Ana P. Johnson

Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis

BACKGROUND The clinical armamentarium for anticoagulation has expanded substantially since the recent approval of dabigatran, rivaroxaban and apixaban for the prevention of stroke in atrial fibrillation. However, patients in the general population often differ from participants in clinical trials. In this study, we assessed the uptake of these novel oral anticoagulants in Ontario, Canada, within the first 2 years after dabigatrans approval for this indication. METHODS Using data on province-wide prescription volumes, we conducted a time-series analysis of prescription trends between October 2010 and September 2012 for all orally administered anticoagulants (warfarin, dabigatran and rivaroxaban) that were available in this period. We stratified dabigatran prescription rates by age group (20-39, 40-59, 60-64, 65-84 and ≥ 85 yr). We compared the proportion of dabigatran prescriptions to patients aged 65 or older with similar data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. RESULTS Over the 24-month study period, we found that prescriptions for the novel anticoagulants rose more than 20-fold, to represent 21.1% of all prescriptions of oral anticoagulants by September 2012. The rise in prescriptions was due primarily to an increase in dabigatran use. Prescription rates of dabigatran were highest among people aged 85 years or more, a group at increased risk of bleeding who are markedly older than the average participant in the clinical trial in which the drug was tested (71 yr). In September 2012, most of the dabigatran prescriptions were for the lower-dose formulation (110 mg) in the older groups (58.8% of dabigatran prescriptions in the 65-84 age group and 93.6% in the oldest group). INTERPRETATION We observed rapid growth in the uptake of the novel oral anticoagulants since their approval for use in patients with atrial fibrillation, especially among those aged 85 years or more. This increase in use in the oldest group, a population at high risk of bleeding, signals the need to evaluate outcomes of use of novel oral anticoagulants in the clinical setting.

Body Mass Index, Outcomes, and Mortality Following Cardiac Surgery in Ontario, Canada

Background The “obesity paradox” reflects an observed relationship between obesity and decreased morbidity and mortality, suggesting improved health outcomes for obese individuals. Studies examining the relationship between high body mass index (BMI) and adverse outcomes after cardiac surgery have reported conflicting results. Methods and Results The study population (N=78 762) was comprised of adult patients who had undergone first-time coronary artery bypass (CABG) or combined CABG/aortic valve replacement (AVR) surgery from April 1, 1998 to October 31, 2011 in Ontario (data from the Institute for Clinical Evaluative Sciences). Perioperative outcomes and 5-year mortality among pre-defined BMI (kg/m2) categories (underweight <20, normal weight 20 to 24.9, overweight 25 to 29.9, obese 30 to 34.9, morbidly obese >34.9) were compared using Bivariate analyses and Cox multivariate regression analysis to investigate multiple confounders on the relationship between BMI and adverse outcomes. A reverse J-shaped curve was found between BMI and mortality with their respective hazard ratios. Independent of confounding variables, 30-day, 1-year, and 5-year survival rates were highest for the obese group of patients (99.1% [95% Confidence Interval {CI}, 98.9 to 99.2], 97.6% [95% CI, 97.3 to 97.8], and 90.0% [95% CI, 89.5 to 90.5], respectively), and perioperative complications lowest. Underweight and morbidly obese patients had higher mortality and incidence of adverse outcomes. Conclusions Overweight and obese patients had lower mortality and adverse perioperative outcomes after cardiac surgery compared with normal weight, underweight, and morbidly obese patients. The “obesity paradox” was confirmed for overweight and moderately obese patients. This may impact health resource planning, shifting the focus to morbidly obese and underweight patients prior to, during, and after cardiac surgery.

Effect of Standard Radiotherapy With Cisplatin vs Accelerated Radiotherapy With Panitumumab in Locoregionally Advanced Squamous Cell Head and Neck Carcinoma: A Randomized Clinical Trial

Importance The Canadian Cancer Trials Group study HN.6 is the largest randomized clinical trial to date comparing the concurrent administration of anti–epidermal growth factor receptor (EGFR) monoclonal antibodies with radiotherapy (RT) to standard chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Objective To compare progression-free survival (PFS) in patients with LA-SCCHN treated with standard-fractionation RT plus high-dose cisplatin vs accelerated-fractionation RT plus the anti-EGFR antibody panitumumab. Design, Setting, and Participants A randomized phase 3 clinical trial in 17 Canadian centers. A total of 320 patients were randomized between December 2008 and November 2011. Interventions Patients with TanyN+M0 or T3-4N0M0 LA-SCCHN were randomized 1:1 to receive standard-fractionation RT (70 Gy/35 over 7 weeks) plus cisplatin at 100 mg/m2 intravenous for 3 doses (arm A) vs accelerated-fractionation RT (70 Gy/35 over 6 weeks) plus panitumumab at 9 mg/kg intravenous for 3 doses (arm B). Main Outcomes and Measures Primary end point was PFS. Due to an observed declining event rate, the protocol was amended to a time-based analysis. Secondary end points included overall survival, local and regional PFS, distant metastasis-free survival, quality of life, adverse events, and safety. Results Of 320 patients randomized (268 [84%] male; median age, 56 years), 156 received arm A and 159 arm B. A total of 93 PFS events occurred. By intention-to-treat, 2-year PFS was 73% (95% CI, 65%-79%) in arm A and 76% (95% CI, 68%-82%) in arm B (hazard ratio [HR], 0.95; 95% CI, 0.60-1.50; P = .83). The upper bound of the HR 95% CI exceeded the prespecified noninferiority margin. Two-year overall survival was 85% (95% CI, 78%-90%) in arm A and 88% (95% CI, 82%-92%) in arm B (HR, 0.89; 95% CI, 0.54-1.48; P = .66). Incidence of any grade 3 to 5 nonhematologic adverse event was 88% in arm A and 92% in arm B (P = .25). Conclusions and Relevance With a median follow-up of 46 months, the PFS of panitumumab plus accelerated-fractionation RT was not superior to cisplatin plus standard-fractionation RT in LA-SCCHN and noninferiority was not proven. Despite having negative results, HN.6 has contributed important data regarding disease control and toxic effects of these treatment strategies. Trial Registration clinicaltrials.gov Identifier: NCT00820248

An Epidemiological Study of Neuropathic Pain Symptoms in Canadian Adults.

The reported prevalence of neuropathic pain ranges from 6.9% to 10%; however the only Canadian study reported 17.9%. The objective of this study was to describe the epidemiology of neuropathic pain in Canada. A cross-sectional survey was conducted in a random sample of Canadian adults. The response rate was 21.1% (1504/7134). Likely or possible neuropathic pain was defined using a neuropathic pain-related diagnosis and a positive outcome on the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS) or the Douleur Neuropathique 4 (DN4) Questions. The prevalence of likely neuropathic pain was 1.9% (S-LANSS) and 3.4% (DN4) and that of possible neuropathic pain was 5.8% (S-LANSS) and 8.1% (DN4). Neuropathic pain was highest in economically disadvantaged males. There is a significant burden of neuropathic pain in Canada. The low response rate and a slightly older and less educated sample than the Canadian population may have led to an overestimate of neuropathic pain. Population prevalence varies by screening tool used, indicating more work is needed to develop reliable measures. Population level screening targeted towards high risk groups should improve the sensitivity and specificity of screening, while clinical examination of those with positive screening results will further refine the estimate of prevalence.

Economics of chronic pain: How can science guide health policy?

Prevalence estimates between 15-40% of the general population have been reported in epidemiologic studies of chronic noncancer pain which includes headache, arthritis, fibromyalgia, low back and neck, post-traumatic, neuropathic, visceral and other causes of pain. Recognizing the biopsychosocial complexity of chronic pain and the fact that diagnosis and/or cure of underlying conditions is often unsuccessful, John Bonica et al. pioneered the concept of multidisciplinary pain clinics over 50 years ago to manage these devastating conditions. Although chronic pain generally presents first to primary care practitioners, pain clinic referrals are made often for resistance to first-line treatments, severe unremitting pain and/or complex psychosocial situations. A wide variety of chronic pain treatment interventions are aimed at reducing pain, improving mood, promoting better physical, occupational, and social function, and teaching individual and family coping skills. A longstanding recognition of the value of pain clinics together with an increasing prevalence of chronic pain have led to growth in demand, waiting list size, and international concerns over limited pain treatment resources. In Canada, a task force was recently established to study pain treatment waiting times. In this issue of the Journal, STOP-PAIN Research Group investigators report on the biopsychosocial and economic burden of pain in individuals waiting to consult with a pain specialist. In STOP-PAIN-1, 728 of the 3,343 invitees from a waiting list to be seen at any of eight Canadian universitybased pain clinics completed several validated questionnaires regarding demographics, pain, sleep, and physical and emotional functioning. To evaluate changes over time, 271 of the 512 randomly selected respondents repeated the questionnaires three months afterwards. In the linked STOP-PAIN-2 study, a subgroup of 272 of the 512 randomly selected respondents completed daily questionnaires about publicly and privately funded healthcarerelated costs (direct and indirect) over a three-month period. STOP-PAIN-1 results indicated a shockingly high level of pain burden with ratings of severe pain, sleep disturbance, and interference with normal activities in approximately 66% of respondents, moderate or severe depression in 50% of respondents, and suicidal ideation in 35% of respondents. Compared with the general population, the results of the SF-36 questionnaire suggested profound quality of life impairments of 40-70% of respondents. Despite some small statistical differences, changes over the three-month follow up were unremarkable. STOP-PAIN-2 results indicated median participant care costs of

Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study

1,462 (CDN)/month or an overwhelming

Effect of early supervised physiotherapy on recovery from acute ankle sprain: randomised controlled trial

17,544/year, the vast majority of which was indirect, e.g., lost labour time, and privately funded. As with other surveys, these investigations need to be considered in the context of some important methodological limitations, including likely heterogeneity of the study population, limited generalization to broader treatment settings, and potential for selection bias given a relatively low response rate. With this in mind, it is notable that the STOP-PAIN-1 results are comparable with a recent report of similar measures from a pain clinic sample of 6,124 patients. I. Gilron, MD (&) Departments of Anesthesiology and Pharmacology & Toxicology, Queen’s University, Kingston General Hospital, 76 Stuart St, Kingston, ON K7L 2V7, Canada e-mail: gilroni@queensu.ca

Increasing Incidence and Prevalence of World Health Organization Groups 1 to 4 Pulmonary Hypertension: A Population-Based Cohort Study in Ontario, Canada

Background Direct oral anticoagulants (DOACs) have expanded the armamentarium for antithrombotic therapy. Although DOAC‐related major bleeding was associated with favorable outcomes compared with warfarin in clinical trials, warfarin effects were reversed in < 40% of cases, raising concerns about the generalizability of this finding. Methods Consecutive patients ≥ 66 years presented to five tertiary care hospitals across three cities in Ontario, Canada from October 2010 to March 2015 with diagnoses that included hemorrhage. Charts were screened for association with DOAC or warfarin use; eligible cases were abstracted and linked to administrative databases. Results Among 19,061 records screened, 2,002 (460 receiving DOAC, 1,542 receiving warfarin) were eligible. Reversal agents (72.9% vitamin K, 40.7% prothrombin complex concentrates) were frequently used in warfarin bleeding events. Red blood cell transfusions occurred more often in DOAC bleeding events than in warfarin events (52.0% vs 39.5%; adjusted relative risk [aRR], 1.32; 95% CI, 1.19‐2.47). However, units of blood products transfused were not different between the two groups. Thirty‐four DOAC cases (7.4%) received activated prothrombin complex concentrates or recombinant factor VIIa. In‐hospital mortality was lower following DOAC bleeding events (9.8% vs 15.2%; aRR, 0.66; 95% CI, 0.49‐0.89), although differences in 30‐day mortality did not reach statistical significance (12.6% vs 16.3%; aRR, 0.79; 95% CI, 0.61‐1.03). Conclusions In this unselected cohort of patients with oral anticoagulant‐related hemorrhage with high rates of warfarin reversal, in‐hospital mortality was lower among DOAC‐associated bleeding events. These findings support the safety of DOACs in routine care and present useful baseline measures for evaluations of DOAC‐specific reversal agents.

Epidemiology and management of thoracic aortic dissections and thoracic aortic aneurysms in Ontario, Canada: A population-based study

Objective To assess the efficacy of a programme of supervised physiotherapy on the recovery of simple grade 1 and 2 ankle sprains. Design A randomised controlled trial of 503 participants followed for six months. Setting Participants were recruited from two tertiary acute care settings in Kingston, ON, Canada. Participants The broad inclusion criteria were patients aged ≥16 presenting for acute medical assessment and treatment of a simple grade 1 or 2 ankle sprain. Exclusions were patients with multiple injuries, other conditions limiting mobility, and ankle injuries that required immobilisation and those unable to accommodate the time intensive study protocol. Intervention Participants received either usual care, consisting of written instructions regarding protection, rest, cryotherapy, compression, elevation, and graduated weight bearing activities, or usual care enhanced with a supervised programme of physiotherapy. Main outcome measures The primary outcome of efficacy was the proportion of participants reporting excellent recovery assessed with the foot and ankle outcome score (FAOS). Excellent recovery was defined as a score ≥450/500 at three months. A difference of at least 15% increase in the absolute proportion of participants with excellent recovery was deemed clinically important. Secondary analyses included the assessment of excellent recovery at one and six months; change from baseline using continuous scores at one, three, and six months; and clinical and biomechanical measures of ankle function, assessed at one, three, and six months. Results The absolute proportion of patients achieving excellent recovery at three months was not significantly different between the physiotherapy (98/229, 43%) and usual care (79/214, 37%) arms (absolute difference 6%, 95% confidence interval −3% to 15%). The observed trend towards benefit with physiotherapy did not increase in the per protocol analysis and was in the opposite direction by six months. These trends remained similar and were never statistically or clinically important when the FAOS was analysed as a continuous change score. Conclusions In a general population of patients seeking hospital based acute care for simple ankle sprains, there is no evidence to support a clinically important improvement in outcome with the addition of supervised physiotherapy to usual care, as provided in this protocol. Trial registration ISRCTN 74033088 (www.isrctn.com/ISRCTN74033088)

Perspectives, perceptions and experiences in postoperative pain management in developing countries: A focus group study conducted in Rwanda.

Background: The World Health Organization recognizes 5 groups of pulmonary hypertension (PH), categorized by pathogenesis or comorbidity: 1-pulmonary arterial hypertension 2-left-heart disease, 3-lung disease and hypoxia 4-chronic thromboembolic disease, and 5-miscellaneous. The epidemiology of PH, apart from group 1, is largely unknown. Methods and Results: We describe incidence, prevalence, comorbidities, mortality and prescribing patterns for groups 1 to 4 PH from 1993 to 2012. Case definitions are based on hospitalizations and emergency department visits, using the Institute for Clinical Evaluative Sciences data, which comprises linked databases of universal coverage health service records for Ontario residents. This cohort included 50 529 patients with PH. The annual incidence of adult PH increased from 2003 to 2012 from 24.1 to 28.7 cases/100 000 population and the annual prevalence from 1993 to 2012 from 99.8 to 127.3 cases/100 000 population, respectively. The most common form of adult PH was group 2, alone (34.2%) or combined with group 3 PH (29.3%). A diagnosis of PH increased the 1-year standardized mortality ratio 7.2-fold. Mortality in adults with PH was 13.0%, 36.4%, and 62.4%, at 30 days, 1 year, and 5 years, respectively. Mortality was highest in groups 2 and 3 and lowest in group 1. PH was present in only 3.6% of people with left heart disease, 0.7% with lung disease, and 1.4% with thromboembolic disease, suggesting that PH is a relatively rare complication of these common diseases. Children (age<16 years) accounted for 3.6% of the cohort. In children group 1 PH was most common (65.2%), and 5-year mortality was lower (21.4%) than in adults. Group 1–specific PH therapies were increasingly prescribed over time and paradoxically were often used in patients who seemed to have group 2, PH based on diagnostic codes indicating left heart disease. Conclusions: The incidence and prevalence of adult PH are increasing. Groups 2 and 3 are the most common and lethal forms of PH. This study identifies an emerging epidemic of PH that likely has substantial adverse health and economic implications.