Samuel Z. Goldhaber

Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND This article addresses the treatment of VTE disease. METHODS We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. RESULTS For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). CONCLUSION Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences.

Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER)

BACKGROUND Pulmonary embolism (PE) remains poorly understood. Rates of clinical outcomes such as death and recurrence vary widely among trials. We therefore established the International Cooperative Pulmonary Embolism Registry (ICOPER), with the aim of identifying factors associated with death. METHODS 2454 consecutive eligible patients with acute PE were registered from 52 hospitals in seven countries in Europe and North America. The primary outcome measure was all-cause mortality at 3 months. The prognostic effect of baseline factors on survival was assessed with multivariate analyses. FINDINGS 2110 (86.0%) patients had PE proven by necropsy, high-probability lung scan, pulmonary angiography, or venous ultrasonography plus high clinical suspicion; ICOPER accepted without independent review diagnoses and interpretation of imaging provided by participating centres; 3-month follow-up was completed in 98.0% of patients. The overall crude mortality rate at 3 months was 17.4% (426 of 2454 deaths, including 52 patients lost to follow-up): 179 of 397 (45.1%) deaths were ascribed to PE and 70 of 397 (17.6%) to cancer, and no information on the cause of death was available for 29 patients. After exclusion of 61 patients in whom PE was first discovered at necropsy, the mortality rate at 3 months was 15.3% (365 of 2393 deaths). On multiple-regression modelling, age over 70 years (hazard ratio 1.6 [95% CI 1.1-2.3]), cancer (2.3 [1.5-3.5]), congestive heart failure (2.4 [1.5-3.7]), chronic obstructive pulmonary disease (1.8 [1.2-2.7]), systolic arterial hypotension (2.9 [1.7-5.0]), tachypnoea (2.0 [1.2-3.2]), and right-ventricular hypokinesis on echocardiography (2.0 [1.3-2.9]) were identified as significant prognostic factors. INTERPRETATION PE remains an important clinical problem with a high mortality rate. Data from ICOPER provide rates and highlight adverse prognostic categories that will help in planning of future trials of high-risk PE patients.

Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism

BACKGROUND The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. METHODS In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests. RESULTS A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05). CONCLUSIONS For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. (ClinicalTrials.gov number, NCT00291330.)

Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension A Scientific Statement From the American Heart Association

Venous thromboembolism (VTE) is responsible for the hospitalization of >250 000 Americans annually and represents a significant risk for morbidity and mortality. Despite the publication of evidence-based clinical practice guidelines to aid in the management of VTE in its acute and chronic forms, the clinician is frequently confronted with manifestations of VTE for which data are sparse and optimal management is unclear. In particular, the optimal use of advanced therapies for acute VTE, including thrombolysis and catheter-based therapies, remains uncertain. This report addresses the management of massive and submassive pulmonary embolism (PE), iliofemoral deep vein thrombosis (IFDVT),and chronic thromboembolic pulmonary hypertension (CTEPH). The goal is to provide practical advice to enable the busy clinician to optimize the management of patients with these severe manifestations of VTE. Although this document makes recommendations for management, optimal medical decisions must incorporate other factors, including patient wishes, quality of life, and life expectancy based on age and comorbidities. The appropriateness of these recommendations for a specific patient may vary depending on these factors and will be best judged by the bedside clinician.

Moderate Alcohol Intake, Increased Levels of High-Density Lipoprotein and Its Subfractions, and Decreased Risk of Myocardial Infarction

BACKGROUND Previous studies have suggested that moderate alcohol intake exerts a protective effect against coronary heart disease. Alterations in plasma lipoprotein levels represent one plausible mechanism of this apparent protective effect. METHODS We therefore examined the interrelation among alcohol consumption, plasma lipoprotein levels, and the risk of myocardial infarction in 340 patients who had had myocardial infarctions and an equal number of age- and sex-matched controls. The case patients were men or women less than 76 years of age with no history of coronary disease who were discharged from one of six hospitals in the Boston area with a diagnosis of a confirmed myocardial infarction. Alcohol consumption was estimated by means of a food-frequency questionnaire. RESULTS We observed a significant inverse association between alcohol consumption and the risk of myocardial infarction (P for trend, < 0.001 after control for known coronary risk factors). In multivariate analyses, the relative risk for the highest intake category (subjects who consumed three or more drinks per day) as compared with the lowest (those who had less than one drink a month) was 0.45 (95 percent confidence interval, 0.26 to 0.80). The levels of total high-density lipoprotein cholesterol (HDL) and its HDL2 and HDL3 subfractions were strongly associated with alcohol consumption (P for trend, < 0.001 for each). The addition of HDL or either of its subfractions to the multivariate model substantially reduced the inverse association between alcohol intake and myocardial infarction, whereas the addition of the other plasma lipid measurements did not materially alter the relation. CONCLUSIONS These data confirm the inverse association of moderate alcohol intake with the risk of myocardial infarction and support the view that the effect is mediated, in large part, by increases in both HDL2 and HDL3.

Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion

Data from a non-randomised study have hinted that in patients with acute pulmonary embolism (PE), thrombolysis followed by heparin more rapidly reverses right-ventricular dysfunction and restores pulmonary tissue perfusion than does heparin alone. We have pursued this idea in a randomised protocol. 46 haemodynamically stable patients were randomised to recombinant tissue plasminogen activator (alteplase, rt-PA) 100 mg over 2 h followed by intravenous heparin and 55 to heparin alone. Right-ventricular wall motion was assessed qualitatively, and right-ventricular end diastolic area was estimated by planimetry from echocardiograms at baseline and at 3 and 24 hours. Pulmonary perfusion scans were obtained at baseline and 24 hours. In 39% of rt-PA patients but in only 17% of heparin alone patients right-ventricular wall motion at 24 hours had improved from baseline and in 2% and 17%, respectively, it worsened (p = 0.005). rt-PA patients also had a significant decrease in right-ventricular end-diastolic area during the 24 hours after randomisation and a significant absolute improvement in pulmonary perfusion (14.6% vs 1.5%). No clinical episodes of recurrent PE were noted among rt-PA patients, but there were 2 fatal and 3 non-fatal clinically suspected recurrent PEs within 14 days in patients randomised to heparin alone. rt-PA rapidly improves right-ventricular function and pulmonary perfusion among patients with PE and may lead to a lower rate of adverse clinical outcomes.

Extended Use of Da bi gat ran, Warfarin, or Placebo in Venous Thromboembolism

BACKGROUND Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. METHODS In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. RESULTS In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. CONCLUSIONS Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. (Funded by Boehringer Ingelheim; RE-MEDY and RE-SONATE ClinicalTrials.gov numbers, NCT00329238 and NCT00558259, respectively.).

Prospective study of exogenous hormones and risk of pulmonary embolism in women

BACKGROUND Current use of oral contraceptives (OCs) is a well-recognised risk factor for venous thrombosis and consequent pulmonary embolism (PE). Little is known about residual effects of past OC use. Furthermore, few epidemiological studies have assessed the relation between postmenopausal use of hormones and thrombotic disease. METHODS In this prospective study information was obtained through questionnaires sent every 2 years (1976-92) to 1125,93 women aged 30-55 in 1976. We excluded women with previously diagnosed cardiovascular disease or cancer in 1976 and at the beginning of each subsequent 2-year follow-up period. FINDINGS From self-reports and medical records, we documented 123 cases of primary PE (no identified antecedent cancer, trauma, surgery, or immobilisation). Current users of postmenopausal hormones had an increased risk of primary PE (relative risk adjusted for multiple risk factors 2.1 [95% CI 1.2-3.8]). However, past use showed no relation to PE (1.3 [0.7-2.4]). In current users of OCs the risk of primary PE was about twice that in non-users (2.2 [0.8-5.9]), but this finding was based on only five cases who were current OC users. Users of OCs in the past had no increase in risk of PE (0.8 [0.5-1.2]). These relations were consistent irrespective of cigarette-smoking status. INTERPRETATION Primary PE was uncommon in this cohort. The risk was increased by current though not past use of postmenopausal hormones or OCs.

Ventricular Dysfunction and the Risk of Stroke after Myocardial Infarction

BACKGROUND In patients who have had a myocardial infarction, the long-term risk of stroke and its relation to the extent of left ventricular dysfunction have not been determined. We studied whether a reduced left ventricular ejection fraction is associated with an increased risk of stroke after myocardial infarction and whether other factors such as older age and therapy with anticoagulants, thrombolytic agents, or captopril affect long-term rates of stroke. METHODS We performed an observational analysis of prospectively collected data on 2231 patients who had left ventricular dysfunction after acute myocardial infarction who were enrolled in the Survival and Ventricular Enlargement trial. The mean follow-up was 42 months. Risk factors for stroke were assessed by both univariate and multivariate Cox proportional-hazards analysis. RESULTS Among these patients, 103 (4.6 percent) had fatal or nonfatal strokes during the study (rate of stroke per year of follow-up, 1.5 percent). The estimated five-year rate of stroke in all the patients was 8.1 percent. As compared with patients without stroke, patients with stroke were older (mean [+/-SD] age, 63+/-9 years vs. 59+/-11 years; P<0.001) and had lower ejection fractions (29+/-7 percent vs. 31+/-7 percent, P=0.01). Independent risk factors for stroke included a lower ejection fraction (for every decrease of 5 percentage points in the ejection fraction there was an 18 percent increase in the risk of stroke), older age, and the absence of aspirin or anticoagulant therapy. Patients with ejection fractions of < or = 28 percent after myocardial infarction had a relative risk of stroke of 1.86, as compared with patients with ejection fractions of more than 35 percent (P=0.01). The use of thrombolytic agents and captopril had no significant effect on the risk of stroke. CONCLUSIONS During the five years after myocardial infarction, patients have a substantial risk of stroke. A decreased ejection fraction and older age are both independent predictors of an increased risk of stroke. Anticoagulant therapy appears to have a protective effect against stroke after myocardial infarction.

Massive Pulmonary Embolism

Background— Acute massive pulmonary embolism (PE) carries an exceptionally high mortality rate. We explored how often adjunctive therapies, particularly thrombolysis and inferior vena caval (IVC) filter placement, were performed and how these therapies affected the clinical outcome of patients with massive PE. Methods and Results— Among 2392 patients with acute PE and known systolic arterial blood pressure at presentation, from the International Cooperative Pulmonary Embolism Registry (ICOPER), 108 (4.5%) had massive PE, defined as a systolic arterial pressure <90 mm Hg, and 2284 (95.5%) had non–massive PE with a systolic arterial pressure ≥90 mm Hg. PE was first diagnosed at autopsy in 16 patients (15%) with massive PE and in 29 patients (1%) with non–massive PE (P<0.001). The 90-day mortality rates were 52.4% (95% CI, 43.3% to 62.1%) and 14.7% (95% CI, 13.3% to 16.2%), respectively. In-hospital bleeding complications occurred in 17.6% versus 9.7% and recurrent PE within 90 days in 12.6% and 7.6%, respectively (P<0.001). In patients with massive PE, thrombolysis, surgical embolectomy, or catheter embolectomy were withheld in 73 (68%). Thrombolysis was performed in 33 patients, surgical embolectomy in 3, and catheter embolectomy in 1. Thrombolytic therapy did not reduce 90-day mortality (thrombolysis, 46.3%; 95% CI, 31.0% to 64.8%; no thrombolysis, 55.1%; 95% CI, 44.3% to 66.7%; hazard ratio, 0.79; 95% CI, 0.44 to 1.43). Recurrent PE rates at 90 days were similar in patients with and without thrombolytic therapy (12% for both; P=0.99). None of the 11 patients who received an IVC filter developed recurrent PE within 90 days, and 10 (90.9%) survived at least 90 days. IVC filters were associated with a reduction in 90-day mortality (hazard ratio, 0.12; 95% CI, 0.02 to 0.85). Conclusions— In ICOPER, two thirds of the patients with massive PE did not receive thrombolysis or embolectomy. Counterintuitively, thrombolysis did not reduce mortality or recurrent PE at 90 days. The observed reduction in mortality from IVC filters requires further investigation.