Henry Eriksson

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.)

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.).

Treatment of Acute Venous Thromboembolism With Dabigatran or Warfarin and Pooled Analysis

Background— Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings. Methods and Results— In a randomized, double-blind, double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days, we compared dabigatran 150 mg twice daily with warfarin. The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients (2.3%) compared with 28 of the 1289 warfarin patients (2.2%; hazard ratio, 1.08; 95% confidence interval [CI], 0.64–1.80; absolute risk difference, 0.2%; 95% CI, −1.0 to 1.3; P<0.001 for the prespecified noninferiority margin for both criteria). The safety end point, major bleeding, occurred in 15 patients receiving dabigatran (1.2%) and in 22 receiving warfarin (1.7%; hazard ratio, 0.69; 95% CI, 0.36–1.32). Any bleeding occurred in 200 dabigatran (15.6%) and 285 warfarin (22.1%; hazard ratio, 0.67; 95% CI, 0.56–0.81) patients. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 (95% CI, 0.76–1.57), for major bleeding of 0.73 (95% CI, 0.48–1.11), and for any bleeding of 0.70 (95% CI, 0.61–0.79). Conclusion— Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifiers: NCT00680186 and NCT00291330.

Bundle-Branch Block in a General Male Population The Study of Men Born 1913

BACKGROUND Interest in bundle-branch block has focused primarily on its role as a predictor of mortality and coexisting cardiovascular diseases. Previous studies of prevalence, correlation to cardiovascular disease, and mortality have produced conflicting results. METHODS AND RESULTS We studied a random-sampled population of 855 men who were 50 years old in 1963 and followed them up for 30 years with repeated examinations. Men who developed bundle-branch block were studied with regard to cumulative incidence, relationship with cardiovascular disease/risk factors, and survival. The prevalence of bundle-branch block increases from 1% at age 50 years to 17% at age 80 years, resulting in a cumulative incidence of 18%. No significant relationship with ischemic heart disease or mortality was found. Men who would develop bundle-branch block had a bigger heart volume at age 50 years and developed diabetes mellitus and congestive heart disease during follow-up more often than control subjects. CONCLUSIONS Bundle-branch block correlates strongly to age and is common in elderly men. Our results support the theory that bundle-branch block is a marker of a slowly progressing degenerative disease that also affects the myocardium.

A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I

Summary.  This randomized, controlled, multicentre study evaluated the efficacy and tolerability of the oral direct thrombin inhibitor ximelagatran, compared with a low‐molecular‐weight heparin (dalteparin) followed by warfarin, in the treatment of deep vein thrombosis (DVT) of the lower extremity. Patients with acute DVT received oral ximelagatran (24, 36, 48 or 60 mg twice daily) or dalteparin and warfarin for 2 weeks. Evaluation of paired venograms from 295 of 350 patients showed regression of the thrombus in 69% of patients treated with ximelagatran and 69% of patients treated with dalteparin and warfarin. Progression was observed in 8% and 3% of patients, respectively. Changes in thrombus size according to the Marder score were similar in all groups. Treatment discontinuation due to bleeding occurred in two patients receiving ximelagatran (24‐ and 36‐mg groups) and in two patients receiving dalteparin and warfarin. Reduction in pain, edema and circumference of the affected leg was similar in all groups. Oral ximelagatran appears to be a promising alternative to current anticoagulant therapy to limit the progression of acute DVT, and it seems to possess a wide therapeutic window.

Psychosocial factors and venous thromboembolism: a long‐term follow‐up study of Swedish men

Summary.  Background: The link between psychosocial factors and coronary heart disease is well established, but although effects on coagulation and fibrinolysis variables may be implicated, no population‐based study has sought to determine whether venous thromboembolism is similarly related to psychosocial factors. Objective: To determine whether venous thromboembolism (deep vein thrombosis or pulmonary embolism) is related to psychosocial factors. Patients/methods:  A stress questionnaire was filled in by 6958 men at baseline from 1970 to 1973, participants in a cardiovascular intervention trial. Their occupation was used to determine socio‐economic status. Results: After a maximum follow‐up of 28.8 years, 358 cases of deep vein thrombosis and/or pulmonary embolism were identified through the Swedish hospital discharge and cause‐specific death registries. In comparison with men who, at baseline, had no or moderate stress, men with persistent stress had increased risk of pulmonary embolism [hazard ratio (HR)=1.80, 95% CI: 1.21–2.67]. After multivariable adjustment, the HR decreased slightly to 1.66 (95% CI: 1.12–2.48). When compared with manual workers, men with white‐collar jobs at intermediate or high level and professionals showed an inverse relationship between occupational class and pulmonary embolism (multiple‐adjusted HR=0.57, 95% CI: 0.39–0.83). Deep vein thrombosis was not significantly related to either stress or occupational class. Conclusion: Both persistent stress and low occupational class were independently related to future pulmonary embolism. The mechanisms are unknown, but effects on coagulation and fibrinolytic factors are likely.

Lead time associated with screening for prostate cancer

Screening serum levels of prostate‐specific antigen (PSA) is now a major strategy for early detection of prostate cancer (PC). Quantification of the lead time thus obtained is important both for understanding the development of PC and for evaluating the advantages and disadvantages of widespread screening. In our study, 1,233 randomly selected men living in Stockholm in 1988 were invited to participate in an early detection (ED) program, in which suspicious findings provided by digital rectal examination (DRE), transrectal ultrasonography (TRUS) and/or a PSA value ≥10.0 ng/mL were followed up by biopsy. The cumulative incidence (Kaplan‐Meier) of PC in the 946 participants (ED) during 12 years of follow‐up was compared to that of an age‐matched, randomly selected reference population (RP) of 657 men for whom PSA values (from frozen serum samples) could also be obtained. The PC incidence in men in the RP with PSA values ≥3.0 ng/mL reached the corresponding level for the ED group after 10.6 years (the “catch‐up” point). After 12 years of follow‐up, the estimated median lead time for men with PSA values in this interval was 4.5 years in the ED population, compared to 7.8 years in the RP. With 20 years of follow‐up, the estimated median lead time of the RP was enhanced to 10.7 years. The lead time in connection with PC was influenced by the initial PSA level (although with large variations), length of follow‐up and sensitivity of the ED procedure employed. The ED program described here was not associated with major overdetection.

The prognosis for individuals on disability retirement An 18-year mortality follow-up study of 6887 men and women sampled from the general population

BackgroundSeveral studies have shown a markedly higher mortality rate among disability pensioners than among non-retired. Since most disability pensions are granted because of non-fatal diseases the reason for the increased mortality therefore remains largely unknown. The aim of this study was to evaluate potential explanatory factors.MethodsData from five longitudinal cohort studies in Sweden, including 6,887 men and women less than 65 years old at baseline were linked to disability pension data, hospital admission data, and mortality data from 1971 until 2001. Mortality odds ratios were analyzed with Poisson regression and Coxs proportional hazards regression models.Results1,683 (24.4%) subjects had a disability pension at baseline or received one during follow up. 525 (7.6%) subjects died during follow up. The subjects on disability pension had a higher mortality rate than the non-retired, the hazards ratio (HR) being 2.78 (95%CI 2.08–3.71) among women and 3.43 (95%CI 2.61–4.51) among men. HR was highest among individuals granted a disability pension at young ages (HR >7), and declined parallel to age at which the disability pension was granted. The higher mortality rate among the retired subjects was not explained by disability pension cause or underlying disease or differences in age, marital status, educational level, smoking habits or drug abuse. There was no significant association between reason for disability pension and cause of death.ConclusionSubjects with a disability pension had increased mortality rates as compared with non-retired subjects, only modestly affected by adjustments for psycho-socio-economic factors, underlying disease, etcetera. It is unlikely that these factors were the causes of the unfavorable outcome. Other factors must be at work.

Trousseau’s syndrome – what is the evidence? A population-based autopsy study

Despite numerous studies documenting the association between cancer and venous thromboembolism (VTE), the reason for the excessive risk in certain cancers remains obscure. No large-scale studies have yet investigated the independent effects of cancer type, site and growth pattern. Between 1970 and 1982, 23,796 standardised autopsies were performed, representing 84% of all in-hospital deaths in an urban Swedish population. The relationship between cancer and PE was evaluated with logistic regression. The overall PE prevalence was 23%, and 10% of the population had a fatal PE. Forty-two per cent of pancreatic cancer patients had PE (OR 2.55; 95% CI 2.10-3.09) (p<0.001); gall bladder, gastric, colorectal and pulmonary adenocarcinomas were similarly independently associated with PE. In comparison with squamous cell lung cancer, patients with pulmonary adenocarcinoma had 1.65 times higher odds for PE (95% CI 1.20-2.29). Adenocarcinoma and metastatic cancer were independently associated with PE risk (OR 1.27; 95% CI 1.16-1.40; p<0.001, and OR 1.10;95% CI 1.01-1.20; p=0.024, respectively) but when controlling for cancer type and spread, pancreatic cancer was still associated with an OR of 2.10 (95% CI 1.71-2.58) of PE (p<0.001). We conclude that the risk of PE in cancer patients depends not only on the cancer site and spread but also on the histological type. The excess independent risk in pancreatic cancer is intriguing and should warrant further research.

Secular changes in cardiovascular risk factors over 30 years in Swedish men aged 50: the study of men born in 1913, 1923, 1933 and 1943

Abstract. Rosengren A, Eriksson H, Larsson B, Svärdsudd K, Tibblin G, Welin L, Wilhelmsen L (Sahlgrenska University Hospital/östra, Göteborg and Uppsala University, Uppsala, Sweden). Secular changes in cardiovascular risk factors over 30 years in Swedish men aged 50: The Study of Men Born in 1913, 1923, 1933 and 1943. J Intern Med 2000; 247: 111–118.