Gustavo B.F. Oliveira

Evaluation and management of thrombocytopenia and suspected heparin-induced thrombocytopenia in hospitalized patients: The Complications After Thrombocytopenia Caused by Heparin (CATCH) registry

BACKGROUND Thrombocytopenia and heparin-induced thrombocytopenia (HIT) are potentially devastating paradoxical side effects of heparin therapy. We explored the evaluation, management, and clinical consequences of thrombocytopenia occurring during heparin therapy in diverse clinical settings. METHODS CATCH was a prospective observational study that enrolled 3,536 patients in 48 US hospitals. Data were collected on 3 strata: patients receiving any form of heparin for > or =96 hours (n = 2,420); cardiac care unit (CCU) patients treated with heparin who developed thrombocytopenia (n = 1,090); patients who had an HIT assay performed (n = 449). RESULTS Thrombocytopenia occurred in 36.4% of patients in the prolonged heparin stratum and was associated with an increased risk of death or thromboembolic complication (OR 1.5, 95% CI 1.2-1.9). Among a subset of patients whose clinical presentation suggested they were at high risk for HIT, suspicion for HIT was uncommon (prolonged heparin stratum 19.8%, CCU stratum 37.6%) and often did not arise until > or =1 day after patients developed thrombocytopenia. Often patients were not evaluated for HIT until after they had had a thromboembolic complication (prolonged heparin stratum 43.8%, CCU stratum 61%). Even after HIT was suspected, patients often continued to receive heparin. Direct thrombin inhibitor use was infrequent (prolonged heparin stratum 29.4%, CCU stratum 35.6%). Among the few patients who underwent evaluation, HIT was confirmed in 46.7% of the prolonged heparin stratum and 31.4% of the CCU stratum. CONCLUSIONS Thrombocytopenia is common among patients receiving heparin, and it is associated with substantial risk for catastrophic complications. Despite the high risk for HIT in this population, recognition, evaluation, and appropriate treatment are infrequent and delayed.

Delay to reperfusion in patients with acute myocardial infarction presenting to acute care hospitals: an international perspective

AIMS To examine the extent of delay from initial hospital presentation to fibrinolytic therapy or primary percutaneous coronary intervention (PCI), characteristics associated with prolonged delay, and changes in delay patterns over time in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS We analysed data from 5170 patients with STEMI enrolled in the Global Registry of Acute Coronary Events from 2003 to 2007. The median elapsed time from first hospital presentation to initiation of fibrinolysis was 30 min (interquartile range 18-60) and to primary PCI was 86 min (interquartile range 53-135). Over the years under study, there were no significant changes in delay times to treatment with either strategy. Geographic region was the strongest predictor of delay to initiation of fibrinolysis >30 min. Patients transfer status and geographic location were strongly associated with delay to primary PCI. Patients treated in Europe were least likely to experience delay to fibrinolysis or primary PCI. CONCLUSION These data suggest no improvements in delay times from hospital presentation to initiation of fibrinolysis or primary PCI during our study period. Geographic location and patient transfer were the strongest predictors of prolonged delay time, suggesting that improvements in modifiable healthcare system factors can shorten delay to reperfusion therapy even further.

Cardiovascular Disease Burden: Evolving Knowledge of Risk Factors in Myocardial Infarction and Stroke through Population-Based Research and Perspectives in Global Prevention.

Current knowledge and research perspectives on the top ranking causes of mortality worldwide, i.e., ischemic heart disease and cerebrovascular diseases have developed rapidly. In fact, until recently, the evidence describing the incidence of acute myocardial infarction, the underlying risk factors, and the clinical outcomes of those who have this acute ischemic coronary event has largely been based on studies conducted in developed countries, with limited data for women and usually of low-ethnic diversity. Recent reports by the WHO have provided striking public health information, i.e., the global burden of cardiovascular mortality for the next decades is expected to predominantly occur among developing countries. Therefore, multiethnic population-based research including prospective cohorts and, when appropriate, case–control studies, is warranted. These studies should be specifically designed to ascertain key public health measures, such as geographic variations in non-communicable diseases, diagnosis of traditional and potential newly discovered risk factors, causes of death and disability, and gaps for improvement in healthcare prevention (both primary and secondary) and specific treatments. As an example, a multinational, multiethnic population-based cohort study is the Prospective Urban and Rural Epidemiology study, which is the largest global initiative of nearly 200,000 adults aged 35–70 years, looking at environmental, societal, and biological influences on obesity and chronic health conditions, such as ischemic heart disease, stroke, and cancer among urban and rural communities in low-, middle-, and high-income countries, with national, community, household, and individual-level data. Implementation of population-based strategies is crucial to optimizing limited health system resources while improving care and cardiovascular morbidity and mortality.

Six-Month Follow-Up of Patients With In-Hospital Thrombocytopenia During Heparin-Based Anticoagulation (from the Complications After Thrombocytopenia Caused by Heparin [CATCH] Registry)

Thrombocytopenia is a predictor of adverse outcomes in patients with acute coronary syndromes and in critically ill patients. The Complications After Thrombocytopenia Caused by Heparin (CATCH) registry was designed to explore the incidence, management, and clinical consequences of in-hospital thrombocytopenia occurring during heparin-based anticoagulation in diverse clinical settings. We conducted a prospective observational study of 37 United States hospitals participating in the CATCH registry to assess the relation of in-hospital thrombocytopenia to long-term outcomes. A total of 2,104 patients at increased risk of developing in-hospital thrombocytopenia or thrombosis were identified, and the 6-month mortality and rehospitalization rates were determined. Thrombocytopenia was not a significant predictor of 6-month mortality. In an adjusted model for in-hospital death in this cohort, thrombocytopenia had an odds ratio of 3.59 (95% confidence interval 2.24 to 5.77). The postdischarge mortality rate at 6 months was 9.7%. No significant difference was observed in the long-term mortality between patients who developed thrombocytopenia and those who did not. Thrombocytopenia was a weak, but statistically significant, predictor of a composite of mortality and rehospitalization at 6 months (hazards ratio 0.80, 95% confidence interval 0.65 to 0.98, p = 0.03). In conclusion, the 6-month mortality rate among heparin-treated patients with thrombocytopenia is high, although the risk independently related to thrombocytopenia appears to be restricted to the acute hospital phase.

Association of Urinary Sodium Excretion With Blood Pressure and Cardiovascular Clinical Events in 17,033 Latin Americans.

BACKGROUND Information on actual sodium intake and its relationships with blood pressure (BP) and clinical events in South America is limited. The aim of this cohort study was to assess the relationship of sodium intake with BP, cardiovascular (CV) events, and mortality in South America. METHODS We studied 17,033 individuals, aged 35-70 years, from 4 South American countries (Argentina, Brazil, Chile, and Colombia). Measures of sodium excretion, estimated from morning fasting urine, were used as a surrogate for daily sodium intake. We measured BP and monitored the composite outcome of death and major CV events. RESULTS Overall mean sodium excretion was 4.70±1.43g/day. A positive, nonuniform association between sodium and BP was detected, with a significant steeper slope for the relationship at higher sodium excretion levels (P < 0.001 for interaction). With a median follow-up of 4.7 years, the primary composite outcome (all-cause death, myocardial infarction, stroke, or heart failure) occurred in 568 participants (3.4%). Compared with sodium excretion of 5-6g/day (reference group), participants who excreted >7g/day had increased risks of the primary outcome (odds ratio (OR) 1.73; 95% confidence interval (CI) 1.24 to 2.40; P < 0.001), as well as death from any cause (OR 1.87; 95% CI 1.23 to 2.83; P = 0.003) and major CV disease (OR 1.77; 95% CI 1.12 to 2.81; P = 0.014). Sodium excretion of <3g/day was associated with a statistically nonsignificant increased risk of the primary outcome (OR 1.20; 95% CI 0.86 to 1.65; P = 0.26) and death from any cause (OR 1.25; 95% CI 0.81 to 1.93; P = 0.29), and a significant increased risk of major CV disease (OR 1.50; 95% CI 1.01 to 2.24; P = 0.048), as compared to the reference group. CONCLUSIONS Our results support a positive, nonuniform association between estimated urinary sodium excretion and BP, and a possible J-shaped pattern of association between sodium excretion over the entire range and clinical outcomes.

Validation of the Killip-Kimball Classification and Late Mortality after Acute Myocardial Infarction

Background The classification or index of heart failure severity in patients with acute myocardial infarction (AMI) was proposed by Killip and Kimball aiming at assessing the risk of in-hospital death and the potential benefit of specific management of care provided in Coronary Care Units (CCU) during the decade of 60. Objective To validate the risk stratification of Killip classification in the long-term mortality and compare the prognostic value in patients with non-ST-segment elevation MI (NSTEMI) relative to patients with ST-segment elevation MI (STEMI), in the era of reperfusion and modern antithrombotic therapies. Methods We evaluated 1906 patients with documented AMI and admitted to the CCU, from 1995 to 2011, with a mean follow-up of 05 years to assess total mortality. Kaplan-Meier (KM) curves were developed for comparison between survival distributions according to Killip class and NSTEMI versus STEMI. Cox proportional regression models were developed to determine the independent association between Killip class and mortality, with sensitivity analyses based on type of AMI. Results: The proportions of deaths and the KM survival distributions were significantly different across Killip class >1 (p <0.001) and with a similar pattern between patients with NSTEMI and STEMI. Cox models identified the Killip classification as a significant, sustained, consistent predictor and independent of relevant covariables (Wald χ2 16.5 [p = 0.001], NSTEMI) and (Wald χ2 11.9 [p = 0.008], STEMI). Conclusion The Killip and Kimball classification performs relevant prognostic role in mortality at mean follow-up of 05 years post-AMI, with a similar pattern between NSTEMI and STEMI patients.

Contribution of Bleeding and Thromboembolic Events to In-Hospital Mortality Among Patients With Thrombocytopenia Treated With Heparin

In a population of patients experiencing thrombocytopenia while treated with heparin, bleeding and thromboses are well-appreciated complications, but their relative contributions to mortality have been less well described. In this population, the aims of this study were (1) to identify the independent predictors of bleeding and (2) to compare the incidence and the strength of association of bleeding and of new thromboses to in-hospital mortality. The independent predictors of bleeding and in-hospital mortality were identified using multivariate logistic regression models on the 1,478 patients who developed thrombocytopenia after their enrollment in the Complications After Thrombocytopenia Caused by Heparin (CATCH) study. The independent predictors of bleeding were chronic hematologic disorders, intra-aortic balloon pump, congestive heart failure, and platelet count nadir <120 x 10(9)/L. Although bleeding (n = 141 [10%]) and thromboembolic complications (n = 135 [9%]) were equally prevalent, the former was less strongly associated than the latter with in-hospital mortality (odds ratio 1.75, 95% confidence interval 1.01 to 3.03, and odds ratio 2.77, 95% confidence interval 1.67 to 4.61, respectively). In conclusion, medical management should be directed mainly at the prevention of thromboembolic complications, while additionally considering the risk for bleeding.

Serum adiponectin and cardiometabolic risk in patients with acute coronary syndromes

Background The adipose tissue is considered not only a storable energy source, but mainly an endocrine organ that secretes several cytokines. Adiponectin, a novel protein similar to collagen, has been found to be an adipocyte-specific cytokine and a promising cardiovascular risk marker. Objectives To evaluate the association between serum adiponectin levels and the risk for cardiovascular events in patients with acute coronary syndromes (ACS), as well as the correlations between adiponectin and metabolic, inflammatory, and myocardial biomarkers. Methods We recruited 114 patients with ACS and a mean 1.13-year follow-up to measure clinical outcomes. Clinical characteristics and biomarkers were compared according to adiponectin quartiles. Cox proportional hazard regression models with Firths penalization were applied to assess the independent association between adiponectin and the subsequent risk for both primary (composite of cardiovascular death/non-fatal acute myocardial infarction (AMI)/non-fatal stroke) and co-primary outcomes (composite of cardiovascular death/non-fatal AMI/non-fatal stroke/ rehospitalization requiring revascularization). Results There were significant direct correlations between adiponectin and age, HDL-cholesterol, and B-type natriuretic peptide (BNP), and significant inverse correlations between adiponectin and waist circumference, body weight, body mass index, Homeostasis Model Assessment (HOMA) index, triglycerides, and insulin. Adiponectin was associated with higher risk for primary and co-primary outcomes (adjusted HR 1.08 and 1.07/increment of 1000; p = 0.01 and p = 0.02, respectively). Conclusion In ACS patients, serum adiponectin was an independent predictor of cardiovascular events. In addition to the anthropometric and metabolic correlations, there was a significant direct correlation between adiponectin and BNP.

Secondary CV Prevention in South America in a Community Setting: The PURE Study

BACKGROUND Despite the availability of evidence-based therapies, there is no information on the use of medications for the secondary prevention of cardiovascular disease in urban and rural community settings in South America. OBJECTIVES This study sought to assess the use, and its predictors, of effective secondary prevention therapies in individuals with a history of coronary heart disease (CHD) or stroke. METHODS In the PURE (Prospective Urban Rural Epidemiological) study, we enrolled 24,713 individuals from South America ages 35 to 70 years from 97 rural and urban communities in Argentina, Brazil, Chile, and Colombia. We assessed the use of proven therapies with standardized questionnaires. We report estimates of drug use at national, community, and individual levels and the independent predictors of their utilization through a multivariable analysis model. RESULTS Of 24,713 individuals, 910 had a self-reported CHD event (at a median of 5 years earlier) and 407 had stroke (6 years earlier). The proportions of individuals with CHD who received antiplatelet medications (30.1%), beta-blockers (34.2%), angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers (36.0%), or statins (18.0%) were low; with even lower proportions among stroke patients (antiplatelets 24.3%, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers 37.6%, statins 9.8%). A substantial proportion of patients did not receive any proven therapy (CHD 31%, stroke 54%). A minority of patients received either all 4 (4.1%) or 3 proven therapies (3.3%). Male sex, age >60 years, better education, more wealth, urban location, diabetes, and obesity were associated with higher rates of medication use. In a multivariable model, markers of wealth had the largest impact in secondary prevention. CONCLUSIONS There are large gaps in the use of proven medications for secondary prevention of cardiovascular disease in South America. Strategies to improve the sustained use of these medications will likely reduce cardiovascular disease burden substantially.

Efficacy and safety of dabigatran versus warfarin from the RE-LY trial

Background Current data for atrial fibrillation (AF) and stroke are predominantly derived from North American and European patients. Although the burden of AF is high in Latin America (LA), little is known about current management of AF in the region. Methods We aimed to assess the consistency of efficacy and safety outcomes associated with dabigatran etexilate (DE) versus warfarin in patients with AF in LA from the RE-LY (Randomised Evaluation of Long-Term Anticoagulant Therapy) trial. Data from 956 LA patients and 17 157 non-LA patients were included in this analysis. χ2 test and Cox proportional regression analysis were performed. The primary efficacy outcome included all strokes or systemic embolism (SE). Main safety outcome was major bleeding. Results LA patients were more often female, had higher proportion of permanent AF and lower creatinine clearance, among other characteristics. Vitamin K antagonist use at randomisation and time in therapeutic range were lower in LA than in non-LA patients (44% vs 63%, p<0.001; and 61.3±22.6% vs 64.6±19.6%, p=0.015, respectively). Efficacy endpoints were 0.91% versus 1.68% for DE 150 mg twice daily versus warfarin, respectively. Stroke/SE risk was lower in LA patients treated with DE 150 mg twice daily compared with warfarin, although not significant (HR 0.54; 95% CI 0.18 to 1.62). The annual stroke/SE rates for DE 110 mg twice daily versus warfarin were 1.82 versus 1.68, also not significantly different (HR 1.09; CI 0.44 to 2.67). There were no treatment-by-region interactions for either dose of DE on efficacy and safety outcomes. Conclusion Despite differences in the clinical profile and AF management, the efficacy and safety benefits of dabigatran over warfarin in LA patients relative to non-LA patients are consistent with those observed in the main RE-LY trial.