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Tranexamic Acid Administration During On-Pump Cardiac Surgery: A Survey of Current Practices Among Canadian Anesthetists Working in Academic Centers

Spence, Jessica MD*,†,‡; Long, Steven BSc§; Tidy, Antonella BSc*; Raymer, Karen MD, MSc, FRCPC*; Devereaux, P. J. MD, PhD, FRCPC†,‡,∥; Lamy, Andre MD, MHSc, FRCSC†,‡,¶; Whitlock, Richard MD, PhD, FRCSC†,‡,¶; Syed, Summer BSc, MD, MSc, FRCPC*

doi: 10.1213/ANE.0000000000002422
Cardiovascular Anesthesiology: Original Clinical Research Report
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BACKGROUND: Tranexamic acid (TXA) is commonly administered during on-pump cardiac surgery to minimize bleeding. However, an optimal dosing regimen has not been described, and recent studies suggest that higher doses may be associated with seizure. Little is known about current practice among cardiac anesthetists.

METHODS: We contacted all academic anesthesia departments in Canada to identify cardiac anesthetists, who represent the majority of practitioners. This group constituted our sampling frame. Information regarding participant demographics, TXA dose, and administration details were obtained by electronic survey. Responses were analyzed descriptively. To compare dose, we assumed an 80-kg patient and 3 hours of infusion time. The Kruskal-Wallis test was used to compare average dose across provinces.

RESULTS: Among 341 Canadian academic cardiac anesthetists, 234 completed the survey (68.2% response rate). Among respondents, 86.3% administer TXA to all patients; 13.7% administer it to some. Most (68.4%) administer an infusion after a bolus; other modes included infusion (4.7%), single bolus (13.2%), 2 or more boluses (12.0%), or another regimen (1.7%). The mean (standard deviation) dose given was 49 mg/kg (24), with a range from 10 to 100 mg/kg. The mean dose varied across provinces from 23 to 55 mg/kg (P = .001).

CONCLUSIONS: TXA is given to nearly all patients undergoing on-pump cardiac surgery at academic hospitals in Canada. However, there is significant heterogeneity in practice between individuals and across provinces. Further research is needed to determine the TXA dose that maximizes efficacy and minimizes side effects.

Published ahead of print August 30, 2017.

From the *Department of Anesthesia

Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

Population Research Health Institute (PHRI), Hamilton, Ontario, Canada

§Michael G DeGroote School of Medicine

Division of Cardiology, Department of Medicine

Division of Cardiac Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada.

Published ahead of print August 30, 2017.

Accepted for publication July 11, 2017.

Funding: P.J.D. is supported by a Heart and Stroke Foundation of Ontario Career Investigator Award and the Yusuf Chair in Cardiology.

Conflicts of Interest: See Disclosures at the end of the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Jessica Spence, MD, Department of Anesthesia, McMaster University, Hamilton, ON, Canada. Address e-mail to jessicaspence13@gmail.com.

Bleeding is a complication of cardiac surgery, particularly in those undergoing cardiopulmonary bypass.1,2 The Society of Thoracic Surgeons Adult Cardiac Surgery Database suggests that 50% of patients undergoing cardiac surgical procedures require a blood transfusion,3 with severe bleeding (requiring transfusion of >10 units of packed red blood cells) occurring in 3%–5% of patients.4 This is costly in terms of direct financial impact and patient outcomes.5–7 To prevent bleeding and anemia, multiple strategies have been used, including preoperative erythropoietin, autologous donation, intraoperative use of antifibrinolytic drugs, algorithmic approaches to transfusion, red blood cell salvage, and changes to cardiopulmonary bypass practice to minimize hemodilution.8

Since a meta-analysis demonstrated their protective effect on perioperative bleeding,9 the intraoperative use of antifibrinolytics has become a near-universal part of intraoperative transfusion sparing practice and, according to the guidelines issued by the Society of Thoracic Surgeons, a standard of care.8 However, after the Food and Drug Administration and Health Canada rulings limited access to aprotinin,10 use of the lysine analogs, tranexamic acid (TXA), and ε-aminocaproic acid (ε-ACA), became more common. Lysine analogs exert their activity by competitive inhibition of the conversion of plasminogen to plasmin and, at high concentrations, directly inhibiting the dissolution and degradation of fibrin clots by plasmin.11 Retrospective studies suggest that TXA reduces blood loss more effectively than ε-ACA, though with a possible risk of seizure.12–17 Given that it is more widely available, TXA is more common in clinical practice.18,19

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Rationale

Despite its widespread use and incorporation into recommendations,8 questions related to dose and ideal mode of administration remain. TXA may be administered at multiple points during the surgical procedure, including induction of anesthesia, surgical incision, and initiation and termination of cardiopulmonary bypass. It may be administered as a bolus, continuous infusion, or a combination of a loading dose and continuous infusion. It is typically given intravenously—either directly to the patient or via the bypass pump prime—but may also be applied topically to the mediastinal tissues or sternum before surgical closure.20 Doses range from 10 to 100 mg/kg, but dosing is not always adjusted for body weight. Higher doses have been shown to be more effective at decreasing bleeding21–24 but have also been associated with seizures.14–16 Studies that have examined dosing have varied in their definitions of “high” and “low” dose and method of administration and involve relatively small numbers of patients.23–27

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Objectives

There is significant heterogeneity in the literature, and little is known about current TXA practice among cardiac anesthetists in Canada. As such, we undertook a survey of academic cardiac anesthesia faculty. Specifically, we sought to describe current practice and to evaluate the relationship between practitioner characteristics and dose administered.

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METHODS

This study was designed and is reported according to the strengthening the reporting of observational studies in epidemiology (STROBE) guidelines.28 Before commencing data collection, we obtained local research ethics board approval, and received a waiver of the requirement for written, informed consent. We developed a 14-item questionnaire (Supplemental Digital Content 1, Appendix 1, http://links.lww.com/AA/B961) that assessed 4 domains: (1) proportion of on-pump cardiac surgery patients receiving TXA, (2) mode of administration, (3) dose administered, and (4) practitioner characteristics. Questionnaire items were generated using an iterative process that included review of pertinent articles,21,23,29–31 informal dialogue with practitioners, and a focus group that included cardiac anesthetists practicing at Hamilton General Hospital, which is affiliated with McMaster University. Survey generation took place over a 6-week period, after which it was piloted by a group of cardiac anesthesia staff to ensure clarity. Through this process, our goal was to develop a succinct tool that balanced the amount of information collected with ease of survey completion.

The target population of the survey were licensed anesthetists who manage adult patients undergoing on-pump cardiac surgery in university-affiliated hospitals in Canada. We chose to exclude all trainees (fellows and residents). We also excluded anesthetists practicing in community hospitals because (1) they represent a minority of practitioners in Canada, and (2) the lack of relationship with an academic institution made it difficult to confidently identify which community hospitals were providing cardiac surgery on cardiopulmonary bypass, which would have resulted in an uncertain denominator for our sampling frame. We developed our sampling frame in a stepwise process. First, we contacted representatives from each university-affiliated department of anesthesia to obtain a contact person for each affiliated hospital providing cardiac surgery. Second, we engaged with the identified faculty to (1) ascertain the number of cardiac anesthetists at that site, (2) establish an agreement for their site to participate in the survey, and (3) develop a plan for survey distribution to eligible faculty. All identified cardiac anesthetists (n = 341) established our sampling cohort.

We sent a recruitment email (Supplemental Digital Content 2, Appendix 2, http://links.lww.com/AA/B962) containing a link to the survey that was distributed to eligible faculty. The email included information about the purpose of the study, a statement about the voluntary nature of participation, and information about participant anonymity. The link to the survey was hosted on the FluidSurveys electronic platform (Fluidware, Ottawa, ON) and used a hypertext transfer protocol cookie-based filter to prevent multiple responses from a single computer. All recruitment and study materials were simultaneously distributed in English and French. The survey was initially sent on December 16, 2015. A modified-Dillman approach was used.32 Three follow-up e-mails were sent every 2 weeks, and nonbinding incentives (coffee cards) were distributed to all 341 members of our sampling frame (regardless of survey participation) to encourage survey completion. The survey was closed on February 1, 2016.

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Statistical Analysis

Survey responses were analyzed descriptively, using counts and percentages. Response rate was calculated by dividing the number of responses by the total number of cardiac anesthetists identified by site contacts (n = 341). To compare dosing between respondents, we used the dose reported to calculate the total antifibrinolytic dose that respondent would give to an 80-kg patient undergoing a procedure with 3 hours from induction until termination of cardiopulmonary bypass (during which TXA was infused). In cases where 2 different doses were reported based on estimated risk of bleeding or seizure, we used the low-risk option (ie, lower dose if response referred to risk of bleeding; higher dose if response referred to risk of seizure) to calculate the total dose. Dose administered was described using mean and standard deviation, with mean doses compared across provinces using the Kruskal-Wallis test.

We evaluated the relationship between practitioner characteristics (excluding province) and dose administered using both univariate and multivariable linear regression. The independent variables included in the model were duration of anesthesia practice in years, duration of cardiac anesthesia practice in years, number of years of cardiac anesthesia fellowship, and proportion of anesthesia practice spent providing cardiac anesthesia. Although all predictor variables were ordinal, they were treated as continuous in the linear regression model as they were equally spaced across categories. This allowed us to assess a linear trend across categories, and resulted in only a single β coefficient for each predictor. We did not include province of practice in the multivariable model because, with only 234 respondents, we were concerned that addition of these predictors would result in statistical overfitting. Statistical analyses were conducted using Stata version 12 (StataCorpLP, College Station, TX). All tests used a threshold α < .05 to determine statistical significance.

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RESULTS

Of 341 cardiac anesthetists practicing at academic centers, 234 responded to the survey (68.6%). One participant did not specify their province of practice. This individual was excluded from the across province dose comparison, but was otherwise included in all analyses.

Table 1 reports respondent characteristics. The largest proportion of respondents had been practicing anesthesia for more than 20 years (58/234; 24.8%). While most (138/234; 59.0%) had completed 1 year of fellowship, a substantial proportion (75/234; 32.0%) had no additional training in the subspecialty of cardiac anesthesia. The most common response (110/234; 47.0%) to the proportion of practice devoted to cardiac anesthesia was 21%–40%.

Table 1.

Table 1.

Table 2 reports the survey responses to practice pattern questions. Regarding the choice of antifibrinolytic regimen, a majority of respondents (ie, 233 of 234; 99.6%) identified TXA as the antifibrinolytic most commonly used; 1 of 234 (0.4%) identified ε-ACA. Most respondents (ie, 203 of 234; 86.8%) gave it to all patients; 31 of 234 (13.2%) gave it to some but not all. The majority (166 of 234; 70.9%) gave it as a bolus followed by an infusion; 59 of 234 (25.2%) gave it as 1 or more boluses; 7 of 234 (3.0%) gave it as an infusion alone, and 2 of 234 (0.9%) endorsed some other mode of administration (Figure 1).

Table 2.

Table 2.

Figure 1.

Figure 1.

Regarding the timing of administration, 225 of 234 (96.1%) initiated TXA at some point before the commencement of cardiopulmonary bypass; 9 of 234 (3.9%) started it either on commencement of or after bypass. Most practitioners (95 of 234; 40.6%) stopped administration after a specific dose had been given; 85 of 234 (36.3%) discontinued it when the chest was being closed, 39 of 234 (16.7%) timed discontinuation to protamine administration, and 15 of 234 (6.4%) stopped at some other point during the procedure.

Regarding factors influencing dose selection, when asked to identify all factors that informed the choice of dose administered, 73.5% (172 of 234) of respondents identified patients’ weight. Respondents also indicated that the following factors informed the dose administered: procedure type (74 of 234; 31.6%), length of the case (70 of 234; 29.9%), duration of cardiopulmonary bypass (49 of 234; 20.9%), estimated risk of bleeding (68 of 234; 29.1%), local practice (74 of 234; 31.6%), and published evidence (75 of 234; 32.1%).

Regarding dosing (Table 3), of those respondents who identified 1 or more boluses as their primary method of administration, the most common response (21 of 59; 35.6%) was a dose of 30 mg/kg. Of the remaining dose options, 2 of 59 (3.4%) gave 100 mg/kg, 17 of 59 (28.8%) gave 50 mg/kg, 2 of 59 (3.4%) gave 10 mg/kg, and 3 of 59 (5.1%) gave some other weight-based dose. An additional 14 of 59 (23.7%) endorsed giving a “standard” dose ranging from 2 to 5 g to all patients, regardless of weight.

Table 3.

Table 3.

Of the respondents who identified a bolus followed by an infusion as their primary method of administration (n = 175), the most common response (68 of 175; 38.9%) was a dose approximating that used in the BART trial35 (30 mg/kg, then 10–16 mg/kg/h). Other regimes used included that described by Horrow et al30 (10 mg/kg, then 1–5 mg/kg/h)—which was used by 27 of 175 (15.4%) of respondents, and Casati et al34 (1 g, then 400 mg/h)—which was used by 12 of 175 (6.8%). The remaining 68 of 175 practitioners (38.9%) described some other approach, with bolus and infusion doses ranging between the Horrow et al30 and BART29 regimes, or not based on weight.

Table 4.

Table 4.

Figure 2.

Figure 2.

Figure 3.

Figure 3.

The mean (standard deviation) dose given to the “standard” patient (80 kg with 3 hours from start of case to coming off bypass) was 49 (24) mg/kg, with a range from 10 to 100 mg/kg (Figure 2). When we examined the relationship between respondent characteristics (excluding province) and the dose administered using linear regression, none of the predictors were statistically significant in either univariate or multivariable analyses (Supplemental Digital Content 3-4, Appendix 3, http://links.lww.com/AA/B963, Appendix 4, http://links.lww.com/AA/B964). When we compared mean dose across provinces (Table 4 and Figure 3), we found a statistically significant difference (P = .001), with mean doses ranging from 23 to 55 mg/kg.

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DISCUSSION

TXA is used during cardiac surgery to minimize bleeding and transfusion, with an assumed morbidity–mortality benefit. Its effect on bleeding has been repeatedly shown.36,37 Its effect on mortality remains unclear, with a recent meta-analysis of 1802 patients identifying a relative risk for mortality of 0.55 (95% confidence interval [CI], 0.24–1.25),38 and the recently published Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) study of 4631 patients failing to demonstrate a mortality benefit of TXA when compared with placebo, with a hazard ratio (95% CI) for their primary composite outcome of 0.92 (0.81–1.05; P = .22).33 The ideal dose and administration regime are also unknown, with a wide variety of practices described in the literature,20 mirroring the heterogeneity found in our survey.

Despite these uncertainties, we found that TXA use in Canada is nearly universal in academic practice, with 86.8% of those surveyed giving it to all patients undergoing on-pump cardiac surgery. A survey of Canadian hospitals before the withdrawal of aprotinin found that TXA was the most commonly used antifibrinolytic for routine cases, although aprotinin was used more frequently for patients at high risk of bleeding.18 After the publication of the BART trial, safety concerns led to changes in the licensing of aprotinin, and as a result, TXA use increased worldwide, with the proportion of United Kingdom practitioners who used TXA at least “frequently” increasing from 55% to 94%.19 However, the use of TXA has not been studied since the withdrawal of aprotinin, and no previous studies have described the details of dosing or administration regime during cardiac surgery using cardiopulmonary bypass.

Although a large proportion of Canadian practitioners use the regime described in the BART trial (the equivalent of 80 mg/kg in our hypothetical patient scenario),29 this did not constitute the majority. We found a 10-fold difference between the largest and smallest doses used. We examined practitioner characteristics, including years of practice, and proportion of practice devoted to cardiac anesthesia, and found no significant relationship with dose. However, when practitioners were stratified by province, we noted a statistically significant difference, with Manitoba, Saskatchewan, and Newfoundland giving lower doses than the remainder of the country.

In response to an anecdotal increase in seizure incidence,14 and published reports linking TXA to seizure in cardiac surgery patients,12,13,16,17 cardiac surgeons and cardiac anesthetists working in Manitoba completed a retrospective cohort study of their province-wide cardiac surgery database, including 5958 patients.14 They reported an adjusted odds ratio of seizure of 7.4 (95% CI, 2.8–19.3) associated with TXA use. They also identified a dose–response relationship, with patients experienced seizure receiving a mean (standard deviation) TXA dose that was 17 mg/kg higher than those who did not. In the discussion section of the article, the authors cite new institutional policies limiting TXA dose to <45 mg/kg and developed in response to this finding. Certainly, this statement explains why lower doses are given within this province, but cannot be extrapolated to Saskatchewan or Nova Scotia.

The initial dose–response studies by Horrow et al30 compared 6 incremental loading doses of 2.5–40 mg/kg followed by infusions of 0.25–4 mg/kg/h, and found that a loading dose of 10 mg/kg followed by an infusion of 1 mg/kg/h was optimal to reduce bleeding, with no additional benefit conferred by higher doses. This administration strategy was endorsed by 11.5% of all survey respondents. However, when the pharmacokinetic effect of the bypass circuit and patient renal function were taken into consideration, this approach was associated with inconsistent plasma concentrations.21,39 In response, Dowd et al21 developed an approach that would ensure complete inhibition of fibrinolysis. This dose, which was endorsed by 29% of all survey respondents, consisted of a 30 mg/kg bolus followed by 16 mg/kg/h infusion and combined with 2 g in the bypass circuit, was higher than those previously reported in the literature, and went on to be used in the BART trial.29 When the pharmacokinetics of the regime were studied clinically, it was found to result in plasma concentrations that were substantially higher than those determined to achieve 100% (>100 μg/mL) inhibition of tissue plasminogen activator.40

More recently, the ATACAS trial used a 2 × 2 partial factorial design to randomize 4662 patients to either 100 mg/kg of TXA or placebo.33 After the trial had randomized 1392 patients, the TXA dose was decreased to 50 mg/kg in response to published reports of dose-related seizure. Only 0.9% of respondents to our survey endorsed using the higher dose regime, with an additional 7.3% using the 50 mg/kg bolus dose. This represents the largest trial to date, and demonstrated that TXA decreases the need for blood transfusion and reduces the risk of major hemorrhage or cardiac tamponade leading to reoperation. In addition, TXA had no impact on a composite outcome of mortality and thrombotic complications (relative risk 0.92; 95% CI, 0.81–1.05; P = .22). ATACAS represents the first prospective, randomized, placebo-controlled trial to demonstrate an increased risk of postoperative seizure with TXA use, with 0.1% of patients in the placebo arm and 0.7% of patients in the TXA developing postoperative seizure (P = .002). The clinical significance of these seizures is unclear, as they tend to be self-limited, and have not been shown to be associated with increased morbidity or mortality when studied prospectively.33,41 Despite the decrease in TXA dose mid-way through the study, neither bleeding nor seizure was impacted. Finally, the population included in ATACAS was heterogenous, and at low risk of both mortality and bleeding. Moreover, the lower boundary of the 95% CI suggests that TXA may have a relative risk of 0.81 for the composite outcome of mortality and thrombotic complications.

When compared to the doses used in the BART29 and ATACAS33 trials, we found that the mean dose used across Canada was 30% lower, with practitioners in 3 provinces giving amounts that were an additional 30%–50% below the national average. We identified a lack of consensus as to what constitutes an appropriate dose and administration regime, as well as a divergence from the largest studies published in the literature, reflected in the fact that only 32.1% of respondents identified published evidence as informing their TXA administration practice. Though it could be argued that the question relating to the mortality benefit of TXA has been answered by ATACAS, the reality is that, when 1 considers the fact that the perioperative mortality related to cardiac surgery is approximately 5%, a trial of more than 10,000 patients would be required to demonstrate an absolute risk reduction in mortality of 1% (and a relative risk reduction of 20%). Given this, ATACAS was underpowered to exclude a clinically important reduction in mortality. In addition, as evidenced by the variability in practice documented by our survey, the mortality benefit of TXA may not be the question that is most relevant to clinicians, but rather the optimal dose of TXA that balances the risk of bleeding against the risk of seizure, depending on the risk of both outcomes in a given patient. Cardiac anesthetists have a need to understand the impact of the interventions that they administer on patient-important outcomes. At this point, based on the published literature, a patient-important benefit or harm associated with TXA dosing or route of administration (ie, intravenous versus topical) cannot be excluded. To obtain the answer to this question, further research is required to determine the ideal dose and mode of administration to maximize efficacy and minimize harm in this population.

Our study has several limitations. First, we surveyed only Canadian academic cardiac anesthetists, whose practice may not reflect that of all practitioners. However, given that knowledge translation activities are common in academic centers and that this group represents the majority of practitioners, we felt that this sampling frame would best allow us to evaluate if the variability in the literature was reflected in practice. Second, though we established that 86.2% of respondents were giving TXA to all patients, we did not establish whether the remaining 13.2% who gave TXA to “some, but not all” were using another agent, or not using any antifibrinolytic. Although clarifying this ambiguity was not part of our original study design, it would be important to establish what is being done to mitigate bleeding in the absence of TXA, and determine if this is adequate in the setting of cardiac surgery, where the benefits of antifibrinolytics have been firmly established.8,9,36,37 Third, our survey was administered before the publication of ATACAS, and cardiac anesthesia practice across Canada may since have changed as a result. Finally, our strategy to compare dose administered involves a number of assumptions. We assumed that the dose specified by survey respondents was the dose most commonly used for all average risk patients. If dose modifications for certain clinical conditions were specified, we used the low-risk option in the calculation of composite dose. We also assumed an infusion time of 3 hours, consistent with the time from the start of the case until coming off cardiopulmonary bypass in a low-risk surgical procedure. However, infusion times (and thus overall dose) may vary from 1 practitioner to another. Given that the overwhelming majority of respondents who used infusion or bolus plus infusion dosing had specified these time points for TXA administration, we believe that this assumption would not have had a significant impact on composite dose.

Despite these limitations, we believe that our study provides important information about cardiac anesthesia practice in Canada. The heterogeneity in practice, and overall lower doses compared to those studied in the largest trials, suggest either an absence of knowledge translation or concern about adverse effects associated with higher doses. The differences in practice across provinces reflect the impact of local practice patterns on the development of local standards of care.

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CONCLUSIONS

Dose, timing, and mode of TXA administration to patients undergoing on-pump cardiac surgery in Canada are highly variable. There are significant discrepancies, not only between current practice and published evidence but also across provinces. While the most common dosing regimen used approximates that used in the BART trial (30 mg/kg bolus followed by 10–16 mg/kg/h infusion), this only represents 19.8% of survey respondents. Across Canada, an 80-kg patient undergoing an average risk on-pump cardiac surgery with 3 hours infusion time could receive anywhere from 10 to 100 mg/kg of TXA. To resolve this lack of consensus among practitioners, further research evaluating the effect of TXA route of administration and dose on patient-important outcomes is required.

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DISCLOSURES

Name: Jessica Spence, MD.

Contribution: This author helped develop the protocol, collect and analyze data, interpret results, and draft the final manuscript.

Conflicts of Interest: None.

Name: Steven Long, BSc.

Contribution: This author helped develop the protocol, collect data, and draft the final manuscript.

Conflicts of Interest: None.

Name: Antonella Tidy, BSc.

Contribution: This author helped develop the protocol, collect data, and draft the final manuscript.

Conflicts of Interest: None.

Name: Karen Raymer, MD, MSc, FRCPC.

Contribution: This author helped develop the protocol and draft the final manuscript.

Conflicts of Interest: None.

Name: P. J. Devereaux, MD, PhD, FRCPC.

Contribution: This author helped develop the protocol and draft the final manuscript.

Conflicts of Interest: P. J. Devereaux is part of a group that has a policy of not accepting honorariums or other payments from industry for their own personal financial gain. They do accept honorariums or other payments from industry to support research endeavors and for reimbursement of costs to participate in meetings such as scientific or advisory committee meetings. Based on study questions he originated and grants he wrote, he has received grants from Abbott Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Octapharma, Philips Healthcare, Roche Diagnostics, and Stryker. He has also participated in an advisory boarding meeting for GlaxoSmithKline, an expert panel meeting for AstraZeneca, and a consultancy meeting for Boehringer Ingelheim.

Name: Andre Lamy, MD, MHSc, FRCSC.

Contribution: This author helped develop the protocol and draft the final manuscript.

Conflicts of Interest: None.

Name: Richard Whitlock, MD, PhD, FRCSC.

Contribution: This author helped develop the protocol, interpret results, and draft the final manuscript.

Conflicts of Interest: None.

Name: Summer Syed, BSc, MD, MSc, FRCPC.

Contribution: This author helped oversee protocol development, data collection and analysis, interpreted results, and oversee drafting of the final manuscript.

Conflicts of Interest: None.

This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.

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