Bradley A. Bart

Diuretic Strategies in Patients with Acute Decompensated Heart Failure

BACKGROUNDnLoop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use.nnnMETHODSnIn a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patients previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.nnnRESULTSnIn the comparison of bolus with continuous infusion, there was no significant difference in patients global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function.nnnCONCLUSIONSnAmong patients with acute decompensated heart failure, there were no significant differences in patients global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).

Clinical Determinants of Mortality in Patients With Angiographically Diagnosed Ischemic or Nonischemic Cardiomyopathy

OBJECTIVESnWe sought to characterize the clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy.nnnBACKGROUNDnPatients with ischemic cardiomyopathy may have a worse prognosis than patients with nonischemic cardiomyopathy. Few studies have assessed the effect of ischemic versus nonischemic etiology on outcomes.nnnMETHODSnWe analyzed prospectively collected data on 3,787 patients with a left ventricular ejection fraction < or = 40% who underwent coronary angiography. Patients were considered to have ischemic cardiomyopathy (n = 3,112) if they had a history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery or at least one major epicardial coronary artery with > or = 75% stenosis; all others were considered to have nonischemic cardiomyopathy (n = 675).nnnRESULTSnThe median age, ejection fraction and proportion of patients with New York Heart Association functional class III or IV symptoms for the nonischemic and ischemic groups were 55 years versus 63 years, 27% versus 32% and 57% versus 25%, respectively. After adjustment for baseline clinical risk factors and presenting characteristics, ischemic etiology remained an important independent predictor of 5-year mortality (p < 0.0001). The extent of coronary artery disease was a better predictor of survival than ischemic or nonischemic etiology (log likelihood chi-square 700 vs. 675, respectively).nnnCONCLUSIONSnIschemic etiology is a significant independent predictor of mortality in patients with cardiomyopathy. However, the extent of coronary artery disease contributes more prognostic information than the clinical diagnosis of ischemic or nonischemic cardiomyopathy. Further research is needed to refine the clinical definition of ischemic cardiomyopathy so that physicians can appropriately prescribe treatment and accurately predict outcome.

Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors

BACKGROUNDnMany patients with congestive heart failure do not receive the benefits of angiotensin-converting enzyme (ACE) inhibitors because of intolerance. We sought to determine the tolerability of an angiotensin II receptor blocker, candesartan cilexetil, among patients considered intolerant of ACE inhibitors.nnnMETHODSnPatients with CHF, left ventricular ejection fraction less than 35%, and history of discontinuing an ACE inhibitor because of intolerance underwent double-blind randomization in a 2:1 ratio to receive candesartan (n = 179) or a placebo (n = 91). The initial dosage of candesartan was 4 mg/d; the dosage was increased to 16 mg/d if the drug was tolerated. A history of intolerance of ACE inhibitor was attributed to cough (67% of patients), hypotension (15%), or renal dysfunction (11%).nnnRESULTSnThe study drug was continued for 12 weeks by 82.7% of patients who received candesartan versus 86.8% of patients who received the placebo. This 4.1% greater discontinuation rate with active therapy was not significant; the 95% confidence interval ranged from 4.8% more discontinuation with placebo to 13% more with candesartan. Titration to the 16-mg target dose was possible for 69% of patients who received candesartan versus 84% of those who received the placebo. Frequencies of death and morbidity were not significantly different between the candesartan and placebo groups (death 3.4% and 3.3%, worsening heart failure 8.4% and 13.2%, myocardial infarction 2.8% and 5.5%, all-cause hospitalization 12.8% and 18.7%, and death or hospitalization for heart failure 11.7% and 14.3%).nnnCONCLUSIONSnCandesartan was well tolerated by this population. The effect of candesartan on major clinical end points, including death, remains to be determined.

Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease.

BACKGROUND AND OBJECTIVESnSympathetic activation is a hallmark of ESRD and adversely affects cardiovascular prognosis. Efferent sympathetic outflow and afferent neural signalling from the failing native kidneys are key mediators and can be targeted by renal denervation (RDN). Whether this is feasible and effective in ESRD is not known.nnnDESIGN, SETTING, PARTICIPANTS AND MEASUREMENTSnIn an initial safety and proof-of-concept study we attempted to perform RDN in 12 patients with ESRD and uncontrolled blood pressure (BP). Standardized BP measurements were obtained in all patients on dialysis free days at baseline and follow up. Measures of renal noradrenaline spillover and muscle sympathetic nerve activity were available from 5 patients at baseline and from 2 patients at 12 month follow up and beyond.nnnRESULTSnAverage office BP was 170.8 ± 16.9/89.2 ± 12.1 mmHg despite the use of 3.8 ± 1.4 antihypertensive drugs. All 5 patients in whom muscle sympathetic nerve activity and noradrenaline spillover was assessed at baseline displayed substantially elevated levels. Three out of 12 patients could not undergo RDN due to atrophic renal arteries. Compared to baseline, office systolic BP was significantly reduced at 3, 6, and 12 months after RDN (from 166 ± 16.0 to 148 ± 11, 150 ± 14, and 138 ± 17 mmHg, respectively), whereas no change was evident in the 3 non-treated patients. Sympathetic nerve activity was substantially reduced in 2 patients who underwent repeat assessment.nnnCONCLUSIONSnRDN is feasible in patients with ESRD and associated with a sustained reduction in systolic office BP. Atrophic renal arteries may pose a problem for application of this technology in some patients with ESRD.

Reasons for underuse of angiotensin-converting enzyme inhibitors in patients with heart failure and left ventricular dysfunction

We reviewed the records of 242 patients admitted over 1 year with heart failure and an ejection fraction < or = 45% to assess the use of angiotensin-converting enzyme inhibitors. Most patients were treated with angiotensin-converting enzyme inhibitors. However, an important minority (8%) had no apparent reason for the lack of this treatment, highlighting the need for strategies to increase the use of these beneficial agents.

Long-term survival in patients with refractory angina

AIMSnAn increasing number of patients with severe coronary artery disease (CAD) are not candidates for traditional revascularization and experience angina in spite of excellent medical therapy. Despite limited data regarding the natural history and predictors of adverse outcome, these patients have been considered at high risk for early mortality.nnnMETHODS AND RESULTSnThe OPtions In Myocardial Ischemic Syndrome Therapy (OPTIMIST) program at the Minneapolis Heart Institute offers traditional and investigational therapies for patients with refractory angina. A prospective clinical database includes detailed baseline and yearly follow-up information. Death status and cause were determined using the Social Security Death Index, clinical data, and death certificates. Time to death was analysed using survival analysis methods. For 1200 patients, the mean age was 63.5 years (77.5% male) with 72.4% having prior coronary artery bypass grafting, 74.4% prior percutaneous coronary intervention, 72.6% prior myocardial infarction, 78.3% 3-vessel CAD, 23.0% moderate-to-severe left-ventricular (LV) dysfunction, and 32.6% congestive heart failure (CHF). Overall, 241 patients died (20.1%: 71.8% cardiovascular) during a median follow-up 5.1 years (range 0-16, 14.7% over 9). By Kaplan-Meier analysis, mortality was 3.9% (95% CI 2.8-5.0) at 1 year and 28.4% (95% CI 24.9-32.0) at 9 years. Multivariate predictors of all-cause mortality were baseline age, diabetes, angina class, chronic kidney disease, LV dysfunction, and CHF.nnnCONCLUSIONnLong-term mortality in patients with refractory angina is lower than previously reported. Therapeutic options for this distinct and growing group of patients should focus on angina relief and improved quality of life.

Cardiorenal rescue study in acute decompensated heart failure: rationale and design of CARRESS-HF, for the Heart Failure Clinical Research Network.

BACKGROUNDnWorsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function.nnnMETHODS AND RESULTSnThe National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network designed a clinical trial to determine if ultrafiltration results in improved renal function and relief of congestion compared with stepped pharmacologic care when assessed 96 hours after randomization inxa0patients with ADHF and cardiorenal syndrome. Enrollment began in June 2008. This paper describes the rationale and design of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF).nnnCONCLUSIONSnTreating the signs and symptoms of congestion in ADHF is often complicated by worsening renal function. CARRESS-HF compares treatment strategies (ultrafiltration vs stepped pharmacologic care) for the management of worsening renal function in patients with ADHF. The results of the CARRESS-HF trial are expected to provide information and evidence as to the most appropriate approaches for treating this challenging patient population.

Treatment of Congestion in Congestive Heart Failure: Ultrafiltration Is the Only Rational Initial Treatment of Volume Overload in Decompensated Heart Failure

“If you have always done it that way, it is probably wrong.” nn— Charles F. Kettering, 1876–1958 nnThe morbidity of decompensated heart failure is due to volume overload, a consequence of increased total body sodium.1,2 Failure to adequately reduce total body sodium contributes to progressive ventricular dysfunction, worsening heart failure, and excess morbidity. Ultrafiltration is the gold standard for sodium-volume removal and is the only intervention shown to improve outcomes in a randomized controlled trial of patients hospitalized with decompensated heart failure.3 Diuretics are inherently inferior because they produce hypotonic urine4,5and undesirable hemodynamic and neurohormonal changes.6,7 Therefore, ultrafiltration is the preferred initial treatment for patients hospitalized with decompensated heart failure and sodium-volume overload.nnResponse by Shin and Dec on p 499 nnThe earliest descriptions of heart failure date back more than 3500 years to the Egyptian civilization. Even then, symptoms were correctly attributed to volume excess.8 It was not until the early 20th century that researchers recognized the role of salt in the formation of edema. In 1901, researchers found that salt fed to patients with congestive heart failure could not be recovered as chloride in the urine.8 This represents one of the earliest descriptions of heart failure as a sodium avid state. Later, it was demonstrated that liberal salt intake increased congestive symptoms and pulmonary edema in patients with heart failure whereas patients on salt-restricted diets could tolerate large amounts of water without any further increases in congestion or edema.8 Other studies confirmed the primary role of salt, not water, in the formation of edema in heart failure. By 1948, sodium was widely recognized as the major determinant in extracellular fluid volume.1nnToday, it is understood that sodium retention in heart failure is under the influence of the sympathetic and …

Decongestion Strategies and Renin-Angiotensin-Aldosterone System Activation in Acute Heart Failure

OBJECTIVESnThe purpose of this study was to assess the relationship between biomarkers of renin-angiotensin-aldosterone system (RAAS) activation and decongestion strategies, worsening renal function, and clinical outcomes.nnnBACKGROUNDnHigh-dose diuretic therapy in patients with acute heart failure (AHF) is thought to activate the RAAS; and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation.nnnMETHODSnThis study analyzed 427 AHF patients enrolled in the DOSE-AHF (Diuretic Optimization Strategies in Acute Heart Failure) and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trials. We assessed the relationship between 2 markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72 h and 96 h and decongestion strategy: high- versus low-dose and continuous infusion versus bolus furosemide for DOSE-AHF and UF versus stepped pharmacologic care for CARRESS-HF. We determined the relationships between RAAS biomarkers and 60-day outcomes.nnnRESULTSnPatients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium levels, andxa0higher blood urea nitrogen (BUN) concentration. Continuous infusion furosemide and UF were associated with greater PRA increases (median:xa0+1.66 vs.xa0+0.66 ng/ml/h with continuous vs. bolus infusion, respectively, pxa0= 0.021;xa0+4.05 vs.xa0+0.56 ng/ml/h with UF vs. stepped care, respectively, pxa0= 0.014). There were no significant differences in RAAS biomarker changes with high- versus low-dose diuretic therapy (both: p > 0.5). Neither baseline log PRA nor log aldosterone was associated with increased death or HF hospitalization (hazard ratio [HR] for a doubling of 1.05; 95% confidence interval [CI]: 0.98 to 1.13; pxa0= 0.18; and HR: 1.13; 95% CI: 0.99 to 1.28; pxa0= 0.069, respectively). The change in RAAS biomarkers from baseline to 72 and 96 h was not associated with outcomes (both: p > 0.5).nnnCONCLUSIONSnHigh-dose loop diuretic therapy did not result in RAAS activation greater than that with low-dose diuretic therapy. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. (Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure [DOSE-AHF]; NCT00577135; Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome [CARRESS]; NCT00608491).

Is optimal angiotensin-converting enzyme inhibitor dosing neglected in elderly patients with heart failure?

BACKGROUNDnThe benefit of angiotensin-converting enzyme (ACE) inhibitors on mortality in heart failure has been proved in randomized controlled trials.nnnMETHODSnWe prospectively evaluated the prescribing of ACE inhibitors and the prescribing of target ACE inhibitor doses in 43 ambulatory patients with heart failure to identify differences in ACE inhibitor utilization among elderly and nonelderly patients. The prescribed ACE inhibitor dose and other variables were assessed by direct patient interview and information contained in the medical record. Telephone calls were conducted at 3 months to identify the occurrence of clinical events.nnnRESULTSnFewer elderly patients were prescribed target ACE inhibitor doses compared with nonelderly patients (21.4% vs 68.8%; p = 0.0136). Elderly patients were more likely to experience an event than nonelderly patients (11 vs 4; p = 0.0074). Elderly patients not receiving target ACE inhibitor doses demonstrated a trend toward more events than elderly patients who were at target doses.nnnCONCLUSIONnThe data suggest that this group of elderly patients with heart failure who received lower ACE inhibitor doses appeared to be at higher risk for clinical events.