Branislav Stefanovic

Fibrinolysis for patients with intermediate-risk pulmonary embolism

BACKGROUND The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Immediate Versus Delayed Invasive Intervention for Non-STEMI Patients : The RIDDLE-NSTEMI Study

OBJECTIVES This study aimed to assess the clinical impact of immediate versus delayed invasive intervention in patients with non-ST-segment myocardial infarction (NSTEMI). BACKGROUND Previous studies found conflicting results on the effects of earlier invasive intervention in a heterogeneous population of acute coronary syndromes without ST-segment elevation. METHODS We randomized 323 NSTEMI patients to an immediate-intervention group (<2 h after randomization, n = 162) and a delayed-intervention group (2 to 72 h, n = 161).The primary endpoint was the occurrence of death or new myocardial infarction (MI) at 30-day follow-up. RESULTS Median time from randomization to angiography was 1.4 h and 61.0 h in the immediate-intervention group and the delayed-intervention group, respectively (p < 0.001). At 30 days, the primary endpoint was achieved less frequently in patients undergoing immediate intervention (4.3% vs. 13%, hazard ratio: 0.32, 95% confidence interval: 0.13 to 0.74; p = 0.008). At 1 year, this difference persisted (6.8% in the immediate-intervention group vs. 18.8% in delayed-intervention group; hazard ratio: 0.34, 95% confidence interval: 0.17 to 0.67; p = 0.002). The observed results were mainly attributable to the occurrence of new MI in the pre-catheterization period (0 deaths + 0 MIs in the immediate-intervention group vs. 1 death + 10 MIs in the delayed-intervention group). The rate of deaths, new MI, or recurrent ischemia was lower in the immediate-intervention group at both 30 days (6.8% vs. 26.7%; p < 0.001) and 1 year (15.4% vs. 33.1%; p < 0.001). CONCLUSIONS Immediate invasive strategy in NSTEMI patients is associated with lower rates of death or new MI compared with the delayed invasive strategy at early and midterm follow-up, mainly due to a decrease in the risk of new MI in the pre-catheterization period. (Immediate Versus Delayed Invasive Intervention for Non-STEMI Patients [RIDDLE-NSTEMI]; NCT02419833).

D-dimer in acute pancreatitis: a new approach for an early assessment of organ failure.

Objectives: Studies on the clinical value of parameters of hemostasis in predicting pancreatitis-associated complications are still scarce. The aim of this prospective study was to identify the useful hemostatic markers for accurate determination of the subsequent development of organ failure (OF) during the very early course of acute pancreatitis (AP). Methods: In 91 consecutive primarily admitted patients with AP, prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin III, protein C, plasminogen activator inhibitor 1, d-dimer, and plasminogen were measured in plasma within the first 24 hours of admission and 24 hours thereafter. Two study groups comprising 24 patients with OF and 67 patients without OF were compared. Results: Levels of prothrombin time, fibrinogen, and d-dimer on admission were significantly different between the OF and non-OF groups, and all these parameters plus antithrombin III were significantly different 24 hours later. A d-dimer value of 414.00 &mgr;g/L on admission was the best cutoff value in predicting the development of OF with sensitivity, specificity, and positive and negative predictive values of 90%, 89%, 75%, and 96%, respectively. Conclusions: Measurement of plasma levels of d-dimer on the admission is an accurate method for the identification of patients who will develop OF in the further course of AP.Abbreviations: AP - acute pancreatitis, PT - prothrombin time, APTT - activated partial thromboplastin time, AT III - antithrombin III, PAI-1 - plasminogen activator inhibitor 1, ROC - receiver operating characteristic, AUC - area under the curve

Disorders of Hemostasis During the Surgical Management of Severe Necrotizing Pancreatitis

Objectives: Several clinical studies of severe necrotizing pancreatitis (SNP) suggest profound activation of coagulation as well as activation of the fibrinolytic system. The aim of this study was to evaluate the hemostatic derangements in patients who were managed for SNP. Methods: Forty-one operated-on patients with SNP were analyzed regarding clinical outcome and activation of the coagulation systems. Serial measurement of coagulation, anticoagulation, and fibrinolysis parameters: prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, antithrombin III (AT III), protein C, plasminogen activator inhibitor-1 (PAI-1), d-dimer, &agr;2-antiplasmin, and plasminogen were performed on days 1, 3, 5, 7, 10, and 14 after the initial operation. According to treatment outcome at the end of study, groups of 26 survivors and 15 nonsurvivors were compared. Results: Nonsurvivors had significantly lower levels of activity of protein C and AT III, and higher concentrations of d-dimer and PAI-1 than survivors. The other measured parameters did not show significant differences between the compared groups of patients. Conclusions: Changes in protein C, AT III, d-dimer and PAI-1 levels indicate exhaustion of fibrinolysis and coagulation inhibitors in patients with poor outcome during the course of SNP.

Protein C as an Early Marker of Severe Septic Complications in Diffuse Secondary Peritonitis

To evaluate the predictive value of protein C as a marker of severity in patients with diffuse peritonitis and abdominal sepsis, protein C levels were repeatedly determined and compared with serum levels of antithrombin III, plasminogen, α2-antiplasmin, Plasminogen activator inhibitor, D-dimer, C1-inhibitor, high molecular weight kininogen, and the C5a, C5b-9 fragments of the complement system. We carried out a prospective study from 44 patients with severe peritonitis confirmed by laparotomy and 15 patients undergoing elective ventral hernia repair who acted as controls. Analyzed biochemical parameters were determined before operations and on days 1, 2, 3, 5, 7, 10, and 14 after operations. For the study group, preoperative average protein C level was significantly lower in the patients who developed septic shock in the late course of the disease, with lethal outcome, than in the patients with severe peritonitis and sepsis who survived (p = 0.0001). In non-survivors, protein C activity remained decreased below 70%, whereas the course of survivors was characterized by increased values that were significantly higher (p < 0.03) at every time point than in those patients who died. Protein C was of excellent predictive value and achieved a sensitivity of 80% and a specificity of 87.5% in discriminating survivors from non-survivors within the first 48 hours of the study (AUC-0.917; p < 0.001), with a “cut-off” level of 66.0%. As for the control group, throughout the study period, protein C activity was permanently maintained within the range of normal, with significant differences with reference to the study group (p < 0.01). These results suggest that protein C represents a sensitive and early marker for the prediction of severe septic complications during diffuse peritonitis, and of outcome.

Outcome of patients with right heart thrombi: the Right Heart Thrombi European Registry.

Our aim was the assessment of the prognostic significance of right heart thrombi (RiHT) and their characteristics in pulmonary embolism in relation to established prognostic factors. 138 patients (69 females) aged (mean±sd) 62±19 years with RiHT were included into a multicenter registry. A control group of 276 patients without RiHT was created by propensity scoring from a cohort of 963 contemporary patients. The primary end-point was 30-day pulmonary embolism-related mortality; the secondary end-point included 30-day all-cause mortality. In RiHT patients, pulmonary embolism mortality was higher in 31 patients with systolic blood pressure <90 mmHg than in 107 normotensives (42% versus 12%, p=0.0002) and was higher in the 83 normotensives with right ventricular dysfunction (RVD) than in the 24 normotensives without RVD (16% versus 0%, p=0.038). In multivariable analysis the simplified Pulmonary Embolism Severity Index predicted mortality (hazard ratio 2.43, 95% CI 1.58–3.73; p<0.0001), while RiHT characteristics did not. Patients with RiHT had higher pulmonary embolism mortality than controls (19% versus 8%, p=0.003), especially normotensive patients with RVD (16% versus 7%, p=0.02). 30-day mortality in patients with RiHT is related to haemodynamic consequences of pulmonary embolism and not to RiHT characteristics. However, patients with RiHT and pulmonary embolism resulting in RVD seem to have worse prognosis than propensity score-matched controls. Prognosis in patients with PE and RiHT is related to haemodynamic effects of PE, not RiHT morphology http://ow.ly/UCpja

The Timing of Infarction Pain in Patients with Acute Myocardial Infarction after Previous Revascularization

Circadian variation of onset of acute myocardial infarction (AMI) has been noted in many studies, but there are no data about subgroups of patients with previous coronary artery bypass grafting (CABG). Because of abnormalities in the circadian rhythm of autonomic tone after surgery, it was very interesting to analyze the circadian patterns in the onset of symptoms of AMI in various subgroups of 1784 patients with previous CABG. As in the other studies, a peak occurred in the morning hours with 26.3% of the patients, but there was a second nearly equal, but higher, peak (26.4%) in the evening hours. The subgroups with specific clinical characteristics exhibited different patterns that determined these peaks in all populations. In patients older than 70 years of age, in both sexes, in smokers, diabetics, in patients with hypertension, in those undergoing beta-blocker therapy, and in patients without previous angina, two nearly equal peaks were observed, with higher evening peaks, except in those patients with hypertension and without angina. Only one peak in the evening hours was observed in a subgroup of patients with previous congestive heart failure (CHF) and non-STEMI. The subgroup of patients with previous angina and previous AMI exhibited no discernible peaks. The distribution of time of onset within the four intervals was not uniform, and the difference was statistically significant only for patients undergoing beta-blocker therapy at time of onset (p = 0.0013), nonsmokers (p = 0.0283), and patients with non-STEMI (p = 0.0412). It is well known that patients with AMI have a dominant morning peak of circadian variation of onset. However, analyzing a different subgroup of patients with AMI after previous CABG, it was found that some subgroups had two peaks of onset, but a higher evening peak (patients older than 70 years of age, smokers, diabetics, and a group of patients who were taking beta-blocker therapy). This subgroup of patients, together with the subgroups of patients with a dominant evening peak (patients with CHF and those with non-STEMI) and with patients with no peak (patients with previous angina and previous AMI), probably appear to modify characteristic circadian variation of infarction onset, expressing a higher evening peak, respectively to the previous CABG, with adverse consequences for central nervous system functioning.

In-Hospital and Long-Term Prognosis after Myocardial Infarction in Patients with Prior Coronary Artery Bypass Surgery; 19-Year Experience

To present a 19-year experience of the prognosis of patients with acute myocardial infarction (AMI) and prior coronary artery bypass surgery (CABS), 748 patients with AMI after prior CABS (postbypass group) and a control group of 1080 patients with AMI, but without prior CABS, were analyzed. All indexes of infarct size were lower in the postbypass group. There was more ventricular fibrillation in the postbypass group. In-hospital mortality was similar (p = 0.3675). In the follow-up period, postbypass patients had more heart failure, recurrent CABS, reinfarction, and unstable angina than did control patients. Cumulative survival was better in the control group than in the postbypass group (p = 0.0403). Multiple logistic regression model showed that previous angina (p = 0.0005), diabetes (p = 0.0058), and age (p = 0.0102) were independent predictor factors for survival. Use of digitalis and diuretics, together with previous angina, also influenced survival (p = 0.0092), as well as male gender, older patients, and diabetes together (p = 0.0420). Patients with AMI after prior CABS had smaller infarct, but more reinfarction, reoperation, heart failure, and angina. Previous angina, diabetes, and age, independently, as well as use of digitalis and diuretics together with angina, and male gender, older patients, and diabetes together, influenced a worse survival rate in these patients.

Three-Year Impact of Immediate Invasive Strategy in Patients With Non–ST-Segment Elevation Myocardial Infarction (from the RIDDLE-NSTEMI Study)

Previous studies compared clinical outcomes of early versus delayed invasive strategy in patients with non-ST-elevation acute coronary syndrome up to 1-year follow-up, but long-term data remain scarce. Our aim was to evaluate the long-term effects of immediate invasive intervention in patients with Non-ST-Segment Elevation Myocardial Infarction (NSTEMI). The Randomized Study of Immediate Versus Delayed Invasive Intervention in Patients With Non-ST-Segment Elevation Myocardial Infarction (RIDDLE-NSTEMI) was a randomized, investigator-initiated, parallel-group trial that assigned 323 patients with NSTEMI (1:1) to either immediate (median time to intervention 1.4 hours) or delayed invasive strategy (61.0 hours). The primary end point was the composite of death or new myocardial infarction (MI). At 3 years, immediate invasive intervention was associated with a lower rate of death or new MI, compared with a delayed invasive strategy (12.3% vs 22.5%, hazard ratio 0.50, 95% confidence interval 0.29 to 0.87, p = 0.014). The observed benefit of immediate intervention was mainly driven by an increased early reinfarction risk in delayed strategy, with similar new MI rates beyond 30 days (4.4% in the immediate and 5.6% in the delayed group, p = 0.61). Three-year mortality was 9.3% in the immediate invasive strategy, and 10.0% in the delayed strategy (p = 0.83). High baseline Global Registry of Acute Coronary Events score (>140) was associated with a significant increase in long-term mortality, regardless of the timing of invasive intervention. In conclusion, whereas immediate invasive intervention significantly reduced the early risk of new MI, the timing of invasive intervention appears to have no significant impact on clinical outcomes beyond 30 days, which seem to mostly be related to the baseline clinical risk profile.

Dabigatran after Short Heparin Anticoagulation for Acute Intermediate-Risk Pulmonary Embolism: Rationale and Design of the Single-Arm PEITHO-2 Study

Patients with intermediate-risk pulmonary embolism (PE) may, depending on the method and cut-off values used for definition, account for up to 60% of all patients with PE and have an 8% or higher risk of short-term adverse outcome. Although four non-vitamin K-dependent direct oral anticoagulants (NOACs) have been approved for the treatment of venous thromboembolism, their safety and efficacy as well as the optimal anticoagulation regimen using these drugs have not been systematically investigated in intermediate-risk PE. Moreover, it remains unknown how many patients with intermediate-high-risk and intermediate-low-risk PE were included in most of the phase III NOAC trials. The ongoing Pulmonary Embolism International Thrombolysis 2 (PEITHO-2) study is a prospective, multicentre, multinational, single-arm trial investigating whether treatment of acute intermediate-risk PE with parenteral heparin anticoagulation over the first 72 hours, followed by the direct oral thrombin inhibitor dabigatran over 6 months, is effective and safe. The primary efficacy outcome is recurrent symptomatic venous thromboembolism or death related to PE within the first 6 months. The primary safety outcome is major bleeding as defined by the International Society on Thrombosis and Haemostasis. Secondary outcomes include all-cause mortality, the overall duration of hospital stay (index event and repeated hospitalizations) and the temporal pattern of recovery of right ventricular function over the 6-month follow-up period. By applying and evaluating a contemporary risk-tailored treatment strategy for acute PE, PEITHO-2 will implement the recommendations of current guidelines and contribute to their further evolution.