Seems a fairly weak pair of letters with a pretty cogent response. The key point about intravenous nitroglycerin is that the patients need more intensive monitoring than Nesiritide and also need dose titration.
Nesiritide vs Nitroglycerin for Decompensated Congestive Heart Failure
To the Editor: Dr Young and the Vasodilation in the
Management of Acute [congestive heart failure] CHF (VMAC) investigators1 found that, among patients with decompensated CHF, nesiritide resulted in only a 2-mm improvement in pulmonary capillary wedge pressure (PCWP) compared with nitroglycerin and a 4-mm improvement compared with placebo at both 3 and 24 hours. Although they claimed nesiritide improves hemodynamic function, this small change is of no clinical significance. Subjective dyspnea, as well as all other parameters, were not different between the groups. At 7 days, there were 4 deaths in the nesiritide group and 1 death in the nitroglycerin group, as well as a 4% greater 6-month mortality with nesiritide. The similar baseline characteristics argue against the differences being due to sicker patients randomized to nesiritide. Another recent study of nesiritide2 also showed minimal improvement, but in the presence of significant and persistent hypotension.
As a clinician, I welcome new advancements in the treatment of heart failure. There is still insufficient evidence to suggest that we should replace existing therapy. Until that proof exists, it would be premature to dismiss an effective treatment (nitroglycerin) before a clearly superior alternative has been demonstrated.
Scott Dunavant, MD
Department of Emergency Medicine
St Joseph Hospital
Lexington, Ky
1. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531-1540. ABSTRACT | FULL TEXT | PDF | MEDLINE
2. Colucci WS, Elkayam U, Horton DP, et al, for the Nesiritide Study Group. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med. 2000;343:246-253. MEDLINE
To the Editor: I have 3 concerns about the study by Dr Young
and the VMAC investigators.1 First, patients were not adequately randomized. Six (32%) of the 19 baseline characteristics in Table 1 are statistically and perhaps clinically significantly different between treatment groups. These include underlying clinical status, such as baseline use of intravenous pressors (2.5-fold difference between groups). The authors did not address or control for such variation other than to state that the primary outcome, greater reduction in PCWP in the nesiritide group, was also found in patients who were not receiving pressors at baseline. Although pressor use may not have directly confounded the results, it is still likely that the 2 treatment groups were not equivalent.
Second, the VMAC investigators do not provide baseline characteristics of the group that underwent right heart catheterization. Given that the primary finding of the study concerned only patients who were catheterized and that assignment to catheterization was not random, but based on clinical judgment, presentation of such variables would be important in assessing validity and generalizability.
Finally, the investigators' conclusion that nesiritide improves both hemodynamic, as well as self-reported symptoms, seems unwarranted. They do not present any statistically significant data demonstrating nesiritide's superiority in terms of clinical outcomes. They do mention (data not shown) that differences in scores on one scale were significant in a 2-way analysis, but not in the nonparametric analysis presented in Figure 3. A more conservative interpretation of the data would be that while nesiritide did lower PCWP more effectively than did nitroglycerin, this is of unknown importance especially as there was no demonstration of improved clinical outcomes. Likewise, it will be important to assess (in studies with enough power to assess adverse events) the trend toward higher 6- month mortality in the nesiritide group (25.1% vs 20.8%).
William Rifkin, MD
Department of Medicine
Maimonides Medical Center
Brooklyn, NY
1. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531-1540. ABSTRACT | FULL TEXT | PDF | MEDLINE
2. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002;287:1541- 1547. ABSTRACT | FULL TEXT | PDF | MEDLINE
In Reply: We agree with Dr Dunavant that no single clinical
trial should be considered in isolation. We point out that another study1 has found that nesiritide is safe and effective in improving hemodynamics, specifically PCWP and pulmonary artery pressures in patients with decompensated CHF. Our trial, as well as the earlier report by Colucci et al,1 demonstrated that nesiritide led to rapid reduction in PCWP, which is directly related to improvement of CHF symptoms. Indeed, in our trial, nesiritide consistently was associated with a greater decrease in PCWP during the first 24 hours than nitroglycerin at all time points except at 2 hours.
We disagree with Dunavant's view that the decrease in PCWP was "of no clinical significance." The mean decrease from baseline in PCWP at 3 hours was almost 6 mm Hg. This degree of hemodynamic change is statistically significant when compared with the placebo and nitroglycerin groups and also usually clinically significant in patients with decompensated CHF. It is also important that, unlike nitroglycerin, nesiritide did not induce tolerance. The previous study1 has, however, demonstrated that higher doses of nesiritide provided even greater reductions in PCWP and pulmonary artery pressures. Nesiritide also had a more rapid onset of clinical effects and proved to be easier to use than nitroglycerin because dose titration was not generally required. Dunavant's comment regarding "significant and persistent hypotension" with nesiritide referred to the previous study,1 which used doses 150% to 300% greater than the dose in our trial. At the recommended dose,2 which we used, hypotension occurred with a similar frequency as observed with nitroglycerin during the first 24 hours of dosing with symptomatic hypotension4% in the nesiritide group and 5% in the nitroglycerin group.
In response to Dr Rifkin, it is not unusual for clinical trials to have some imbalance in a few baseline parameters when treatment groups are compared. If anything, the group receiving nesiritide appeared to have more severe CHF. Because of space constraints, we could not present the specific baseline characteristics of the group stratified by the results of right heart catheterization. However, in this cohort, baseline characteristics were not significantly different between nitroglycerin, nesiritide, and placebo groups with the exception of slightly more patients in the placebo group having a history of frequent premature ventricular contractions.
Dunavant and Rifkin also comment on issues related to mortality and longer-term clinical outcomes. These are important end points, but our study was not designed as a mortality study (either short-term or long-term). We did point out that there was no statistically significant difference in mortality rates at either the 7-day or 6-month follow-up and that the confidence intervals overlap for this observation. Nesiritide does not appear to be associated with atrial or ventricular arrhythmias.3 This may translate into improvements in mortality, and such a study would be valuable.
Finally, we believe that our study results are applicable to managing hospitalized patients with CHF. We did not exclude patients who are usually eliminated from such trials (such as patients with CHF due to ischemic events or diastolic dysfunction) and allowed aggressive concomitant heart failure therapy, such as parenteral diuretics, other vasodilators (except nitroglycerin), and even inotropic agents if appropriate.
Peter |
