Furosemide is the most commonly used loop diuretic in patients with heart failure (HF) despite data suggesting potential pharmacologic and antifibrotic benefits with torsemide. We investigated patients with HF in Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure who were discharged on either torsemide or furosemide. Using inverse probability weighting to account for the nonrandom selection of diuretic, we assessed the relation between choice of diuretic at discharge with 30-day mortality or HF hospitalization and 180-day mortality. Of 7,141 patients in the trial, 4,177 patients were included in this analysis, of which 87% (n = 3,620) received furosemide and 13% (n = 557) received torsemide. Torsemide-treated patients had lower ejection fraction and blood pressure and higher creatinine and natriuretic peptide level compared with furosemide. Torsemide was associated with similar outcomes on unadjusted analysis and nominally lower events on adjusted analysis (30-day mortality/HF hospitalization odds ratio 0.89, 95% CI 0.62 to 1.29, p = 0.55 and 180-day mortality hazard ratio 0.86, 95% CI 0.63 to 1.19, p = 0.37). In conclusion, these data are hypothesis-generating and randomized comparative effectiveness trials are needed to investigate the optimal diuretic choice.
Highlights
- •
Furosemide is the most commonly used loop diuretic in patients with heart failure despite data suggesting potential pharmacologic and antifibrotic benefits with torsemide.
- •
In this large international acute heart failure trial, a minority of patients received torsemide and commonly had indicators of more severe disease.
- •
After risk adjustment, torsemide was associated with a nonsignificant reduction in 30- and 180-day events.
Loop diuretics including furosemide and torsemide are prescribed for most of the patients with symptomatic heart failure (HF). Guidelines indicate that the optimal use of diuretics is a cornerstone of HF therapy. However, despite preclinical and clinical data supporting benefits with torsemide, furosemide is the most commonly used loop diuretic. Several small studies of torsemide versus furosemide and a recent meta-analysis suggest a decrease in HF morbidity and potentially mortality with torsemide compared with furosemide. These previous studies were limited by modest sample sizes in cohorts of patients from more than a decade ago. To investigate the potential role of torsemide in contemporary clinical practice, we assessed loop diuretics in a large, international acute HF trial and evaluated the association with baseline characteristics and postdischarge outcomes.
Methods
The design and results of the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial have been reported previously. Briefly, the trial was an international, double-blind, placebo-controlled study evaluating the effectiveness and safety of nesiritide in addition to standard care in 7,141 patients with acute HF. The trial was conducted from May 2007 to August 2010 at 398 centers in 30 countries throughout the world. Detailed inclusion and exclusion criteria have been described previously. The 2 primary end points were a composite end point of all-cause mortality or HF readmission up to 30 days after randomization and the change in early dyspnea relief after study drug initiation.
Data on patient characteristics were collected during the baseline hospitalization. Loop diuretic use was documented at hospital admission and discharge. Rehospitalization and fatal events within 30 days after randomization were reviewed and categorized by an independent, blinded clinical events committee. HF hospitalization was classified as previously described. In brief, HF hospitalization required typical clinical manifestations of worsening HF and the addition of or increase in treatment specifically for worsening HF. All-cause mortality was assessed through 180 days.
For the primary analyses, we limited the cohort to patients discharged alive on either furosemide or torsemide. Given significant regional variation in the use of torsemide, we restricted the analyses to those countries having at least 20 patients on either torsemide or furosemide and having some patients on torsemide.
The primary outcome for the present analysis was all-cause mortality or HF hospitalization through 30 days after discharge. Secondary outcomes were 30-day all-cause mortality, 30-day HF hospitalization, and 180-day all-cause mortality after discharge. We were also interested in identifying clinical factors associated with patients being discharged on torsemide as compared with furosemide.
We summarized the patterns of loop diuretic use in ASCEND-HF patients. Demographics, physical and laboratory findings, medical history, and therapies were summarized as frequencies and percentages for categorical variables and by the medians and 25th and 75th percentiles for continuous variables in patients discharged on either torsemide or furosemide. Baseline characteristics were compared using the Student t test or Wilcoxon rank-sum test for continuous variables, and chi-square tests for categorical variables as appropriate. We generated a multivariate logistic regression model to determine admission variables associated with discharge torsemide use (over furosemide). We assessed the number of events for the outcomes of interest on the basis of the discharge diuretic.
Because the choice of diuretic at discharge was not randomized, we developed a propensity score model to predict the use of furosemide versus torsemide. The propensity score model was fitted using a logistic regression model with baseline covariates identified in previous ASCEND-HF models. The covariates were country of randomization, age, previous hospitalization for HF, baseline systolic blood pressure (SBP), baseline sodium, baseline blood urea nitrogen (BUN), and having a qualifying episode with jugular venous distension (JVD). The estimated propensity scores were used in inverse propensity weighted (IPW) models to assess the association of furosemide or torsemide use with clinical end points. IPW methods are a set of statistical techniques that reweight the data to create a pseudo-population in which patient characteristics are independent of the treatment received. This condition where there is independence of observed baseline factors and treatment is similar to what would be expected in a randomized study. Thus, IPW is a powerful method for using observational data to compare the effectiveness of 2 or more treatments. This technique offers a method to address concerns that any observed difference in outcome between 2 groups may reflect inherent differences between the groups (e.g., one group has an increased severity of disease) rather than effects caused by the 2 treatments. In the present analysis, covariate balance was assessed using standardized differences. Logistic regression analyses (for 30-day end points) and Cox proportional hazards (for the 180-day end point) models were generated to assess the association between loop diuretics and clinical outcomes, weighted by the inverse of the estimated probability of the choice of a particular diuretic. Multivariate regression analysis adjusting for covariates mentioned previously was also performed as a secondary analysis. Hazard ratios (HRs) for 180-day mortality and odds ratios (ORs) for other end points were calculated with corresponding 95% CIs relative to discharge diuretic. Event rate curves were shown using unadjusted and IPW-adjusted Kaplan–Meier estimates. Statistical significance was assessed using 2-sided p values. A p value <0.05 was considered statistically significant. All statistical computations were generated using SAS, version 9.4, (SAS Institute Inc., Cary, North Carolina). No extramural funding was used to support this work. The investigators are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the report and its final contents.
Results
Figure 1 presents the patients included in this analysis. Of the 7,141 patients in ASCEND, there was discharge diuretic information on 6,398 patients. Most of the patients discharged on a loop diuretic received furosemide (n = 5,305; 82.9%). Torsemide was the next most common loop diuretic (n = 628; 9.8%) and 267 patients (4.2%) were prescribed bumetanide. There were 72 patients discharged on a combination of loop diuretics and 126 patients (2.0%) who were not discharged on a loop diuretic. The analysis cohort restricted to patients from countries with at least 20 participants on either torsemide or furosemide and having some patients on torsemide consisted of 4,177 patients from 7 countries: China, India, Korea, Poland, Russia, Ukraine and the United States ( Table 1 ). Of the 4,177 patients in the outcomes analysis cohort, 87% (n = 3,620) received furosemide and 13% (n = 557) received torsemide. Patients enrolled in the United States constituted nearly half of the overall torsemide cohort (n = 265, 47.6%), where there was 11.4% use of torsemide compared to 88.6% use of furosemide.
| Characteristic | Furosemide (N=3620) | Torsemide (N=557) | P-Value |
|---|---|---|---|
| Age (years) | 65 (54-75) | 65 (54-74) | 0.34 |
| Women | 1255 (34.7%) | 179 (32.1%) | 0.24 |
| Race | <.001 | ||
| White | 1750 (48.3%) | 257 (46.1%) | |
| Black | 814 (22.5%) | 86 (15.4%) | |
| Asian | 1027 (28.4%) | 207 (37.2%) | |
| Other | 29 (0.8%) | 7 (1.3%) | |
| Country ∗ | <.001 | ||
| China | 182 (90.6%) | 19 (9.4%) | |
| India | 730 (81.3%) | 168 (18.7%) | |
| Korea | 99 (84.6%) | 18 (15.4%) | |
| Poland | 224 (93.7%) | 15 (6.3%) | |
| Russia | 211 (86.8%) | 32 (13.2%) | |
| Ukraine | 117 (74.5%) | 40 (25.5%) | |
| United States | 2057 (88.6%) | 265 (11.4%) | |
| Heart failure history | |||
| HF hospitalization within prior year | 1476 (40.8%) | 239 (42.9%) | 0.35 |
| Ischemic etiology | 2228 (61.5%) | 38 (69.5%) | <.001 |
| Ejection fraction (%) | 30 (20-35) | 25 (20-35) | 0.025 |
| Ejection fraction ≥50% | 346 (9.6%) | 52 (9.3%) | 0.87 |
| NYHA Class | 0.12 | ||
| I | 77 (2.6%) | 8 (1.7%) | |
| II | 501 (17.0%) | 79 (16.6%) | |
| III | 1572 (53.5%) | 238 (50.0%) | |
| IV | 791 (26.9%) | 151 (31.7%) | |
| Past medical history | |||
| Hypertension | 2667 (73.7%) | 383 (68.8%) | 0.015 |
| Diabetes mellitus | 1537 (42.5%) | 271 (48.7%) | 0.006 |
| Hyperlipidemia | 1473 (40.7%) | 233 (41.8%) | 0.62 |
| Coronary artery disease | 2025 (56.0%) | 361 (64.8%) | <.001 |
| Myocardial infarction | 1267 (35.0%) | 223 (40.0%) | 0.021 |
| Atrial fibrillation or flutter | 1206 (33.3%) | 214 (38.4%) | 0.018 |
| Ventricular tachycardia | 340 (9.4%) | 73 (13.1%) | 0.006 |
| Cerebrovascular disease | 445 (12.3%) | 65 (11.7%) | 0.68 |
| Peripheral vascular disease | 393 (10.9%) | 65 (11.7%) | 0.57 |
| Chronic respiratory disease | 595 (16.4%) | 101 (18.1%) | 0.32 |
| Prior percutaneous coronary intervention | 604 (16.7%) | 101 (18.1%) | 0.40 |
| Prior coronary bypass | 643 (17.8%) | 129 (23.2%) | 0.002 |
| Qualifying Episode Symptoms | |||
| Dyspnea | 0.50 | ||
| At Rest | 2148 (59.3%) | 339/557 (60.9%) | |
| With Minimal Activity | 1472 (40.7%) | 218/557 (39.1%) | |
| Orthopnea | 2723 (75.3%) | 424/556 (76.3%) | 0.63 |
| Weight Gain | 2333 (64.6%) | 387/557 (69.5%) | 0.026 |
| Physical Examination | |||
| BMI (kg/m 2 ) | 28 (24-33) | 28 (24-34) | 0.70 |
| Systolic BP (mmHg) | 125 (110-140) | 120 (110-131) | <.001 |
| Diastolic BP (mmHg) | 76 (68-85) | 72 (66-80) | <.001 |
| Heart rate (bpm) | 82 (72-95) | 82 (72-94) | 0.36 |
| Elevated JVP documented | 1968 (54.4%) | 340 (61.0%) | 0.003 |
| S3 gallop | 971 (26.8%) | 144 (25.9%) | 0.63 |
| Mitral regurgitation | 983 (27.2%) | 170 (30.5%) | 0.098 |
| Pulmonary edema | 3072 (84.9%) | 450 (80.9%) | 0.018 |
| Peripheral edema | 2641 (73.0%) | 431 (77.4%) | 0.028 |
| Laboratories and imaging | |||
| Sodium (mmol/L) | 139 (136-141) | 138 (135-141) | <.001 |
| Creatinine (mg/dL) | 1.2 (1.0-1.5) | 1.3 (1.1-1.6) | 0.002 |
| Blood urea nitrogen (mg/dL) | 23 (17-34) | 28 (19-39) | <.001 |
| Hemoglobin (g/dL) | 12.6 (11.3-13.9) | 12.5 (11.2-14.0) | 0.54 |
| NT-proBNP (pg/mL) | 4307 (2112-8770) | 5345 (2661-9315) | 0.006 |
| X-ray indicating pulmonary congestion | 2560 (78.1%) | 329 (70.0%) | <.001 |
| Baseline medications and devices | |||
| Furosemide-equivalent dose (mg) | 40 (40, 80) | 40 (20, 80) | 0.0013 |
| ACE-inhibitor or ARB | 2145 (59.3%) | 332 (59.6%) | 0.88 |
| Beta blocker | 2133 (58.9%) | 336 (60.3%) | 0.54 |
| Aldosterone antagonists | 969 (26.8%) | 199 (35.7%) | <.001 |
| Oral or Topical Nitrates | 843 (23.3%) | 170 (30.5%) | <.001 |
| Digoxin or Digitalis Glycoside | 973 (26.9%) | 195 (35.0%) | <.001 |
| Hydralazine | 311 (8.6%) | 55 (9.9%) | 0.32 |
| Implantable Cardioverter Defibrillator | 685 (18.9%) | 143 (25.7%) | <.001 |
| Biventricular pacemaker | 325 (9.0%) | 74 (13.3%) | 0.001 |
∗ For country, the data are presented as the number of patients (%) on each medication such that the row adds up to 100% for each country.
The baseline patient characteristics by discharge diuretic are presented in Table 1 . Patients receiving torsemide had more co-morbidities than those receiving furosemide. For instance, torsemide-treated patients had more diabetes mellitus, and atrial and ventricular arrhythmias compared with furosemide-treated patients. The median ejection fraction (EF) was lower in those receiving torsemide. Ischemic causes were more common in patients treated with torsemide. Torsemide-treated patients had lower SBP, and greater creatinine, BUN, and natriuretic peptide level. Patients discharged on torsemide more often received mineralocorticoid receptor antagonists (MRAs) and digoxin on admission compared with patients treated with furosemide. They also had greater baseline use of implantable cardiac devices compared with furosemide-treated patients.
Factors associated with torsemide use at discharge as presented in Table 2 . Country was the variable most strongly predictive of baseline torsemide use. Clinical factors associated with torsemide use were higher BUN, lower SBP, and JVD noted during the qualifying episode.
| Variable | OR (95% CI) | P-value |
|---|---|---|
| Country (reference=US) | <.001 | |
| China | 0.94 (0.57 – 1.56) | |
| Korea | 1.62 (0.92 – 2.84) | |
| Poland | 0.44 (0.23 – 0.86) | |
| Russia | 1.22 (0.80 – 1.85) | |
| Ukraine | 3.74 (2.48 – 5.63) | |
| India | 1.61 (1.28 – 2.03) | |
| BUN (per doubling) | 1.37 (1.21 – 1.55) | <.001 |
| Baseline systolic BP (per 10 mmHg increase) | 0.87 (0.83 – 0.92) | <.001 |
| Prior HF hospitalization | 1.15 (0.94 – 1.40) | 0.175 |
| Qualifying episode JVD | 1.29 (1.05 – 1.59) | 0.015 |
Table 3 presents the outcomes data in patients treated with furosemide or torsemide. Torsemide was associated with similar outcomes on unadjusted analysis (30-day mortality/HF hospitalization OR 1.03, 95% CI 0.73 to 1.45, p = 0.88 and 180-day mortality HR 0.97, 95% CI 0.73 to 1.29, p = 0.83). On IPW-adjusted analysis, torsemide use was associated with nominally lower 30-day mortality or HF hospitalization (OR 0.89, 95% CI 0.62 to 1.29, p = 0.55), 30-day mortality (OR 0.89, 95% CI 0.40 to 1.97, p = 0.78), 30-day HF hospitalization (OR 0.87, 95% CI 0.58 to 1.30, p = 0.49), and 180-day mortality (HR 0.86, 95% CI 0.63 to 1.19; p = 0.37) compared with furosemide. Figures 2 and 3 present the unadjusted and IPW-adjusted event rate curves and forest plots, respectively.
