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Statins are widely prescribed for cardiovascular disease prevention, and also commonly used in patients at high risk for colorectal cancer (CRC). We report the results of a planned secondary analysis of the relationship between statin use and colorectal adenoma risk in a large chemoprevention trial.
The Adenoma Prevention with Celecoxib (APC) trial randomized 2035 adenoma patients to receive placebo (679 patients), 200 mg celecoxib twice daily (685 patients), or 400 mg celecoxib twice daily (671 patients). The study collected complete medical history and medication use data, and performed colonoscopic surveillance to 5 years after study enrollment. Effects of statin use on newly detected adenomas and cardiovascular adverse events were analyzed as time-dependent variables by multivariable Cox regression.
Statins were used by 36% (N=730) of APC trial participants. When adjusted for covariates including cardioprotective aspirin use, age, and sex, participants on the placebo arm who used statins at any time had no benefit over 5 years compared to never users (Risk Ratio (RR) 1.24; 95% confidence interval (CI) (0.99-1.56); p=0.065). Statin use for >3 years increased adenoma risk over 5 years (RR 1.39; 95%CI 1.04-1.86; p=0.024). For all comparisons of patients treated with celecoxib, adenoma detection rates for statin users and non-users were equivalent. Consistent with their use in patients at high risk, cardiovascular serious adverse events were more common among statin users.
For patients at high risk of CRC, statins do not protect against colorectal neoplasms and may even increase the risk of developing colorectal adenomas.
HMG-CoA reductase inhibitors, also known as statins, are widely prescribed medications for prevention of hypercholesterolemia and related diseases. Statins demonstrate pleotropic effects, with activities both related to and independent of their ability to block cholesterol synthesis. Pre-clinical studies suggest that statins suppress CRC growth. In model systems, statins inhibit angiogenesis, induce apoptosis in CRC cell lines, and alter cell-cell adhesion(1). Statins also prevent tumor formation in azoxymethane-induced and APC-deficient rodent models(2, 3).
Early clinical trials suggested that statins use and/or low cholesterol levels might increase cancer risk(4-7). Cancer as an endpoint was therefore carefully scrutinized in secondary analyses of large statin cardiovascular trials and in a number of case-control and cohort studies(8). The results with respect to CRC incidence are mixed. One population-based case-control study in elderly patients found a 47% reduced CRC risk for those using statins for at least 5 years(9). A second observational study also showed a protective statin effect, superior to that seen with low dose aspirin(10). A statin-associated reduction in CRC incidence, however, was not confirmed in other prospective cohort or retrospective case-control studies(11-16), nor was it seen by meta-analysis(17).
The first statin, lovastatin, was approved by the FDA in 1987, and statins did not achieve widespread use until about a decade later. Because CRC takes approximately 10-20 years to develop, it is possible that lack of consensus concerning statin use and CRC incidence results from inadequate drug exposure and follow-up intervals. The study with longest follow-up duration was a population-based study from Finland that examined cancer incidence in 472,481 case-control pairs, where cases were statin users with a 3.06 year median duration of medication(16). Over an average follow-up duration of 8.8 years, this study found no difference in incidence of colon or rectal cancers. Adenoma formation is an earlier indicator of CRC risk, but the current literature contains very little statin use data concerning this endpoint. Two retrospective database studies suggested benefit(18, 19). A secondary analysis of three large colorectal adenoma prevention trials pooled data for 2,915 subjects of which 8.1% used statins(20). Despite small numbers, this study could rule out a ≥14% protective effect with 95% confidence, and found a null result for an association between statin use and adenoma recurrence.
The Adenoma Prevention with Celecoxib (APC) Trial was a randomized placebo-controlled trial of celecoxib for prevention of colorectal adenomas in patients at high CRC risk. This study randomized 2035 patients to receive placebo (679 patients), 200mg celecoxib twice daily (685 patients), or 400mg celecoxib twice daily (671 patients), with follow-up for up to 5 years post-randomization. The primary endpoints of the APC trial have been reported(21, 22). For patients on placebo, the incidence of newly detected adenomas by year 3 was 60.7%, confirming that the APC trial included a high adenoma risk cohort. New adenoma detection during 3-year surveillance interval was reduced 33% for those on 200mg celecoxib bid, and 45% for those on 400mg celecoxib bid.
The APC trial captured clinical data relevant to understanding both overall health and adenoma risk. Prospectively gathered data included complete medical history, with a detailed medication use history recording duration of drug use that was updated every 6 months during the active treatment portion of the trial. Because the trial was designed before the cardiovascular toxicity of selective Cox-2 inhibitors and NSAIDs was recognized, patients with a history of cardiovascular disease were eligible. As a result, 75% of participants had at least one cardiovascular risk factor(23), and 36% used statins. The relationship between statin use and adenoma recurrence was a planned secondary objective of the APC trial.
The APC trial tested whether celecoxib reduced the occurrence of endoscopically-detected colorectal adenomas, comparing treatment with placebo, celecoxib 200mg bid, or celecoxib 400mg bid. Randomization was stratified based upon low dose aspirin use (doses of ≤ 325 mg qod or 162.5 mg qd) and clinical site. The trial involved 91 sites in the United States, Australia, Canada, and Great Britain. Each site received human subjects committee approval of the study, and all patients provided written consent for participation. During the treatment portion of the trial, an independent data and safety monitoring board reviewed safety data monthly and efficacy data semianually.
Details of the APC trial have been published(21). Participants ranged from 31 to 88 years of age at enrollment and had a high risk of recurrent colorectal adenomas based upon either multiple adenomas or removal of a single adenoma ≥6 mm diameter. Within 3 months before enrollment, participants had a colonoscopy with removal of all polyps, one or more of which was a histologically confirmed adenoma. Exclusion criteria included a history of FAP, hereditary nonpolyposis colon cancer, inflammatory bowel disease, or large bowel resection other than appendectomy.
APC trial participants who completed an initial 3 year study interval were offered the option of continuing on an extension study, allowing them to continue taking study medication in a blinded manner for an additional 2 years. Participants not wishing to remain on study medication were allowed to continue in an additional 2 year surveillance arm. At 5 years after randomization, participants in the extension study underwent a final colonoscopy.
APC trial accrual was completed in March, 2002. In late 2004, rofecoxib was withdrawn from the market due to recognition of its association with increased risk of serious cardiovascular adverse events. At this time, APC trial investigators conducted an independent adjudicated review of cardiovascular safety. This analysis showed 2.6- and 3.4-fold increases in selected cardiovascular events compared to placebo in patients receiving celecoxib at doses of 200mg bid and 400mg bid, respectively(22). In response, study medication use was discontinued on December 17, 2004, approximately 3 months before the final randomized patients were scheduled to complete the 3 year treatment interval. Patients returned to usual care, which entailed colonoscopic surveillance without chemoprevention, and all participants who wished to do so remained on study for continued collection of safety data and completion of the year 5 colonoscopy.
The APC trial collected detailed medication use data at baseline and during the trial, including the length of statin use prior to study entry. Subjects on treatment were contacted every 2 months to update concomitant medication use and report adverse events. Subjects who were no longer using study medication were contacted by telephone every 6-12 months for adverse event reporting. A study investigator performed a complete colonoscopy with visualization of the cecum and endoscopic removal of all polyps at 1 year, 3 years, and 5 years after randomization. All polyps removed during these colonoscopies were reviewed by a central study pathologist. Investigator-reported adverse events were classified according to MedRA 8.1 criteria.
Associations between baseline characteristics and statin use were assessed using chi-square and analysis of variance for categorical and continuous variables, respectively. For these analyses, statin use was subdivided by baseline and post-baseline use according to whether first use of statin medication began by the randomization date. The total duration of statin use was calculated from statin start date until the date of final on-study colonoscopy to estimate the maximum length of use. Specific details of how duration of statin use was quantified are provided in the Supplemental Data. The effect of statin use duration on adenoma recurrence was assessed as a time-dependent variable. Analysis of time to adenoma recurrence and cardiovascular adverse events was performed using time-dependent Cox models. The significance of parameter estimates from the fitted regression model was assessed by the conventional Wald test. Since adenoma recurrence could only be detected at colonoscopies performed at 1, 3 or 5 years of follow-up, the tied event times were handled by the exact method in PHREG procedure in SAS. All demographic and clinical characteristics associated with statin use were evaluated as covariates. A propensity score for a patient's predicted likelihood of receiving statins conditional on observed factors was also evaluated as a covariate on statin effect. Propensity scores were estimated by a multivariable logistic regression model fitted with statin use-associated baseline factors, including age (≥65 vs. <65), sex, aspirin use, history of cardiovascular events, hypertension, and diabetes. Since controlling for the propensity score variable yielded the same result on statin effect as directly adjusting for aspirin use, age and sex, all subsequent analyses on newly detected adenoma were modeled with the three covariates as separate variables(24). Analyses were conducted separately for the placebo group and for the celecoxib groups. All statistical analysis was performed using SAS 9.2 (SAS Institute, Cary, NC).
Baseline statin use data were available for 2028/2035 (99.7%) of participants. Statins were used at baseline by 502 patients (24.7%) and were started during the first 3 years of the trial in 228 patients (11.2%), resulting in a total number of statin users of 730 (36%) as follows: lipophilic statins: atorvastatin N=406 (55.6%), lovastatin N=16 (2.2%), and simvastatin N=214 (29.3%), and hydrophilic statin: pravastatin N=94 (12.9%). The overall median duration of statin use was 3.6 years (range 0.01-28.7 years) (Table 1). Statin use was more common in participants ≥age 65 at study entry and in men (Table 2). Statin users were more likely to be using cardioprotective aspirin (45.6% of statin users vs. 22.7% of statin non-users; p<0.001). A baseline history of significant cardiovascular events (e.g. angina, myocardial infarction, congestive heart failure, cardiovascular or cerebrovascular disease) was present in 14% of participants, and 67.1% of patients with this history used statins. Other subsets with a higher proportion of statin users included those with a history of smoking, hypertension, and diabetes. Statin use was balanced across all three treatment arms, and was also balanced for variables associated with adenoma risk, including CRC family history and adenoma size and number prior to treatment (Table 2).
This planned secondary analysis investigated the association between statin use and adenoma risk during 3- and 5-year surveillance intervals. First, we determined the relationship between on-study adenoma detection and statin use at any time from baseline to study exit (Table 3). For patients receiving placebo, the unadjusted relative risk (RR) of adenoma detection for statin users was 1.27 (95%CI 1.01-1.58, p=0.038) over 3 years and 1.28 (95%CI 1.03-1.59; p=0.024) over 5 years. Of 221 subjects who used statins and received placebo, 149 (67.4%) had one or more adenomas detected over 5 years. Adjustment for significant covariates by different methods, including propensity analysis, produced a 3-year adenoma risk ranging from 1.17 (95% CI 0.94-1.47) to 1.29 (95%CI 1.03-1.62) and a 5-year adenoma risk ranging from 1.19 (95%CI 0.95-1.48) to 1.31 (95%CI 1.05-1.63) (results not shown). Celecoxib treatment appeared to eliminate this risk based upon unadjusted analyses for both 200 mg bid (3-yr RR 0.92; 95%CI 0.70-1.21) and 400 mg bid (3-yr RR 1.13; 95%CI 0.86-1.50) doses. The conclusions are consistent after adjustment for aspirin, age and sex for both 200 mg bid (3-yr RR 0.86; 95%CI 0.65-1.13) and 400 mg bid (3-yr RR 1.06; 95%CI 0.79-1.41) doses.
Next we considered the duration of statin use prior to colonoscopy, assuming that once statin use started it was not discontinued. This analysis was informed by data showing that only 10% of all statin users discontinued this drug before study exit, with a median duration of statin use among those discontinuing statins of 1.8 years (range 0-21.4 years). Duration analysis showed that statin use of >3 years was associated with a significantly increased adenoma risk, with rates among placebo users, adjusted for aspirin use, age, and sex, of 1.37 (95%CI 1.02-1.86, p=0.038 over 3 years and 1.39 (95%CI 1.04-1.86, p=0.024 over 5 years of surveillance (Table 4). As for the prior analysis, statin use was not associated with an increased risk of adenoma detection among patients using celecoxib. A similar analysis was conducted using advanced adenomas as an endpoint. The power of this analysis was limited, as the advanced adenoma outcome that was observed by 5 years for only 21.3% of placebo users overall(23). The RR for advanced adenoma development, adjusted for aspirin use, age, and sex, was 1.31 over 3 years (95%CI 0.85-2.0; p=0.217) and 1.37 over 5 years (95%CI 0.91-2.05; p=0.130) (Supplemental data Table A).
Previous analyses of the APC trial safety database, using a treatment-emergent approach, showed that 3.8% of placebo users experienced one or more cardiovascular and thrombotic adverse events, compared to 6.0% (RR 1.6; 95%CI 1.0, 2.5) and 7.5% (RR 1.9; 95%CI 1.2,3.1) of those using celecoxib 200mg bid and celecoxib 400mg bid, respectively(23). In addition, a baseline history of atherosclerotic heart disease was significantly associated with celecoxib dose and CV event risk (p value for interaction 0.004). In this study, we determined the relationship between statin use at baseline and cardiovascular adverse events, using the same definition as the previous analysis, i.e., a combined endpoint including myocardial infarction, cardiovascular therapeutic procedure, cerebrovascular disease, peripheral vascular disease, peripheral vascular therapeutic procedure, venous thrombosis or thromboembolism, and death or circulatory collapse due to cardiovascular causes (Table 5). Events were included if they occurred during the time from first study medication dose to 30 days after the last study medication dose. Because the majority of patients with year 5 study data had been off study medication for more than a year, we considered this treatment-emergent safety analysis to be the most accurate reflection of drug-associated toxicity. Of 221 patients who used statins and received placebo, 16 (7.2%) experienced cardiovascular adverse events. With this limited number of events, analysis was adjusted for aspirin use and showed that statin use was associated with an increased risk of cardiovascular adverse events (RR 2.53 95%CI (1.11-5.74); p=0.027). This analysis failed to demonstrate an interaction with celecoxib use (p=0.366).
This study represents the largest report of statin use from a prospective randomized trial of patients at high CRC risk. The results show that, at best, statins did not protect against the development of sporadic colorectal adenomas. In fact, even after controlling for multiple co-variates, statin users of >3 years on the placebo arm showed a 40% increase in adenoma detection during 5 years of surveillance. Celecoxib use produced significant anti-tumor effect, which appeared to counteract the tumor-promoting effect of statins. The lack of significant effect of statins against an advanced adenoma endpoint was likely due to the small number of patients with this outcome. The APC trial demonstrated an increased cardiovascular risk associated with celecoxib use, particularly for the higher dose(22), with a significant association between a baseline history of cardiovascular disease and celecoxib-associated cardiovascular toxicity(23). As expected therefore, because statin use and cardiovascular disease are strongly linked, baseline statin use in participants also emerged as a significant factor in identifying celecoxib-associated cardiovascular risk.
Several factors make these data convincing. First, the APC trial was designed at the outset to assess the effect of concomitant medications, including statins, on study endpoints. Because of this, detailed medication use histories that included pre-randomization treatment duration were obtained from all participants, and were updated at 6 month intervals during the 3 year treatment phase of the trial. Second, the APC trial began before the cardiovascular risks of celecoxib were evident. As a result, subjects with significant cardiovascular risk were enrolled on the trial and a substantial proportion of participants used statins, allowing sufficient numbers within the placebo arm to control for important covariates such as age, sex and cardioprotective aspirin use. Finally, the type of statin used may influence tissue response. Lipophilic statins achieve higher drug levels in non-hepatic tissues, and are theoretically more likely to alter the biology of the colorectal mucosa than hydrophilic statins, which are hepatoselective. Of the participants using statins, 87.1% used lipophilic agents, therefore the results should reflect significant drug effects in the target tissue.
There are some factors limiting the confidence of these results. Although the distribution of treatment assignment was equal for statin users and non-users, and analyses were adjusted for co-dependent variables, the randomization to treatment for this trial was not stratified for statin use, and it is possible that imbalances affecting the outcome were introduced. In addition, selection for study entry required the presence of a colorectal adenoma at a baseline clearance colonoscopy. As a result, it is possible that patients who entered the study using statins constituted a population pre-selected to develop adenomas while on statins. We saw a similar effect in the overall APC trial when aspirin use was considered. All of the aspirin users on the APC trial were routinely taking aspirin prior to study entry, and were required to remain on aspirin during the duration of the trial. The study showed that aspirin users had the same overall rate of adenoma recurrence as non-aspirin users on the placebo arm, and we did not see an additive or synergistic effect with celecoxib for the efficacy endpoints(19). We propose that this occurred because patients on the APC trial who used aspirin were resistant to the beneficial anti-tumor effects of this NSAID. An additional minor issue is that statin use was discontinued during the APC trial surveillance period in 10% of users, and the duration analyses that we performed did not correct for this. This assumption, however, should decrease the risk associated with statin use. Finally, these data do not clearly indicate that statin use promotes adenoma development. An increased risk of adenoma development (RR~1.27-1.37) does appear to be the case by the overall unadjusted analysis, and for both the unadjusted and multivariable analyses in the subset of patients using statins for greater than three years. However, the significance at both 3- and 5-year endpoints is lost in the multivariable analysis for all placebo users when adjusted for important covariates of aspirin use, age, and sex, and it is possible that the significance in the duration subset analysis is due to small sample size.
In conclusion, we find no evidence that statin use decreases colorectal adenoma incidence. On the contrary, our data show that long-term statin use may increase the risk of these CRC precursor lesions, although this result is interpreted with caution due to the observational nature of this study.
Funding: This work was funded by the National Cancer Institute (CA-N01-95015, Monica Bertagnolli, Principal Investigator) and by Pfizer, Inc.
The following persons participated in the APC Study: Steering Committee: M.M. Bertagnolli, E.T. Hawk, C.J. Eagle; Statistical Team: A.G. Zauber, K.M. Kim, D. Corle, R. Rosenstein, J. Tang, T. Hess, A. Wilton, M. Hsu; Medical Monitors: W. Anderson, L. Doody; Central Pathology Review: M. Redston, K.R. Geisinger; Project Directors: G.M. Woloj, D. Bagheri, A. Crawford, M. Schietrum, V. Ladouceur; Data and Safety Monitoring Board: S. Rosen (chair), L. Friedman, R. Makuch, R. Phillips, P. Taylor; Principal Investigators, United States: S. Auerbach (California Professional Research, Newport Beach), C.F. Barish (Wake Research Associates, Raleigh, NC), T. Barringer (Carolinas Medical Center, Charlotte, NC), R.W. Bennetts (Northwest Gastroenterology Clinic, Portland, OR), M. Blitstein (Associates in Gastroenterology and Liver Disease, Lake Forest, IL), J. Bruggen (Wake Forest University Baptist Medical Center, Winston Salem, NC), P Carricaburu (Veterans Affairs Hospital, Sheridan, WY), D. Chung (Massachusetts General Hospital, Boston, MA), F. Colizzo (Pentucket Medical Associates, Haverhill, MA), R. Curtis (Newton-Wellesley Hospital, Newton, MA), T. Dewar (Harris Methodist Hospital Fort Worth, Ft. Worth, TX), R. DuBois (Vanderbilt University Medical Center, Nashville, TN), T. Feinstat (Gastroenterology Consultants of Sacramento, Roseville, CA), T.R. Foley (Regional Gastroenterology Associates of Lancaster, Lancaster, PA, D. Gabbaizadeh (Huntington Research Group, Huntington Station, NY), J. Geenen (Wisconsin Center for Advanced Research, Milwaukee, WI), F. Giardiello (Johns Hopkins Hospital, Baltimore, MD), A. Goetsch (nTouch Research, Huntsville, AL), M. Goldberg (Regional Gastroenterology Associates of Lancaster, Evanston, IL), J.L. Goldstein (University of Illinois at Chicago, Chicago, IL), W. Harlan, III (Asheville Gastroenterology Associates, Asheville, NC), R. Hogan (Gastrointestinal Associates, Jackson, MS), M. Kamionkowski (Gastroenterology Associates of Cleveland, Mayfield Heights, OH), M. Kelfer (Fallon Clinic, West Boylston, MA), B. Kerzner (Health Trends Research, Baltimore, MD), K. Kim (University of Chicago Medical Center, Chicago, IL), I. Klimberg (Gastroenterology Associates of Ocala, Ocala, FL), G. Koval (West Hills Gastroenterology Associates, Portland, OR), C. Krone (Advanced Clinical Therapeutics, Tucson, AZ), S.Krumholz (Waterside Clinical Research, West Palm Beach, FL), M.W. Layton (South Puget Sound Clinical Research Center, Olympia, WA), C. Lightdale (Columbia-Presbyterian Medical Center, New York, NY), P.J. Limburg (May Clinic, Rochester, MN), C. Lind (Vanderbilt University Medical Center, Nashville, TN), D. Lipkis (Institute for Health Care Assessment, San Diego, CA), M. Lloyd (Idaho Gastroenterology, Meridian, ID), D. Maccini (Spokane Digestive Disease Center, Spokane, WA), F. MacMillan, Sr. (Pentucket Medical Associates, Haverhill, MA), R. Madoff (University of Minnesota, Minneapolis, MN), A. Malik (Advanced Clinical Research, North Providence, RI), A. Markowitz (Memorial Sloane-Kettering Cancer Center, New York, NY), R. Marks (Alabama Digestive Research Center, Alabaster, AL), C. J. McDougall (Manhattan Associates, New York, NY), P. Miner (Oklahoma Foundation for Digestive Research, Oklahoma City, OK), M. Murphy (Southern Digestive and Liver Disease Institute, Savannah, GA), A. Namais (Gastrointestinal Physicians, Salem, MA), N. Nickl (University of Kentucky Medical Center, Lexington, KY), M. Pochapin (Jay Monahan Center for Gastrointestinal Health, New York, NY), R.E. Pruitt (Nashville Medical Research Institute, Nashville, TN), J Puolos (Cumberland Research Associates, Fayetteville, NC), D.S. Riff (AGMG Clinical Research, Anaheim, CA), R. Roman (South Denver Gastroenterology, Englewood, CO), L. Rubin (New Jersey Physicians, Passaic, NJ), D. Ruff (Healthcare Discoveries, San Antonio, TX), M. Safdi (Consultants for Clinical Research, Cincinnati, OH), J. Saltzman (Brigham and Women's Hospital, Boston, MA), B. Salzberg (Atlanta Gastroenterology Associates, Atlanta, GA), J.A. Sattler (Western Clinical Research, Torrence, CA), P. Schleinitz (Americas Doctors Research, Medford, OR), J. Schwartz (Northwest Gastroenterologists, Arlington Heights, IL), M. Schwartz (Jupiter Research Association, Jupiter, FL), M. Silpa (Gastroenterology Associates of the East Bay Medical Group, Berkeley, CA), D. Silvers (Drug Research Services, Metairie, LA), D. Smoot (Howard University Cancer Center, Washington, DC), S. Sontag (Veterans Affairs Medical Center, Hines, IL), R.J. Sorrell (Gastroenterology Specialties, Lincoln, NE), D. Stanton (Community Clinical Trials, Orange, CA), J. Sturgeon (Americas Doctors Research, Shawnee Mission, KS), J.P. Tracey (Hawthorne Medical Associates, North Dartmouth, MA), T. Werth (Charlotte Gastroenterology and Hepatology, Charlotte, NC), C.M. Wilcox (University of Alabama at Birmingham, Birmingham, AL), R. Wohlman (Northwest Gastroenterology Associates, Bellevue, WA), S. Woods (Gastroenterology Associates of Fairfield County, Bridgeport, CT); United Kingdom: J. Burn (South Cleveland Hospital, Middlesbrough); Australia: H. Ee (Sir Charles Gairdner Hospital, Nedlands, W.A.), M. Korman (Monash Medical Centre, Clayton, Victoria), A. Lee (Concord Repatriation and General Hospital, Concord, NSW), B. Leggett (Royal Brisbane Hospital, Herston, Queensland), F. Macrae (Royal Melbourne Hospital, Melbourne, Victoria), L. Mollison (Freemantle Hospital, Freemantle, WA), N. Yeomans (Western Hospital, Footscray, Victoria), G. Young (Flinders Medical Center, Bedford, SA); Canada: G. Aumais (Hospital Maisonneuve-Rosemont, Montreal), R. Bailey (Hys Medical Center, Edmonton, Alberta), C. Bernstein (Winnipeg Health Sciences Centre, Winnipeg, Manitoba), L. Cohen (Sunnybrook and Women's Hospital, Toronto), C. Dallaire, R. Dube (Centre Hospitalier Universitaire de Quebec, Quebec), D. Morgan (McMaster University, Hamilton, Ontario), T. Sylwestrowicz (St. Paul's Hospital, Saskatoon, Saskatoon), G. Van Rosendaal (University of Calgary, Alberta), S.J. Van Zantan (Queen Elizabeth II Health Sciences Centre, Halifax, NS).