The Journal of Informed Pharmacotherapy 2000;4:211-213.
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Reviewer: Stephen Shalansky, Pharm.D., FCSHP
Reviewer's email address: email@example.com
Reviewer's profession/specialty: Cardiology/Research
Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, et al. for the IMPRESS investigators. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 2000;356:615-20. PubMed Cit
Omapatrilat is the first vasopeptide inhibitor being studied for hypertension and heart failure. This class of drugs inhibits both angiotensin converting enzyme (ACE), and neutral endopeptidease (NEP) which metabolizes endogenous vasodilator peptides. Animal studies suggest that, compared to ACE inhibitors, the dual mechanism of action of vasopeptide inhibitors may better correct the imbalance between endogenous vasoconstrictors and vasodilators in congestive heart failure (CHF). (1). The primary objective of the IMPRESS trial was to compare the effects of omapatrilat with those of lisinopril on exercise tolerance in patients with congestive heart failure (CHF) after 12 weeks of therapy. Secondary endpoints included exercise tolerance at 24 weeks, adverse events, death, and comorbid events for worsening heart failure (hospital admission, discontinuation of study treatment). On study entry, patients had stable (>3 months) symptomatic heart failure (NYHA II-IV), decreased left-ventricular ejection fraction, and were receiving a stable (>4 weeks) dose of ACE inhibitors.
1. Was assignment of patients randomized?
Yes. Patients qualified for this study through a series of exercise tolerance tests, first while taking baseline medications (which had to include an ACE inhibitor) and then placebo. If all entry criteria were met, ACE inhibitor treatment was stopped and patients were randomized the next day to omapatrilat or lisinopril. Omapatrilat was initiated at an oral dose of 10mg once daily with a target dose of 40mg daily; lisinopril was initiated at an oral dose of 5mg once daily with a target dose of 20mg daily. The doses were force-titrated to target or maximum tolerated dose at weekly intervals for up to 3 weeks.
Yes. Baseline and demographic variables were similar between the two treatment groups including gender, ethnic origin, age, severity and cause of CHF, laboratory and hemodynamic measurement, and concomitant medications. However, there were slightly more patients in the lisinopril group taking long-acting nitrates (32% versus 27%) and calcium-channel blockers (4% versus 2%).
There is no information in the original publication to suggest that the two study groups were treated differently.
1. How large was the treatment effect?
The adjusted mean change from baseline in exercise duration at 12 weeks was 24 seconds for the omapatrilat group and 31 seconds for the lisinopril group (p=0.45). The difference at 24 weeks was also not statistically significant. There was no significant difference between the treatment groups with respect to total number of adverse events (25% for omapatrilat versus 33% for lisinopril) or total number of patients experiencing at least one adverse event (15% for omapatrilat versus 21% for lisinopril). However, more patients in the lisinopril group experienced cardiovascular side effects and elevated creatinine, while more patients in the omapatrilat group experienced dizziness, vision disturbance, diarrhea, and tracheobronchitis. One patient receiving lisinopril and none of the omapatrilat patients experienced angioedema (see Commentary for a discussion of angioedema).
In terms of clinical outcomes (all were secondary endpoints), there was no statistically significant difference in death from any cause (2% for omapatrilat versus 4% for lisinopril). There was a non-significant difference in the composite of death or admission for worsening heart failure favouring omapatrilat (5% versus 9%, p=0.052) and a significant difference in the composite of death, admission or discontinuation of study treatment favouring omapatrilat (6% versus 10%, p=0.035). Assessment of NYHA functional class suggested omapatrilat had more benefit in patients with more severe CHF (NYHA class III or IV).
2. How precise was the estimate of the treatment effect?The only reported measurement of precision relevant to the primary outcome was standard error of the mean for change from baseline exercise duration (6 seconds for both treatment groups). For the secondary outcomes, the hazard ratio for the composite of death or admission was 0.52 (95% CI 0.27-1.02) and for the composite of death, admission or study treatment discontinuation was 0.52 (95% CI 0.28-0.96).
2. Were all clinically important outcomes considered?
The IMPRESS trial results are not definitive, but provide evidence to support further research assessing the risk versus benefit of vasopeptidase inhibition. Since vasopeptidase inhibitors likely increase bradykinin levels more that ACE inhibitors, it is logical that they could lead to a higher incidence of angioedema (1, 3). However, this mechanism may also result in added clinical benefit. The results of several large ongoing trials will be key in determining the fate of omapatrilat in the treatment of CHF and hypertension. Bristol Myers Squibb (BMS), the developers of omapatrilat, launched the Omapatrilat Cardiovascular Treatment Assess Versus Enalapril (OCTAVE) trial at least in part to address the concerns of the FDA. The investigators plan to include 25,000 hypertension patients in 5000 clinical centers, and hope the results will be available in Spring 2001. In addition, a large trial in CHF, Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE), is ongoing and expects to report results in 2002 (4). A meta-analysis including data from IMPRESS and an unpublished safety study (a total of 1242 patients) was presented in March 2000 at the American College of Cardiology meeting. The results suggest a significant reduction in the composite of death and CHF hospitalization compared to lisinopril (RR 0.72, 95% CI 0.53-0.97, p=0.03). However, approval of omapatrilat in Canada and the U.S. likely hinges on the efficacy and safety data which will be available from OCTAVE.
1. Raut R, Rouleau JL, Blais C Jr, Gosseling H, Molinaro G, Sirois MG, et al.
Bradykinin metabolism in the postinfarcted rat heart: role of ACE and neutral
endopeptidase 24.11. Am J Physiol 1999;276(suppl):H1769-79.
2. Messerli FH, Nussberger J. Vasopeptidase inhibition and angioedema. Lancet 2000;356:608-9.
3. Jeffrey S. IMPRESS study results: Omapatrilat may offer "some advantages" over lisinopril in CHF patients. Aug. 17, 2000. www.theheart.org.
4. Hughes S. Further encouraging data with omapatrilat in heart failure. Mar. 23, 2000. www.theheart.org.
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