Can a Single Measurement of Apixaban Levels Identify Patients at Risk of Overexposure? A Prospective Cohort Study.

Background Patients with atrial fibrillation (AF) are frequently treated with apixaban 2.5-mg twice daily (BID) off-label, presumably to reduce the bleeding risk. However, this approach has the potential to increase the risk of ischemic stroke. If a single measurement could reliably identify patients with high drug levels, the increased stroke risk may be mitigated by confining off-label dose reduction to such patients. Objectives This study aimed to determine whether a single high apixaban level is predictive of a similarly high level when the test is repeated in 2 months. Methods In this prospective cohort study of clinic patients receiving apixaban 5-mg BID for AF or venous thromboembolism, peak and trough apixaban levels were measured using the STA-Liquid anti-Xa assay at baseline and 2 months. We calculated the proportions of patients with levels that remained in the upper quintile. Results Of 100 enrolled patients, 82 came for a second visit, 55 of whom were treated with apixaban 5-mg BID. Seven (63.6%, 95% confidence interval [CI]: 35.4-84.8%) and nine (81.8%, 95% CI: 52.3-94.9%) of 11 patients with a baseline trough and peak level in the upper quintile, respectively, had a subsequent level that remained within this range. Only one (9.1%, 95% CI: 1.6-37.7%) patient had a subsequent level that fell just lower than the median. Conclusion The trough and peak levels of apixaban in patients who have a high level on a single occasion, usually remain high when the assay is repeated in 2 months. Accordingly, the finding of a high apixaban level in patients deemed to be at high risk of bleeding, allows physicians contemplating off-label use of the 2.5-mg BID dose to limit its use to selected patients who are less likely to be exposed to an increased risk of thrombosis.

Plasma Rivaroxaban Level to Identify Patients at Risk of Drug Overexposure: Is a Single Measurement of Drug Level Reliable?

Introduction Dose adjustment based on laboratory monitoring is not routinely recommended for patients treated with rivaroxaban but because an association has been reported between high drug level and bleeding, it would be of interest to know if measuring drug level once could identify patients at risk of bleeding who might benefit from a dose reduction. Objective This study was aimed to investigate the reliability of a single measurement of rivaroxaban level to identify clinic patients with persistently high levels, defined as levels that remained in the upper quintile of drug-level distribution. Methods In this prospective cohort study of 100 patients with atrial fibrillation or venous thromboembolism, peak and trough rivaroxaban levels were measured using the STA-Liquid Anti-Xa assay at baseline and after 2 months. Values of 395.8 and 60.2 ng/mL corresponded to the 80th percentile for peak and trough levels, respectively, and levels above these cut-offs were categorized as high for our analyses. Results Among patients with a peak or trough level in the upper quintile at baseline, only 26.7% (95% confidence interval [CI]: 10.9-52.0%), and 13.3% (95% CI: 2.4-37.9%), respectively, remained above these thresholds. Conclusion Our findings do not support the use of a single rivaroxaban level measurement to identify patients who would benefit from a dose reduction because such an approach is unable to reliably identify patients with high levels.

Mortality benefit in the COMPASS trial: is it related to superior statistical power or better efficacy and safety?

Until recently, attempts to improve the benefit of aspirin by adding another antithrombotic agent have not resulted in a mortality reduction in patients with chronic symptomatic atherosclerosis. In this population, COMPASS is the only one among six trials to show a significant mortality reduction, thereby providing evidence of a clear net clinical benefit with the combination of low-dose rivaroxaban plus aspirin. In this systematic review, we sought to determine whether the mortality benefit of the combination arm in COMPASS is best explained by greater statistical power or by a more favorable efficacy-safety profile than the other regimens evaluated in patients with chronic symptomatic atherosclerosis.

Apixaban for Stroke Prevention in Atrial Fibrillation: Why are Event Rates Higher in Clinical Practice than in Randomized Trials?-A Systematic Review.

BACKGROUND: Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients. OBJECTIVES: To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis. RESULTS AND DISCUSSION: We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs. CONCLUSION: The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

Long-term risk of recurrence in patients with a first unprovoked venous thromboembolism managed according to d-dimer results; A cohort study.

Essentials Long-term recurrence risk after a first unprovoked VTE with negative d-dimer levels is uncertain. Anticoagulation was stopped if d-dimer was negative, and was continued if d-dimer was positive. Five years after stopping anticoagulants, recurrent VTE was 30% in men and 17% in women. Negative d-dimers do not justify stopping anticoagulants in most men but appear to in most women. BACKGROUND: The long-term risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative d-dimer results is uncertain. OBJECTIVES: To determine this risk, including in subgroups based on sex. PATIENTS AND METHODS: ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if d-dimer was negative on therapy and 1 month after stopping therapy. Other patients remained on anticoagulant therapy. We previously reported findings after a mean of 2.2 years. The current report includes 3 years of additional follow-up in 293 of these patients. RESULTS: During a median follow-up of 5.0 years, recurrent VTE after stopping therapy in response to negative d-dimer testing was 5.1% (95% confidence interval [CI], 3.6-6.5) per patient-year overall, 7.5% (95% CI, 5.5-10.0) in men, 3.8% (95% CI, 2.0-6.6) in women with VTE not associated with estrogens, and 0.4% (95% CI, 0.0-2.3) in women with VTE associated with estrogens (P < 0.001 for three-group comparison). Risk of recurrence at 5 years was 21.5% (95% CI, 16.4-26.5) overall, 29.7% (95% CI, 22.1-37.3) in men, 17.0% (95% CI, 8.1-25.9) in non-estrogen women, and 2.3% (95% CI, 0.0-6.8) in estrogen women. CONCLUSION: The long-term risk of recurrence in patients with a first unprovoked VTE who have negative d-dimer results is not low enough to justify stopping anticoagulant therapy in men, but appears to be low enough in women for many to choose stopping therapy (ClinicalTrials.gov; NCT00720915).

In Vitro Reversal of the Anti-Aggregant Effect of Ticagrelor Using Untreated Platelets.

BACKGROUND: Ticagrelor is an anti-platelet agent that is indicated for prevention of thrombosis after acute coronary syndrome or intra-coronary artery stent implantation, but it increases the risk of bleeding. Platelet transfusion has the potential to treat or prevent bleeding in patients taking ticagrelor, but the optimal quantity of platelets and timing of administration have not been fully defined. METHODS AND RESULTS: Ten healthy subjects took ticagrelor in combination with acetylsalicylic acid for 5 days, and had blood collected prior to treatment and at 2, 10, 24, 48, 72 and 96 hours after the last doses. The potential of platelet transfusion to prevent or reverse bleeding was evaluated by mixing subject and donor platelet-rich plasma in vitro in nine different proportions, and measuring adenosine diphosphate-mediated aggregation by light transmission aggregometry. Spontaneous offset of the anti-aggregant effect of ticagrelor occurred gradually and was complete at 72 hours after the last dose. The addition of donor platelets enhanced the recovery. The addition of the equivalent of six apheresis platelet units produced a 50% relative reversal at 10 hours, and > 90% reversal at 24 hours. CONCLUSION: Donor platelets enhance reversal of the anti-aggregant effect of ticagrelor in vitro. Donor platelets given in clinically relevant amounts partially reversed ticagrelor at 10 hours after the last dose, and almost fully reversed ticagrelor at 24 hours. The results inform on the potential to reverse ticagrelor in patients who develop bleeding or require emergency surgery.

Quantifying immature platelets as markers of increased platelet production after coronary artery bypass grafting surgery.

OBJECTIVES: An increased rate of platelet production is a possible cause of reduced antithrombotic response to once-daily aspirin. Markers of immature platelets (IPs), such as immature platelet count (IPC), immature platelet fraction (IPF), and mean platelet volume (MPV) might be useful for identifying patients who have an increase in their rate of platelet production. However, their potential as markers of platelet production has not been rigorously evaluated. We aimed to investigate the utility of the IPC, IPF, and MPV as surrogates for increased platelet production using coronary artery bypass grafting (CABG) as a model of enhanced thrombopoiesis. METHODS: Daily changes in platelet count, IPC, IPF, and MPV were followed in 45 patients undergoing CABG. RESULTS: The rise in IP markers preceded that in the platelet count. IPC (16% per day increase from nadir) but not IPF or MPV showed a significant and sustained rise, which paralleled the pattern observed with platelet count (18% per day increase from nadir). CONCLUSIONS: Of the 3 markers, IPC was the most promising as surrogates for platelet production. Future studies should evaluate the utility of the IPC to identify patients with cardiovascular disease with reduced response to aspirin who might benefit from twice-daily aspirin.

Impact of cost on use of non-vitamin K antagonists in atrial fibrillation patients in Ontario, Canada.

Canadian guidelines recommend non vitamin K antagonists (NOACs) in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF), but NOACs are more expensive than VKAs. Canada has a universal healthcare system that covers the cost of NOACs for select patient groups. Ability to pay for NOACs may influence their use. We reviewed medical charts of Hamilton General Hospital outpatients under the age of 65 with a new diagnosis of AF who were referred for initiation of OAC therapy. We contacted these patients by phone and asked them to complete a questionnaire regarding their OAC choice, economic factors that may have influenced this choice (income, insurance) and the financial burden of OAC therapy. We included 110 patients, mean age 56 years, and 26.4% females. NOAC users had a higher median neighborhood income than VKA users (p = 0.0144, n = 110). 73 patients responded to the questionnaire. NOAC users reported higher annual household income (p = 0.0038, n = 73). Patients with private insurance were more likely to use NOACs than those without insurance (p = 0.0496, n = 73). The cost of NOACs and ability to pay is a determinant of their use Ontario patients under the age of 65. This two tiered provision of care appears to contradict the values of Canada's universal healthcare system.

Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism.

It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-ß2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915.

The development and validation of an instrument to measure the quality of health research reports in the lay media.

BACKGROUND: The media serves as an important link between medical research, as reported in scholarly sources, and the public and has the potential to act as a powerful tool to improve public health. However, concerns about the reliability of health research reports have been raised. Tools to monitor the quality of health research reporting in the media are needed to identify areas of weakness in health research reporting and to subsequently work towards the efficient use of the lay media as a public health tool through which the public's health behaviors can be improved. METHODS: We developed the Quality Index for health-related Media Reports (QIMR) as a tool to monitor the quality of health research reports in the lay media. The tool was developed according to themes generated from interviews with health journalists and researchers. Item and domain characteristics and scale reliability were assessed. The scale was correlated with a global quality assessment score and media report word count to provide evidence towards its construct validity. RESULTS: The items and domains of the QIMR demonstrated acceptable validity and reliability. Items from the 'validity' domain were negatively skewed, suggesting possible floor effect. These items were not eliminated due to acceptable content and face validity. QIMR total scores produced a strong correlation with raters' global assessment and a moderate correlation with media report word count, providing evidence towards the construct validity of the instrument. CONCLUSIONS: The results of this investigation indicate that QIMR can adequately measure the quality of health research reports, with acceptable reliability and validity.

Impact of research investment on scientific productivity of junior researchers.

There is a demand for providing evidence on the effectiveness of research investments on the promotion of novice researchers' scientific productivity and production of research with new initiatives and innovations. We used a mixed method approach to evaluate the funding effect of the New Investigator Fund (NIF) by comparing scientific productivity between award recipients and non-recipients. We reviewed NIF grant applications submitted from 2004 to 2013. Scientific productivity was assessed by confirming the publication of the NIF-submitted application. Online databases were searched, independently and in duplicate, to locate the publications. Applicants' perceptions and experiences were collected through a short survey and categorized into specified themes. Multivariable logistic regression was performed. Odds ratios (OR) with 95 % confidence intervals (CI) are reported. Of 296 applicants, 163 (55 %) were awarded. Gender, affiliation, and field of expertise did not affect funding decisions. More physicians with graduate education (32.0 %) and applicants with a doctorate degree (21.5 %) were awarded than applicants without postgraduate education (9.8 %). Basic science research (28.8 %), randomized controlled trials (24.5 %), and feasibility/pilot trials (13.3 %) were awarded more than observational designs (p < 0.001). Adjusting for applicants and application factors, awardees published the NIF application threefold more than non-awardees (OR = 3.4, 95 %, CI = 1.9, 5.9). The survey response rate was 90.5 %, and only 58 % commented on their perceptions, successes, and challenges of the submission process. These findings suggest that research investments as small as seed funding are effective for scientific productivity and professional growth of novice investigators and production of research with new initiatives and innovations. Further efforts are recommended to enhance the support of small grant funding programs.

Bleeding in patients with atrial fibrillation treated with dabigatran, rivaroxaban or warfarin: A retrospective population-based cohort study.

BACKGOUND: Randomized controlled trials (RCTs) have shown that dabigatran, rivaroxaban and warfarin cause similar bleeding rates. METHODS: We performed a retrospective population-based cohort study to determine the incidence of bleeding in patients with atrial fibrillation (AF) beginning dabigatran, rivaroxaban or warfarin. Consecutive patients initiating anticoagulation for AF during a 3year period were identified using a computerized database. Patients who bled and required hospitalization underwent chart review. Bleeding incidences were calculated per 100 patient-years of treatment. RESULTS: 18,249 patients were included: 9564 (52.4%) received warfarin, 5976 (32.7%) dabigatran, and 2709 (14.8%) rivaroxaban. Bleeding incidences were 3.9 (95% CI, 3.6-4.4) in warfarin-treated patients, 4.2 (95% CI, 3.7-4.7) in dabigatran patients, and 4.1 (95% CI, 3.0-5.3) in rivaroxaban patients. Intracranial hemorrhage (ICH) rates were 0.71 (95% CI, 0.56-0.90) for warfarin, 0.4 (95% CI, 0.18-0.87) for dabigatran, and 0.27 (95%CI, 0.10-0.80) for rivaroxaban. GI hemorrhage rates were 1.88 (95%CI, 1.62-2.20) for warfarin, 2.98 (95% CI, 2.4-3.5) for dabigatran and 2.39 (95%CI, 1.6-3.5) for rivaroxaban. CONCLUSIONS: We demonstrate similar bleeding rates with both dabigatran 150mg and 110mg and rivaroxaban compared to warfarin.

Guidance for the prevention and treatment of the post-thrombotic syndrome.

The post-thrombotic syndrome (PTS) is a frequent, potentially disabling complication of deep vein thrombosis (DVT) that reduces quality of life and is costly. Clinical manifestations include symptoms and signs such as leg pain and heaviness, edema, redness, telangiectasia, new varicose veins, hyperpigmentation, skin thickening and in severe cases, leg ulcers. The best way to prevent PTS is to prevent DVT with pharmacologic or mechanical thromboprophylaxis used in high risk patients and settings. In patients whose DVT is treated with a vitamin K antagonist, subtherapeutic INRs should be avoided. We do not suggest routine use of elastic compression stockings (ECS) after DVT to prevent PTS, but in patients with acute DVT-related leg swelling that is bothersome, a trial of ECS is reasonable. We suggest that selecting patients for catheter-directed thrombolytic techniques be done on a case-by-case basis, with a focus on patients with extensive thrombosis, recent symptoms onset, and low bleeding risk, who are seen at experienced hospital centers. For patients with established PTS, we suggest prescribing 20-30 mm Hg knee-length ECS to be worn daily. If ineffective, a stronger pressure stocking can be tried. We suggest that intermittent compression devices or pneumatic compression sleeve units be tried in patients with moderate-to-severe PTS whose symptoms are inadequately controlled with ECS alone. We suggest that a supervised exercise training program for 6 months or more is reasonable for PTS patients who can tolerate it. We suggest that management of post-thrombotic ulcers should involve a multidisciplinary approach. We briefly discuss upper extremity PTS and PTS in children.

Lack of consistency in the relationship between asymptomatic DVT detected by venography and symptomatic VTE in thromboprophylaxis trials.

Asymptomatic deep-vein thrombosis (DVT) detected by mandatory venography, a surrogate outcome, comprises most of the efficacy outcome events in recent thromboprophylaxis trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in these clinical trials requires a consistent relationship between asymptomatic DVT and symptomatic venous thromboembolism (VTE). In this systematic review of high quality VTE prevention trials, we examined the consistency of the ratios of asymptomatic DVT to symptomatic VTE across a broad range of indications. Studies were identified from citations listed in the chapters on VTE prevention in the antithrombotic guidelines by the American College of Chest Physicians, 2012. A study was eligible if it: 1) was a randomised trial comparing an anticoagulant with standard of care; 2) included at least 500 participants; 3) reported asymptomatic or all DVT rates; and 4) reported symptomatic VTE rates. Of the 26 eligible trials, 19 trials were conducted in orthopaedic patients, five in general surgery patients and two in general medical patients. The overall median rates (ranges) for asymptomatic DVT and symptomatic VTE were 9.11 % (0.75 to 54.87 %) and 0.49 % (0.00 to 3.10 %), respectively. The median ratio was 14.53, with a wide range (2.75 to 103.86). Wide variability in the ratios persisted despite indication- and anticoagulant-specific analyses. In VTE prevention trials of alternative anticoagulants, the wide variability in the ratios of asymptomatic DVT to symptomatic VTE precludes judging the trade-off between thrombotic and bleeding events on the basis of composite outcomes dominated by venographic DVT.

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.

D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study.

BACKGROUND: Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment. OBJECTIVE: To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence. DESIGN: Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915). SETTING: 13 university-affiliated clinical centers. PATIENTS: 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy. INTERVENTION: Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month. MEASUREMENTS: Recurrent VTE during an average follow-up of 2.2 years. RESULTS: In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison). LIMITATIONS: Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study. CONCLUSION: The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

A systematic review of contemporary trials of anticoagulants in orthopaedic thromboprophylaxis: suggestions for a radical reappraisal.

In the last decade, major advances in venous thromboembolism (VTE) prophylaxis in orthopaedic surgery have included the development of new anticoagulants that are poised to replace low molecular weight heparins (LMWHs) and improvements in operative and perioperative care that have likely led to a decline in the rates of symptomatic VTE and mortality independent of anticoagulant use. A systematic review of the literature was performed to identify phase III randomized controlled trials of VTE prevention that compared new anticoagulants (fondaparinux, rivaroxaban, dabigatran, apixaban) with LMWH (enoxaparin) in major elective orthopaedic surgery. Our aims were to obtain best estimates of the rates of patient important events (symptomatic VTE, mortality, and bleeding) in contemporary trials of VTE prevention, and to consider the implications of these contemporary rates for clinical practice and future research. Fourteen studies, which enrolled 40,285 patients, were included in the analyses. The combined median rates (ranges) for all five anticoagulants for symptomatic VTE and mortality to the end of follow-up were 0.99 % (0.15-2.58 %) and 0.26 % (0-0.92 %) respectively, whereas the median rate (range) of clinically important bleeding was 3.44 % (2.25-7.74 %). In contemporary trials of anticoagulants, the rates of symptomatic VTE and mortality are low, but the rates of clinically important post-operative bleeding remain relatively high. Based on these results, we propose that approaches that minimize bleeding without substantially reducing efficacy merit investigation, particularly if improvement in surgical and perioperative care have also resulted in falling baseline patient important VTE rates independent of anticoagulant use.