Patient autonomy and the regulation of direct-to-consumer advertising

BACKGROUND: The current direction of the US Food and Drug Administration (FDA) policy on direct-to-consumer advertising (DTCA) of pharmaceuticals is a subject of debate. The literature addresses the benefits and drawbacks of DTCA, but the foundations for such policies have not been investigated in detail. OBJECTIVE: This paper explores the most recent FDA guidance on broadcast DTCA based on a critical examination of the principle of autonomy. CONCLUSIONS: Autonomy is determined not by the ability to choose a therapy, but by the ability to actively participate in choices about health care. DTCA can be an effective tool to increase patient awareness of their therapeutic choices, encourage patients to seek more information, and help them draw closer to autonomous choices, but only if the presentations provide fair and balanced information on the benefits and risks of therapy.     

Predictors of major bleeding in peri‐procedural anticoagulation management

Summary. Background: Appropriate periprocedural management for chronically anticoagulated patients requires assessment of patient‐specific thrombosis and bleeding risks. However, predictors of post‐procedure bleeding are unknown. Objectives: To determine the 3‐month cumulative incidence and independent predictors of peri‐procedural bleeding in chronically anticoagulated patients requiring temporary warfarin interruption for an invasive procedure. Methods: In a protocol driven, cohort study design, all patients referred to the Mayo Clinic Thrombophilia Center for peri‐procedural anticoagulation management (1997–2007; n = 2182), were followed forward in time to determine the 3‐month cumulative incidence of peri‐procedural bleeding (Kaplan–Meier product limit) and potential predictors of bleeding (Cox proportional hazards). Decisions to ‘bridge’ with low‐molecular‐weight heparin were based on estimated thromboembolism and bleeding risk. Results: Indications for chronic anticoagulation included venous thromboembolism (38%), atrial fibrillation (30%) and mechanical heart valves (27%). Of these, 1496 (69%) patients received bridging therapy. The 3‐month cumulative incidence rates of major and overall bleeding were 2.1% and 5.1%, respectively. Major bleeding occurred more frequently in patients receiving bridging therapy (3% vs. 1%; P = 0.017). Independent predictors (hazard ratio; 95% confidence interval) of major bleeding included mitral mechanical heart valve (2.2; 1.1–4.3), active cancer (1.8; 1.0–3.1), prior bleeding history (2.6; 1.5–4.5) and re‐initiation of heparin therapy within 24 h after the procedure (1.9; 1.1–3.4). Conclusion: Factors predisposing to peri‐procedural bleeding are primarily patient‐specific. Premature heparin re‐initiation is an avoidable provider‐specific variable to consider.     

Low‐molecular‐weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST‐elevation myocardial infarction: a meta‐analysis

Summary. Background: The aim of the current study was to perform two separate meta‐analyses of available studies comparing low‐molecular‐weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST‐elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. Methods: All‐cause mortality was the pre‐specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. Results: Ten studies comprising 16 286 patients were included. The median follow‐up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41–0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49–0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta‐regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). Conclusions: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta‐analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.     

Homozygous F5 deep‐intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet‐rich plasma

Summary. Background: Coagulation factor (F) V deficiency is associated with a bleeding tendency of variable severity, but phenotype determinants are largely unknown. Recently, we have shown that three patients with undetectable plasma FV and mild bleeding symptoms had sufficient residual platelet FV to support thrombin generation in platelet‐rich plasma (PRP). Therefore, we hypothesized that FV‐deficient patients with severe bleeding manifestations may lack platelet FV. Objectives: To characterize a FV‐deficient patient with a severe bleeding diathesis. Patients/Methods: We performed FV mutation screening and functional studies in a 31‐year‐old male (FV:C < 1%) with umbilical bleeding at birth, recurrent hemarthrosis and muscle hematomas, and a recent intracranial hemorrhage. Results: The proband was homozygous for a deep‐intronic mutation (F5 IVS8 +268A→G) causing the inclusion of a pseudo‐exon with an in‐frame stop codon in the mature F5 mRNA. Although platelet FV antigen was detectable by immunoprecipitation followed by Western blotting, no FV activity could be demonstrated in the proband’s plasma or platelets with a prothrombinase‐based assay. Moreover, no thrombin generation was observed in PRP triggered with 1–50 pm tissue factor (even in the presence of platelet agonists), whereas an acquired FV inhibitor was excluded. Clot formation in the proband’s whole blood, as assessed by thromboelastometry, was markedly delayed but not abolished. Conclusions: This is the first report of a pathogenic deep‐intronic mutation in the F5 gene. Our findings indicate that the minimal FV requirement for viability is extremely low and suggest that thrombin generation in PRP may predict bleeding tendency in patients with undetectable plasma FV.     

Patient and cardiologist perceptions on decision making for implantable cardioverter-defibrillators: a qualitative study

Background: Although implantable cardioverter‐defibrillators (ICDs) reduce mortality in selected patients, they are also associated with potential risks. Periprocedural decision making requires understanding both benefits and risks. Methods: This qualitative study aims to understand cardiologists’ and patients’ perspectives about decision making surrounding ICD implantation using semi‐structured, in‐depth interviews. We interviewed 11 cardiologists (including four electrophysiologists) and 20 patients (14 with ICDs; six who declined ICDs). The data were analyzed through the theoretical lens of patient‐centered care using the constant comparative method. Results: Cardiologists emphasized the benefits of ICD therapy but varied substantially in the extent to which they emphasized the various risks associated with ICD implantation with patients. Cardiologists indicated that they were influenced by the benefits of therapy as presented in published guidelines. Many patients who chose to receive an ICD indicated that they followed the advice of their physician without questioning the risks and benefits of the device. Some ICD recipients described not learning many of the risks until after device implantation or when they experienced these side effects. Patients who declined ICD implantation were concerned that the ICD was unnecessary or believed that the risks related to sudden death without an ICD did not apply to them. Only one patient considered the trade‐off between dying quickly versus living longer with progressive heart failure. Conclusions: In our sample, cardiologists’ desire to adhere to published guidelines appears to inhibit shared decision making. The marked variability in the discussions surrounding ICD decisions highlights a need for an improved process of ICD decision making. (PACE 2011; 34:1634–1644)     

Effectiveness of pharmacist‐participated warfarin therapy management: a systematic review and meta‐analysis

Summary. Objective: Although pharmacist‐participated warfarin therapy management (PWTM) has been accepted and implemented in various parts of the world, the evidence demonstrating the effects of PWTM compared with usual care on clinical outcomes is lacking. We performed a systematic review and meta‐analysis to compare the effects of PWTM with usual care on bleeding and thromboembolic outcomes. Methods: We searched MEDLINE, SCOPUS, EMBASE, IPA, CINAHL, Cochrane CENTRAL, Thai Index Medicus and Thai Medical Index, and reference lists of studies, without language restriction. Databases were searched from their inception to July 2009. The studies using warfarin as an anticoagulant with sufficient data for compilation of 2 × 2 tables were included. Both randomized controlled trials (RCTs) and non‐RCTs were considered. Two authors independently reviewed each study, assigned quality scores and extracted data for all outcomes using a standardized form. Pooled effect estimates (risk ratio; RR) were obtained using a random effects model. Result: Of 661 articles identified, 24 studies with 728,377 patients were included. In the random‐effects meta‐analysis of RCTs, the PWTM group had statistically significant effects on the prevention of total bleeding [RR, 0.51; 95% confidence interval (CI), 0.28–0.94]. However, the effects on major bleeding (RR, 0.64; 95% CI, 0.18–2.36), thromboembolic events (RR, 0.79; 95% CI, 0.33–1.93), all‐cause mortality (RR, 0.93; 95% CI, 0.41–2.13) and warfarin‐related mortality (RR, 0.65; 95% CI, 0.18–2.42) were not significant. Conclusion: Pharmacist’s participation in the management of warfarin therapy significantly reduces total bleeding, with a non‐significant trend towards decreases in other warfarin‐related complications.     

Early glycoprotein IIb‐IIIa inhibitors in primary angioplasty‐abciximab long‐term results (EGYPT‐ALT) cooperation: individual patient’s data meta‐analysis

Summary. Background: Even although time to treatment has been shown to be a determinant of mortality in primary angioplasty, the potential benefits are still unclear from early pharmacological reperfusion by glycoprotein (Gp) IIb‐IIIa inhibitors. Therefore, the aim of this meta‐analysis was to combine individual data from all randomized trials conducted on upstream as compared with late peri‐procedural abciximab administration in primary angioplasty. Methods: The literature was scanned using formal searches of electronic databases (MEDLINE and EMBASE) from January 1990 to December 2010. All randomized trials on upstream abciximab administration in primary angioplasty were examined. No language restrictions were enforced. Results: We included a total of seven randomized trials enrolling 722 patients, who were randomized to early (n = 357, 49.4%) or late (n = 365, 50.6%) peri‐procedural abciximab administration. No difference in baseline characteristics was observed between the two groups. Follow‐up data were collected at a median (25th–75th percentiles) of 1095 days (720–1967). Early abciximab was associated with a significant reduction in mortality (primary endpoint) [20% vs. 24.6%; hazard ratio (HR) 95% confidence interval (CI) = 0.65 (0.42–0.98) P = 0.02, P_het = 0.6]. Furthermore, early abciximab administration was associated with a significant improvement in pre‐procedural thrombolysis in myocardial infarction (TIMI) 3 flow (21.6% vs. 10.1%, P < 0.0001), post‐procedural TIMI 3 flow (90% vs. 84.8%, P = 0.04), an improvement in myocardial perfusion as evaluated by post‐procedural myocardial blush grade (MBG) 3 (52.0% vs. 43.2%, P = 0.03) and ST‐segment resolution (58.4% vs. 43.5%, P < 0.0001) and significantly less distal embolization (10.1% vs. 16.2%, P = 0.02). No difference was observed in terms of major bleeding complications between early and late abciximab administration (3.3% vs. 2.3%, P = 0.4). Conclusions: This meta‐analysis shows that early upstream administration of abciximab in patients undergoing primary angioplasty for ST‐segment elevation myocardial infarction (STEMI) is associated with significant benefits in terms of pre‐procedural epicardial re‐canalization and ST‐segment resolution, which translates in to significant mortality benefits at long‐term follow‐up.     

Safety and efficacy of protease‐activated receptor‐1 antagonists in patients with coronary artery disease: a meta‐analysis of randomized clinical trials

Summary. Background: Thrombin receptor antagonists blocking protease‐activated receptor‐1 (PAR‐1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. Objectives: We investigated the safety and efficacy of PAR‐1 antagonists in patients with coronary artery disease (CAD). Patients/Methods: Randomized, placebo‐controlled trials of the PAR‐1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. Results: A total of 41 647 patients from eight trials were included. PAR‐1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39–1.57, P < 0.001), major (OR 1.46, 95% CI 1.28–1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40–2.00, P < 0.001) bleeding than placebo in the fixed‐effects model. PAR‐1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81–0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78–0.92, P < 0.001). Conversely, PAR‐1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90–1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84–1.10, P = 0.59). Conclusions: PAR‐1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.     

Relationship between post‐treatment platelet reactivity and ischemic and bleeding events at 1‐year follow‐up in patients receiving prasugrel

Summary. Background: Post‐treatment platelet reactivity (PR) is associated with ischemic and bleeding events in patients receiving P2Y12 receptor antagonists. Objectives: We aimed to study the relationship between post‐treatment PR after a 60‐mg loading dose (LD) of prasugrel and 1‐year thrombotic and bleeding events. Method: Patients were prospectively included in this multicenter study if they had a successful percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and received prasugrel. The platelet reactivity index (PRI) was measured using the Vasodilator‐Stimulated Phosphoprotein index (VASP) after a prasugrel LD. Endpoints included the rate of thrombotic events and bleeding events at 1 year. Results: Among the 301 patients enrolled, 9 (3%) were lost to follow‐up at 1 year. The rates of thrombotic and bleeding events at 1 year were of 7.5% and 6.8%, respectively. Receiver‐operating curve (ROC) analysis demonstrated an optimal cut‐off value of 53.5% of PRI to predict thrombotic events at 1 year. Using this cut‐off value we observed that patients exhibiting high on‐treatment platelet reactivity (HTPR) had a higher rate of thrombotic events (22.4% vs. 2.9%; P < 0.001). In parallel the optimal cut‐off value of PRI to predict bleeding was 16%. Patients with a PRI ≤ 16% had a higher rate of bleeding events compared with those with a PRI > 16% (15.6% vs. 3.3%; P < 0.001). In multivariate analysis, the PRI predicted both thrombotic and bleeding events (OR: 1.44, 95% confidence interval [CI]: 1.2–1.72; P < 0.001 and OR: 0.75, 95% CI: 0.59–0.96; P = 0.024 [respectively, per 10% increase]). Conclusion: Platelet reactivity measurement after a prasugrel LD predicts both ischemic and bleeding events at 1 year follow‐up for ACS patients undergoing PCI.     

Clopidogrel 150 vs. 75 mg day−1 in patients undergoing percutaneous coronary intervention: a meta‐analysis

Summary. Background: Whether an increase in the daily oral maintenance dose of clopidogrel may improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) is still debated. Objectives: This meta‐analysis aimed to estimate the relative effect of a 150‐ vs. 75‐mg daily maintenance dosage of clopidogrel on clinical and laboratory end‐points in patients undergoing PCI. Methods: We searched electronic and printed sources (up to 14 December 2010) for both randomized control trials and observational studies satisfying the predefined inclusion criteria. Results: We retrieved 12 reports of studies including a total of 23 814 patients. Clopidogrel, 150 mg day^?1, was associated with significant reductions in major adverse cardiac and/or cerebrovascular events (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.48–0.94), myocardial infarction (OR, 0.72; 95% CI, 0.60–0.86), target vessel revascularization (OR, 0.27; 95% CI, 0.12–0.62) and stent thrombosis (OR, 0.64; 95% CI, 0.53–0.77) and decreased adenosine diphosphate‐induced maximal platelet aggregation. However, as compared with 75 mg day^?1, the 150‐mg daily maintenance dosage significantly increased the risk of minor bleeding (OR, 1.21; 95% CI, 1.08–1.36). Conclusion: As compared with the currently recommended 75‐mg day^?1 maintenance dosage of clopidogrel, the 150‐mg day^?1 dosage can reduce major adverse cardiac and/or cerebrovascular events but may increase the risk of minor bleeding.     

Heparin‐induced non‐necrotizing skin lesions: rarely associated with heparin‐induced thrombocytopenia

See also Warkentin TE, Linkins L‐A. Non‐necrotizing heparin‐induced skin lesions and the 4T’s score. This issue, pp 1483–. Summary. Background: Recently, there has been an increasing number of reports regarding adverse skin reactions to subcutaneous heparin administration. Case series have implied that heparin‐induced skin lesions are predominantly associated with life‐threatening heparin‐induced thrombocytopenia (HIT) in at least 22% of patients. Skin lesions, therefore, have been included in clinical scores for HIT. Objectives: To determine the association of heparin‐induced skin lesions with HIT. This would have a pivotal impact on further anticoagulatory management in patients with heparin‐induced skin lesions. Patients/Methods: In our observational cohort study, 87 consecutive patients with heparin‐induced skin lesions (85 occurring during low‐molecular‐weight heparin administration) were evaluated using a standardized internal protocol, including HIT diagnostics (heparin‐platelet factor 4‐ELISA, heparin‐induced platelet activation assay), platelet count monitoring, clinical/sonographical screening for thrombosis, skin allergy testing and, if necessary, histology. Results: None of the observed heparin‐induced skin lesions was due to HIT; all lesions were caused by delayed‐type IV‐hypersensitivity reactions (DTH) instead. Even the cutaneous reaction in one patient with concomitant HIT could be classified histologically as DTH reaction, amounting to an association of heparin‐induced skin lesions and HIT in 1.2% (1/87; 95% confidence interval, 0.00–0.06). Conclusion: Heparin‐induced skin lesions associated with use of low‐molecular‐weight heparins do not seem to be strongly associated with a systemic immunologic reaction in terms of HIT and might rather be due to DTH reactions than due to microvascular thrombosis. Hence, we propose refining existing pretest probability scores for HIT, unless underlying causes have been clarified.     

The gain‐of‐function variant allele CYP2C19*17: a double‐edged sword between thrombosis and bleeding in clopidogrel‐treated patients

Summary. Background: A large number of clinical studies have documented that a loss‐of‐function variant CYP2C19*2 affects clinical profiles of clopidogrel (efficacy and safety). However, data on the impact of a gain‐of‐function variant CYP2C19*17 on the response to that drug seem to be less consistent. Objectives: To systematically summarize all available clinical data assessing the role of the CYP2C19*17 variant in patients taking clopidogrel. Methods: A literature search was conducted and a meta‐analysis was performed for 11 eligible studies. The endpoints included the major adverse cardiovascular events (MACE, representing non‐fatal myocardial infarction, stroke, revascularization, or death), bleeding events, mortality, stent thrombosis and high platelet reactivity (HPR). Results: Data from six clinical studies demonstrated that carriers of the CYP2C19*17 variant had a marked protection against recurrent cardiovascular events in patients with coronary artery disease compared with non‐carriers, as measured by a 16% decrease in the incidence of MACE (10.0% vs. 11.9%; OR, 0.82; 95% CI, 0.72–0.94; P = 0.005). On the other hand, carriers had an increased risk of developing bleeding as expected (8.0% vs. 6.5%; OR, 1.25; 95% CI, 1.07–1.47; P = 0.006; four studies). Moreover, the presence of the CYP2C19*17 variant might lead to increased response to clopidogrel, as shown by a marked lower prevalence of HPR in carriers than in non‐carriers (37.9% vs. 50.8%; OR, 0.60; 95% CI, 0.45–0.79; P = 0.0003; three studies). Conclusions: Carriers of the CYP2C19*17 variant have greater therapeutic responsiveness to clopidogrel than non‐carriers, but they have an increased risk of developing bleeding as well.     

Bleeding risk in ‘real world’ patients with atrial fibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort

Summary. Background: Oral anticoagulation (OAC) in patients with atrial fibrillation (AF) is a double‐edged sword, because it decreases the risk of stroke at the cost of an increased risk of bleeding. We compared the performance of a new bleeding prediction scheme, HAS‐BLED, with an older bleeding prediction scheme, HEMORR₂HAGES, in a cohort of ‘real‐world’ AF patients. Methods: By individual‐level‐linkage of nationwide registers, we identified all patients (n = 118 584) discharged with non‐valvular AF in Denmark during the period 1997–2006, with and without OAC. Major bleeding rates during 1 year of follow‐up were determined, and the predictive capabilities of the two schemes were compared by c‐statistics. The risk of bleeding associated with individual risk factors composing HAS‐BLED was estimated using Cox proportional‐hazard analyses. Results: Of AF patients receiving OAC (n = 44 771), 34.8% and 47.3% were categorized as ‘low bleeding risk’ by HAS‐BLED and HEMORR₂HAGES, respectively, and the bleeding rates per 100 person‐years were 2.66 (95% confidence interval [CI], 2.40–2.94) and 3.06 (2.83–3.32), respectively. C‐statistics for the two schemes were 0.795 (0.759–0.829) and 0.771 (0.733–0.806), respectively. The risk factors composing HAS‐BLED were associated with varying risks, with a history of bleeding (hazard ratio [HR] 2.98; 95% CI 2.68–3.31) and being elderly (HR 1.93; 95% CI 1.71–2.18) being associated with the highest risks. Comparable results were found in AF patients not receiving OAC (n = 77 813). Conclusions: In an unselected nationwide cohort of hospitalized patients with atrial fibrillation, the HAS‐BLED score performs similarly to HEMORR₂HAGES in predicting bleeding risk but HAS‐BLED is much simpler and easier to use in everyday clinical practise.     

Neuroprotective effects of ultra‐low‐molecular‐weight heparin in vitro and vivo models of ischemic injury

This study was conducted to demonstrate ultra‐low‐molecular‐weight heparin’s neuroprotective effects on ischemic injury both in vivo and in vitro studies. In vitro, the effect of ultra‐low‐molecular‐weight heparin was tested in cultured PC12 cells exposed to Earle’s solution containing sodium dithionite, to identify its neuroprotection to PC12 cells damaged by oxygen‐glucose deprivation (OGD). The cell injury was detected by the tetrazolium salt 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5 diphenyl‐2H tetrazolium bromide (MTT) assay. In vivo, male Wistar rats with middle cerebral artery occlusion were evaluated for infarct volume followed by the treatment with ultra‐low‐molecular‐weight heparin. The results in vitro showed that ultra‐low‐molecular‐weight heparin significantly inhibited PC12 cells damage induced by OGD. Results in vivo showed that vein injection of Ultra‐Low‐molecular‐weight heparin at doses of 0.5 and 1.0 mg/kg exerted significant neuroprotective effects on rats with focal cerebral ischemic injury by significantly reducing the infarct volume compared with the injury group. All the findings suggest that ultra‐low‐molecular‐weight heparin might act as a neuroprotective agent useful in the treatment of cerebral ischemia.     

Major bleeding risks of different low‐molecular‐weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis

Essentials

• Low‐molecular‐weight‐heparins (LMWH) kinetics differ which may result in different bleeding risks.
• A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding.
• The absolute major bleeding risk was low among patients registered at the anticoagulation clinic.
• Once‐daily dosing was associated with a lower bleeding risk as compared with twice‐daily.

Summary

Background

Low‐molecular‐weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events.

Objectives

To determine major bleeding risks for different LMWH agents and dosing schedules.

Methods

A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center.

Results

The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7–3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2–17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0‐fold increased major bleeding risk (95% CI, 0.8‐5.1) as compared with a nadroparin o.d. dosing schedule.

Conclusions

Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice‐daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once‐daily dosing, as also suggested in a meta‐analysis of controlled clinical trials.     

Performance outcomes of a pharmacist‐managed anticoagulation clinic in the rural,resource‐constrained setting of Eldoret,Kenya

Summary. Background: It is recommended that warfarin therapy should be managed through an anticoagulation monitoring service to minimize the risk of bleeding and subsequent thromboembolic events. There are few studies in Sub‐Saharan Africa that describe warfarin management in spite of the high incidence of venous thromboembolism (VTE) and rheumatic heart disease. Objective: To examine the feasibility of the Moi Teaching and Referral Hospital anticoagulation monitoring service and compare its performance with clinics in resource‐rich settings. Methods: A retrospective chart review compared the percentage time in the therapeutic range (TTR) and rates of bleeding and thromboembolic events to published performance targets using the inference on proportions test. Wilcoxon’s rank sum analyses were used to establish predictors of TTR. Results: For the 178 patients enrolled, the mean TTR was 64.6% whereas the rates of major bleeds and thromboembolic events per year were 1.25% and 5%, respectively. In the primary analysis, no statistically significant differences were found between the results of TTR, major bleeds and thromboembolic events for the clinic and published performance rates. In the secondary analysis, having an artificial heart valve and a duration of follow‐up of > 120 days were positively associated with a higher TTR (P < 0.05) whereas venous thromboembolism, history of tuberculosis, HIV and a duration of follow‐up of < 120 days were associated with having a lower TTR (P < 0.05). Conclusions: The performance of the MTRH anticoagulation clinic is non‐inferior to published metrics on the performance of clinics in resource‐rich settings.     

Herbal medicine Shakuyaku‐kanzo‐to reduces paclitaxel‐induced painful peripheral neuropathy in mice

Objectives: Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors such as breast, ovarian and lung cancer. However, it sometimes induces moderate to severe muscle pain, and impairs the patients’ quality of life. An appropriate method for relieving this pain is not well established. Shakuyaku‐kanzo‐to, a herbal medicine, is known to relieve menstrual pain, muscle spasm, and muscle pain, and its effectiveness is expected. To ascertain the effectiveness of Shakuyaku‐kanzo‐to on paclitaxel‐induced pain, we investigated the effects of Shakuyaku‐kanzo‐to and its constituent herbal medicines in a mouse model. Methods: Seven‐week‐old male ddY mice were used. To make a mouse model of paclitaxel‐induced pain, different single, intraperitoneally injected doses of this drug were tested in various groups of mice, and the optimal dose was determined. To estimate the effects of Shakuyaku‐kanzo‐to, the constituent herbal medicines Shakuyaku and Kanzo, and loxoprofen sodium as a non‐steroidal anti‐inflammatory drug on paclitaxel‐induced pain, mechanical allodynia and hyperalgesia of the hind paw were assessed. Results: Paclitaxel administered at a dose of 10mg/kg or more produced allodynia and hyperalgesia; the time courses were similar to those of pain after paclitaxel administration in cancer patients. Shakuyaku‐kanzo‐to significantly relieved the allodynia and hyperalgesia induced by paclitaxel (10mg/kg). Shakuyaku and Kanzo inhibited the allodynia and hyperalgesia to some extent, but not significantly, while loxoprofen sodium was without effects. Conclusions: A single administration of paclitaxel (10mg/kg) produced allodynia and hyperalgesia in mice, suggesting that it could be used as an animal model resembling the painful conditions observed in humans medicated with this drug. Using this model, Shakuyaku‐kanzo‐to was shown to relieve paclitaxel‐induced painful peripheral neuropathy.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT

Summary. Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org ) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.