Predictive value of the Seattle Heart Failure Model in patients undergoing left ventricular assist device placement.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly used in advanced heart failure patients. Despite proven efficacy, optimal timing of LVAD implantation is not well defined. METHODS: Patients receiving an LVAD were prospectively recorded. Laboratory and clinical data were extracted and used to calculate the predicted survival with medical therapy using the Seattle Heart Failure Model (SHFM). This was compared with observed survival, hospital length of stay and timeliness of discharge. RESULTS: We identified 104 patients. Survival with an LVAD vs SHFM predicted survival was 69% vs 11% at 1 year, corresponding to a hazard ratio of 0.17 (p < 0.0001). SHFM-estimated 1-year survival with medical therapy increased from 4% in 1997 to 2004 to 25% in 2007-2008 (p < 0.0001). Subgroup analysis of higher vs lower risk LVAD patients showed observed 1-year survival of 83% vs 57% (p = 0.04). The lower risk group had a shorter length of stay (46 vs 75 days, p = 0.03), along with higher rates of discharge prior to transplant (88% vs 61%, p = 0.01) and discharge within 60 days of LVAD placement (77% vs 52%, p = 0.03). CONCLUSIONS: The SHFM allows prediction of important features of a patient's hospital course post-operatively, including length of stay and 1-year survival. Given evidence of improved survival and shorter hospital stay in lower risk patients, earlier LVAD placement based on a prediction model like the SHFM should be considered in advanced heart failure patients. The SHFM may have utility as a virtual control arm for single-arm LVAD trials.

Clevidipine: an ultra short-acting calcium channel antagonist for acute hypertension.

OBJECTIVE: To review the safety, efficacy, and pharmacologic characteristics of clevidipine, a new ultra short-acting intravenous antihypertensive agent for the treatment of moderate-to-severe hypertension. DATA SOURCES: A literature search was conducted through MEDLINE (1966-March 2009), International Pharmaceutical Abstracts (1970-March 2009), and EMBASE (1988-March 2009) using the search terms clevidipine, H324/38, hypertension, and hypertensive crisis. STUDY SELECTION AND DATA EXTRACTION: Available studies, abstracts, and review articles published in English that evaluated the pharmacology, pharmacokinetics, safety, and clinical efficacy of clevidipine were reviewed and critically evaluated. DATA SYNTHESIS: Clevidipine is a new third-generation dihydropyridine calcium-channel blocker available for intravenous management of moderate-to-severe hypertension. Clevidipine is an ultra short-acting, selective arteriolar vasodilator that acts similar to other L-type dihydropyridine calcium-channel blockers by inhibiting influx of extracellular calcium into the vascular smooth muscle. Its safety and efficacy have been primarily evaluated in the perioperative setting in patients undergoing cardiac surgery requiring management of elevated blood pressure. In comparison to most other intravenous antihypertensives, clevidipine has a rapid onset of action, is ultra short-acting, easily titratable with a predictable dose response, and is void of drug-drug interactions and need for dose adjustment in patients with hepatic or renal insufficiency, thus making it a valuable antihypertensive in both the intraoperative and critical care settings. In clinical trials, clevidipine was well tolerated at infusion rates from 2-32 mg per hour, for up to 72 hours. CONCLUSIONS: Clevidipine is the first intravenous antihypertensive approved by the Food and Drug Administration in nearly a decade. Based on available published clinical trials, clevidipine appears to be safe and effective in the acute management of moderate-to-severe elevations in blood pressure and a viable alternative to other agents such as nitroglycerin, sodium nitroprusside, and nicardipine.

Years-needed-to-treat to add 1 year of life: a new metric to estimate treatment effects in randomized trials.

AIMS: A standard metric to estimate absolute treatment effects is numbers-needed-to-treat (NNT), which implicitly assumes that all benefits reverse at trial-end. However, in-trial survival benefits typically do not reverse until long after trial-end, so that NNT will substantially underestimate lifetime benefits. METHODS AND RESULTS: We developed a new concept, years-needed-to-treat (YNT) to add 1 year of life, that quantifies the expected average life expectancy for two treatments including the estimated years of life remaining post-trial. Numbers-needed-to-treat and YNT were calculated in the COMET trial, in which carvedilol vs. metoprolol tartrate resulted in 17% lower mortality over 4.8 years. A multivariate Cox model was used to predict survival. Remaining years of life were estimated using the mortality-life-table method. At trial-end, survival was 9% higher in the carvedilol arm. Assuming that patients remained on the same therapy post-trial, the average total years of life for carvedilol vs. metoprolol were 10.63 +/- 0.19 vs. 9.48 +/- 0.18 (P < 0.0001) or 1.15 (95% confidence interval 0.64-1.66) additional years of life. The YNT was 9.2, indicating that 9.2 person-years of treatment added 1 person-year of life, compared with NNT of 59. CONCLUSION: Compared with NNT, the YNT method more accurately accounts for potential long-term benefits of interventions in randomized trials.

Incidence and clinical features of ganciclovir-resistant cytomegalovirus disease in heart transplant recipients.

BACKGROUND: The incidence and clinical and virologic aspects of ganciclovir-resistant cytomegalovirus (CMV) disease have not been well-characterized in heart transplant recipients. METHODS: We retrospectively analyzed all patients who underwent their first heart transplantation during the period from 1 January 1995 through 30 June 2005 at a single health care center. Cox proportional hazard regression was used to assess the relationship between clinical variables and CMV disease. Portions of the UL97 gene were sequenced in patients with slow clinical and/or virologic response to ganciclovir therapy. RESULTS: Cytomegalovirus disease developed in 32 (11.7%) of 274 patients at a median of 4.2 months after transplantation (range, 1.8-11.6 months after transplantation) and was independently associated with donor-seropositive/recipient-seronegative (D+/R-) serostatus (adjusted hazard ratio, 6.93; P<.001). The incidence of ganciclovir-resistant CMV disease was 1.5% overall (4 of 274 patients), 5% among D+/R- serostatus recipients (4 of 80 patients), and 12.5% among patients who developed CMV disease (4 of 32 patients). Ganciclovir-resistant CMV disease was significantly associated with D+/R- serostatus (4 [5%] of 80 vs. 0 [0%] of 153 patients; P=.02), greater prior exposure to ganciclovir (median duration of exposure, 150 vs. 69 days; P=.003), and substantial morbidity, including prolonged CMV-associated hospitalization (median duration of hospitalization, 66 vs. 0 days; P<.01). CONCLUSIONS: CMV disease, including ganciclovir-resistant disease, is an important clinical problem in D+/R- heart transplant recipients who receive antiviral prophylaxis. Strategies specifically designed to reduce the incidence and impact of CMV disease in this population are warranted.

The role of oral direct thrombin inhibitors in atrial fibrillation.

Atrial fibrillation is a common rhythm disturbance; its most significant adverse events are ischemic stroke and systemic arterial occlusion. Oral anticoagulation with warfarin is an effective therapy for stroke prevention but remains underused due to numerous complications and barriers. Ximelagatran, an oral direct thrombin inhibitor, may become an alternative strategy for clinicians. This agent was developed to overcome many of the limitations associated with warfarin. Its consistent antithrombotic effect and wide therapeutic index allow fixed dosing without the need for routine coagulation monitoring, and without concerns related to drug, food, and disease state interactions. Ximelagatran has been investigated in patients with atrial fibrillation and has been as effective as warfarin for stroke prevention.

Cost effectiveness of ibutilide with prophylactic magnesium in the treatment of atrial fibrillation.

BACKGROUND: In the Treatment with Ibutilide and Magnesium Evaluation (TIME) study, a retrospective multicentre cohort trial, prophylactic magnesium was found to improve the antiarrhythmic efficacy of ibutilide as demonstrated by an increase in the rate of successful chemical conversion and reduction in the need for direct current cardioversion (DCC). OBJECTIVE: The primary objective of this piggyback cost-effectiveness analysis of the TIME study was to compare the cost per successful conversion of atrial fibrillation (AF) for ibutilide in the presence and absence of magnesium prophylaxis. A secondary objective was to determine whether specific factors predict costs in the conversion of AF. METHOD: The study was conducted from the US hospital-payer perspective. Direct medical costs (USD, 2002 values) including drugs, intravenous admixture and administration, DCC, electrocardiographs and physicians' fees were obtained directly from the provider. Nonparametric bootstrapping was conducted to calculate confidence intervals for the incremental cost-effectiveness ratios. One-way sensitivity analysis was conducted varying efficacy, and drug, hospital and physician costs. Multivariate analysis was conducted to determine whether specific baseline factors were predictors of total cost. RESULTS: Total costs per patient were lower in the ibutilide plus magnesium group compared with ibutilide alone (USD1075 vs USD1201); however, the difference was not statistically significant (p = 0.116). Patients receiving ibutilide plus magnesium had lower DCC costs compared with those receiving ibutilide alone (USD261 vs USD399; p = 0.036), but higher magnesium-associated costs (USD0.50 vs USD0; p < 0.001). Bootstrapping revealed that the ibutilide plus magnesium strategy would result in lower costs and greater efficacy 93.4% of the time. These results remained robust to changes in both cost and efficacy. No baseline factors were found to be independent predictors of total costs. CONCLUSION: Our data suggest that adding prophylactic magnesium to ibutilide may be cost effective, from a US hospital-payer perspective, for the acute conversion of patients in AF or flutter compared with ibutilide alone.

Impact of prophylactic i.v. magnesium on the efficacy of ibutilide for conversion of atrial fibrillation or flutter.

The impact of prophylactic i.v. magnesium on the efficacy of ibutilide for conversion of atrial fibrillation and flutter to normal sinus rhythm was studied. In this multicenter cohort study, all patients in three large, tertiary care centers who received ibutilide for acute chemical conversion of atrial fibrillation or flutter from August 1996 through December 2001 were identified through pharmacy or billing records. Patients who did not receive magnesium before or during ibutilide therapy served as the control group, while those who received magnesium less than two hours before or during ibutilide administration served as the study group. The rate of administration of direct-current cardioversion (DCC) and the occurrence of ventricular arrhythmia were compared between those who did and did not receive magnesium. The rates of successful cardioversion were also assessed. Categorical data were analyzed using chi-square analysis or Fisher's exact test. Demographic data were analyzed using Student's t test. The medical records of 321 patients were analyzed. Successful chemical cardioversion in the study group was approximately 19% higher than in those who did not receive magnesium (p = 0.040). The use of DCC in the group who received magnesium was reduced by approximately 34% (p = 0.045). The conversion rate of atrial fibrillation or flutter with ibutilide was enhanced by magnesium administration (p = 0.040), and the rate of administration of DCC was reduced (p = 0.045) in patients who received magnesium. There was a nonsignificant reduction in the occurrence of ventricular arrhythmias (p = 0.533). The efficacy of ibutilide was enhanced by concomitant administration with intravenous magnesium.

Bosentan for the treatment of pulmonary arterial hypertension.

OBJECTIVE: To describe the pharmacology, pharmacokinetics, efficacy, and safety of bosentan in the treatment of pulmonary arterial hypertension (PAH). DATA SOURCES: A MEDLINE and Current Contents search (1966-June 2002) of the English-language literature was conducted to identify published dose-ranging, pharmacokinetic, pivotal efficacy trials and review articles of bosentan and endothelin antagonists. Additional references were identified from the bibliographies of the retrieved articles. DATA SYNTHESIS: Bosentan is the first orally active, nonpeptide endothelin receptor antagonist approved by the Food and Drug Administration for use in patients with World Health Organization (WHO) functional class III and IV PAH. Titrated to a dose of 125 mg twice daily, bosentan produces pulmonary vasodilation, improving cardiopulmonary hemodynamics leading to better outcomes for patients. It is metabolized primarily by the hepatic system via the cytochrome P450 enzyme pathway and eliminated by biliary excretion. Bosentan is an inducer of the isoenzymes CYP3A4 and 2C9. It possesses a unique pharmacokinetic profile with a terminal elimination half-life of approximately 5 hours, yet steady-state plasma concentrations are not achieved for 3-5 days as a result of enhanced drug clearance and autoinduction following multiple daily dosing. The major adverse effects of bosentan are the potential for birth defects and hepatotoxicity. CONCLUSIONS: The use of bosentan in patients with WHO functional class III and IV PAH is associated with improved exercise tolerance, cardiopulmonary hemodynamics, and increased time to clinical worsening when compared with placebo. It offers significant advantage in ease of administration and quality of life compared with epoprostenol therapy, with similar efficacy.