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Cardiovascular medicine has led the drive for creativity and innovation with a culture that has been at the forefront of evidence generation. However, we are functioning at only a fraction of our evidence generation capacity. Despite the leadership of cardiovascular medicine, very few guideline recommendations are supported by high levels of evidence, and the proportion of recommendations for which there is no conclusive evidence is substantial. Clinical research has proven to be too slow, unreliable, and expensive as conducted in the past. In the current era, a new model of unlimited information, better access to care, and better payer coverage has the potential to change our evidence base to support clinical guidelines. We now have the opportunity to use volumes of data to support US Food and Drug Administration labeling and practice guidelines. The electronic health record can be used to feed decisions and provide an information feedback loop. In addition, learning health systems can contribute to providing networks and registries for information sharing. In this Special Communication, we summarize opportunities of the cardiovascular community to build on its pioneering leadership in evidence-based medicine through major initiatives now under way. By joining in broad efforts to create an efficient national evidence generation system, larger proportions of clinical practice can be guided by high-quality evidence; clinicians and their practice organizations will be increasingly able to focus on interpreting, applying, and communicating research findings to improve outcomes; and patients and consumers will be increasingly informed and empowered to play active roles in managing their own health and health care.

Background— Depression is a common comorbidity in heart failure and is strongly associated with increased mortality, morbidity, and reduced health status. Whether depression treatment may result in improvement of health status in heart failure patients with comorbid depression remains unknown. Methods and Results— The Sertraline Against Depression and Heart Disease in Chronic Heart Failure study randomized 469 participants with chronic heart failure (left ventricular ejection fraction 45% and New York Heart Association class II) and major depressive disorder based on Diagnostic Statistics Manual fourth edition criteria to sertraline or placebo for 12 weeks. The Kansas City Cardiomyopathy Questionnaire, 36-Item Short-Form Health Survey, and 6-minute walk test were used to assess health status. Health status changes between treatment arms and remission status were evaluated adjusting for baseline variables and treatment assignment. The final Hamilton Depression Rating Scale scores were 3.50±2.08 and 12.97±4.33 in the remission and nonremission groups, respectively ( P value=0.0001). Of 469 total participants, 378 (80.6%) completed the 6-minute walk test and 285 (70.1%) completed Kansas city cardiomyopathy questionnaire and 36-item short-form health survey, at baseline and at week 12. Depression remission was significantly associated with higher improvements in Kansas City Cardiomyopathy Questionnaire subscale scores ( P P =0.18) and Symptom Stability ( P =0.91). On the 36-Item Short-Form Health Survey, depression remission was associated with significant improvement in subscales of the physical and mental component summary except the Pain Index ( P =0.34). The 6-minute walk test improved more in depression remission compared with nonremission group (difference from baseline: 63.51±238.78 versus 16.24±115.70 m, P =0.03). Conclusions— Patients with heart failure whose depressive symptoms remitted had significantly greater improvement in physical function, social function, and quality of life.

Understanding of chronic heart failure (HF) has progressed from a syndrome of disordered hemodynamics caused by alterations in the structure of the heart to one that involves intertwined molecular pathways in disarray. Accordingly, the assessment and treatment of patients with chronic HF has shifted from a focus on hemodynamics to modification of maladaptive molecular processes. Accumulating evidence shows that molecular biomarkers of disease could provide a unique window into the pathophysiology of chronic HF, potentially improving our ability to predict adverse outcomes, provide novel drug targets, and even help gauge therapeutic efficacy. The more 'traditional' biomarkers such as cardiac troponin, natriuretic peptides, and C-reactive protein have been studied in large cohorts of patients with chronic HF and have relatively established clinical applications. In this Review, we summarize the properties, clinical data, and potential applications of some emerging biomarkers that could uniquely indicate the level of biomechanical stretch, inflammation, ventricular remodeling, myocardial injury, and renal dysfunction that occurs in chronic HF. We will also discuss the potential role for these biomarkers within a multimarker-based strategy that could, in the future, lead to better care for these patients.

Myocardial ischemic origin is a significant independent predictor of mortality in patients with heart failure (HF). The implications of angina pectoris (AP) in HF are less well characterized. The aim of this study was to compare the clinical characteristics and outcomes of patients with and without AP in a cohort of patients with reduced ejection fractions and ischemic cardiomyopathy (iCM). Patients who underwent coronary angiography at Duke University Medical Center from January 2000 to September 2009 with ejection fractions40% and diagnoses of iCM with AP in the previous 6 weeks were compared to similar patients without AP. Time to event was examined using Kaplan-Meier methods for 5 end points: death; death or nonfatal myocardial infarction (MI); death, MI, or revascularization; death or hospitalization; and cardiovascular (CV) death or CV hospitalization. Of 2,376 patients with iCM, 1,412 (59%) had AP. They had more co-morbidities and more previous revascularization than patients without AP. After multivariate adjustment, those with and without AP had similar risks for death (p = 0.32), death or MI (p = 0.15), and death or hospitalization (p = 0.37) (5-year event rates 41% vs 41%, 46% vs 47%, and 87% vs 85%, respectively), but those with AP had lower rates of death, MI, or revascularization (p = 0.01) and higher rates of CV death or CV hospitalization (p = 0.03) (5-year event rates 85% vs 87% and 77% vs 73%, respectively). In conclusion, AP is common in patients with iCM despite medical therapy and previous revascularization and is associated with increased CV death or CV rehospitalization.

Phase3clinicaltrialsinacuteheartfailure(AHF)are conducted to allow safety and efficacy data to be collected for the evaluation of treatment strategies, including drugs, devices, diagnostics, or nonpharmacological interventions. Phase 3 trials occur after there has been satisfactory information gathered on animal studies and early phase studies, such that the safety, pharmacokinetic, and dosing profiles have been adequately ascertained. The phase 3 study is then designed to test the efficacy and safety of the intervention in a larger sample size. There are several important features regarding the conduct of phase 3 clinical trials in AHF. This article describes in detail these important aspects of conducting phase 3 clinical trials in an AHF population.

Clinical trials are often conducted globally. A recent study found that approximately one-third of phase 3 industry-sponsored trials (157 of 509) in the ClinicalTrials.gov registry were being conducted solely outside the United States. 1 Differences in standard of care, patient populations including genetic and phenotypic differences, disease etiologies, rates of comorbidities, ascertainment of endpoints, and differences in concomitant therapies and medical culture may influence subsequent outcomes. Because many cardiovascular trials have demonstrated differences in clinical outcomes by continent and geographic region, careful consideration of these factors is warranted. 2–6 Heart failure trials have also demonstrated varying results based on geographic region of the world. 7–9 Despite these reports, little consensus has emergedregardinghowtheseresultsshouldbeevaluated. This article reviews the differences in cardiovascular trial results by geographic region, offers potential explanations for these differences, and suggests methods for standardization of trialresults.

he cl in ic s. co m This issue of Heart Failure Clinics is dedicated to an in-depth analysis of the conduct of clinical investigation in patients with acute decompensated heart failure (ADHF). We would like to start with a reflection on the history of ADHF research over the past 50 years. For many years, ADHF was thought to be a temporary inconvenience in the course of the chronic heart failure patient, in which a short-term disturbance resulted in a need for intravenous therapies, subsequent hospitalization, and a return to baseline. It was not until the observations from the OPTIME trial that we found an extraordinarily high rate of readmission and death at 60 days in these patients. This heightened risk of morbidity and mortality led us to believe that this was a very important condition that required in-depth attention and investigation. Before the completion of the OPTIME trial in 2002, much of our reasoning for the goal of intervention was based on physiologic response. For example, some of the first articles described by Dr Eugene Stead offered insight into the important complex interaction between the heart and kidney in heart failure patients. Dr Walter Kempner further elaborated on this complex interaction between the heart and kidney by demonstrating that significant sodium restriction could result in improvement in the clinical edematous state and

The omega-3 fatty acid (FA) concentration is low in patients with coronary heart disease (CHD). Supplement of omega-3 FA improves cardiovascular outcomes in patients with CHD and heart failure (HF). However, plasma omega-3 FA and its role for prognosis in HF patients have not been examined previously. In this study, we explore the prognostic value of omega-3 polyunsaturated FA in HF patients with major depressive disorder (MDD). Plasma was obtained from HF patients with MDD who participated in the Sertraline Against Depression and Heart Disease in Chronic Heart Failure trial. FA methyl esters were analyzed by the method of a flame ionization detector. Weight percent is the unit of the omega compounds. The primary outcome was survival which was analyzed using Cox proportional hazards regression modeling. A total of 109 depressed HF patients had adequate volume for completion of the FA assays. Plasma total omega-3 (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.43-0.98) and EPA_(0.1 unit) (HR 0.73, 95% CI 0.56-0.96) were significantly associated with survival of patients with HF and co-morbid MDD. The results suggest that low plasma omega-3 FA is a significant factor for reduced survival in HF patients with MDD.

We sought to describe the United States and the rest of the world (ROW) outcomes from the major β-blocker heart failure (HF) trials.HF trials have demonstrated differences in outcomes by geographic region.Randomized, double-blind, placebo-controlled studies that evaluated β-blockers in HF patients, had a primary endpoint of mortality, and enrolled U.S. patients were included. Relative risk (RR) was calculated for patients enrolled in the United States and ROW. Meta-analysis of the combined mortality rates was performed using the Cochran-Mantel-Haenszel statistic, stratified by study.A total of 8,988 patients were enrolled in the MERIT-HF (Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure), COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival trial), and BEST (β-Blocker Evaluation of Survival Trial) combined; 4,198 (46.7%) were from the United States. In the U.S. cohort, the RR reduction for each β-blocker was of smaller magnitude than in the overall cohort and no longer significant, whereas in the ROW subgroup, the mortality benefit for β-blockade persisted. In the pooled analysis (n = 11,635), the RR of death was reduced by 23% (p0.001) with β-blockade compared with placebo. In contrast, the mortality reduction associated with β-blockade in the U.S. cohort was small and not statistically significant (RR: 0.92, 95% confidence interval [CI]: 0.82 to 1.02, p = 0.11). The survival benefit persisted in the ROW cohort (RR: 0.64, 95% CI: 0.56 to 0.72, p0.001).Among patients enrolled in the United States, β-blockade was associated with a lower magnitude of survival benefit, whereas the ROW response was similar to the total study population. This geographic difference in treatment response may be a reflection of population differences, genetics, cultural or social differences in disease management, or low power and statistical chance.

Background— Cardiac troponin T (cTnT) elevation is common and is a predictor of outcomes in patients with acute heart failure (AHF). The degree and progression of cTnT release during hospitalization of patients with AHF is unclear. We evaluated the incidence of cTnT release during AHF hospitalization and the relationship of cTnT release with outcomes. Methods and Results— The P lacebo-controlled R andomized study of the selective A(1) adenosine receptor antagonist rolofylline for patients hospitalized with acute heart failure and volume O verload to assess T reatment E ffect on C ongestion and renal func T ion (PROTECT) pilot study was a multicenter, double-blind study of patients with AHF. Measurements of cTnT were collected at randomization and days 2, 3, 4, and 7. Patients were classified on the basis of their serum cTnT levels at baseline: positive (>0.03 ng/mL), detectable (>0.01 ng/mL), and negative (≤0.01 ng/mL). A detectable cTnT level developed during the study (after baseline) was classified as cTnT conversion: 288 patients were included; 172 (60%) patients had detectable cTnT levels and 97 (34%) had positive values (>0.03 ng/mL) at baseline. Of the 116 patients with negative troponin at baseline, 24 (21%) had elevated cTnT levels by day 7. On multivariable analysis, positive cTnT at baseline was an independent predictor of the composite end point of cardiovascular/renal rehospitalization or death at 60 days (hazard ratio, 1.84; 95% confidence interval, 1.04–3.26; P =0.036). Kaplan-Meier curves showed similar worse outcomes in patients with troponin conversion and positive troponin at baseline. Conclusions— There was a high prevalence of baseline cTnT elevation in this cohort; 21% of those negative at baseline converted to detectable levels by day 7. Positive troponin at baseline, and conversion to positive levels, were associated with worse outcomes at 60 days. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00328692 and NCT00354458.

Hospitalization for acute heart failure syndromes (AHFS) predicts a poor prognosis, with postdischarge mortality and rehospitalization rates reaching 45% within 60 to 90 days. Despite the use of evidence-based therapies and adherence to national process measures, these event rates have largely remained the same over the past decade. Given the current and growing burden of AHFS, there exists a substantial unmet need for novel therapies that improve outcomes. However, attempts to improve symptoms and/or reduce postdischarge events have failed to produce positive results, either because of safety and/or efficacy. These negative results may be related to the drug itself, the protocol in terms of patient selection and/or end points, and/or the trial execution. Although experts may not agree on the exact reasons to explain the lack of success to date of phase III trials in AHFS, there is agreement that clinical benefits observed in phase II trials were not reproduced in phase III trials. A different approach may be needed. In November of 2009, a meeting was held at the Food and Drug Administration with the primary purpose of identifying the reasons why benefits observed during phase II did not translate into benefits in phase III to improve future trial design. Although multiple domains of trial design were discussed, the participants identified a lack of in-depth understanding of novel molecules before pivotal trials in AHFS as a possible contributor to the disappointing results of recent large trials. In this brief report, we outline the T1 or translational phase of research for AHFS clinical development as an important first step toward greater success in AHFS clinical trials.

End point committees are routinely used to adjudicate efficacy and safety end points in clinical trials. The 2,708-patient β-Blocker Evaluation of Survival Trial (BEST) originally determined hospitalization type via investigator case report forms (CRFs), which captured whether a hospitalization was due to worsening heart failure (HF). Recently, the BEST End Points Committee (EPC) completed a blinded adjudication of all hospitalizations, allowing a comparison of the CRF method to the EPC method of determining hospitalization type. We sought to compare the investigator-determined mode of hospitalizations with the adjudicated events, to quantify the degree of agreement, and to compare the clinical trial results by method of event classification.The BEST EPC reviewed all 5,086 hospitalizations that occurred in BEST. Events were identified using investigator-reported hospitalizations, as well as those documented by FDA Form 3500 (MedWatch) reports.The investigators identified more HF hospitalization events than adjudication (2,466 vs 1,729, P.0001, paired analysis). Eight hundred thirty-four (34%) HF hospitalizations identified in CRFs were not confirmed by adjudication. Ninety-seven (6%) adjudicated events were not identified by the investigator reported method. One thousand six hundred thirty-two events were similarly identified by both methods.The EPC adjudication identified fewer HF hospitalizations than did the investigator reported method with no change in the hazard ratio for this end point. Our findings suggest that independent end point committees may improve reliability through reduced variance, thus providing similar outcome results with fewer events and no increase in CIs.

Identifying high-risk heart failure (HF) patients at hospital discharge may allow more effective triage to management strategies.Heart failure severity at presentation predicts outcomes, but the prognostic importance of clinical status changes due to interventions is less well described.Predictive models using variables obtained during hospitalization were created using data from the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial and internally validated by the bootstrapping method. Model coefficients were converted to an additive risk score. Additionally, data from FIRST (Flolan International Randomized Survival Trial) was used to externally validate this model.Patients discharged with complete data (n = 423) had 6-month mortality and death and rehospitalization rates of 18.7% and 64%, respectively. Discharge risk factors for mortality included BNP, per doubling (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.15 to 1.75), cardiopulmonary resuscitation or mechanical ventilation during hospitalization (HR: 2.54, 95% CI: 1.12 to 5.78), blood urea nitrogen, per 20-U increase (HR: 1.22, 95% CI: 0.96 to 1.55), serum sodium, per unit increase (HR: 0.93, 95% CI: 0.87 to 0.99), age70 years (HR: 1.05, 95% CI: 0.51 to 2.17), daily loop diuretic, furosemide equivalents240 mg (HR: 1.49, 95% CI: 0.68 to 3.26), lack of beta-blocker (HR: 1.28, 95% CI: 0.68 to 2.41), and 6-min walk, per 100-foot increase (HR: 0.955, 95% CI: 0.99 to 1.00; c-index 0.76). A simplified discharge score discriminated mortality risk from 5% (score = 0) to 94% (score = 8). Bootstrap validation demonstrated good internal validation of the model (c-index 0.78, 95% CI: 0.68 to 0.83).The ESCAPE study discharge risk model and score refine risk assessment after in-hospital therapy for advanced decompensated systolic HF, allowing clinicians to focus surveillance and triage for early life-saving interventions in this high-risk population. (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness [ESCAPE]; NCT00000619).

Introduction: Bucindolol is a nonselective beta-adrenergic blocker with potent sympatholytic properties. The Beta-blocker Evaluation of Survival Trial (BEST) reported that the administration of bucindolol resulted in a nonsignificant decrease in total mortality (HR = 0.89 (0.78, 1.02), unadjusted p=0.10) in patients with advanced, NYHA Class III-IV heart failure (HF). Recent observations from that trial also reported that the amino acid arginine (Arg/Arg) or glycine (any Gly) in position 389 of the beta-1 receptor plays a significant role on the clinical response to bucindolol. The impact of bucindolol on cardiovascular mortality and morbidity (cardiovascular hospitalizations) has been incompletely investigated, because hospitalizations had been evaluated from case report forms (CRFs) only, and never adjudicated by the endpoints committee (EPC). Methods: The BEST data base consists of 2708 patients with a mean follow-up of 2.0 years. Cardiovascular (CV) mortality and hospitalizations have now been evaluated by EPC, which further subclassified total hospitalizations into cardiovascular (CV) and those due to worsening heart failure (HF). The impacts of Arg or Gly encoded at amino acid position 389 on endpoints were further investigated in the 1040 patient substudy. Results: Time to event results for adjudicated CV endpoints are presented below. Conclusions: Chronic administration of bucindolol results in a significant reduction in cardiovascular hospitalizations and mortality. Effects on either are strikingly beta-1 389 Arg/Gly specific, with the higher functioning, Arg/Arg version of the receptor associated with large treatment effects and Gly carriers exhibiting little or no evidence of efficacy. Genetic targeting of the β 1 -ΑR 389 polymorphism may improve the clinical responses to bucindolol for CV mortality and morbidity.

Background The progressive nature of heart failure (HF) coupled with high mortality and poor quality of life mandates greater attention to palliative care as a routine component of advanced HF management. Limited evidence exists from randomized, controlled trials supporting the use of interdisciplinary palliative care in HF. Methods PAL-HF is a prospective, controlled, unblinded, single-center study of an interdisciplinary palliative care intervention in 200 patients with advanced HF estimated to have a high likelihood of mortality or rehospitalization in the ensuing 6 months. The 6-month PAL-HF intervention focuses on physical and psychosocial symptom relief, attention to spiritual concerns, and advanced care planning. The primary end point is health-related quality of life measured by the Kansas City Cardiomyopathy Questionnaire and the Functional Assessment of Chronic Illness Therapy with Palliative Care Subscale score at 6 months. Secondary end points include changes in anxiety/depression, spiritual well-being, caregiver satisfaction, cost and resource utilization, and a composite of death, HF hospitalization, and quality of life. Conclusions PAL-HF is a randomized, controlled clinical trial that will help evaluate the efficacy and cost effectiveness of palliative care in advanced HF using a patient-centered outcome as well as clinical and economic end points.

Prognosis in heart failure (HF) patients (pts) is commonly assessed based on baseline clinical characteristics. The association between marital and socioeconomic status (SES) and outcomes in chronic HF requires further study. We performed an analysis of HF-ACTION, which randomized 2331 HF pts with

Objective: To determine whether mechanical dyssynchrony detected by phase analysis of GSPECT MPI can identify patients with Coronary Disease (CAD) at increased risk of All-Cause Death (ACD) and/or Cardiovascular Death (CVD). Methods: We identified all patients with angiographically significant CAD and a GSPECT MPI in the Duke Databank for Cardiovascular Disease (July 2003 and August 2009). The range of time during which 95% of the left ventricle is initiating contraction phase bandwidth (PB) and the degree of heterogeneity in the distribution of segmental initiation of mechanical contraction (phase standard deviation (PSD)) by GSPECT MPI were measured. To evaluate the relationship between each measure of dyssynchrony and long-term survival, Cox proportional hazards models were fitted. Results: A total of 1428patients were identified. The median age was 64 (interquartile range (IQR) 55-72) years. A majority were male (69.6%), were white (73.7%), and had hypertension (76.2%). A minority had chronic obstructive pulmonary disease (6.6%), congestive heart failure (24.2%), diabetes mellitus (36.2%), peripheral vascular disease (10.4%), prior myocardial infarction (32.9%), or renal insufficiency (5.4%). The median duration follow-up was 4.2 (IQR 2.8-6.3) years. A total of 377 deaths were observed. After adjustment for standard clinical covariates, PB and PSD were significantly associated with ACD and CVD. Among patients with LVEF>35% PB was able to further identify patients at a higher risk for ACD and/or CVD (TABLE). View this table: Conclusions: Mechanical dyssynchrony detected by phase analysis of GSPECT MPI can identify patients with CAD at signifincatly increased risk of ACD and CVD. Moreover, PB is associated with adverse outcomes among patients with LVEF > 35% and may help identify patients who do not meet current criteria for cardiac resynchronization therapy that may benefit from device placement.

Elevations in NTproBNP, hsCRP, and cTnT are associated with increased risk of adverse outcomes in patients with chronic HF. The effect of exercise training on these markers and the association of changes in biomarkers with outcomes has not been well studied. NTproBNP, hsCRP, and cTnT levels were

Background Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β1 adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α2C AR Ins [wild-type (Wt)] 322–325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. Methodology In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β1389 and α2C322–325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β1389 AR variants was measured in human explanted left ventricles. Principal Findings The combination of β1389 Arg+α2C322–325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β1389 Arg homozygotes+α2C322–325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β1389 Arg vs. Gly ARs, which converts α2CDel minor allele-associated NE lowering from a therapeutic liability to a benefit. Conclusions On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β1389 Arg homozygotes), intermediate (β1389 Gly carriers+α2C322–325 Wt homozygotes), and no (β1389 Gly carriers+α2C322–325 Del carriers) efficacy.

effect of AZA use in HTX recipients who are heterozygotes for TPMT variants on clinical outcomes is unknown. Aim: To investigate the relationship between genetic variation in TPMT, TPMT activity, active metabolite levels, and AZA efficacy and safety in HTX recipients. Methods: Genotyping for TPMT variants (TPMT *2 G238C, *3B G460A, and *3C A719G) was performed on 101 patients treated with AZA who underwent orthotopic HTX. Erythrocyte TPMT enzyme activity was measured in 94 of these patients and was considered normal (15.1-26.4 U/mL), intermediate (6.3-15.0 U/mL) and reduced (!6.3 U/mL). AZA metabolite level (6TGN) was measured in a subset of 23 recipients. All clinical and demographic data was abstracted by retrospective chart review. Results: There were 10 patients who were heterozygous for TPMT variants and 91 who were wild-type (WT). Heterozygotes have lower TPMT activity level as compared to WT (14.1 6 4.35 vs. 21 6 4.47, p!0.001). There was a moderate inverse correlation between TPMT activity and 6-TGN levels (p50.07). The mean AZA dose at baseline was similar in the two groups (1406 53 mg vs. 166 6 45 mg, p50.074) but 6 months after HTX, AZA dose was lower in heterozygotes as compared to WT (35 6 66 mg vs. 99 6 82 mg, p50.025). The reason for lower mean AZA dose in heterozygotes was due to a high discontinuation rate as compared to WT (8/10 vs. 31/91, p!0.05). The most common reason for discontinuation in both groups was rejection. There was no significant difference in incidence and time to onset of leukopenia between the two groups. Conclusions: TPMT variant heterozygotes have lower TPMT activity levels compared to WT. Carriers of TPMT variants do not have increased risk for leukopenia with AZA therapy, but are more likely to discontinue the drug due to development of rejection. Based on our results, HTX recipients with TPMT heterozygosity do not need AZA dose adjustment to prevent leukopenia. These patients should be monitored closely for rejection, similar to WT HTX recipients.

β-Adrenoceptor antagonists or β-blockers are a cornerstone of therapy in chronic heart failure (CHF). Bucindolol hydrochloride is a fourth-generation β-blocker in development for the treatment of CHF. Two trials have been conducted to evaluate its use in CHF, and a third is under way to investigate bucindolol for the reduction of cardiovascular mortality and cardiovascular hospitalizations in a genotype-defined heart failure population. This review aims to summarize the history, pharmacology and clinical trials of bucindolol.

high-dose furosemide (HDF, IV furosemide 20 mg/h for 8 hours) or low-dose furosemide combined with low-dose dopamine (LDFD, IV furosemide 5 mg/h plus IV dopamine 5mg/ kg/min) and were categorized according to pretreatment with a BB to form 4 study groups: HDFBB(+), HDFBB( ), LDFDBB(+), and LDFDBB( ) (n5 8, 9, 16, 8, respectively) in order to compare the effects of each therapy on diuresis, perceived dyspnea, renal function, and 60-day post-discharge outcomes. Results: Urine volume/hour for the first 8 hours was similar in the 4 groups (HDFBB(+): 3186 81ml, HDFBB( ): 2276 96ml, LDFDBB(+): 403 6 440ml, LDFDBB( ): 274 6 165ml; p 5 0.51) as were the changes in perceived dyspnea assessed by the Borg index score (HDFBB(+): -4.1 6 2.9, HDFBB( ): -4.3 6 0.9, LDFDBB(+): -4.9 6 2.2, LDFDBB( ): -4.5 6 1.7; p 5 0.77). Worsening of renal function by various definitions was less commonly seen in the LDFD groups regardless beta-blocker pretreatment (Table). Length of stay and 60-day outcomes (all-cause, cardiovascular, non-cardiovascular, and due to worsening HF) were similar in the 4 groups. Conclusion: Pretreatment with a BB does not affect the diuretic and renoprotective effects of low-dose dopamine in patients hospitalized for ADHF.

BACKGROUND: Antidepressants are commonly prescribed medications, but their effect on cardiovascular morbidity and mortality remains unclear. METHODS: Prospective cohort study of 136 293 community-dwelling postmenopausal women in the Women’s Health Initiative (WHI). Women taking no antidepressants at study entry and who had at least 1 follow-up visit were included. Cardiovascular morbidity and all-cause mortality for women with new antidepressant use at follow-up (n=5496) were compared with those characteristics for women taking no antidepressants at follow-up (mean follow-up, 5.9 years). RESULTS: Antidepressant use was not associated with coronary heart disease (CHD). Selective serotonin reuptake inhibitor (SSRI) use was associated with increased stroke risk (hazard ratio [HR],1.45, [95% CI, 1.08-1.97]) and all-cause mortality (HR,1.32 [95% CI, 1.10-1.59]). Annualized rates per 1000 person-years of stroke with no antidepressant use and SSRI use were 2.99 and 4.16, respectively, and death rates were 7.79 and 12.77. Tricyclic antidepressant (TCA) use was associated with increased risk of all-cause mortality (HR,1.67 [95% CI, 1.33-2.09]; annualized rate, 14.14 deaths per 1000 person-years). There were no significant differences between SSRI and TCA use in risk of any outcomes. In analyses by stroke type, SSRI use was associated with incident hemorrhagic stroke (HR, 2.12 [95% CI, 1.10-4.07]) and fatal stroke (HR, 2.10 [95% CI, 1.15-3.81]). CONCLUSIONS: In postmenopausal women, there were no significant differences between SSRI and TCA use in risk of CHD, stroke, or mortality. Antidepressants were not associated with risk of CHD. Tricyclic antidepressants and SSRIs may be associated with increased risk of mortality, and SSRIs with increased risk of hemorrhagic and fatal stroke, although absolute event risks are low. These findings must be weighed against quality of life and established risks of cardiovascular disease and mortality associated with untreated depression.