Vasopeptide Inhibition for Congestive Heart Failure: Are You IMPRESS’ed?

Original Citation

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.

Overall Study Question

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). 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.

Are the Results of the Study Valid?

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.

Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Seven hundred and sixteen patients were enrolled, but 143 were considered ineligible or withdrew before randomization. This left 289 patients assigned to omapatrilat and 284 assigned to lisinopril.  Twenty-four patients withdrew from each arm (21 omapatrilat and 16 lisinopril patients due to adverse events), while 7 omapatrilat and 10 lisinopril patients died before study completion.  Therefore, 258 omapatrilat and 250 lisinopril patients completed the study protocol.  These results are clearly outlined in a figure in the original publication.  The investigators identify that analysis of the primary outcome was done by intention to treat, however 12-week exercise tolerance tests (ETT) results are reported for fewer patients than were assigned to each treatment arm (274 versus 289 for omapatrilat, and 265 versus 284 for lisinopril).  Although no explanation is provided in the text of the article, it may be assumed that the difference in these numbers is attributed to patients who did not complete study treatment and failed to return for follow-up ETT.

Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Although the abstract states the study was “double-blind”, no details of the blinding procedure are outlined in the original publication.
Were the groups similar at the start of the trial?

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%).

Aside from the experimental intervention, were the groups treated equally?

There is no information in the original publication to suggest that the two study groups were treated differently.

Overall, are the results of the study valid?
Yes.  Unfortunately, however, much media attention has focused on the secondary endpoints (e.g. composite of death, hospitalization, and discontinuation of study treatment due to worsening heart failure) which cannot be considered definitive.

What were the Results?

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).

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).

Will the Results Help Me in Caring for My Patients?

Can the results be applied to my patient care?

 

Since omapatrilat is not available in Canada or the U.S., these results cannot currently be applied to North American patients. The relatively small size of this trial and the use of a surrogate endpoint as the primary outcome make it difficult to draw conclusions regarding the potential place of omapatrilat in the treatment CHF.  The results of large ongoing studies in CHF and hypertensive patients will better define the place of vasopeptidase inhibitors if approved for use in North America (see Commentary).

Were all clinically important outcomes considered?

 

Yes, but not as the primary outcome.

 

Are the likely treatment benefits worth the potential harms and costs?

 

Since omapatrilat is not currently marketed in North America, the cost of therapy is unknown.  Potential harm seems limited based on the results of this trial, however the new drug application for omapatrilat was voluntarily withdrawn in April 2000 when the FDA raised concern over the incidence of angioedema in the pre-approval database.  There were 44 cases in over 6000 patients, four of which required intubation.  This is thought to be higher than the incidence for ACE inhibitors over a comparable treatment duration.

Commentary

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. 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. 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.

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