trials evaluating aliskiren to date, involving over 7000 patients with mild to moderate hypertension. In these early-phase studies, doses ranged from 75 to 600 mg/day. The primary outcome was the change in mean seated diastolic BP (DBP) from baseline at week 6.

In general, the effect on BP was dose-dependent and tended to plateau between 300 and 600 mg/day. Adjusted for placebo response, active treatment reduced DBP in the overall cohort by 7 to 8 mm Hg at week 6. The same was generally true for systolic BP (SBP), where with placebo subtraction of SBP response, the net reduction was between 10 and 11 mm Hg across all monotherapy studies. Importantly, neither gender nor age had any impact on BP response. Dr. Weir concluded that aliskiren at 150 and 300 mg/day exhibits placebo-like tolerability and is similar in antihypertensive effect to that of the ARBs (Figure 2).

Figure 2. Addition of DRI to Other Antihypertensi
mpromise Tolerability

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Combination Therapy

Given that most patients need two or more antihypertensive agents to achieve target BP goals, it is important to assess the effect of combining this compound with other antihypertensive agents. The impact of adding the DRI to the CCB amlodipine was evaluated in patients who did not achieve target BP goals on the CCB alone. Patients received either aliskiren 150 mg plus amlodipine 5 mg (n=187), amlodipine 5 mg (n=180) or amlodipine 10 mg (n=178). In all, 523 patients completed the study.

Dr. Mark Munger, Professor of Internal Medicine and Pharmacology, University of Utah, Salt Lake City, presented results showing that this combination led to statistically greater reductions in both mean DBP and SBP compared with amlodipine 5 mg alone and comparable reductions in DBP to those achieved with amlodipine 10 mg. Of course, combining agents at a lower dose reduces the risk of side effects.

Interestingly, 2.1% of patients developed peripheral edema in the combination arm vs. 3.4% of those in the amlodipine 5 mg arm and 11.2% in the amlodipine 10 mg arm. The tolerability profile in the combination arm was similar to that seen with amlodipine 5 mg alone. It is believed by many that ACE inhibitors and ARBs help to block the edema seen with CCBs and this may also be the case with aliskiren.

While investigating the impact of adding aliskiren to other blockers of the renin-angiotensin-aldosterone system (RAAS), Dr. Charles Kilo, Professor of Medicine, Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, found that aliskiren 300 mg produced a significantly greater reduction in SBP compared to ramipril 10 mg (14.7 vs. 12.0 mm Hg, respectively). However, when both agents were combined, it led to a significant, additional 4.6/2.1 mm Hg reduction in mean BP values compared with ramipril alone with an overall BP reduction of 16.6/12.8 mm Hg. In this study, as expected, all treatments increased renin levels from baseline and significantly more so with the combination. However, the PRA effect of the ACE inhibitor was counteracted by the DRI, leading to an overall PRA reduction from baseline.

The ability of the DRI to suppress PRA when given in combination with an ACE inhibitor might be clinically important, as increased generation of Ang I by renin is associated with the “escape” effect peculiar to ACE inhibitor monotherapy. In this study, serum potassium elevations (>5.5 mmol/L) were more common in the combination arm, indicating greater blockade of the RAAS than with either agent alone. When this combination is used in routine clinical practice, the same clinical monitoring of patients receiving this combination as for those on high dose-ACE inhibitors or ARBs or the combination should be sufficient to detect and address this effect.

Dr. Dominic Sica, Professor of Medicine and Pharmacology, Medical College of Virginia Commonwealth University, Richmond, presented 12-month results of the safety, tolerability and withdrawal effects of aliskiren 150 and 300 mg, given with or without hydrochlorothiazide (HCTZ) 12.5 or 25 mg. Patients received daily DRI doses of 150 mg (n=1179) or 300 mg (n=776). Those who did not achieve target BP goals of <140/90 mm Hg after two months on initial therapy received either dose titration with the DRI or additional HCTZ. At the end of 11 months, mean BP reduction from baseline was 17.5/12.4 mm Hg in the group initially randomized to 150 mg. Among those randomized to the 300-mg dose, the mean reduction was 18.8/ 13.3 mm Hg from baseline. Twenty-four-hour ambulatory BP monitoring carried out in a subset of the cohort showed that BP reductions with aliskiren were sustained and consistent throughout the 24-hour dosing interval.

Withdrawal Effects

In this latter trial, a patient subgroup was randomized at the end of month 11 to continue DRI monotherapy or placebo during a four-week, double-blind withdrawal phase. Results demonstrated a persistence of effect when treatment was withdrawn, with BP gradually rising but still below baseline levels, for up to four weeks. During the withdrawal period, no evidence of rebound hypertension in the placebo group was observed. According to Dr. Sica, this observation suggests that there may be a long-lived washout effect with this agent, which may prove beneficial in many instances.

Following the 11-month, open-label trial, the withdrawal effect on PRA and renin concentrations were evaluated by Dr. James Pool, Professor of Medicine and Pharmacology, Baylor College of Medicine, Houston, Texas, and colleagues. Long-term treatment with the DRI led to similar sustained reductions in PRA whether given as monotherapy or in combination with HCTZ. At study end, PRA had fallen by 68% from baseline in the monotherapy arm and by 65.4% in the combination arm. Predictably, renin concentrations increased in both treatment groups during the open-label study. In the withdrawal period, PRA reductions were maintained at least 50% below baseline levels for up to four weeks, while renin concentrations returned to approximately baseline levels at the end of this period. This prolonged impact on PRA suggests that aliskiren continues to have an inhibitory effect on the renin system beyond its plasma half-life. The continuing beneficial effect on both BP and PRA following DRI withdrawal may be important in a clinical setting where patients are not fully compliant with treatment and missed doses.

End-organ Protection

Results from animal models have shown that aliskiren has renoprotective effects. A double transgenic rat model study was designed to determine the target organ effects of a DRI or an ARB. These data were presented by Dr. Friedrich Luft, Professor of Internal Medicine, Nephrology and Hypertension, Humboldt University of Berlin, Germany, and demonstrated that albuminuria levels were reduced with aliskiren at either low-dose (0.3 mg/kg/day) or high-dose (30 mg/kg/day) as well as high-dose ARB (10 mg/kg/day). In the experimental model, both DRI doses and higher-dose ARB reduced markers of renal inflammation and significantly reduced left ventricular hypertrophy. With high-dose DRI, there were significantly greater reductions in left ventricular wall thickness and the cardiac hypertrophy index score was lower than with either valsartan doses.

Results from these experimental studies indicate that this agent provides at least comparable protection against renal and cardiac damage as the ARBs. Ongoing and planned studies will continue to evaluate its benefits on end-organ protection in humans.

Summary

Achieving target BP goals in the majority of hypertensive patients requires the combination of a number of different classes of antihypertensive agents. Until we can discern an individual’s specific medication needs from their own genome, success largely depends on the use of more than one antihypertensive agent and logical combinations of different classes of agents which are more likely to produce greater reductions in both DBP and SBP. RAS inhibition has been shown to protect patients against end-organ damage and is frequently favoured as initial therapy because of its protective properties. As the first oral DRI, aliskiren has been shown to be effective and well tolerated when given alone. In combination with other antihypertensive agents, it led to additional reductions in both DBP and SBP. The incidence of adverse effects was reduced when combined to either a CCB or an ACE inhibitor. It also has demonstrable, 24-hour BP control and a prolonged antihypertensive effect following discontinuation of treatment. Thus, the advent of an agent acting at the point of renin activation may prove to be, alone or in combination, an important addition to our existing antihypertensive agents.

Note: At the time of printing, aliskiren is not available for use in Canada.

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