March 2001
Michael J. Bloch, MD
University of Nevada
February 2001
Despite the explosion in the number of medications available for the treatment of hypertension, rates of blood pressure control remain woefully suboptimal. Part of the reason for this lack of adequate control stems from the fact that monotherapy with the agents currently available will usually not suffice in bringing a patient to goal. Compared with placebo, most available anti-hypertensive agents will only decrease diastolic blood pressure (DBP) by about 5-8 mm Hg and systolic blood pressure (SBP) by about 7-14 mm Hg. We are also realizing that not all anti-hypertensive agents are alike. There is a growing belief that agents which have beneficial effects on a number of vasoactive peptides may have an advantage in preventing cardiovascular events, especially in high risk (JNC VI Class C) patients.
For these reasons, there remains a need to develop new, powerful, well-tolerated antihypertensive medications, which have beneficial effects on cardiovascular and endothelial structure and function. This article will focus on a new emerging class of blood pressure medications, vasopeptidase inhibitors (VPIs). These novel drugs work through effects on both the renin-angiotensin-aldosterone system (RAS) and the natriuretic peptide system (NPS). This article will critically examine the rationale for the use of these drugs and the clinical evidence that has been accumulated to date.
The Renin-Angiotensin-Aldosterone System (RAS)
Evidence of the importance of the RAS in cardiovascular disease continues to grow. The RAS is an enzymatic cascade that leads to the production of two important peptide hormones: angiotensin II (AngII) and aldosterone. AngII is an extremely potent vasoconstrictor, which has been shown to have deleterious effects on cardiovascular and endothelial structure and function. It also has direct renal effects which lead to sodium and water retention, and there is increasing evidence that angiotensin II has negative non-hemodynamic effects as well. Through interactions with various proto-oncogenes, AngII has been shown to play an important role in fibrosis and cellular hypertrophy (in the hypertrophied heart, the end-stage fibrotic kidney, and smooth muscle cells in the vasculature). The importance of the hormone aldosterone, which causes sodium and water retention at the distal tubule and may have other adverse non-hemodynamic effects as well, increasingly appears to have a significantly deleterious effect, especially in congestive heart failure.
The relevance of RAS activation to cardiovascular disease has been highlighted by the striking results of studies using ace-inhibitors (and ARBs) to interrupt this system. Impressive survival benefits have been seen using ace-inhibitors in congestive heart failure and post-myocardial infarction (CONSENSUS, SAVE, SOLVD, and AIRE). Further demonstrating the importance of this system in congestive heart failure, in the RALES Trial the addition of a small dose of spiranolactone (an aldosterone antagonist) to standard therapy had a significant impact in reducing subsequent cardiovascular events and cardiovascular death.
ACE-Inhibitors have also been shown to decrease proteinuria and the incidence of end-stage renal disease in diabetes mellitus. And, most recently the importance of interruption of the RAS in patients at high risk for cardiovascular disease was demonstrated in the HOPE Trial. In HOPE, 9297 high-risk patients were randomized to receive ramipril (10 mg/day) or placebo; at the conclusion of the trial, subjects randomized to ramipril had a significant decrease in the incidence of heart attack, stroke, and cardiovascular death.
The Natriuretic Peptide System (NPS)
As important as the RAS appear to be, it really is only a part of a much larger system of vasoactive peptides. These peptides can be divided into two groups: 1) those which cause vasoconstriction and sodium retention and 2) those which cause vasodilation and natriuresis (NPS). The major peptides, their origins, and hemodynamic effects are given in Table 1. In general, the vasoconstrictor peptides and the vasodilatory peptides have opposing effects and appear to act as a combined pathway which remains in counter-regulatory balance (Figure 1). In the setting of cardiovascular disease, it seems that the balance is tipped in favor of over-expression of the vasoconstrictor peptides and under-expression of the vasodilatory peptides. Agents, which interrupt activation of the RAS (ACE-inhibitors and ARBs), return the balance towards equilibrium; however, they only act upon one side of this system.
The peptides which make up the NPS cause vasodilation, natriuresis, decreases in sympathetic tone, decreased production of aldosterone and endothelin, and inhibition of fibrosis and cellular hypertrophy. Since all of these actions would be beneficial in patients with hypertension and cardiovascular disease, there has been a great deal of enthusiasm towards developing agents that increase activation of the NPS. The most widely used method has been blockade of the enzyme that is responsible for the degradation of these peptides, neutral endopeptidase or NEP.
Unfortunately, studies using pure NEP inhibitors have been largely disappointing. This lack of efficacy is likely secondary to increased activation of the RAS that is seen in the setting of pure NEP inhibition. However, when NEP inhibitors were given in combination with ACE-Inhibitors, blood pressure decreases were substantial and much greater than that found using ACE-inhibitors alone.
It appears that a blockade of both ACE and NEP could be advantageous in returning the vasopeptide balance towards equilibrium, thus lowering blood pressure significantly and preventing cardiac, vascular, and renal complications. Because both ACE and NEP are zinc metalloproteases it became possible to develop a single agent, which could simultaneously inhibit both enzymes (Figure 2). The first of these agents, known as vasopeptidase inhibitors or VPIs, to reach clinical trials is omapatrilat.
Vasopeptidase Inhibitors (VPIs): Early Clinical Results
The majority of the early clinical trial experience with VPIs comes from studies done using omapatrilat. Omapatrilat has been studied in a variety of patients with hypertension and congestive heart failure. The results of these early studies are reviewed below. It is important to realize that some of these results have been presented only in abstract form and have not yet undergone peer review.
Efficacy of VPIs in Hypertension
Early animal studies demonstrated that omapatrilat was effective in lowering blood pressure in both salt-loaded and salt-depleted models. In clinical trials, this compound has been shown to decrease blood pressure more robustly than most previously studied agents. Most studies have shown a 15-25 mmHg decrease in SBP and a 10-16 mmHg decrease in DBP compared to placebo. In one notable trial, withdrawal of omapatrilat after chronic use led to average increases in blood pressure of 16 mmHg systolic and 9 mmHg diastolic as compared to those who were continued on the drug (Figure 3). In other studies, 80 mg/day of omapatrilat has been shown to lead to greater blood pressure reductions than either 40 mg/day of lisinopril or 10 mg/day of amlodipine (abstracts presented at the 2000 American Society of Hypertension Meetings).
In isolated systolic hypertension, 40 mg/day of omapatrilat has been shown to decrease SBP by approximately 25 mmHg, while dropping DBP by < 5mmHg.
Significant blood pressure reductions have been seen in both caucasian and african american subjects, and VPIs seem to be effective blood pressure lowering agents regardless of plasma renin levels. These robust decreases in blood pressure do not appear to be associated with any worsening of renal function, and both urinary flow rate and sodium excretion have been shown to increase in healthy volunteers despite dramatic falls in blood pressure.
This data suggests that these agents may be more effective at lowering blood pressure than monotherapy with currently available agents while still offering the vascular benefits of ace-inhibition. Due to their favorable effects on renal hemodynamics, it is also hoped that these agents will preserve renal function in patients with diabetic and other forms of nephropathy, but further research is clearly needed.
There are two large-scale ongoing hypertension trials with omapatrilat (Table 2). The first is known as OPERA, and it is a placebo-controlled trial of approximately 12,600 subjects with Stage I Isolated Systolic Hypertension, which will examine the effect of treatment on a composite endpoint of stroke, myocardial infarction, heart failure, and cardiovascular mortality. The second trial is known as OCTAVE. This trial is designed to compare the safety and blood pressure lowering efficacy of omapatrilat compared to enalapril.
Efficacy of VPIs in Congestive Heart Failure
Since these agents interrupt the activity of the RAS and promote natriuresis, there is considerable enthusiasm to study VPIs in congestive heart failure. Both animal models and early clinical trials have shown improvement in cardiovascular hemodynamics with omapatrilat. These effects include decreases in left ventricular end-diastolic pressure, increases in cardiac output, and decreases in peripheral vascular resistance.
In the largest clinical experience to date, Rouleau et al compared the effects of omapatrilat (10-40 mg/day) to lisinopril (5-20 mg/day) in the IMPRESS Trial. In this trial, 573 subjects with Class II to IV congestive heart failure were randomized in double-blind fashion. After 24 weeks of treatment there was no change in the primary endpoint of maximum treadmill exercise tolerance. However, there were significantly fewer cardiovascular system adverse events in the omapatrilat group, and there was a trend in favor of omapatrilat on the combined endpoint of death or admission for worsening heart failure.
Although the results of IMPRESS are promising, the number of patients is small and the follow-up was relatively short. A larger follow-up trial is currently underway (Table 2). Known as OVERTURE, this study compares the use of omapatrilat with enalapril in patients with Class II to IV heart failure; however, unlike IMPRESS it is sufficiently powered to evaluate the effect on cardiovascular endpoints.
Safety of VPIs
VPIs are currently available only as part of clinical trials. In this setting, omapatrilat and other VPIs have been given to over 10,000 subjects. In general, these agents have been very well tolerated. In the IMPRESS trial, among the most common side-effects were dizziness, edema, fatigue, diarrhea, and cough. As is the case with ACE-Inhibitors, a particularly troublesome safety issue with these agents is the risk of angioedema. This potentially fatal adverse event occurs in approximately 0.5% of patients treated with ACE-Inhibitors. Although the exact incidence with omapatrilat is unknown, it has been suggested in an editorial in the Lancet that the incidence is slightly higher than seen with ACE-Inhibitors. One of the endpoints in the OCTAVE Study is to determine the relative incidence of angioedema with omapatrilat compared to ACE-Inhibitors.
Conclusion
Due to their dual blockade of both the ACE and NEP enzymes, VPIs may be able to correct the imbalance of vasoactive peptides that is found in patients with cardiovascular disease. Due to this unique dual action, these agents appear to have greater anti-hypertensive efficacy than other monotherapies. Also, since they act simultaneously as vasodilators, growth suppressors, and diuretics, these agents may have a theoretical advantage over ACE-inhibitors in the management of congestive heart failure and related disorders. However, until the completion of ongoing clinical trials examining the safety of these agents and their ability to decrease actual cardiovascular events, enthusiasm should be tempered. The hope is that these agents will prove to be a very powerful addition to our pharmaceutical armamentarium especially for patients with resistant hypertension and those at high cardiovascular risk.
References:
Asher JR, Naftilan AJ. Vasopeptidase inhibition: a new direction in cardiovascular treatment. Current Hypertens Reports 2000;2:384-391.
Black HR, Chang PI, Reeves RA, et al. Monotherapy treatment success rate of omapatrilat, a vasopeptidase inhibitor compared with lisinopril and amlodipine in mild to moderate hypertension [abstract]. Am J Hypertens 1999;12(pt2):26A.
Guthrie R, Graff A, Mroczek WJ, et al. Double-blind withdrawal of omapatrilat after long-term stable administration demonstrates persistence of antihypertensive efficacy. Abstract Presented at the 14th Annual ASH Scientific Meeting, 2000.
LaRochelle P, Smith DHG, Ouellet JP, et al. Efficacy and safety of omapatrilat in subjects with isolated systolic hypertension. Abstract presented at the 14th annual ASH Scientific Meeting, 2000.
Rouleau JL, Pfeffer MA, Stewart DJ et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomized trial. Lancet 2000;356:615-620.
The Heart Outcomes Prevention Study Evaluation Study Investigators. Effects of angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Eng J Med 2000;355:253-259.
Trippodo NC, Robl JA, Assad MM et al. Effects of omapatrilat in low, normal and high renin experimental hypertension. Am J Hypertens 1998;11:363-372.
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