Characteristics of patients who die with heart failure and a low ejection fraction in the new millennium.

BACKGROUND: Therapies for heart failure (HF) with a low ejection fraction (EF) have delayed disease progression and prolonged survival, but the implications of these therapies on the end stages of HF have not been examined. METHODS AND RESULTS: Patients seen by the Brigham and Women's cardiomyopathy service with an EF < or =35%, at least 1 outpatient visit or at least 30 days of follow-up who died between January 1, 2000, and October 20, 2003, were evaluated retrospectively. Of the 160 patients who died since 2000, 80 (50%) were outpatients. In the 6 months before death, 93% of patients had New York Heart Association (NYHA) class III or IV symptoms. The NYHA class, clinical characteristics, medications, and comorbidities differed little between inpatient and outpatient deaths. Renal insufficiency and hyponatremia were worse in the months preceding death than at the time of death (creatinine: 3.2 versus 2.3 mg/dL, P < .0001; sodium: 128 versus 135 mmol/L, P < .0001, respectively). Death was considered sudden in only 21% of patients. CONCLUSION: Deaths in the current era of HF management occur in patients with long-standing HF characterized by biventricular dysfunction and advanced symptoms. Most deaths are heralded by hyponatremia, acute on chronic renal insufficiency, and frequent hospitalizations.

Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure.

OBJECTIVES: This study was designed to determine the relevance of a proposed classification for advanced heart failure (HF). Profiles based on clinical assessment of congestion and perfusion at the time of hospitalization were compared with subsequent outcomes. BACKGROUND: Optimal design of therapy and trials for advanced HF remains limited by the lack of simple clinical profiles to characterize patients. METHODS: Prospective analysis was performed for 452 patients admitted to the cardiomyopathy service at the Brigham and Women's Hospital with a diagnosis of HF. Patients were classified by clinical assessment into four profiles: profile A, patients with no evidence of congestion or hypoperfusion (dry-warm, n = 123); profile B, congestion with adequate perfusion (wet-warm, n = 222); profile C, congestion and hypoperfusion (wet-cold, n = 91); and profile L, hypoperfusion without congestion (dry-cold, n = 16). Other standard predictors of outcome were included and patients were followed for the end points of death (n = 117) and death or urgent transplantation (n = 137) at one year. RESULTS: Survival analysis showed that clinical profiles predict outcomes in HF. Profiles B and C increase the risk of death plus urgent transplantation by univariate (hazard ratio [HR] 1.83, p = 0.02) and multivariate analyses (HR 2.48, p = 0.003). Moreover, clinical profiles add prognostic information even when limited to patients with New York Heart Association (NYHA) class III/IV symptoms (profile B: HR 2.23, p = 0.026; profile C: HR 2.73, p = 0.009). CONCLUSIONS: Simple clinical assessment can be used to define profiles in patients admitted with HF. These profiles predict outcomes and may be used to guide therapy and identify populations for future investigation.

Frequency and impact of delayed decisions regarding heart transplantation on long-term outcomes in patients with advanced heart failure.

OBJECTIVES: We sought to characterize decisions regarding listing of heart transplant candidates and to determine the impact of delayed listing for a transplant on survival. BACKGROUND: Evaluation and listing for heart transplantation have evolved over the past decade, with the complex decision process often extending beyond the time of initial review. Little is known about the current impact of decisions and timing of listing on outcomes. METHODS: Decisions were prospectively recorded during the initial committee discussions regarding patients referred for heart transplant evaluation. Survival and transplantation rates were assessed. RESULTS: A total of 214 patients were evaluated for heart transplantation (age 49 +/- 11 years, ejection fraction 21 +/- 9%, New York Heart Association class III +/- I, peak oxygen consumption 13 +/- 4 ml/kg/min). At the initial evaluation, 44% of patients were deemed eligible, 25% were potentially eligible, 19% were ineligible, and 12% were deferred. For eligible patients, 37% of patients were listed within 10 days of evaluation, and a total of 71% of patients were ever listed. Regardless of transplantation, the three-year survival rate in eligible patients not listed early was similar to that in patients listed immediately (85% vs. 77%, p = 0.34). Ineligible and potentially eligible patients had a higher three-year mortality rate than did eligible patients if transplantation occurred (51% vs. 17%, p < 0.001) or not (57% vs. 19%, p = 0.04). CONCLUSIONS: Using current accepted guidelines, many patients referred for transplant evaluation were not considered eligible for transplantation, and those who were eligible were not often listed immediately. Eligible patients not listed initially did well in the long term, and patients with relative contraindications had worse outcomes with or without a transplant.

Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine.

BACKGROUND: Cyclosporine (INN, ciclosporin) increases the systemic exposure of all statins. Therefore rosuvastatin pharmacokinetic parameters were assessed in an open-label trial involving stable heart transplant recipients (> or =6 months after transplant) on an antirejection regimen including cyclosporine. Rosuvastatin has been shown to be a substrate for the human liver transporter organic anion transporting polypeptide C (OATP-C). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. Therefore the effect of cyclosporine on rosuvastatin uptake by cells expressing OATP-C was also examined. METHODS: Ten subjects were assessed while taking 10 mg rosuvastatin for 10 days; 5 of these were then assessed while taking 20 mg rosuvastatin for 10 days. Rosuvastatin steady-state area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] and maximum observed plasma concentration (Cmax) were compared with values in controls (historical data from 21 healthy volunteers taking 10 mg rosuvastatin). Rosuvastatin uptake by OATP-C-transfected Xenopus oocytes was also studied by use of radiolabeled rosuvastatin with and without cyclosporine. RESULTS: In transplant recipients taking 10 mg rosuvastatin, geometric mean values and percent coefficient of variation for steady-state AUC(0-24) and Cmax were 284 ng. h/mL (31.3%) and 48.7 ng/mL (47.2%), respectively. In controls, these values were 40.1 ng. h/mL (39.4%) and 4.58 ng/mL (46.9%), respectively. Compared with control values, AUC(0-24) and Cmax were increased 7.1-fold and 10.6-fold, respectively, in transplant recipients. In transplant recipients taking 20 mg rosuvastatin, these parameters increased less than dose-proportionally. Rosuvastatin had no effect on cyclosporine blood concentrations. The in vitro results demonstrate that rosuvastatin is a good substrate for OATP-C-mediated hepatic uptake (association constant, 8.5 +/- 1.1 micromol/L) and that cyclosporine is an effective inhibitor of this process (50% inhibition constant, 2.2 +/- 0.4 micromol/L when the rosuvastatin concentration was 5 micromol/L). CONCLUSIONS: Rosuvastatin exposure was significantly increased in transplant recipients on an antirejection regimen including cyclosporine. Cyclosporine inhibition of OATP-C-mediated rosuvastatin hepatic uptake may be the mechanism of the drug-drug interaction. Coadministration of rosuvastatin with cyclosporine needs to be undertaken with caution.