Reports

In the treatment of hypertension, there are two important issues. The first is treating to blood pressure (BP) goals established by current guidelines. The second is selecting a class of antihypertensive drug that will improve, or at least not exacerbate, pathogenic processes that contribute to progressive processes associated with hypertension, such as cardiac hypertrophy and renal dysfunction. Many of the current BP-lowering agents are not associated with any organ-specific benefits independent of BP control, and in the majority of patients, none of the agents achieve BP goals when used alone. This latter point—failure to reach goals—remains a major public health issue. In Canada, for example, a survey carried out in 2004 indicated that fewer than 20% of patients receiving antihypertensive treatment were at recommended targets of <140/90 mm Hg and these figures are even lower for European countries.

In the aim of both improved BP control and end-organ protection, “there is definitely room for improvement,” noted Dr. Michel Burnier, Division of Hypertension and Vascular Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. He indicated that current research is being directed at identifying strategies that both increase BP control and build on benefits of those agents which appear to offer target protection independent of BP control.

For example, inhibitors of the renin-angiotensin system (RAS) reduce proteinuria and slow progression of kidney disease, but more effective BP control and greater inhibition of RAS might improve both markers of benefit. Indeed, Dr. Burnier stated that more complete RAS blockade is likely to improve end-organ protection; however, given the current options, this strategy does not come without challenges.

In particular, as noted by several experts addressing this topic, high-dose therapy with ACE inhibitors often leads to a rate of adverse events that patients are not willing to tolerate. High doses of angiotensin receptor blockers (ARBs) are attractive, but there are insufficient data to support this approach. Moreover, it is clear from many studies that increased doses of RAS inhibitors do not necessarily provide greater reductions in BP, arguably the most important step in achieving optimal end-organ protection. Furthermore, as Dr. Luis Ruilope, Director, Hypertension Unit, Hospital Universitario 12 de Octubre, Madrid, Spain, commented at the meeting, “If I used 900 mg of irbesartan, I would increase the cost by threefold.”

These limitations have been the basis for interest in the clinical development of drugs in the direct renin inhibitor (DRI) class. Such agents inhibit renin and consequently block the RAS cascade at its point of activation. This earlier, more complete blockade prevents the phenomenon of alternate pathways and compensatory feedback mechanisms that lead to an undesirable increase in plasma renin activity (PRA) that are provoked by other RAS inhibitors. In initial clinical work, these agents have been found safe and effective as monotherapy and in combination with other BP-lowering agents, including other RAS inhibitors, a combination that may result in even more effective BP control.

RAS Pathophysiology

Dr. Ruilope characterized the combination of a DRI and an ARB as pharmacologically “very logical.” The DRIs inhibit the activity of renin, thereby blocking the rate-limiting step in the RAS pathway and all subsequent downstream events. In contrast, the ACE inhibitors block only one of the steps in the RAS where angiotensin I is converted to angiotensin II, which is why prolonged ACE inhibition leads to the well described phenomenon of angiotensin II escape through its generation by alternative pathways. The ARBs in turn block the actions of angiotensin II but only after circulating levels have been increased. Moreover, by suppressing the activity of angiotensin II, both the ACE inhibitors and the ARBs indirectly stimulate PRA. There is evidence to suggest that high levels of PRA in untreated patients are associated with a poorer cardiovascular prognosis.

As a DRI, aliskiren (which is the farthest along in clinical development) has been associated with potent PRA suppression which is maintained even in the presence of either an ACE inhibitor or an ARB. Thus, Dr. Ruilope suggested, “Whatever negative effects that PRA may exert in the kidney and the vasculature could potentially be attenuated when a DRI is combined with either an ACE inhibitor or an ARB.”

BP Control

Despite a bioavailability of 2.6%, aliskiren has demonstrated significant BP-lowering ability, according to clinical trials. Seven randomized trials evaluating the new DRI as monotherapy for hypertension indicated that once adjusted for placebo response, aliskiren reduced mean seated diastolic BP by between 7 and 8 mm Hg by week 6 (P<0.05), and mean systolic BP by between 10 and 11 mm Hg (P<0.05), again adjusted for placebo response. Investigators also observed that the effect on BP was dose-dependent and typically plateaued between 300 and 600 mg/day. Across all the monotherapy studies, aliskiren at both 150 and 300 mg/day had a placebo-like adverse event profile, suggesting that either dose could be used as monotherapy or in combination with other antihypertensive agents. The DRI has demonstrated BP-lowering effects similar to both ACE inhibitor and ARB monotherapy.

In the ongoing clinical trials program evaluating the DRI in hypertension and related sequelae, the new compound has consistently been shown to lead to further reductions in both systolic and diastolic BP when added to all commonly used classes of current antihypertensive medications, with the exception of beta blockers,which have not been studied in combination with DRIs. These findings strongly suggest that more patients could successfully reach target BP goals if a DRI was used in combination with a diuretic, a calcium channel blocker (CCB), or another RAS-blocking agent. The same ongoing clinical trials program has also shown that when given in combination with either an ACE inhibitor or a CCB, aliskiren appears to attenuate the usual side effects seen with either drug class, especially when higher doses of an ACE inhibitor or a CCB are required.

Combination Therapy

According to Dr. Michel Azizi, Head, Clinical Investigation Centre, Hôpital européen Georges-Pompidou, Paris, France, a current trend towards improving BP control and optimizing end-organ protection is to use combinations of RAS inhibitors. He cited a meta-analysis (Doulton TW, He FJ, MacGregor GA. Hypertension 2005;45:880-6) in which a combination of an ACE inhibitor and an ARB was more effective than either agent alone. Although the combination reduced BP overall by 4.7/3.0 mm Hg more than ACE inhibitor monotherapy and by 3.8/2.9 mm Hg more than ARB monotherapy, the lead investigator noted that if larger doses of either a short- or long-acting ACE inhibitor were used, there was generally no additive effect of the ARB on BP.

Another combination study discussed at this meeting evaluated the interactive BP-lowering effects between an ACE inhibitor and a DRI. This study, led by Kilo et al., reported that co-administration of ramipril 10 mg/aliskiren 300 mg provided clinically relevant additional BP lowering (4.6/2.1 mm Hg) over that of ramipril 10 mg monotherapy, delivering an overall BP reduction of 16.6/12.8 mm Hg. In addition to improving BP control, PRA activity was found to decrease in both the aliskiren monotherapy and combination arms. Consequently, the DRI was considered to have counteracted the process by which PRA increased in the ramipril monotherapy arm.

The attenuation of PRA levels was also observed by Azizi et al. when the DRI was combined with an ARB (J Am Soc Nephrol 2004;15:3126-33). Hormonal and BP effects were compared for 48 h after administration of aliskiren 300 mg, valsartan 160 mg, or a combination of half-dose aliskiren 150 mg/valsartan 80 mg. As with the DRI and ACE inhibitor combination, PRA was reduced when the DRI was co-administered with an ARB and when used as monotherapy. The combined half-doses of both agents lowered BP at least as effectively as either higher-dose monotherapy.

Summary

While these results are encouraging, more data are needed to confirm if any single combination of RAS blockade—be it a DRI plus an ARB, a DRI plus an ACE inhibitor or an ACE inhibitor plus an ARB—simultaneously provides optimal BP control and protection against end-organ damage. Speakers here agreed that there is clearly “room for improvement,” both in terms of achieving tight BP control, especially in high-risk patients (diabetes/renal disease), as well as better end-organ protection, the ultimate goal in antihypertensive therapy but which cannot be achieved without first getting patients to target BP.