Timing the First Postoperative Dose of Anticoagulants: Lessons Learned From Clinical Trials.

The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban, and dabigatran, have been shown in phase 3 trials to be effective for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first postoperative dose was delayed for at least 6 h after surgery. The timing of the first postoperative dose of the NOACs tested in phase 2 studies differed among the three NOACs: dabigatran was started 1 to 4 h postoperatively, whereas rivaroxaban and apixaban were started at least 6 and 12 h, postoperatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first postoperative dose of anticoagulant is delayed for at least 6 h after surgery.

Transesophageal echocardiography in patients with cryptogenic ischemic stroke: a systematic review.

BACKGROUND: The clinical utility of routine transesophageal echocardiography (TEE) for patients with unexplained ischemic stroke is controversial. We performed a systematic review to determine the frequency of detection of new cardiac findings in patients with cryptogenic ischemic stroke (IS) undergoing transesophageal echocardiography (TEE). METHODS: Systematic review and meta-analysis of cohort studies of consecutive patients with "cryptogenic" IS undergoing TEE after routine etiologic workup. Patients were categorized into 2 groups: A (< 55 years) and B (≥ 55 years). Outcomes included proportion of patients with new TEE-detected cardiac findings and proportion of patients commenced on oral anticoagulation after TEE. RESULTS: Twenty-seven studies were included (n = 5,653). We identified significant heterogeneity among studies and report a range of prevalence rates and I2 statistic as our primary analysis. Prevalence of individual cardiac findings on TEE varied significantly among studies; patent foramen ovale (A: 12.0%-57.8%, I2 = 89.9%; B: 3.9%-43.5%, I2 = 86.7%), atrial septal aneurysm (A: 0-48.9%, I2 = 91.9%; B: 3.5%-25.0%, I2 = 84.5%), left atrial thrombus (A: 0-10.9%, I2 = 61.1%; B: 0-21.2%, I2 = 91.7%), spontaneous echo contrast (A: 0-11.9%, I2 = 57.2%; B: 0-21.3%, I2 = 89.8%), and aortic atheroma (A: 0-9.6%, I2 = 53.8%; B: 2.8%-44.4%, I2 = 89.7%). Definitions of common findings were not provided for many studies. Five studies (n = 591) reported on the proportion of patients who were commenced on anticoagulant therapy after TEE (range 0-30.7%). CONCLUSIONS: Routine TEE in patients with cryptogenic IS identifies cardiac findings in a large proportion. However, there is marked interstudy variation in the definition and prevalence of common findings. Transesophageal echocardiography-detected findings prompted the introduction of anticoagulant therapy in up to one-third of patients. However, these were mostly not for established guideline-based indications based on randomized controlled trial evidence. It is unclear if routine use of TEE in patients with cryptogenic IS is indicated.

Rofecoxib does not appear to increase the risk of venous thromboembolism: a systematic review of the literature.

BACKGROUND AND OBJECTIVE: Rofecoxib, a selective cyclo-oxygenase-2 (COX-2) inhibitor, has been associated with increased arterial thrombosis. It is unknown whether (COX-2) inhibition is associated with venous thromboembolism (VTE).We investigated, using a systematic review of the literature, the association between rofecoxib and venous thrombosis. METHODS: A search strategy was developed and implemented to identify all English language studies in which rofecoxib was compared with placebo, irrespective of the primary outcome of the study. Study methodology and results were reviewed in a standardized manner using RefMan software. Confidence intervals and risk difference were calculated using a Poisson distribution. RESULTS: The search strategy identified 1339 papers; 15 studies met our pre-specified inclusion criteria. The majority of trials were short in duration (~12 weeks). All studies met at least two of the three quality criteria. In 15,160 (9217 person years follow up) patients allocated to rofecoxib there were 8 VTEs reported, compared with 9 VTEs in 13147 (9092 person years) patients allocated to placebo (relative risk 0.87, 95% CI 0.29-2.56, p=NS). The estimated incidence of VTE was 86.8 per 100,000 (95% CI 37.5 -171.2) person years with rofecoxib, and 99.1 per 100,000 person years with placebo (95%CI 45.3 - 188). This difference is not statistically significant (p=0.78). CONCLUSIONS: Our findings are limited by the relatively small number of events, although, the contributing sample size of 28307 subjects (18309 person years) is reasonable. From our best available data outlined in this manuscript, there is no increase in the risk of VTE with rofecoxib use.

New oral anticoagulants for stroke prevention in atrial fibrillation: impact of study design, double counting and unexpected findings on interpretation of study results and conclusions.

Four recently introduced new oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban) have been shown to be at least as efficacious and safe as warfarin for stroke prevention in patients with atrial fibrillation in their respective trials. The first three have been approved, while edoxaban is awaiting regulatory approval. Several guidelines have endorsed the approved new oral anticoagulants over warfarin because of their favourable risk-benefit ratio, low propensity for food and drug interactions, and lack of requirement for routine coagulation monitoring. In this invited review, we summarise the results of the four studies and discuss widely held conclusions. We take a step further and discuss how differences in study design, analysis plan, and unexpected events affect the interpretation of the study results. Finally, we take our re-interpretation of study results and discuss how they might impact clinical practice and anticoagulant choice for patients.

Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction?

Compared with warfarin, dabigatran is associated with less intracranial hemorrhage, but an increased risk of myocardial infarction. To explore these phenomena, we compared their effects on thrombin generation. Thrombin generation in plasma from 10 patients taking therapeutic doses of warfarin (mean INR 2.6) was compared with that in plasma containing 250 ng/mL dabigatran. Although lag times were similar when thrombin generation was induced by recalcification or with a range of tissue factor concentrations, there was a greater reduction in peak thrombin generation and endogenous thrombin potential in plasma from warfarin-treated patients than in dabigatran-containing plasma. Similar results were obtained when thrombin generation was determined in plasma samples from 18 warfarin or 36 dabigatran treated patients entered into the RE-LY trial. Warfarin suppresses thrombin generation more efficiently than dabigatran. Greater suppression of normal hemostatic mechanisms in the brain and pathological thrombosis at sites of atherosclerotic plaque disruption may explain the higher rate of intracranial bleeding and lower rate of myocardial infarction with warfarin compared with dabigatran.

Rivaroxaban for stroke prevention in atrial fibrillation: a critical review of the ROCKET AF trial.

Oral anticoagulation is the mainstay of therapy for stroke prevention in patients with atrial fibrillation (AF). Vitamin K antagonists such as warfarin have many drawbacks that reduce their uptake, safety and effectiveness. The ROCKET AF trial compared rivaroxaban (20 mg/day; 15 mg/day in patients with creatinine clearance 30-49 ml/min) with dose-adjusted warfarin (international normalized ratio 2-3) in 14,264 patients with AF and a prior history of stroke or at least two other additional risk factors for stroke. The ROCKET AF trial demonstrated the noninferiority of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism, with a similar rate of major bleeding and a substantial reduction in intracranial hemorrhage. These results, in conjunction with its convenient once-daily dosing regimen, make rivaroxaban an attractive alternative to warfarin for stroke prevention in AF.

Subtle differences in commercial heparins can have serious consequences for cardiopulmonary bypass patients: A randomized controlled trial.

OBJECTIVE: To compare the potency, reversibility, and perioperative bleeding risk of Hepalean with those of PPC heparin. METHODS: Because in vitro testing failed to detect differences in the potency or protamine reversibility of the 2 heparin preparations, we conducted a parallel group, single-center, double-blind, randomized, controlled trial to compare the anticoagulant effects of Hepalean to those of PPC heparin in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. RESULTS: From June 1, 2011, to June 30, 2011, we randomly assigned 11 patients to receive PPC heparin and 10 to receive Hepalean. Despite similar initial doses of heparin, the median initial activated clotting time was numerically lower in the PPC heparin group than in the Hepalean group (median, 516.0 seconds; interquartile range, 481.0-633.0; vs median, 584.0 seconds, interquartile range, 520.0-629.0; P = .418). Those given PPC heparin required a greater total heparin dose (median, 46,000.0 U; interquartile range, 39,500.0-60,000.0 vs median, 34,500.0 U; interquartile range, 32,250.0-37,000.0; P = .011) and a greater dose of heparin per kilogram than those given Hepalean (median, 572.9 U/kg; interquartile range, 443.0-659.7 vs median, 401.1 U/kg; interquartile range, 400.0-419.4; P = .003). The key secondary results included an increased median total protamine dose (median, 600.0 mg; interquartile range, 550.0-700.0; vs median, 500.0 mg; interquartile range, 425.0-542.5; P = .026) and a trend toward increased chest tube output within 24 hours (median, 830.0 mL; interquartile range, 425.0-1135.0; vs median, 702.5 mL; interquartile range, 550.0-742.5; P = .324). CONCLUSIONS: PPC heparin use was associated with greater heparin and protamine dose requirements than Hepalean. These findings indicate that heparin preparations are not interchangeable and suggest that a direct comparison of the potency with the brand in use is needed if a change is made to ensure that the agents exert similar anticoagulant effects in vivo.

Aspirin response variability after major orthopedic surgery.

INTRODUCTION: Variability in platelet response to aspirin has been reported in patients undergoing cardiac surgery but has rarely been described in other operative settings and its mechanism remains uncertain. We performed a prospective cohort study to investigate the variability in platelet response to aspirin and to explore its mechanism in patients undergoing major orthopedic surgery. MATERIALS AND METHODS: Twelve aspirin-treated patients undergoing elective hip or knee replacement were recruited. Once-daily aspirin was continued throughout the perioperative period. We measured platelet function using light transmission aggregation (LTA) in response to arachidonic acid (PL(AA)) and serum thromboxane B(2) (TXB(2)) at baseline (before surgery) as well as on days 1, 2, 3, 4, 5, 6, and 8 after surgery. We defined aspirin low response as a PL(AA)>20%. RESULTS: Six patients exhibited aspirin low response, which typically started on post-operative days 3 or 4; the remaining 6 patients had normal response to aspirin. Compared to aspirin responders, patients with aspirin low response showed significantly higher serum TXB(2) levels, a more pronounced early decrease in platelet count, and a significantly more rapid recovery of the platelet count after surgery. CONCLUSION: Aspirin response variability occurred in patients after major orthopedic surgery, with one-half of the patients in our study exhibiting post-operative aspirin low response. Increased platelet turnover might be a contributor to aspirin response variability after orthopedic surgery.

Effectiveness and safety of combined antiplatelet and anticoagulant therapy: a critical review of the evidence from randomized controlled trials.

Antiplatelet and anticoagulant drugs are effective for the prevention of arterial and venous thrombosis but patients continue to experience major cardiovascular events despite their use. Strategies to improve the effectiveness of antithrombotic therapies include selecting the optimal drug and dosing regimen, the use of combinations of antiplatelet and anticoagulant drugs and the development of new more effective drugs to replace existing therapies. Evidence from randomized controlled trials indicates that the combination of aspirin and an anticoagulant is more effective than aspirin alone for the prevention of recurrent cardiovascular events in patients with acute coronary syndrome and is more effective than anticoagulation alone for the prevention of thromboembolic events in patients with mechanical heart valves, but at a cost of increased bleeding. Randomized controlled trials provide no evidence for improved effectiveness of combination therapy compared with antiplatelet therapy alone for the prevention of recurrent cardiovascular events in patients with non-cardioembolic stroke or peripheral artery disease, or compared with anticoagulant therapy alone for the prevention of stroke in patients with atrial fibrillation. Despite lack of evaluation in randomized controlled trials, combination therapy is commonly used in patients with separate indications for antiplatelet therapy (e.g., acute coronary syndrome, recent coronary artery stent) and anticoagulant therapy (e.g., atrial fibrillation with at least one additional risk factor for stroke). Randomized trials are urgently required to evaluate the effectiveness and safety of combining antiplatelet and anticoagulant therapy in these settings.

Dabigatran for stroke prevention in atrial fibrillation: the RE-LY trial.

Oral anticoagulation is the mainstay of therapy for stroke prevention in patients with atrial fibrillation. Vitamin K antagonists such as warfarin reduce the risk of cardioembolic stroke by approximately two-thirds compared with no treatment, but are limited by their unpredictable anticoagulant effect and narrow therapeutic index. Warfarin therapy requires routine coagulation monitoring, which is inconvenient for patients and costly for the healthcare system. The limitations of the vitamin K agonists have spurred the development of new oral anticoagulants that selectively inhibit thrombin or factor Xa. The Randomized Evaluation of Long-Term Anticoagulation (RE-LY) trial of 18,113 patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke demonstrated that dabigatran etexilate given at a dose of 150 mg twice daily compared with warfarin, reduced the rate of stroke or systemic embolism by one-third with a similar rate of major bleeding, whereas dabigatran etexilate given at a dose of 110 mg twice daily compared with warfarin had a similar rate of stroke or systemic embolism and reduced the rate of major bleeding by one-fifth. Both doses of dabigatran etexilate reduced intracranial bleeding by approximately two-thirds compared with warfarin. Based on the results of the RE-LY trial, both the US FDA and Health Canada recently approved dabigatran etexilate for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

New antithrombotic agents--insights from clinical trials.

Antithrombotic agents are the cornerstones of therapy for thrombosis. The compositions of arterial and venous clots differ, rendering antiplatelet agents more effective for arterial thrombosis and anticoagulants more effective for venous disease. Despite taking acetylsalicylic acid, some patients with arterial disease experience thrombotic events. The addition of the ADP-receptor antagonist clopidogrel to therapeutic regimens containing acetylsalicylic acid improves outcomes in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. However, clopidogrel has several limitations, including variable absorption, drug-drug interactions and genetic factors that lead to reduced generation of the active metabolite, and a delayed onset and offset of action. A search for new ADP-receptor inhibitors has yielded drugs such as prasugrel, ticagrelor, and cangrelor. For patients with venous thrombosis, the coumarins have been the only available oral anticoagulants for more than 60 years. Despite their effectiveness in preventing and treating thromboembolism, coumarins have well-documented limitations, including drug-drug and drug-dietary interactions, a narrow therapeutic range, and inconvenience and cost of monitoring therapy. A search for new oral anticoagulants has yielded drugs such as dabigatran etexilate, rivaroxaban, and apixaban. In this article, we review these new antithrombotic agents and provide plausible explanations for the results of phase III randomized controlled trials of these drugs.

Creatine monohydrate and conjugated linoleic acid improve strength and body composition following resistance exercise in older adults.

Aging is associated with lower muscle mass and an increase in body fat. We examined whether creatine monohydrate (CrM) and conjugated linoleic acid (CLA) could enhance strength gains and improve body composition (i.e., increase fat-free mass (FFM); decrease body fat) following resistance exercise training in older adults (>65 y). Men (N = 19) and women (N = 20) completed six months of resistance exercise training with CrM (5g/d)+CLA (6g/d) or placebo with randomized, double blind, allocation. Outcomes included: strength and muscular endurance, functional tasks, body composition (DEXA scan), blood tests (lipids, liver function, CK, glucose, systemic inflammation markers (IL-6, C-reactive protein)), urinary markers of compliance (creatine/creatinine), oxidative stress (8-OH-2dG, 8-isoP) and bone resorption (Nu-telopeptides). Exercise training improved all measurements of functional capacity (P<0.05) and strength (P<0.001), with greater improvement for the CrM+CLA group in most measurements of muscular endurance, isokinetic knee extension strength, FFM, and lower fat mass (P<0.05). Plasma creatinine (P<0.05), but not creatinine clearance, increased for CrM+CLA, with no changes in serum CK activity or liver function tests. Together, this data confirms that supervised resistance exercise training is safe and effective for increasing strength in older adults and that a combination of CrM and CLA can enhance some of the beneficial effects of training over a six-month period. Trial Registration. ClinicalTrials.gov NCT00473902.