Muthiah Vaduganathan

The Global Health and Economic Burden of Hospitalizations for Heart Failure: Lessons Learned From Hospitalized Heart Failure Registries

Heart failure is a global pandemic affecting an estimated 26 million people worldwide and resulting in more than 1 million hospitalizations annually in both the United States and Europe. Although the outcomes for ambulatory HF patients with a reduced ejection fraction (EF) have improved with the discovery of multiple evidence-based drug and device therapies, hospitalized heart failure (HHF) patients continue to experience unacceptably high post-discharge mortality and readmission rates that have not changed in the last 2 decades. In addition, the proportion of HHF patients classified as having a preserved EF continues to grow and may overtake HF with a reduced EF in the near future. However, the prognosis for HF with a preserved EF is similar and there are currently no available disease-modifying therapies. HHF registries have significantly improved our understanding of this clinical entity and remain an important source of data shaping both public policy and research efforts. The authors review global HHF registries to describe the patient characteristics, management, outcomes and their predictors, quality improvement initiatives, regional differences, and limitations of the available data. Moreover, based on the lessons learned, they also propose a roadmap for the design and conduct of future HHF registries.

Rehospitalization for Heart Failure Problems and Perspectives

With a prevalence of 5.8 million in the United States alone, heart failure (HF) is associated with high morbidity, mortality, and healthcare expenditures. Close to 1 million hospitalizations for heart failure (HHF) occur annually, accounting for over 6.5 million hospital days and a substantial portion of the estimated

Role of Reticulated Platelets and Platelet Size Heterogeneity on Platelet Activity After Dual Antiplatelet Therapy With Aspirin and Clopidogrel in Patients With Stable Coronary Artery Disease

37.2 billion that is spent each year on HF in the United States. Although some progress has been made in reducing mortality in patients hospitalized with HF, rates of rehospitalization continue to rise, and approach 30% within 60 to 90 days of discharge. Approximately half of HHF patients have preserved or relatively preserved ejection fraction (EF). Their post-discharge event rate is similar to those with reduced EF. HF readmission is increasingly being used as a quality metric, a basis for hospital reimbursement, and an outcome measure in HF clinical trials. In order to effectively prevent HF readmissions and improve overall outcomes, it is important to have a complete and longitudinal characterization of HHF patients. This paper highlights management strategies that when properly implemented may help reduce HF rehospitalizations and include adopting a mechanistic approach to cardiac abnormalities, treating noncardiac comorbidities, increasing utilization of evidence-based therapies, and improving care transitions, monitoring, and disease management.

Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial

OBJECTIVES The aim of this study was to evaluate the relationship between reticulated platelets (RPs), platelet size, and platelet function in patients with stable coronary artery disease (CAD) taking aspirin and clopidogrel. BACKGROUND Reticulated platelets are young platelets that are larger and possibly more active than non-RPs. METHODS Flow cytometry was used to measure RPs after staining with thiazole orange and to define the upper 20% and lower 20% of platelets by size. Platelet aggregation was measured with light transmission aggregometry (LTA); platelet activation was assessed by measuring activated platelet surface expression of P-selectin and glycoprotein (GP) IIb/IIIa. RESULTS Ninety patients were recruited and stratified into tertiles of %RPs. Patients in the upper tertile displayed greater platelet aggregation to 5-mumol/l adenosine diphosphate (ADP) (50.7 +/- 16.4% vs. 34.2 +/- 17.3%, p < 0.001), 1.5-mmol/l arachidonic acid (AA) (27.3 +/- 16.9% vs. 11.7 +/- 9.3%, p < 0.001), and 1-mug/ml collagen (18 +/- 11.6% vs. 12.1 +/- 8.7%, p < 0.05) and greater expression of GP IIb/IIIa (4.7 +/- 1.8% vs. 3.1 +/- 2.2%, p < 0.001). Frequency of low response to aspirin (AA LTA >20%) was higher in the upper tertile (53% vs. 17%, p < 0.001) compared with the lower tertile; low response to clopidogrel (ADP LTA >50%) was also elevated in the upper tertile (50% vs. 13%, p = 0.003). The larger platelet gate had a higher % of RPs compared with the smaller gate (15.4 +/- 16.7% vs. 1.7 +/- 2.3%, p < 0.001) and greater GP IIb/IIIa (5.7 +/- 3.1 vs. 2.1 +/- 1.2, p < 0.001) and P-selectin expression (7.8 +/- 4.9 vs. 4.6 +/- 2.7, p < 0.001). CONCLUSIONS The proportion of circulating RPs strongly correlates with response to antiplatelet therapy in patients with stable CAD. Large platelets exhibit increased reactivity despite dual antiplatelet therapy, compared with smaller platelets.

Thirty-Day Readmissions: The Clock Is Ticking

Abnormal liver function tests (LFTs) are common in ambulatory heart failure (HF). The aim of this study was to characterize abnormal LFTs during index hospitalization.

Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial.

WHAT MAKES 30 DAYS SO SPECIAL? ACROSS DISciplines of medicine, this time frame is used to help define response to initial therapies. Oncologists often require 4 weeks of complete response to initial chemotherapy before declaring patients with acute myeloid leukemia to be in remission. The Society of Thoracic Surgeons uses 30-day mortality as a major indicator of cardiac surgical success. In heart failure, 30day readmission has emerged as a benchmark for reimbursement and an indicator of hospital quality. Today,approximatelyone-quarterofallpatientsdischarged from a hospitalization for heart failure are readmitted within 30 days, and half of these readmissions are directly related to heart failure. On October 1, 2012, the Centers for Medicare &MedicaidServices(CMS)begantopenalizehospitalsforhigher standardizedearlyreadmissionratesforheartfailure,acutemyocardial infarction, and pneumonia. It is anticipated that these penaltieswill increaseandalsoexpandtoincludeotherdiseases, making this provision one of the most severe penalties mandated by the Patient Protection and Affordable Care Act. Herein, we critically explore the widely accepted 30-day timeline and the use of rehospitalization as a target end point. Although heart failure is used to examine the various facets of postdischarge hospital outcomes, this discussion can be applied across many other medical conditions.

Haemoconcentration, renal function, and post-discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial

OBJECTIVES The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes. BACKGROUND Whether and how site enrollment volume affects clinical trials is not known. METHODS A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization). RESULTS Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for <10, 61.7% for 11 to 30, and 68.4% for sites enrolling >30 participants; p < 0.001). CONCLUSIONS Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.

The cGMP Signaling Pathway as a Therapeutic Target in Heart Failure With Preserved Ejection Fraction

Haemoconcentration has been studied as a marker of decongestion in patients with hospitalization for heart failure (HHF). We describe the relationship between haemoconcentration, worsening renal function, post‐discharge outcomes, and clinical and laboratory markers of congestion in a large multinational cohort of patients with HHF.

Response to Prasugrel and Levels of Circulating Reticulated Platelets in Patients With ST-Segment Elevation Myocardial Infarction

Heart failure with preserved ejection fraction (HFpEF) is a growing public health problem that accounts for approximately half of all prevalent heart failure (HF).[1][1]–[2][2] Once believed to carry a favorable prognosis compared with HF and reduced ejection fraction (HFrEF), contemporary data

Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions

OBJECTIVES The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover. METHODS Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P₂Y, G-protein coupled, 12 (P₂Y₁₂) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables. RESULTS Sixty-two patients were included (mean age: 57.5 ± 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P₂Y₁₂ assay (Spearmans correlation coefficient: 0.55 for P₂Y₁₂ reaction units, -0.49 for percent inhibition) and MEA (Spearmans: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P₂Y₁₂ assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI. CONCLUSIONS The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment.