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BACKGROUND: In the RE-DUAL PCI trial of patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI), dabigatran dual therapy (110 or 150 mg bid, plus clopidogrel or ticagrelor) reduced International Society on Thrombosis and Haemostasis bleeding events compared with warfarin triple therapy, with noninferiority in overall thromboembolic events. This analysis assessed outcomes in relation to patient bleeding and stroke risk profiles, based on the modified HAS-BLED and CHA2DS2-VASc scores.METHODS: The primary endpoint, major bleeding event (MBE) or clinically relevant nonmajor bleeding event (CRNMBE), was compared across study arms in patients categorized by modified HAS-BLED score 0-2 or ≥3. The composite endpoint of death, thromboembolic event, and unplanned revascularization rates was compared in patients categorized by CHA2DS2-VASc score 0-1, 2, or ≥3.RESULTS: Risk of MBE or CRNMBE was lower with dabigatran dual therapy (both doses) versus warfarin triple therapy, irrespective of modified HAS-BLED category (treatment-by-subgroup interaction P-value 0.584 and 0.273 for dabigatran 110 and 150 mg dual therapy, respectively, vs warfarin). Risk of the composite thromboembolic endpoint was similar across CHA2DS2-VASc categories and consistent with overall study results (interaction P-value 0.739 and 0.075 for dabigatran 110 and 150 mg dual therapy, respectively, vs warfarin). Higher HAS-BLED scores were associated with higher risks of bleeding in AF patients after PCI in a treatment-independent analysis.CONCLUSION: Dabigatran dual therapy reduced bleeding events irrespective of bleeding risk category and demonstrated similar efficacy regardless of stroke risk category when compared with warfarin triple therapy.

SummaryDabigatran was non-inferior to warfarin for prevention of recurrent venous thromboembolism (VTE), and dabigatran had a lower rate of bleeding compared with warfarin in two large-scale randomised trials, RE-COVER and RE-COVER II. In this study, we investigate the efficacy and safety of dabigatran versus warfarin according to the index event that qualified the patient for enrollment, either symptomatic pulmonary embolism (PE) with or without deep-vein thrombosis (DVT), or DVT alone. We then analyse the anticoagulant effect of dabigatran vs warfarin on patients enrolled with PE. The pooled dataset for the efficacy analysis consisted of 2553 and 2554 patients who were randomised to dabigatran and warfarin, respectively. Recurrent VTE/VTE-related death during the study period and additional 30-day follow-up occurred in 2.7 % of all patients on dabigatran and in 2.4 % on warfarin (hazard ratio [HR] 1.09 [95 % confidence interval 0.77, 1.54]). In patients with PE as their index event, recurrent VTE/VTE-related death occurred in 2.9 % vs 3.1 % of patients (HR 0.93 [0.53, 1.64]). There were significantly fewer major bleeding events in patients treated with dabigatran than with warfarin (HR 0.60 [0.36, 0.99]). The pattern was similar both in patients with PE and in those with DVT alone as the index event. These analyses of the pooled dataset from the RECOVER and RE-COVER II trials indicate that dabigatran is as effective as warfarin in preventing recurrent VTE, regardless of whether patients present with symptomatic PE (with or without DVT) or with symptomatic DVT alone. Dabigatran was also associated with a lower risk of bleeding than warfarin, regardless of the index event.

It is unclear whether thrombophilia causes resistance to anticoagulant therapy. Post hoc analyses of data from RE-COVER®, RE-COVER™ II, and RE-MEDY™ were performed to compare dabigatran etexilate with warfarin for the treatment and prevention of venous thromboembolism (VTE) in patients with thrombophilia or antiphospholipid antibody syndrome (APS). There were no significant differences in symptomatic VTE/VTE-related deaths between dabigatran etexilate and warfarin in patients with or without thrombophilia. All bleeding event categories were less frequent with dabigatran etexilate than with warfarin, regardless of whether patients had thrombophilia, no thrombophilia, or were not tested. However, these differences did not reach significance in every group. In patients with APS, there was no significant difference in VTE/VTE-related deaths between the two treatment arms. Rates of bleeding events tended to be lower with dabigatran etexilate than with warfarin, reaching statistical significance for any bleeding event. In conclusion, the efficacy and safety of dabigatran etexilate were not significantly affected by the presence of thrombophilia or APS. ClinicalTrials.gov RECOVER Identifier: NCT00291330; RECOVER II Identifier: NCT00680186; RE-MEDY Identifier: NCT00329238

SummaryPatients with atrial fibrillation requiring maintenance haemodialysis are at increased risk of ischaemic stroke and bleeds. Currently, vitamin K antagonists such as warfarin are predominantly used in these patients as limited data are available on the use of non-vitamin K oral anticoagulants, including dabigatran etexilate (dabigatran). Dabigatran is approximately 85 % renally eliminated, thus, its half-life is prolonged in renal impairment. This study simulated the dose-exposure relationship of dabigatran in patients undergoing haemodialysis. Dabigatran exposure was modelled at once- and twice-daily doses of 75 mg, 110 mg and 150 mg and at variations in non-renal clearance and dialysis settings. Resultant dose exposure (area under the curve [AUC]) was compared with values simulated from typical patients in the RE-LY® trial (based on a previously characterised pharmacometric model). In this simulation, all twice-daily dosages resulted in exposures above those simulated from typical RE-LY patients (1.5- to 3.3-fold increase in AUC) and thus may not be optimal for use in haemodialysis patients. However, dabigatran doses of 75 mg or 110 mg once daily produced exposures comparable to those simulated in typical RE-LY patients (-13.3 and +4.4 %, respectively). Of patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤30.8 % change). These data could potentially inform dose selection in patients undergoing maintenance haemodialysis and the findings warrant investigation in future clinical trials.

OBJECTIVE—Adiponectin is a plasma protein expressed in adipose tissue. Hypoadiponectinemia is associated with low HDL cholesterol and high plasma triglycerides, which also characterize lipoprotein lipase (LPL) deficiency syndromes. Recently, dramatically increased LPL activity was reported in mice overexpressing adiponectin. We therefore speculated that adiponectin may directly affect LPL in humans. RESEARCH DESIGN AND METHODS—We measured plasma adiponectin and postheparin LPL in 206 nondiabetic men and in a second group of 110 patients with type 2 diabetes. Parameters were correlated with markers of systemic inflammation (C-reactive protein [CRP]) and insulin resistance (homeostatis model assessment of insulin resistance [HOMA-IR]). RESULTS—Nondiabetic subjects with decreased plasma adiponectin had lower LPL activity (r = 0.42, P < 0.0001). This association of plasma adiponectin with LPL activity was confirmed in the second group of patients with type 2 diabetes (r = 0.37, P < 0.0001). Multivariate analysis revealed that adiponectin was the strongest factor influencing LPL activity, accounting for 23% of the variation in LPL activity in nondiabetic subjects and for 26% of the variation in LPL activity in type 2 diabetic patients. These associations were independent of plasma CRP and HOMA-IR. CONCLUSIONS—These results demonstrate an association of decreased postheparin LPL activity with low plasma adiponectin that is independent of systemic inflammation and insulin resistance. Therefore, LPL may represent a link between low adiponectin levels and dyslipidemia in both nondiabetic individuals and patients with type 2 diabetes.

Numerous studies have found polymorphisms in the lipoprotein lipase (LPL) gene to be associated with the risk of coronary artery disease (CAD), implicating LPL in the development of atherothrombotic disease. It remains controversial, however, whether LPL acts in a pro- or anti-atherogenic fashion. We quantitated activity and concentration of LPL in post-heparin plasma from 194 male patients undergoing coronary angiography. HDL cholesterol was significantly associated with LPL activity quartiles (1.09+/-0.26 the highest vs. 0.96+/-0.25 mmol/l the lowest quartile, P0.01). There was also a trend towards higher total (5.61+/-1.33 vs. 5.16+/-1.44 mmol/l, P=0.059) and LDL cholesterol (3.92+/-1.39 vs. 3.46+/-1.06 mmol/l, P=0.09) with higher LPL activity. In contrast, measures of CAD extent showed no differences between LPL quartiles (P0.30 for prior myocardial infarction, number of diseased vessels, Gensini and extent scores). Additionally, there was no difference in LPL activity (CAD: n=158, 168+/-70 nmol/ml/min, no CAD: n=36, 180+/-89 nmol/ml/min, P=0.47) or concentration (280+/-121 ng/ml and 288+/-111 ng/ml, P=0.72) between patients with and without CAD. Our data show that, in spite of an association with lipoprotein parameters, LPL in post-heparin plasma is unrelated to the presence or the extent of CAD. Therefore, lipoprotein lipase determination in plasma does not appear to be a useful marker in the assessment of CAD risk.

To the Editor: Several risk factors for the development of coronary artery disease (CAD) have been identified, correlating with the incidence and progression of atherosclerotic disease. Low adiponectin, an adipocytokine, appears to be a clinically important mediator of atherosclerosis. Thus

In recent years, transcatheter aortic valve implantation has become an emerging alternative for high-risk patients with severe aortic stenosis. Midterm outcomes compare favorably with conventional open heart surgery in selected patients. A promising new indication in this technology could be the interventional treatment of degenerated bioprostheses. Here, we report about a “valve in valve” implantation of the CoreValve prosthesis (Medtronic, Inc; Minneapolis, Minn) in a degenerative, Epic stented biological prosthesis (St Jude Medical; St Paul, Minn) in a patient with acute aortic regurgitation. A male patient aged 79 years with previous surgical valve replacement 5 years ago was admitted to the hospital with acute dyspnea (New York Heart Association class III to IV). At physical examination, a diastolic murmur (grade 4) and a blood pressure of 130/50 mm Hg were noted. Transthoracic and transesophageal echocardiography showed degeneration of the 23-mm Epic stented bioprosthesis with severe central aortic regurgitation …

We have recently shown that 3-deazaadenosine (c3Ado) inhibits atherogenesis in mice. We studied whether its anti-inflammatory capacity would also affect neointima-formation after balloon injury. Sprague Dawley rats underwent balloon angioplasty. C3Ado was administered orally, starting 5 days prior to the balloon injury and continued for 2 weeks. Fourteen days after balloon injury the intima/media ratio in the c3Ado-treated group was reduced by 67% (p

[Graphic][1] 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. | | 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 | Table. Net clinical benefit for dabigatran versus warfarin in pooled analyses of RE-MEDY™ * 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. [1]: /embed/inline-graphic-2.gif

[Graphic][1] Background: Dabigatran etexilate (DE) was noninferior to warfarin for the prevention of recurrent venous thromboembolism (VTE), with a lower risk of bleeding, when administered as extended treatment for VTE in the RE-MEDY™ study (in which we evaluated long-term extension of treatment with dabigatran compared with warfarin). Objectives: Thrombophilia is a major risk factor for VTE recurrence. Therefore, we performed a post-hoc subgroup analysis on data from RE-MEDY™ to investigate the efficacy of DE versus warfarin in patients with and without thrombophilia (congenital or acquired) at baseline. Methods: Patients were aged ≥ 18 years and had objectively-confirmed, symptomatic, proximal deep vein thrombosis or pulmonary embolism (PE) that had been treated with an approved anticoagulant for 3–12 months, or with DE in one of two clinical trials of treatment for acute VTE (RE-COVER™ or RE-COVER™ II). Eligible patients were those at increased risk for recurrent VTE. Patients were randomly allocated to receive DE 150 mg twice daily or warfarin (international normalized ratio range 2.0–3.0) for 6–36 months. The primary efficacy outcome was recurrent, symptomatic, objectively-confirmed VTE or VTE-related death from randomization up to the end of the planned treatment period (6–36 months). No thrombophilia workup was required for enrollment in the trial. Results: Overall, 262/1430 (18.3%) patients randomized to DE and 263/1426 (18.4%) randomized to warfarin had thrombophilia identified at baseline. Factor V Leiden thrombophilia was the most common type (Table). The frequencies of VTE/VTE-related deaths, and of PE, in patients with and without thrombophilia are shown in the Table. Treatment efficacy (DE versus warfarin) was not significantly affected by the presence of thrombophilia. | | DE (n = 1430) | Warfarin (n = 1426) | || | Thrombophilia, n (%) | | | | No | 433 (30.3) | 407 (28.5) | | Yes | 262 (18.3) | 263 (18.4) | | Factor V Leiden | 131 (9.2) | 137 (9.6) | | Prothrombin mutation | 35 (2.4) | 28 (2.0) | | Antithrombin deficiency | 11 (0.8) | 11 (0.8) | | Protein C/S deficiencies | 25 (1.7) | 29 (2.0) | | Antiphospholipid antibodies and/or lupus anticoagulants | 38 (2.7) | 54 (3.8) | | Not tested | 735 (51.4) | 756 (53.0) | | | VTE/VTE-related deaths, n/N (%) | Pulmonary embolism, n/N (%) | | | DE | Warfarin | DE | Warfarin | | Thrombophilia | | | | | | No | 10/433 (2.3) | 3/407 (0.7) | 3/433 (0.7) | 1/407 (0.2) | | Yes | 4/262 (1.5) | 6/263 (2.3) | 3/262 (1.1) | 2/263 (0.8) | | Not tested | 12/735 (1.6) | 9/756 (1.2) | 4/735 (0.5) | 2/756 (0.3) | | Total study population: Hazard ratio (DE vs warfarin) (95% confidence interval) | 1.43 (0.78, 2.61) | 1.97 (0.67, 5.76) | | Treatment (DE vs warfarin) by thrombophilia interaction | p = 0.2277 | p = 0.9003 | | p-value from Chi-square test for overall factor effect. Full analysis set. | Table Conclusions: The frequencies of VTE/VTE-related death, and of PE, were similar for DE and warfarin in patients with thrombophilia who were receiving extended treatment for VTE. Treatment efficacy was not affected by the presence of thrombophilia. Disclosures Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding. 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: 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. Friedman: Boehringer Ingelheim: Consultancy. Kreuzer: Boehringer Ingelheim: Employment. [1]: /embed/inline-graphic-2.gif

Background — The crucial function of hepatic lipase (HL) in lipid metabolism has been well established, but the relationship between HL activity and coronary artery disease (CAD) is disputed. Methods and Results — We measured HL activity in the postheparin plasma of 200 consecutive men undergoing elective coronary angiography and determined the degree of CAD with the extent score, which has been shown to be better correlated with known risk factors than other measures of CAD extent. We found a significant inverse correlation between HL activity and the extent of CAD ( r =−0.19, P 0.96 mmol/L (n=94, r =−0.30, P −1 · min −1 , P r =0.30, P P P =0.01). Conclusions — Our data show that low HL activity is associated with CAD. Therefore, HL might be useful for CAD risk estimation and might be a target for pharmacological intervention.