Low-Dose versus High-Dose Strategy

Patients assigned to the high-dose strategy were more likely to change to oral diuretics at 48 hours than were those assigned to the low-dose strategy (31% vs. 17%, P<0.001). Conversely, patients in the low-dose group were more likely to require a 50% increase in the dose at 48 hours than were those in the high-dose group (24% vs. 9%, P=0.003). The median total dose of loop diuretics received over the course of 72 hours (in intravenous furosemide equivalents) was 358 mg with the low-dose strategy as compared with 773 mg with the high-dose strategy (P<0.001) (for details, see Section 5 in the Supplementary Appendix).

There was a nonsignificant trend toward greater improvement in the primary efficacy end point in the high-dose group than in the low-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06) (Figure 1). There was no significant difference between these two treatment groups in the primary safety end point (mean change in the serum creatinine level, 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] in the low-dose group and 0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] in the high-dose group; P=0.21) (Figure 2).

High-dose furosemide resulted in greater net fluid loss, weight loss, and relief from dyspnea (Table 2). These potentially favorable effects of high-dose furosemide were balanced by a higher proportion of patients who met the prespecified secondary safety end point of worsening renal function (i.e., an increase in the serum creatinine level of more than 0.3 mg per deciliter at any time during the 72 hours after randomization), which occurred in 23% of the patients in the high-dose group, as compared with 14% in the low-dose group (P=0.04). There were no significant differences between the two study groups in serum creatinine and cystatin C levels during the index hospitalization or at 60 days (see Section 6 in the Supplementary Appendix).

Clinical Events

Fewer patients in the high-dose group than in the low-dose group had a serious adverse event (38% vs. 50%, P=0.03). There were no differences between the bolus group and the continuous-infusion group in the proportion of patients with serious adverse events (44% in each group, P=0.92). Individual rates of adverse events are shown in Section 4 in the Supplementary Appendix. There were more cases of ventricular tachycardia with boluses than with continuous infusion (7 vs. 4) and with the low-dose strategy than with the high-dose strategy (7 vs. 4). There were similar differences with respect to cases of myocardial infarction (4 cases vs. 1 case with both boluses vs. continuous infusion and low-dose strategy vs. high-dose strategy). There were more cases of renal failure with continuous infusion than with boluses (11 vs. 8) and with the low-dose strategy than with the high-dose strategy (12 vs. 7).

The median length of stay during the index hospitalization was 5 days and did not differ significantly across the treatment groups. A total of 130 patients (42%) died, were rehospitalized, or had an emergency department visit within the 60-day follow-up period, but there was no significant difference in this composite end point between the continuous-infusion group and the bolus group (67 events and 63 events, respectively; hazard ratio with continuous infusion, 1.15; 95% confidence interval [CI], 0.83 to 1.60; P=0.41) or between the high-dose group and the low-dose group (63 events and 67 events, respectively; hazard ratio with high dose, 0.83; 95% CI, 0.60 to 1.16; P=0.28) (Figure 3 FIGURE 3 Kaplan–Meier Curves for the Clinical Composite End Point of Death, Rehospitalization, or Emergency Department Visit.). The total numbers of days that patients were alive and out of the hospital were similar with the two modes of administration and the two dosing strategies (Table 2).

DISCUSSION

Although loop diuretics are an essential component of therapy for acute decompensated heart failure, there have been few prospective data to guide decision-making regarding the use of these agents. In this trial, we found no significant differences in either patients' global assessment of symptoms or the change in the creatinine level from baseline to 72 hours when diuretic therapy was administered by means of boluses as compared with continuous infusion or with a low-dose strategy as compared with a high-dose strategy.

With respect to the comparison of bolus with continuous infusion, there was no significant difference between the treatment groups across a broad range of efficacy and safety end points. These findings are not consistent with prior, much smaller studies suggesting that continuous infusion, as compared with boluses, is associated with a lesser degree of renal dysfunction and greater diuresis.10-15,21 One possible explanation for the absence of a significant difference in outcomes between boluses and continuous infusion in our study is the use of a continuous placebo infusion in the patients assigned to boluses; this feature of the study design may have served to increase the time the patients were supine, a position that has been shown to enhance diuresis.22In addition, it should be noted that the bolus group tended to receive a higher total dose of diuretic than did the continuous-infusion group.

With respect to the comparison of the low-dose strategy with the high-dose strategy, there was also no significant difference between the treatment groups in the primary efficacy or safety end points. The high-dose strategy was, however, associated with greater relief of dyspnea, greater fluid loss and weight loss, and fewer serious adverse events. In previous studies, greater relief of dyspnea has been associated with more favorable outcomes after discharge from the hospital.23 Although it is often assumed that dyspnea will resolve quickly with standard treatment, a recent study has suggested that moderate or severe dyspnea persists beyond the initial treatment phase in many patients with acute decompensated heart failure.24 Dyspnea was one of several secondary end points in this trial. Although the difference in the AUC measure of dyspnea between the high-dose and low-dose groups met our prespecified threshold for statistical significance, it remains possible that this was a chance finding.

Prior studies have suggested that high doses of diuretics are associated with worsening renal function,6 which has been proposed as a mechanism by which loop diuretics could lead to worse outcomes.5 Although worsening of renal function occurred more frequently with the high-dose strategy in the short term, there was no evidence at 60 days of worse clinical outcomes in the high-dose group than in the low-dose group. This observation is consistent with other recent data suggesting that transient worsening of renal function during hospitalization for heart failure may not affect the outcomes after discharge from the hospital.25,26 These findings suggest that prior observations linking high-dose diuretics with poor outcomes may reflect the severity of the illness rather than a harmful effect of high doses. Whether repeated episodes of transient worsening of renal function (as might occur during sequential hospitalizations) might in the long term have permanent harmful effects cannot be determined from this trial.

There are several limitations of this study. First, the patients who participated in the trial had a history of chronic heart failure and required moderate-to-high doses of loop diuretics (between 80 and 240 mg of furosemide per day or equivalent doses of other loop diuretics) as outpatients. Our findings may not be applicable to patients with newly diagnosed heart failure or those with more modest diuretic requirements. Second, the trial was not powered to detect between-group differences in clinical events. Finally, many participants received open-label diuretic therapy during the period before randomization, and the trial also allowed for adjustments in the diuretic dosing strategy after 48 hours of the randomly assigned strategy. These adjustments may have affected the observed differences between groups at the 72-hour end points.

In conclusion, among patients with acute decompensated heart failure and moderate-to-high baseline diuretic requirements, there were no significant differences in the patients' global assessment of symptoms or in changes from baseline renal function with either bolus as compared with continuous infusion of intravenous furosemide or with a low-dose strategy as compared with a high-dose strategy.

The Heart Failure Clinical Research Network is supported by grants (HL084861, HL084875, HL084877, HL084889, HL084890, HL084891, HL084899, HL084904, HL084907, and HL084931) from the National Heart, Lung, and Blood Institute.

Dr. Felker reports receiving consulting fees from Amgen, Cytokinetics, Corthera, Otsuka, Novartis, and Roche Diagnostics and grant support from Amgen, Cytokinetics, Otsuka, and Roche Diagnostics; Dr. LeWinter, receiving consulting fees from Novartis, grant support from Medtronic, and lecture fees from Medtronic and Novartis; Dr. Anstrom, receiving consulting fees from Johnson & Johnson and Pfizer; Dr. Hernandez, receiving consulting fees from Amgen and grant support from Johnson & Johnson and serving on a clinical end points committee for Corthera; Dr. Velazquez, receiving consulting fees from Novartis and Boehringer Ingelheim, grant support from Johnson & Johnson, and lecture fees from Novartis; Dr. Kfoury, receiving grant support from Novartis and XDx; Dr. Chen, receiving grant support from Scios, Anexon, and Nile Therapeutics, being named as a coinventor on patents for chimeric natriuretic peptides, and receiving royalties from Nile Therapeutics; and Dr. O'Connor, receiving consulting fees from Merck, GE Healthcare, Forest Pharmaceuticals, Medtronic, Novella Clinical, Medpace, Roche, Actelion Pharmaceuticals, Amgen, Trevena, and Martek Biosciences and grant support from Johnson & Johnson.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No other potential conflict of interest relevant to this article was reported.

SOURCE INFORMATION

From Duke University School of Medicine and Duke Heart Center (G.M.F., C.M.O.), and Duke Clinical Research Institute (K.L.L., K.J.A., A.F.H., S.E.M., E.J.V.) — all in Durham, NC; University of Utah, Salt Lake City (D.A.B., A.G.K.); Mayo Clinic, Rochester, MN (M.M.R., H.H.C.); Brigham and Women's Hospital (L.W.S., M.M.G., E.B.) and Massachusetts General Hospital (M.J.S.) — both in Boston; University of Minnesota, Minneapolis (S.R.G., B.A.B.); University of Vermont, Burlington (M.M.L.); Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston (A.D.); University of Montreal and Montreal Heart Institute, Montreal (J.L.R.); Morehouse School of Medicine, Atlanta (E.O.O.); and the National Heart, Lung, and Blood Institute, Bethesda, MD (A.M.M.).

Address reprint requests to Dr. Felker at Duke Clinical Research Institute, 2400 Pratt St., Rm. 0311 Terrace Level, Durham, NC 27705, or at michael.felker@duke.edu.

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