Derrick Tao

Ibrutinib‐associated bleeding: pathogenesis, management and risk reduction strategies

Ibrutinib is an irreversible inhibitor of Brutons tyrosine kinase (Btk) that has proven to be an effective therapeutic agent for multiple B‐cell‐mediated lymphoproliferative disorders. Ibrutinib, however, carries an increased bleeding risk compared with standard chemotherapy. Bleeding events range from minor mucocutaneous bleeding to life‐threatening hemorrhage, due in large part to the effects of ibrutinib on several distinct platelet signaling pathways. There is currently a minimal amount of data to guide clinicians regarding the use of ibrutinib in patients at high risk of bleeding or on anticoagulant or antiplatelet therapy. In addition, the potential cardiovascular protective effects of ibrutinib monotherapy in patients at risk of vascular disease are unknown. Patients should be cautioned against using non‐steroidal anti‐inflammatory drugs, fish oils, vitamin E and aspirin‐containing products, and consider replacing ibrutinib with a different agent if dual antiplatelet therapy is indicated. Patients should not take vitamin K antagonists concurrently with ibrutinib; direct oral anticoagulants should be used if extended anticoagulation is strongly indicated. In this review, we describe the pathophysiology of ibrutinib‐mediated bleeding and suggest risk reduction strategies for common clinical scenarios associated with ibrutinib.

Financial Conflicts of Interest Among Hematologist-Oncologists on Twitter

HEALTH CARE REFORM Financial Conflicts of Interest Among Hematologist-Oncologists on Twitter Twitter, the social media service that permits 140-character posts or “tweets,” is undergoing rapid uptake by physicians.1 Twitter allows physicians to communicate, interpret, highlight, and curate information as well as engage in discussion or debate with other physicians, patients, patient advocates, researchers, investors, and industry employees. More than 60% of tweets authored by medical professionals in the United States are healthrelated, and approximately 14% mention commercial products or services.2 Yet, to our knowledge, there has been no investigation of the prevalence of financial conflict of interest (FCOI) among these users.

Conflicts of interest in Twitter

www.thelancet.com/haematology Vol 4 September 2017 e408 rates is a false equivalence. There are 371 biopharmaceutical companies in the world whose products could be discussed, but more than half of drug mentions refer to a median of six companies that pay these physicians. Moreover, doctors are more positive about drugs whose companies pay them. Our results raise the concern that financial conflict of interest must be considered with the growing use of social media to discuss cancer products and practices, as well as policies regarding disclosure, divesture, audit and recusal may be considered.

Extended thromboprophylaxis with direct oral anticoagulants for medical patients: a systematic review and meta-analysis.

To the editor: The risk for venous thromboembolism (VTE) is increased significantly in hospitalized patients, which can lead to morbidity and, rarely, mortality.[1][1],[2][2] Thromboprophylaxis with low-dose anticoagulation for up to 14 days during hospitalization has been shown to decrease the

Evaluating the Effects of an Evidence-Based Hemostasis and Thrombosis Treatment Algorithm on Medical Practitioner and Trainee Clinical Decision-Making

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is common, killing up to 100,000 Americans annually.1 The overall incidence of VTE has increased over the past decade, particularly in those with advanced age.2 Diagnosis and management of VTE also generate large medical costs, as high as US

More efficacious, equally safe: a meta-analysis comparing the safety of direct oral anticoagulants versus aspirin

15,000 for a single patient with VTE in the United States and up to US

The Safety of Aspirin Vs. Direct Oral Anticoagulants: A Meta-Analysis of Currently Published Clinical Trials

33,000 when factoring in subsequent care and sequelae.3 Though evidence-based guidelines for diagnosis and treatment of VTE exist, mismanagement is common and can lead to serious negative consequences for patients due to either inadequate or excessive treatment.4 In a large observational study, nearly half of new VTE cases are not managed based on evidence-based recommendations.5 Thrombophilia testing is often ordered inappropriately, leading not only to higher costs but also potential harm through unnecessary work-up, treatment, and psychological stress to the patient.6 Inappropriate VTE treatment lengths are also common, likely contributing not only to increased rates of recurrent thrombosis but also to bleeding complications.7 Even with this information, describing the true costs of VTE management, both monetary and otherwise, is difficult. Several factors may be responsible for this discordance between data and practice, including lack of provider awareness of guidelines (cumbersome guideline design), infrequent guideline updates to include the latest high-quality data, low-quality data leading to varying study interpretations, and conflicts between appropriate management and patient wishes. Thrombosis management differs from that of hematological malignancies, as it frequently involves the participation of general practitioners as well as providers in most other fields of medicine, often without direct involvement of a hematologist. Management of hematological malignancies also often benefits from user-friendly and routinely updated evidence-based guidelines, lacking for nonmalignant hematology.8 A noteworthy measure aimed at reducing some of the more frequent areas of VTE mismanagement was the creation of the American Society of Hematology’s (ASH) “Choosing Wisely” guidelines. These include at least five statements pertinent to diagnosis and management of VTE, including recommendations against routine thrombophilia testing, inferior vena cava filter placement, and aggressive use of prothrombin complex concentrates for anticoagulation reversal, among others.9 While these recommendations, as well as those found in major society guidelines, are high-yielding and backed by highquality evidence, locating and integrating these recommendations into daily clinical practice remains challenging. Simplified VTE management guidelines could potentially reduce the burden of this disease on our health-care system. We therefore attempted to address this problembydesigning an evidence-based thrombosis and hemostasis treatment algorithm, modeled after the National Comprehensive Cancer Network guidelines for malignancies and designed to be user-friendly and easily accessible.8 We then prospectively tested this tool’s effect on provider and trainee clinical decision-making for VTE, hypothesizing that our tool would lead to improved VTE management decisions. Using the latest thrombosis guidelines from the American College of Chest Physicians and other major hematological societies, and supplemented by additional high-level data in the fields of thrombosis and hemostasis, we created an electronic diagnostic and treatment algorithm tool for VTE (www.anticoag.net).We then designed a survey consisting of

The tradeoff of cancer drug regulatory policy: Faster approvals for one means less knowledge for another

Whether aspirin carries a favorable safety profile compared to direct oral anticoagulants (DOACs) remains a topic of controversy. A recent study by Hsu et al. illustrates how providers often preferentially choose aspirin for patients they perceive to be at high risk of bleeding, noting that over 38% of patients who qualify for additional anticoagulation per guidelines are actually managed on aspirin alone in real life practice [1]. Past investigations comparing the safety profile of aspirin against warfarin reveal no observable difference in bleeding events [2]. In turn, DOACs have been shown to be consistently safer than warfarin, with pooled analysis demonstrating decreased rates of total bleeding, major bleeding, and fatal bleeding [3]. However, data directly comparing the safety and efficacy of aspirin against DOACs has been sparse until recently. The 2017 publication of the EINSTEIN CHOICE trial marked only the second large randomized controlled trial comparing aspirin to full-dose DOACs [4]. The trial found rivaroxaban to be significantly more effective at preventing recurrent venous thromboembolism (VTE) in highrisk patients than aspirin. Before it, the AVERROES trial showed apixaban was significantly more effective at preventing embolic strokes in patients with atrial fibrillation than aspirin [5]. Importantly, neither trial detected a significant increase in bleeding rates with DOACs when compared to aspirin. The results of the aforementioned studies independently suggest that DOACs are significantly more effective at preventing thromboembolic events than aspirin, while carrying an equivalent safety profile. In order to better clarify the bleeding risks of DOACs versus aspirin, we used data from the two recently-published, phase III trials—EINSTEIN CHOICE and AVERROES-to perform a pooled meta-analysis using a Mantel–Haenszel random-effects model. In total, 3915 patients were treated with a therapeutic dose DOAC (apixaban 5 mg BID or rivaroxaban 20 mg daily) and 3922 were treated with varied doses of aspirin (81 mg [46.9%], 100 mg [27.6%], 162 mg [18.5%], 243 mg [1.9%], 324 mg [5.0%], and unknown dose [0.2%]). Our analysis detected no statistically significant difference in major bleeding events (1.27 vs. 1.07%; p = 0.42) or clinically-relevant, non-major bleeding events (3.22 vs. 2.65%; p = 0.14) between the two groups (Table 1). Based on the results of our pooled analysis, we conclude that aspirin is not appreciably safer than DOACs in terms of bleeding risk. If, by chance, a true difference in bleeding risk does exist, it is likely small and not clinically relevant. Therefore, given the superior efficacy of secondary VTE prevention in high-risk patients (HR 0.34; p < 0.01) [4] and stroke prevention in atrial fibrillation (HR 0.45; p < 0.01) [5], these results suggest that DOACs should always be preferentially used over aspirin in these populations. While current guidelines endorse the use of DOACs for the primary prevention of stroke in atrial fibrillation, these same guidelines continue to include aspirin as a possible therapeutic option for patients with atrial fibrillation with a low CHADS2-VASC score [6]. Furthermore, major society guidelines continue to endorse the consideration of aspirin for secondary prevention of venous thromboembolism in patients perceived to carry too high of a bleeding risk for anticoagulation [7]. We speculate that the persistence of these guidelines is both due to, and helps encourage, a popular but ill-conceived and non-empirical notion that aspirin is “safer”. The resultant real-world prescribing practices are described by Hsu et al. in which nearly 40% of patients * Jeffrey Y. Bien bien@ohsu.edu