ALBERT

Beschreibung: Background: The EXtended CLinical prophylaxis in Acutely Ill Medical patients (EXCLAIM) trial was a randomized, double-blind, placebo-controlled, multicenter, international study that demonstrated a 38% relative risk reduction (RRR) for venous thromboembolism (VTE) with extended-duration enoxaparin prophylaxis compared with placebo (2.5% vs 4.0%; absolute difference [AD], −1.5% 95.8% CI −2.5 to −0.5%; P=0.002). Major bleeding occurred in 0.7% (20/2975) and 0.2% (7/2988) of patients who received enoxaparin and placebo, respectively (AD, 0.4% [CI 0.1% to 0.8%]; P=0.012). As age is a known independent risk factor for VTE, we conducted a pre-specified sub-analysis of the EXCLAIM trial to compare the efficacy and safety of extended-duration enoxaparin prophylaxis in patients 〉75 years old with patients ≤75 years old. Methods: EXCLAIM eligibility required a recent (≤3 days) reduction in mobility due to acute medical illness, an anticipated level 1 (total bed rest/sedentary) or level 2 (level 1 with bathroom privileges) decreased mobility, and age ≥40 years. During the latter part of the study, a protocol amendment required patients with level 2 mobility to have ≥1 of 3 additional pre-specified risk factors (i.e., active or prior cancer, history of VTE, age 〉75 years). Of the 7500 patients enrolled, 7415 received open-label enoxaparin 40 mg SC od for 10±4 days. Of these, 6085 were randomized to double-blind therapy (enoxaparin 40mg SC od or placebo) of 28±4 additional days duration. The incidence of VTE, the primary efficacy end point, was defined as the composite of symptomatic or asymptomatic proximal deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or fatal PE during the double-blind treatment period. Patients were screened for DVT with bilateral proximal lower extremity compression ultrasound at the end of randomized therapy. The incidence of major bleeding, the primary safety end point, was assessed through 48 hours after the last dose of study treatment. Results: Of the 5963 randomized patients that received at least one dose of double-blind therapy, 29.9% (1781) were 〉75 years of age (mean age 81.5 years) and 70.1% (4182) were ≤75 years old (mean age 61.8 years). In patients 〉75 years old, the incidence of VTE was 2.5% (18/725) in the enoxaparin group compared with 6.7% (50/743) in the placebo group (AD −4.2% [95.8% CI −6.5 to −2.0%]; P75 years old (0.6% vs 0.2%; AD 0.3%, 95% CI −0.2 to 0.9%; P=0.282) and significantly higher in patients ≤75 years old (0.7% vs 0.2%; AD 0.5%, 95%CI 0.1 to 0.9%; P=0.041). Though the older group had a higher death rate compared to the younger group (3.2% vs 1.6%), the survival between the treatment groups was similar within the two age groups. Without extended prophylaxis (i.e., placebo group), patients 〉75 years old had a significantly higher risk of VTE than those 75 years of age.

Beschreibung: Background In two phase III trials, RE-COVER and RE-COVER II, dabigatran etexilate was as effective as warfarin for treatment of acute venous thromboembolism (VTE), with a lower risk of bleeding. However, some patients may already be taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA), which can have antihemostatic effects. Objectives We performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without concomitant NSAIDs (half-life 〈 12 hours) or low-dose ASA. Methods Patients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double-dummy; “oral only” treatment period) for 6 months. Concomitant use of ASA ≤ 100 mg/day or NSAIDs with a half-life ≤ 12 hours was permitted. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE, or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy, either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. Results Overall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). The Table shows event rates for dabigatran versus warfarin in subgroups with and without concomitant NSAIDs or low-dose ASA. Cox regression analysis showed no statistically significant interaction, indicating similar treatment effects regardless of presence or absence of these concomitant medications. Overall, MBEs were significantly less frequent with dabigatran than with warfarin during the oral only treatment (double dummy) period (HR 0.60; 95% CI 0.36, 0.99). Likewise, MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Results according to concomitant NSAID or low-dose ASA use at baseline are shown in the Table. There was no significant treatment interaction by concomitant medication status for either MBE or MBE/CRBE. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no treatment interaction by baseline NSAID or low-dose ASA use. Conclusions There was no apparent difference in recurrent VTE or VTE-related mortality across NSAID or low-dose ASA concomitant medication subgroups. The incidence of bleeding events was similar or numerically lower with dabigatran than with warfarin across subgroups. The results suggest that no increased bleeding risk exists when dabigatran is administered with NSAIDs with a half-life 〈 12 hours or low-dose ASA. Disclosures: Schulman: Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc. : Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory Boards, Advisory Boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

Beschreibung: Background: The double-blind, parallel-group, noninferiorityRE-MEDY™ study comparing the direct oral thrombin inhibitor dabigatran etexilate to warfarin in the prevention of secondary venous thromboembolism (VTE) showed non-inferiority of dabigatran to warfarin in both hazard ratio (HR) and risk difference for recurrent symptomatic VTE and related deaths. The benefit-risk balance of dabigatran compared to warfarin in secondary VTE prevention can be further explored by evaluating the net clinical benefit (NCB). Methods: Patients with a diagnosis of VTE received dabigatran 150 mg twice daily (n = 1430), or warfarin adjusted to maintain an international normalized ratio (INR) of 2.0–3.0 (n = 1426), for an additional period of 6–36 months after 3–12 months of anticoagulant therapy. NCB in the RE-MEDY™ study was evaluated narrowly by (1) analyzing nonfatal recurrent VTE, nonfatal myocardial infarction (MI), nonfatal stroke, nonfatal systemic embolism, all-cause death, and major bleeding events (MBEs), and broadly by (2) including clinically relevant bleeding events (CRBEs). The latter is considered more applicable to real-world clinical practice. NCB was also assessed by center time in therapeutic range (cTTR – the mean TTR of all warfarin patients in each center). Results: The narrow NCB (1) was similar between dabigatran and warfarin (HR 1.05, 95% confidence interval [CI]: 0.75–1.46). For the broader NCB (2), a statistically significant difference was evident favoring dabigatran over warfarin (HR 0.73, 95% CI: 0.59–0.91). Stratification of the NCB by cTTR quintiles demonstrated that the positive benefit of dabigatran over warfarin was preserved when comparing to warfarin patients with a good INR control. Conclusion: In the assessment of real-world net clinical benefit in the prevention of secondary VTE, dabigatran was superior to warfarin, irrespective of INR control in the warfarin patients. Table. Net clinical benefit for dabigatran versus warfarin in pooled analyses of RE-MEDY™ Dabigatran (N=1430) n (%) Warfarin (N=1426) n (%) HR (95% CI) p value for superiority Narrow: Composite cardiovascular endpoint* and MBEs (NCB 1) 72 (5.0) 69 (4.8) 1.05 (0.75–1.46) 0.7818 Broad: Composite cardiovascular endpoint*, MBEs and CRBEs (NCB 2) 136 (9.5) 183 (12.8) 0.73 (0.59, 0.91) 0.0058 *Nonfatal recurrent venous thromboembolism (VTE), nonfatal myocardial infarction (MI), nonfatal stroke, nonfatal systemic embolism, all-cause death. Disclosures Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare: Consultancy; Boehringer Ingelheim (Canada): Consultancy. Schellong:Boehringer Ingelheim: advisory boards Other, Consultancy, Honoraria; Bayer Healthcare: advisory boards, advisory boards Other, Consultancy, Honoraria; Daiichi Sankyo: advisory boards, advisory boards Other, Honoraria; BMS/Pfizer: Honoraria. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim: Employment. Kreuzer:Boehringer Ingelheim: Employment. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy.

Beschreibung: Abstract 205 Background: Dabigatran has been compared with warfarin for treatment of acute venous thromboembolism in one previous trial (RE-COVER). Based on the low rate of the primary outcome as the RE-COVER study was running, we undertook this replica study to confirm the results of RE-COVER, and to allow for more rigorous sub-group analyses. Methods: In a randomized, double-blind, double-dummy trial of 2568 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, dose-adjusted to an International Normalized Ratio of 2.0 and 3.0, each given for 6 months. Primary outcome was recurrent symptomatic, objectively confirmed venous thromboembolism and deaths related to venous thromboembolism during 6 months. Safety endpoints included bleeding events, acute coronary syndrome, elevated liver function tests, and adverse events. Results: Of 1279 patients randomized to dabigatran, 30 (2.4%) had recurrent VTE compared with 28 (2.2%) of 1289 patients randomized to warfarin; risk difference 0.2% (95% confidence interval [CI], −1.0 to 1.5); p

Beschreibung: Background: The registry was designed to collect data on bleeding complications in patients under Vitamin-K-antagonist therapy (VKA) during a one year period in a predefined area outside a controlled population and to describe clinical management of these complications. Patients and methods: Between 1.1.05 and 31.12.05, bleeding complications requiring hospital stay in 23 hospitals in eastern saxonia, Germany, were documented. Indication for VKA therapy, type of bleeding, INR at hospital entry, application of packed erythrocytes and fresh-frozen plasma, clinical management and outcome at the end of hospital stay and after 3 months were recorded. Results: 311 episodes of VKA-associated bleeding were documented. Patients were male in 49%, mean age was 73±10 years. Indication for VKA therapy was atrial fibrillation in 64%, mechanical heart valves in 10%, impaired LV-function in 1%, secondary prophylaxis of VTE in 18% and others in 6%. Bleeding affected the gastrointestinum in 23%, 22% were superficial hematomas, 14% were intracranial, 10% epistaxis, 10% hematuria, 7% intraabdominal/retroperitoneal, 5% were overdoses without clinical signs, 10% involved other sites. INR on admission was 3.76±2.45, 40% of INR values were above, and 30% were in the targeted INR range. Vitamin K was administered orally in 26% of episodes, FFP in 9%, factor concentrate in 6%. Per episode, 3±2 units of packed erythrocytes were necessary. 8% of patients died during hospital stay. Surgical therapy was chosen in 25% of episodes, 20% were controlled by endoscopy. 3% of episodes were followed by ongoing detoriation of health status. Mean hospital stay was 13±9 days. Mortality was highest in patients with intracranial bleeding (24%). Retroperitoneal/intraabdominal bleedings required the largest amount of blood products and stabilization of coagulation. Three months after the index episode, mortality was 14%. Conclusions: Complications of VKA-therapy outside of a controlled population occur most often at a supratherapeutic INR level. Gastrointestinal bleeding constitutes the major part of the complications, intra-hospital mortality of 8% is mainly caused by intracranial bleeding.

Beschreibung: Introduction: Findings from the recent EXCLAIM study demonstrate that selected acutely ill medical patients with reduced mobility benefit from extended-duration enoxaparin venous thromboembolism (VTE) prophylaxis (Blood2007;110:1862). However, it is unknown whether the EXCLAIM population is representative of acutely ill medical patients admitted to hospitals worldwide. In this subanalysis, we assessed whether the EXCLAIM population was representative of the medical patients enrolled in the multinational IMPROVE (Chest2007;132:936–45) and ENDORSE (Lancet2008;371:387–94) registries known to be at risk for VTE. Methods: Using patient data from IMPROVE and ENDORSE, we applied the EXCLAIM eligibility criteria to a representative, multinational population of acutely ill medical patients at risk for VTE. The IMPROVE and ENDORSE studies assessed VTE-risk and prophylaxis use of enrolled patients according to the 2004 American College of Chest Physicians (ACCP) guidelines (Chest2004;126:338S–400S). ACCP criteria for VTE risk were met in 46% (6,907/15,156) of IMPROVE and 43% (15,487/36,351) of ENDORSE study patients (Chest2007;132:936–45; Lancet2008;371:387–94). The EXCLAIM eligibility criteria required patients to be confined to total bed rest (level 1 immobility), or bed rest with bathroom privileges (level 2 immobility) and have at least 1 of 3 predefined risk factors for VTE (i.e., age 〉 75 years; history of VTE; active or prior cancer). Results: EXCLAIM eligibility criteria were met in 30% (2,072/6,907) IMPROVE and 36% (5,535/15,487) ENDORSE medical patients considered at risk for VTE by ACCP. During hospitalization, ACCP-recommended prophylaxis was provided to 69% (1,426/2,072) and 46% (2,548/5,535) of EXCLAIM-eligible patients enrolled in IMPROVE and ENDORSE, respectively. Following discharge from hospital (median length of stay 5 days for US, 8 days for non-US), only 9% (153/1,719) of EXCLAIM-eligible patients in the IMPROVE study received any type of ACCP-recommended VTE prophylaxis. Conclusions: Evidence from the EXCLAIM study demonstrated that the benefit-to-risk ratio in selected hospitalized medical patients favors the use of prolonged VTE prophylaxis. This population corresponds to one in three of the representative hospitalized patients with acute medical illness enrolled in IMPROVE and ENDORSE. Data on prophylaxis use from the IMPROVE registry suggest that only 9% of such patients are currently receiving optimal VTE prophylaxis following hospital discharge.

Beschreibung: Feasibility of venous ultrasound as an endpoint measure in multicenter trials critically depends on the type and quality of documents which can be assessed by central adjudication. We evaluated the offline assessability of standardized video documents of complete compression ultrasound (CCUS) in asymptomatic patients 7 days after hip or knee replacement. The study was performed at a single study center. Consecutive asymptomatic patients one week after hip or knee replacement were screened for deep vein thrombosis by complete compression ultrasound of proximal and distal veins including muscle veins by one trained sonographer. Examinations were recorded on video tape in a standardized format. Video sequences with an approximate duration of 60 seconds demonstrated femoral veins, popliteal veins, peroneal veins and tibial posterior veins, respectively. The video documents were digitized and electronically stored in a central adjudication unit. All videos were read by two independent readers, and veins were scored as normal, thrombotic or nonevaluable. All thrombotic findings were re-assessed by two senior readers according to the same protocol. Analysis of inter-observer agreement was performed by Cohen’s Kappa coefficient. Video documents of 300 legs were recorded in 150 patients. Documents of 10 patients (6.7%) or 13 legs (4.3%) were scored as non-evaluable by at least one reader. Reading A revealed 5.5% proximal DVT and 18.7% distal DVT including muscle vein thrombosis. Reading B revealed 4.1% and 23.6%, respectively. Kappa values for different types of DVT are given in the table. Conclusion: In a single center setting, interobserver agreement of centrally adjudicated standardized CCUS documents in the diagnosis of asymptomatic postoperative DVT is strong for all categories of DVT. It remains to be established how these figures will be affected by a multicenter setting. Interobserver Agreement Vein segment Kappa (95% CI) 1) Interobserver agreement according to number of legs (n=300) All vein segments 0.92 (0.84–0.99) Proximal deep vein segments 0.87 (0.70–1.00) Distal deep vein segments 0.84 (0.73–0.94) Femoral veins - Popliteal and confluent veins 0.87 (0.70–1.00) Peroneal veins 0.79 (0.60–0.99) Posterior tibial veins 0.83 (0.60–1.00) Calf muscle veins 0.77 (0.64–0.91) 2) Interobserver agreement according to number of patients (n=150) All vein segments 0.90 (0.81–0.99) Proximal deep vein segments 0.85 (0.65–1.00) Distal deep vein segments 0.81 (0.65–0.97)

Beschreibung: Abstract 1 Background. The direct oral thrombin inhibitor, dabigatran etexilate, has a predictable anticoagulant effect and may be an alternative to warfarin in patients with acute venous thromboembolism (VTE). Methods. In a randomized, double-blind, trial of 2539 patients with acute VTE, treated with low molecular weight or unfractionated heparin for 5 to 11 days, we compared oral dabigatran etexilate, 150 mg twice daily in a fixed-dose, with warfarin dose-adjusted to an International Normalized Ratio of 2.0 and 3.0, each given for 6 months. The primary outcome was symptomatic, objectively confirmed recurrent VTE or VTE-related death up to 6 months of treatment. Safety endpoints included bleeding events, acute coronary syndrome, liver function tests, vital signs and adverse events. Results. Of 1274 patients randomized to dabigatran etexilate, at 6 months 30 (2.4%) had recurrent VTE compared with 27 (2.2%) of 1265 patients randomized to warfarin; risk difference 0.4% [95 percent confidence interval, −0.8 to 1.5]; p

Beschreibung: Introduction In the EXCLAIM study, extended-duration enoxaparin prophylaxis reduced the relative risk of VTE in acutely ill medical patients by 44% compared with placebo, following standard-duration prophylaxis (2.8% vs 4.9%; RR 0.56; 95% CI 0.39–0.80; p=0.0011). We assessed the benefits of extended-duration enoxaparin prophylaxis in subgroups of acutely ill medical patients with the most prominent primary diagnoses enrolled in EXCLAIM. Methods Patients enrolled in EXCLAIM had: recent reduced mobility (≤3 days) due to a medical illness, age ≥40 years, and anticipated level 1 (total bed rest or sedentary without bathroom privileges) or level 2 (level 1 with bathroom privileges) reduced mobility with further risk factors. Eligible patients received enoxaparin 40mg SC once-daily for 10±4 days, and were then double-blind randomized and received enoxaparin 40mg SC once-daily (n=2013) or placebo (n=2027) for a further 28±4 days. Asymptomatic DVT were diagnosed by bilateral compression ultrasound after completion of the randomized treatment. Suspected cases of symptomatic DVT or PE were confirmed by objective tests. Fatal PE were confirmed by autopsy where possible. Univariate logistic regressions were conducted to estimate treatment effects in patient subgroups. The primary safety endpoint was major bleeding. Results Baseline characteristics were similar between treatments within each primary diagnosis subgroup, and the considered primary diagnoses accounted for 〉80% of the enrolled population. The reduced VTE incidence associated with extended-duration enoxaparin prophylaxis was consistent across subgroups of patients with different primary diagnoses (Table). The incidence of major bleeding was generally higher in patients receiving extended-duration prophylaxis (Table). Table: VTE and major bleeding in patient subgroups receiving extended-duration vs standard-duration prophylaxis/placebo Primary diagnosis Incidence of VTE (%)* Odds Ratio [95% CI]** Incidence of Major Bleeding (%)*** Odds Ratio [95% CI] Extended Enox Standard Enox/Placebo Extended Enox Standard Enox/Placebo *N=3347 evaluable patients; **Alpha adjustment for an interim analysis; ***N=4040 treated patients Heart failure, NYHA class III or IV 3.1 4.7 0.64 [0.29–1.39] 0.0 0.2 N/A Acute respiratory insufficiency 2.2 3.7 0.60 [0.27–1.34] 0.6 0.2 3.15 [0.33–30.4] Post ischemic stroke 2.1 8.3 0.24 [0.06–0.91] 0.6 0.0 N/A Acute infection without septic shock 3.6 5.3 0.66 [0.36–1.22] 0.8 0.2 5.16 [0.60–44.3] Conclusion Extended enoxaparin prophylaxis consistently reduced VTE risk in acutely ill medical patients with the most prominent primary diagnoses compared with placebo following standard-duration prophylaxis. Major bleeding was generally higher in the extended-duration enoxaparin arm, but rates of bleeding were low. These findings are consistent with the primary findings of the EXCLAIM study which demonstrated the clinical benefit of the extended-duration enoxaparin regimen.