Michelle Sholzberg

Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials

Thrombocytopenia is common (40–65%) and potentially serious in myelodysplastic syndromes (MDS). A systematic review was conducted to determine the safety and efficacy of adding a thrombopoietin‐receptor (THPO‐R) agonist to standard MDS treatment. MEDLINE, EMBASE and CENTRAL databases were searched. We included randomized controlled trials comparing a THPO‐R agonist to placebo. A meta‐analysis of the effects was performed. Endpoints included bleeding and platelet transfusion rates, risk of progression to acute myeloid leukaemia (AML) and mortality. Three hundred and eighty four patients from five trials were included, four using romiplostim and one using eltrombopag. Overall, the relative risk (RR) of bleeding with romiplostim versus placebo was 0·84 [95% confidence interval (CI): 0·57–1·24]. However, compared to placebo, romiplostim significantly decreased the exposure‐adjusted bleeding rate (RR 0·92; 95% CI: 0·86–0·99), as well as the exposure‐adjusted platelet transfusion rate (RR 0·69; 95% CI: 0·53–0·88). The RR of AML progression with romiplostim was 1·36 (95% CI: 0·54–3·40), however the outcome data were judged as higher risk of bias. Romiplostim is promising in its ability to decrease patient‐important outcomes: bleeding and platelet transfusion need. Although the risk of AML progression was not increased, due to unclear risk of bias in the data, this safety concern is difficult to assess. Therefore, romiplostim cannot yet be routinely recommended. Early eltrombopag data is promising.

Recombinant porcine sequence factor VIII (rpFVIII) for acquired haemophilia A: Practical clinical experience of its use in seven patients

A recombinant porcine factor VIII B‐domain‐deleted product (rpFVIII; OBIZUR, Baxalta Incorporated, Deerfield, IL 60015, USA) was recently approved for treatment of bleeding episodes in adults with acquired haemophilia A (AHA) in the United States. To date, no clinical experience outside the registration study has been reported.

The Influence of Socioeconomic Status on Selection of Anticoagulation for Atrial Fibrillation

Importance Without third-party insurance, access to marketed drugs is limited to those who can afford to pay. We examined this phenomenon in the context of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF). Objective To determine whether, among older Ontarians receiving anticoagulation for NVAF, patients of higher socioeconomic status (SES) were more likely to switch from warfarin to dabigatran prior to its addition to the provincial formulary. Design, Setting and Participants Population-based retrospective cohort study of Ontarians aged 66 years and older, between 2008 and 2012. Exposure Socioeconomic status, as approximated by median neighborhood income. Main Outcomes and Measure We identified two groups of older adults with nonvalvular atrial fibrillation: those who appeared to switch from warfarin to dabigatran after its market approval but prior to its inclusion on the provincial formulary (“switchers”), and those with ongoing warfarin use during the same interval (“non-switchers”). Results We studied 34,797 patients, including 3183 “switchers” and 31,614 “non-switchers”. We found that higher SES was associated with switching to dabigatran prior to its coverage on the provincial formulary (p<0.0001). In multivariable analysis, subjects in the highest quintile were 50% more likely to switch to dabigatran than those in the lowest income quintile (11.3% vs. 7.3%; adjusted odds ratio 1.50; 95% CI 1.32 to 1.68). Following dabigatran’s addition to the formulary, the income gradient disappeared. Conclusions and Relevance We documented socioeconomic inequality in access to dabigatran among patients receiving warfarin for NVAF. This disparity was eliminated following the drug’s addition to the provincial formulary, highlighting the importance of timely reimbursement decisions.

Recurrent Disseminated Intravascular Coagulation Caused by Intermittent Dosing of Rifampin

Daily rifampin therapy is associated with minimal adverse effects, but administration on an intermittent or interrupted basis has been associated with severe immunoallergic reactions such as hemolytic anemia, acute renal failure, and disseminated intravascular coagulation. We describe a patient with Mycobacterium leprae infection who experienced recurrent episodes of disseminated intravascular coagulation after intermittent exposures to rifampin, and review eight previously reported cases of rifampin-associated disseminated intravascular coagulation. In six (75%) cases, previous exposure to rifampin was reported and seven (87.5%) patients were receiving the medication on an intermittent or interrupted basis. Clinical features of rifampin-associated disseminated intravascular coagulation included fever, hypotension, abdominal pain, and vomiting within hours of ingestion. Average time to reaction was 3-6 doses if rifampin was being administered on a monthly schedule. Three (37.5%) of eight reported cases were fatal. A complete history of previous exposure to rifampin is recommended before intermittent therapy with this medication.

Patterns of tertiary prophylaxis in Canadian adults with severe and moderately severe haemophilia B

From a young age patients with severe and moderately severe FIX deficiency (haemophilia B) can experience spontaneous or traumatic bleeding and joint destruction may result. The use of coagulation factor IX concentrate to prevent anticipated bleeding, as primary or secondary prophylaxis, has become a common and recommended practice in children. The current practice of using tertiary prophylaxis, in the presence of established joint arthropathy, in adults with haemophilia B is not well characterized. This observational study was conducted to gain a better understanding of the recent Canadian experience with tertiary prophylaxis in adults with severe and moderately severe haemophilia B. Data were collected from all eligible adult (≥ 18 years of age) males with baseline FIX:C ≤ 2% from seven Canadian Hemophilia Treatment centres over a 2‐year observation period from 2009 to 2011. Thirty‐four per cent of the 67 subjects with moderately severe haemophilia B were exposed to prophylaxis with the majority as continuous prophylaxis (≥45 weeks year‐1). The severe subgroup (FIX:C < 1%) demonstrated a 52% exposure rate. None had primary prophylaxis exposure in childhood. Eighty‐one per cent used once or twice weekly infusion regimens and reported a median annual bleeding rate of five bleeds per year versus four bleeds per year for those using on‐demand treatment. Annual median factor utilization for all subjects using prophylaxis was 196 283 U year‐1 compared to 46 361 U year‐1 for on demand. Approximately 50% of adults with severe haemophilia B are using continuous tertiary prophylaxis in Canada, a practice likely to increase which warrants further study.

Integrated multidisciplinary care for the management of chronic conditions in adults: an overview of reviews and an example of using indirect evidence to inform clinical practice recommendations in the field of rare diseases.

Integrated care models have been adopted for individuals with chronic conditions and for persons with rare diseases, such as haemophilia.

REDucing Unnecessary Coagulation Testing in the Emergency Department (REDUCED)

The PT/INR (prothrombin time/international normalized ratio) and aPTT (activated partial thromboplastin time) were tests developed in the early 20th century for specific and unique indications. Despite this, they are often ordered together routinely. The objective of this study was to determine if a multimodal intervention could reduce PT/INR and aPTT testing in the emergency department (ED). This was a prospective multi-pronged quality improvement study at St. Michaels Hospital. The initiative involved stakeholder engagement, uncoupling of PT/INR and aPTT testing, teaching, and most importantly a revision to the ED order panels. After changes to order panels, weekly rates of PT/INR and aPTT testing per 100 ED patients decreased (17.2 vs 38.4, rate ratio=0.45 (95% CI 0.43-0.47), p<0.001; 16.6 vs 37.8, rate ratio=0.44 (95% CI 0.42-0.46), p<0.001, respectively). Rate of creatinine testing per 100 ED patients, our internal control, increased during the same period (54.0 vs 49.7, rate ratio=1.09 (95% CI 1.06-1.12); p<0.0001) while the weekly rate per 100 ED patients receiving blood transfusions slightly decreased (0.5 vs 0.7, rate ratio=0.66 (95% CI 0.49-0.87), p=0.0034). We found that a simple process change to order panels was associated with meaningful reductions in coagulation testing without obvious adverse effects.

Understanding stakeholder important outcomes and perceptions of equity, acceptability and feasibility of a care model for haemophilia management in the US: a qualitative study

Care for persons with haemophilia (PWH) is most commonly delivered through the integrated care model used by Hemophilia Treatment Centers (HTCs). Although this model is widely accepted as the gold standard for the management of haemophilia; there is little evidence comparing different care models.

The Anticoagulated trauma patient in the age of the direct oral anticoagulants: a Canadian perspective

BackgroundThe anticoagulated trauma patient presents a particular challenge to the critical care physician. Our understanding of these patients is defined and extrapolated by experience with patients on warfarin pre-injury. Today, many patients who would have been on warfarin are now prescribed the Direct Oral Anticoagulants (DOACs) a class of anticoagulants with entirely different mechanisms of action, effects on routine coagulation assays and approach to reversal.MethodsTrauma registry data from Toronto’s (Ontario, Canada) two Level 1 trauma centres were used to identify patients on oral anticoagulation pre-injury from June 1, 2014 to June 1, 2015. The trauma registry and medical records were reviewed and used to extract demographic and clinical data.ResultsWe found 81 patients were on oral anticoagulants pre-injury representing 3.2% of the total trauma population and 33% of the orally anticoagulated patients were prescribed a DOAC prior to presentation. Comparison between the DOAC and warfarin groups showed similar age, mechanisms of injury, indications for anticoagulation, injury severity score and rate of intracranial hemorrhage. Patients on DOACs had higher initial mean hemoglobin vs warfarin (131 vs 120) and lower serum creatinine (94.8 vs 129.5). The percentage of patients receiving a blood transfusion in the trauma bay and total in-hospital transfusion was similar between the two groups however patients on DOACs were more likely to receive tranexamic acid vs patients on warfarin (32.1% vs 9.1%) and less likely to receive prothrombin concentrates (18.5% vs 60%). Patients on DOACs were found to have higher survival to discharge (92%) vs patients on warfarin (72%).ConclusionPatients on DOACs pre-injury now represent a significant proportion of the anticoagulated trauma population. Although they share demographic and clinical similarities with patients on warfarin, patients on DOACs may have improved outcomes despite lack of established drug reversal protocols and challenging interpretation of coagulation assays.Level of Evidence: III; Study Type: Retrospective Review.

A 24-year-old woman with heavy menstrual bleeding

A 24-year-old woman presents to her family physician for follow-up of bloodwork for a history of heavy menstrual bleeding from the onset of menarche. She also describes easy bruising and recurrent episodes of epistaxis. Routine coagulation studies (platelet count, activated partial thromboplastin