Mortality of patients excluded from the Danish Verapamil Infarction Trial II

The 18 month mortality rate in 2180 patients excluded from theDanish Verapamil Infarction Trial II (DAVIT II) was 25.6%. Innon-consenters (n = 368) this was 15.0% compared with 13.8%in 897 placebo-treated patients (hazard ratio 1.09 [P = 0.60]when adjusting for sex and age). The increased mortality ratein excluded patients is attributed to heart failure (45.8% andother severe diseases (38.9%).     

Clinical Trial Design Issues in Systemic Sclerosis: an Update

Systemic sclerosis (scleroderma, SSc) is a multisystem disease characterized by vasculopathy, autoimmunity, and fibrosis. SSc has the highest disease-related mortality rate among the rheumatologic illnesses. In the USA, there remains no FDA-approved therapy. As our understanding of SSc pathogenesis improves, targeted therapies interrupting key pathways and mediators will be studied in clinical trials. However, clinical trials in SSc are fraught with challenges. Validated clinical outcome measures do not exist for all disease manifestations. It can be difficult to discern disease activity from damage. SSc is highly heterogeneous, with multiple different phenotypes, and predicting who will have progressive disease is not currently well understood. Biomarkers are in early stages of development and do not represent surrogate outcomes at this time. Given that SSc is uncommon, studies of similar disease aspects or populations can lead to competition for patients. This review will focus on current issues in SSc clinical trial design.     

Cause-Specific Mortality in Patients With Advanced Chronic Kidney Disease in the ISCHEMIA-CKD Trial

BackgroundIn ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively).ObjectivesThis prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death.MethodsThree-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified.ResultsA total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively; HR: 1.13, 95% CI: 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively; HR: 1.25; 95% CI: 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy.ConclusionsIn ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease [ISCHEMIA-CKD]; NCT01985360)     

Transesophageal Echocardiography to Guide Cardioversion in Patients with Atrial Fibrillation: ACUTE Trial Update

The Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) trial was the first randomized prospective study to compare the conventional strategy of 3 weeks of anticoagulation before direct current cardioversion (DCC) for atrial fibrillation (AF) to a transesophageal echocardiography (TEE) guided approach with an expedited course of anticoagulation. This was a multicenter, international study with 70 sites enrolling 1222 patients between 1994-1999. The primary endpoint of composite embolic events and secondary endpoints including bleeding, functional status, prevalence of sinus rhythm, and death were assessed at 8 weeks following randomization.The ACUTE trial demonstrated that the TEE guided approach was safe and effective. There was no difference in the primary outcome of embolic events for the 2 strategies (0.8% TEE group vs. 0.5% conventional group, p =.50). There was a difference between the groups with respect to the number of bleeding events, with minor and major bleeding seen in 2.9% of patients in the TEE guided group and 5.5% in the conventional group (relative risk 0.53, 95% confidence interval 0.30-0.93, p = 0.03). The remaining secondary endpoints did not differ.Clinicians now have a viable alternative approach to cardioversion for patients with AF. Several factors influence the choice of strategies including (1) severity of symptoms and hemodynamic effect; (2) level and chronicity of anticoagulation; (3) risks of bleeding; (4) duration of AF and likelihood of reversion; and (5) risk and likelihood of left atrial thrombi. Future studies, such as ACUTE II are ongoing, with the aim of using low molecular weight heparin to further streamline the TEE guided approach to DCC and shorten hospital stay and costs.     

TRITON and beyond: new insights into the profile of prasugrel

Prasugrel, a third-generation thienopyridine antiplatelet agent, demonstrated superior efficacy to clopidogrel but with an increased risk of bleeding in the phase III pivotal registration Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). This article reviews and discusses select components of a large literature of prasugrel data that has emerged since the TRITON-TIMI 38 (TRITON) study primary disclosure.     

Antecedent angina pectoris predicts worse outcome after myocardial infarction in patients receiving thrombolytic therapy: experience gleaned from the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

The significance of antecedent angina in predicting clinical outcome was assessed in 8,329 patients with acute myocardial infarction who received thrombolytic therapy with either recombinant tissue-type plasminogen activator or streptokinase. There were 2,370 patients with antecedent angina for greater than 1 month, 1,512 patients with antecedent angina for less than or equal to 1 month and 4,447 patients with no antecedent angina. The longer the duration of angina, the worse the baseline characteristics in the three groups: the mean patient age was 65 versus 62 versus 61 years, respectively (p less than 0.0001); the rate of previous myocardial infarction was 37% versus 18% versus 10% (p less than 0.0001); and the rate of hypertension was 40% versus 31% versus 27% (p less than 0.0001). Antecedent angina was associated with a longer hospital stay (11.3 and 11.7 days vs. 10.8 days, p less than 0.0001), a higher incidence of bypass surgery (2.2% vs. 1.2% vs. 0.7%, p = 0.0001), a worse Killip class at discharge (10.6% of patients in class greater than 1 vs. 8.7% vs. 6.4%, p = 0.0001), and a higher hospital and 6-month mortality (12.1% and 18% vs. 8.9% and 11.6% vs. 6.6% and 9.2%, respectively, p less than 0.0001). A multivariate analysis taking into account all baseline characteristics confirmed the independent association of antecedent angina with mortality, with a relative risk of 1.4 to 1.47 (p less than 0.001). Antecedent angina predicts a worse clinical outcome and a more intense use of medical resources in patients with acute myocardial infarction receiving thrombolytic therapy.