2009: CANNeCTIN Projects Funded

Seven CANNeCTIN pilot projects were approved for funding in the June 2009 Pilot Funding Competition:

Effects of Beta Adrenergic Blocker and Angiotensin Receptor Blocker On Aortic Dilatation in Adults with Bicuspid Aortic Valve - Judith Therrien (McGill University); Co-PI: Eva Lonn (McMaster U.); Co-PI: Samuel Siu (London); Co-PI: Candace Silversides (Toronto); Co-PI: Omid Salehian (McMaster U.); $90,000; Adult Congenital Heart Disease Working Group

Bicuspid valve is the most common congenital heart disease lesion affecting 1-2% of the population. Dilatation of the ascending aorta is a common feature in patients with BAV and is a result of inherent vascular abnormalities with superimposed effects of age and acquired cardiovascular risk factors. Ascending aortic root dilatation increases the risk of premature death from aortic dissection and rupture, as well as increasing the likelihood of requiring future aortic root surgery. Histopathological studies of the aortas in patients with BAVs report similar findings to that of patients with Marfan syndrome. BB therapy and more recently, ARB therapy have been shown to decrease to rate of aortic dilatation and be beneficial in patients with Marfan syndrome. Within the context of a randomized clinical trial, we propose a three arm parallel clinical trial to test the hypothesis that BB and ARB will reduce the rate of progressive aortic dilatation in adults with BAVs and ascending aortopathy. Atenolol has been chosen over the other BB for its proven efficacy in Marfan patients as well as its once a day dosage regimen, which may increase compliance in this young patient population. Losartan has been chosen because of its proven effective in inhibiting vascular smooth muscle cell apoptosis in cultured Marfan aortic media cells as well as stopping aortic root dilatation in genetically altered Marfan syndrome mice. Magnetic resonance imaging (MRI) will be used as the technique of choice to monitor the progression of ascending aorta dilatation and the study hypothesis is that Atenolol or Losartan will significantly reduce the rate of ascending aorta dilatation as compared to placebo over a 5 year period. 

SUPERIOR SVG PATENCY CABG Trial -Stephen Fremes, Steven Singh (Sunnybrook Health Sciences), Richard Novick, Michael Chu (London Health Sciences); $100,000; Cardiac Surgery Working Group 

Coronary artery bypass graft surgery (CABG) success is the result of sustained patency of the conduits grafted. Although saphenous vein grafts (SVG) remain the most widely used conduit for CABG, contemporary 1 year patency remains poor despite optimal medical therapy and quality assurance tools. We aim to perform an International multicenter factorial design RCT to see if a novel atraumatic pedicled (no touch) technique of SVG harvesting (surgical arm) and/or the use of oral fish-oil (pharmacological arm) improve angiographic patency and clinical outcomes at 1 year compared to conventional SVG harvesting and placebo respectively. Each patient will be randomized to a SVG harvested in the conventional fashion or using the no touch technique (single-blinded). The pharmacological arm of the factorial design will have patients also randomized to fish-oil or placebo (double-blinded). The primary outcomes (surgical arm: proportion of study SVG grafts occluded; pharmacological arm: proportion of patients with >1 graft occluded) at 1 year angiography will be compared between the treatment and control groups. Secondary endpoints include incidence of 50-99% study SVG stenosis at 1 year, adverse events, biochemical measure and perioperative and 1 year clinical events (mortality, non-fatal MI, repeat revascularization). Our hypothesis is that the no touch technique and fish oil oral supplements will significantly reduce the incidence of graft occlusion at 1 year with no increase in adverse events; we hypothesize there will be no significant interaction between these two study interventions. 

TOTAL Trial - Sanjit Jolly (McMaster University) and Vladimir Dzavik (Toronto General Hospital); $124,000; Interventional Cardiology Working Group

Reperfusion therapies have significantly reduced mortality in patients with ST elevation myocardial infarction (STEMI). However, amongst patients with STEMI undergoing primary percutaneous coronary intervention (PCI) in hospital mortality remains between 4-6%. Significant limitations of primary PCI are distal embolization and impaired microvascular perfusion which are both independently associated with marked increases in mortality. Aspiration thrombectomy has been shown to improve microvascular perfusion and reduce distal embolization during primary PCI in small randomized trials and a meta-analysis. However, although meta-analyses of small randomized trials suggest that manual aspiration thrombectomy may reduce mortality, the procedure is associated with a trend towards an increased risk of stroke. A large randomized trial is clearly needed to determine if the therapy prevents important clinical outcomes (i.e. death, re-infarction, cardiogenic shock) and determine its safety profile with regards to stroke. We are planning a pilot randomized trial of patients with STEMI undergoing primary PCI comparing routine manual aspiration thrombectomy and PCI vs. PCI alone to demonstrate the feasibility of performing a large multi-center outcomes trial. We plan to proceed to a full clinical trial of approximately 4000 patients with a primary outcome of death, recurrent myocardial infarction, cardiogenic shock or new or worsening congestive heart failure at 180 days. If the full clinical trial is completed and demonstrates that aspiration thrombectomy during primary PCI reduces these important clinical events then this could change how primary PCI is performed in Canada and worldwide. If thrombectomy is shown to be superior, it has the potential to prevent thousands of deaths and recurrent infarctions globally.

Remote Ischemic Preconditioning in Cardiac Surgery Trial - Michael Walsh (University of Calgary) and Sabu Thomas; $124,000; Perioperative Working Group 

Annually, 2 million patients worldwide (30,000 Canadians) undergo cardiac surgery. Although this procedure can prolong life, 4 to 5% of patients will not survive their hospital stay and 10% will not survive the first year after surgery. Perioperative myocardial infarction (MI) and acute kidney injury (AKI) are important mechanisms that lead to postoperative mortality and may result from ischemia reperfusion injury sustained during cardiac surgery. Remote ischemic preconditioning is a promising intervention that may simultaneously reduce perioperative MI and AKI. RIPC involves the inflation of a tourniquet or blood pressure cuff over a limb to induce brief periods of ischemia that activate cellular mechanisms that may protect tissues from further ischemia and reperfusion damage. RIPC is a particularly attractive treatment because it may impact organ dysfunction in several organs at once, has no known adverse effects and costs almost nothing. Although RIPC appears very promising, knowledge of its effects are limited to surrogate endpoints rather than patient-important endpoints and studies have induced RIPC with many different regimens in terms of the limbs (upper vs lower) and number of cycles used. Whether RIPC truly improves surrogate endpoints and the most effective RIPC regimen that maintains simplicity must be determined before performing a large trial that determines whether RIPC improves patient-important outcomes. We will determine the effect of RIPC on surrogate endpoints of cardiac and kidney injury and determine what combination of limbs used and number of cycles of RIPC are most effective in a pilot randomized control trial. This trial will randomize 600 patients to one of 5 different RIPC regimens or one sham comparator group. We call this trial the Remote IscheMia Preconditioning in cArdiaC surgery Trial (Remote IMPACT).

National Bariatric Registry -Arya Sharma (University of Alberta) and Mehran Anvari (McMaster University); $82,500; Prevention Working Group

Bariatric surgical procedures are being increasingly performed to treat extreme obesity. These procedures can have dramatic benefits, such as reversal of type 2 diabetes and reduction in mortality, but also carry substantial risks. Although an increasing number of persons with extreme obesity are undergoing bariatric surgical procedures, there has been little systematic research to help determine the risks and benefits of bariatric surgery, or to provide guidance on appropriate patient selection. Furthermore, bariatric surgery is a dynamic and rapidly evolving field with continuous introduction of new technologies and techniques. The appropriate levels of presurgical assessment, triage, selection of surgical procedures, and long-term follow-up have yet to be defined. Although bariatric surgery is cost-effective compared to non-surgical treatment, conclusions are less clear when bariatric procedures are directly compared. In addition, cost-effectiveness in different populations and settings are still lacking. The aim of the current proposal is to develop a registry database for collecting standardized information on patients undergoing bariatric surgery at the participating clinical centers. Beginning with a pilot centre in Hamilton, the registry will rapidly be expanded to include all bariatric centres of excellence in Ontario and beyond, thereby forming the basis for a National Bariatric Registry. This database will greatly assist in developing evidence-based information regarding the risks and benefits of bariatric surgery. The proposed registry will address all of the above issues and will help identify new risks, develop strategies to address them, inform decision makers, ensure patients safety, and identify practices and health services areas that require optimization and improvement. Importantly, the registry will also be used to generate testable hypotheses for research studies on the etiology, management, efficacy, health economics and health services impact of severe obesity.

Canadian Pediatric Weight Management Registry - Katherine Morrison (McMaster University); $124,000; Prevention Working Group

The prevalence of pediatric obesity has increased markedly in Canadian children with recognized impact on cardiovascular health across the lifespan. In the full registry, we will prospectively monitor children in weight management programs across Canada and characterize metabolic and psychosocial comorbidities, identify the determinants of these comorbidities and examine whether these change over time. The registry development will increase clinical and research capacity in childhood obesity treatment in Canada by providing a national platform for multi-centre trials, creating a vehicle for knowledge translation and exchange activities and involving trainees at each stage of development. This pilot study is the development phase for a full registry. In the first 9 months, the database application will be established and measurement of the metabolic (glycemia, lipids, blood pressure, liver) and psychosocial (health related quality of life, self-esteem, depression) health outcomes to be assessed and their determinants will be harmonized amongst sites, based on current evidence and applicability to the clinical setting. Recruitment and data collection in a clinical setting, preliminary analyses of the prevalence of adverse health outcomes and comparison of the characteristics of our cohort to a contemporary representative national cohort will be evaluated. Expansion to the full registry will include all interested centres across Canada, and include health outcomes and determinants as harmonization of measurement is agreed upon. Thus, the health of obese children presenting to weight management centres at entry and over time and the moderators of health will be assessed and contribute to future intervention studies by contributing knowledge within the Canadian context and establishing a platform for future multi-centre investigations.

Covert Stroke in Canada: An MRI and Outcome Assessment Study - Eric Smith (University of Calgary) and Martin O'Donnell (McMaster University); $124,000; Stroke Working Group

Clinically overt stroke is the leading cause of acquired adult disability. It is now recognized that cerebral ischemia represents a clinical continuum, from severely disabling stroke to truly asymptomatic ischemia. Within this spectrum, covert cerebral infarction and white matter lesions (WML) are responsible for considerable morbidity, as prominent causes of dementia, depression, gait impairment and falls. The overall objective of the proposed study is to determine the prevalence, natural history, determinants and clinical consequences of covert cerebral ischemia in a defined population of community-dwelling participants in low, middle and high-income countries, embedded with the Prospective Urban Rural Epidemiological Study (PURE Study). However, before embarking on the full-scale study, we will determine the feasibility of an MRI study in four PURE sites in Canada. The PURE-MRI study will address limitations of the current literature by generating valid unbiased estimates of the incidence of new infarction, and identifying novel individual, household, community and societal risk factors for covert ischemia.

Steroids In cardiac Surgery: impact on Atrial Fibrillation (SIRS AF) - Richard Whitlock (McMaster University); $30,375; Strategic Investment

Cardiopulmonary bypass (CPB) initiates a systemic inflammatory response that facilitates development of post-operative complications. Investigators have consistently demonstrated the efficacy of steroids as the most potent anti-inflammatory agent for use during CPB. The 2004 AHA guidelines for CABG "support liberal prophylactic use in patients undergoing extracorporeal circulation".  However, the available trials are insufficiently powered to make conclusions on clinical endpoints and uptake has been poor. Our pilot RCT demonstrated the efficacy of a low dose steroid protocol in the suppression of this inflammatory cascade.  We hypothesize that this low dose protocol will yield clinical benefit while avoiding the potential adverse effects of steroids. Atrial fibrillation remains one of the most common postoperative complications in cardiac surgery. Our meta-analysis of steroids in cardiac surgery suggests that steroid prophylaxis may be effective in reducing this complication. The SIRS AF trial is a multi-centre international RCT of 800 patients that will determine if peri-operative methylprednisolone results in reduced postoperative atrial fibrillation in cardiac surgical patients. Secondary aims are to demonstrate the feasibility of a larger study focused on myocardial injury and death which will seek funding from CIHR. Our aim is to have 12 centers participate within SIRS AF which, recruiting at 4 patients per month, would complete recruitment in 10 months.

 Our congratulations to the many investigators, collaborators, and working groups involved in these projects!