High Dose Diuretics Associated with Adverse Outcomes in ADHERE
September 21, 2007 By Grendel Burrell 
Washington, DC: Data from the Acute Decompensated Heart Failure National Registry (ADHERE) demonstrating an association between the use of high dose IV loop diuretics and adverse outcomes for patients with acute decompensated heart failure (ADHF) was presented as a poster at HFSA 2007 by Dr. Frank Peacock, Vice Chief, Department of Emergency Medicine, The Cleveland Clinic, for coauthors Drs. Maria R Costanzo, Teresa De Marco, Charles Emerman, and Margarita Lopatin, MS.
ADHERE (http://www.adhereregistry.com) was initiated in October 2001, and for purposes of this analysis, all records from October 2001 through February 2005 were reviewed. Records for patients on chronic renal dialysis, patients who received IV vasoactive therapy, patient records with missing data regarding gender, race, age, dyspnea at rest, initial heart rate, systolic or diastolic blood pressure, baseline serum sodium, serum creatinine (SCr), blood urea nitrogen (BUN), or chronic diuretic use were excluded. Additionally, records of patients taking multiple diuretics or diuretics other than furosemide, bumetanide, or torsemide were also excluded. The remaining 82,540 case records were divided by low-moderate (furosemide equivalent dose <160 mg/day) and high (furosemide equivalent to ≥ 160 mg/day) use of diuretics. There were 62,866 patient records in the low-moderate group and 19,647 in the high dose group.
Data was analyzed to compare changes in renal function, resource utilization, and in–hospital mortality both before and after adjusting for non-random treatment assignment and differences in risk factors. A propensity analysis was used to account for non-random treatment assignment. Multivariable logistic regression was employed to adjust group comparisons for treatment propensity, risk factors of age, BUN, SCr, systolic blood pressure, diastolic blood pressure, dyspnea at rest, initial heart rate, and serum sodium. Additionally multivariable logistic regression was also used to adjust group comparisons for chronic diuretic use, gender, and race. There was no adjustment made for BUN and SCr in the analysis of dialysis initiation due to a high correlation between dialysis and these covariates.
For all comorbidities assessed, the high IV diuretic use group had a greater percentage of patients, and for all comparisons, p < 0.0001. With respect to diabetes 52.3 % of patients in the high diuretic group had diabetes compared to 39.7% of patients in the low-moderate use group. There was a higher prevalence of patients with hypertension, dyslipidemia, coronary artery disease, atrial fibrillation, chronic renal insufficiency, and chronic obstructive pulmonary disease/asthma is the high IV diuretic use group.
A larger percentage of patients in the high use diuretic group compared to the low-moderate group were taking diuretics, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers, P < 0.0001 for all comparisons. For example, 67.1% of patients in the low-moderate dose group were taking non-IV diuretics compared to 82.3% of patients in the high diuretic dose group.
At the initial evaluation, patients in the high dose group had a systolic blood pressure of 144.2 +/- 30.5 mm Hg, compared to 146.0 +/- 30.4 mm Hg in the low-moderate group. Fewer patients in the high dose group had troponin assessed though more high dose group patients had an elevated troponin. Median creatinine was higher in the high dose group compared to patients in the low dose group. More patients in the high dose group had left ventricular function assessed and the percentage of patients with EF < 40% was higher in the high dose group (for each, P < 0.05).
Nearly 90% of patients admitted to the hospital with ADHF receive IV loop diuretics, and many of these patients have some level of concomitant renal dysfunction (www.adhereregistry.com, National Benchmark Report-Q1 2006). Renal dysfunction lowers the efficiency of diuretics, leading to the use of increased doses of diuretics, and this has been previously shown to be associated with increased risk of mortality (1,2). In a single center study by Eshagian, Horwich, and Fonarow, of 1354 patients with advanced systolic heart failure, patients were divided into quartiles of equivalent total daily loop diuretic dose: 0 to 40, 41 to 80, 81 to 160, and >160 mg. After extensive co-variate adjustment (age, gender, ischemic cause of HF, the ejection fraction, body mass index, pulmonary capillary wedge pressure, peak oxygen consumption, beta-blocker use, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, digoxin use, statin use, serum sodium, blood urea nitrogen, creatinine, hemoglobin, cholesterol, systolic blood pressure, and smoking history), diuretic quartile remained an independent predictor of mortality (quartile 4 vs quartile 1 hazard ratio 4.0, 95% confidence interval 1.9 to 8.4). They concluded that in this cohort of patients with advanced HF, there was an independent, dose-dependent association between loop diuretic use and impaired survival. Higher loop diuretic dosages identify patients with HF at particularly high risk for mortality (3).
In the poster presented at HFSA, another retrospective assessment of patients hospitalized with ADHF, but in multiple centers, Peacock and coauthors conclude, “…there is an association between the use of high-dose diuretics and adverse outcomes.” They suggest that further studies should evaluate therapeutic strategies for minimization of the use of high dose IV diuretics in hospitalized patients with ADHF.
- ref1 pmid=9691107
- ref2 pmid=12094185
- ref3 pmid=16765130