Highlighted Trials

This clinical trial was funded primarily by the Canadian Institutes of Health Research (CIHR) and in part by the Ministry of Health and Long-Term Care in Ontario. The study was coordinated by the University of Ottawa Heart Institute (UOHI), led by Nominated Principal Investigator David Birnie, MD. It was a large international study involving 681 patients at 17 centres in Canada and one in Brazil.

At the time of the study, the clinical practice guidelines stated that patients at moderate to high risk for blood clots who were taking Coumadin and required the implantation of a device (pacemaker or implantable cardioverter defibrillator) should normally stop their Coumadin before surgery and be “bridged” with another drug, called heparin, between the pre- and post-operative period. This was thought to prevent excessive bleeding during the surgery, while still providing protection against the formation of blood clots. As heparin is a shorter acting drug and was stopped several hours prior to surgery, the surgery was performed without blood thinner in the patient’s system. However, no extensive trial had ever examined the safety and efficacy of this approach.

This trial sought to establish whether this practice was the best patient care option in terms of safety (e.g., limiting bleeding at the site of the surgery and presence of other adverse events) and efficacy of continued prevention of blood clots. In the trial, patients either underwent the current standard of care when getting the device implanted (bridging to heparin) [the control group] or continued to take Coumadin with no interruption during the surgical period [the test group].

Results

Patients assigned continuous Coumadin experienced less bleeding at the site of the device surgery (3%) compared to those undergoing the current standard of care of bridging with heparin (16%). Associated with this, patients who remained on their Coumadin reported less pain and an increased quality of life. Other incidences such as stroke did not differ between the two groups. In fact, the results were so statistically strong in favour of the Coumadin arm that the trial was stopped early by the safety board.

The results of the trial strongly indicated that these patients should continue on Coumadin at the time of device surgery. There are three benefits from the results of this trial:

1. Improved outcomes for patients
2. Easier, more straightforward treatment strategy for the health care team
3. Significant savings to the healthcare system, since Coumadin is substantially cheaper than heparin.

 The results of the trial have changed clinical practice worldwide. For example the Canadian Cardiovascular Society guidelines were updated in October 2013 and the European Society of Cardiology guidelines in 2015.

What Next

A second trial, BRUISE 2, is currently being conducted which examines this question for patients who are on newer anti-clotting drugs. Results are expected in 2016.

Related Publications

• Birnie DH, Healey JS, Wells GA, Verma A, Tang AS, Krahn AD, Simpson CS, Ayala-Paredes F, Coutu B, Leiria TL, Essebag V; BRUISE CONTROL Investigators. Pacemaker or defibrillator surgery without interruption of anticoagulation. New England Journal of Medicine. 2013 May 30;368(22):2084-93.
• Birnie, David H., Healey J., Essebag, V., Management of Anticoagulation Around Pacemaker and Defibrillator Surgery. Circulation 2014;129:2062-2065
• Doug Coyle and Others. Cost Effectiveness of Continued-Warfarin Versus Heparin-Bridging Therapy During Pacemaker and Defibrillator Surgery. Journal of the American College of Cardiology 2015; 65:957.
• Proietti R, Birnie DH, Healey JS, Verma A, Essebag V, Continued oral anticoagulation during cardiac pacing: the BRUISE CONTROL study. Giornale Italiano di Cardiologia (Rome) 2013 Nov;14(11):724-5

Cardiac PET imaging trials, conducted under the leadership of Rob Beanlands, MD, are directed to the translation of clinical research using advanced imaging techniques and radiotracers to routine clinical practice and impact on health care policy.

PET and Recovery following Revascularization (PARR 2) and the Ottawa-FIVE studies have shown that FDG guided therapy used in the management of patients with severe left ventricular failure and coronary artery disease demonstrates a reduction in outcomes and events. PARR2 was the first and largest, multicentre, RCT imaging trial to assess the utility of FDG PET compared to standard care, in patients with severe LV dysfunction and referred for revascularization. Outcomes were assessed to 5 years post randomization and while the results were not statistically significant, there was a trend for benefit in the PET guided arm. When the data was further evaluated (post-hoc analysis – Ottawa-FIVE); it was determined that for those patients in whom the PET recommendation was followed, a statistically significant benefit was found. This post hoc subgroup analysis of the PARR 2 trial suggests that 18F-FDG PET–guided management reduces the composite of cardiovascular events in patients with ischemic cardiomyopathy in a center with an experienced imaging team; established synergies between cardiac imaging, heart failure, and revascularization services; and ready access to 18F-FDG.

Clinical trial data from the Ottawa-FIVE study enabled the University of Ottawa Heart Institute Radiochemistry Lab to submit a New Drug Submission (NDS) and obtain a Notice of Compliance from Health Canada for the manufacture of FDG (18F-fluorodeoxyglucose) under the name FluorOHmet.

The Cardiac FDG PET (CADRE) registry, supported by the Ministry of Health and Long Term Care evaluated standardized resource utilization in patients undergoing cardiac FDG PET imaging for viability assessment in Ontario. As a result, FDG PET is an insured service for viability imaging. The Provincial Cardiac FDG PET Special Access Program, is run by the PET research team, providing review and access to cardiac FDG PET for such indications as sarcoidosis, aortitis, endocarditis, viability in EF >40%.

To further assess imaging and its impact on patient care, IMAGE-HF (Imaging Modalities to Assist with Guiding therapy and the Evaluation of patients with Heart Failure) is our largest endeavour yet. IMAGE-HF contains 3 multicentre RCT’s, evaluating the impact of imaging strategies (PET, SPECT,CMR, Echo, Cath, CT) on relevant clinical outcomes, quality of life, cost effectiveness, diagnosis and decision making in patients with heart failure at 18 participating sites in Canada, Finland, US, and South America; a total of 2,300 patients will be enrolled. The primary objectives are to determine the impact of imaging strategies (advanced vs standard) on relevant clinical outcomes, quality of life, cost effectiveness, diagnosis and decision making in patients with heart failure and facilitate policy development. Since imaging is the fastest growing health care expenditure in Canada, it is imperative to ensure imaging technology is developed, implemented and used effectively to maximize value to both patients and society at large. – Completion date: September 2016.

Cardiac PET imaging is a valuable research and clinical technique. Current research activities include: sarcoidosis, arrhythmias, cardiac blood flow, sleep apnea and heart failure, cardiac allograft vasculopathy.

Related Publications

• Abraham A., Nichol G., Williams K.A., Guo A., deKemp R.A., Garrard L., Davies R.A., Duschene L. Haddad H., Chow B., DaSilva J., Beanlands R.S.B 18F-FDG PET Imaging of Myocardial Viability in an Experienced Center with Access to 18F-FDG and Integration with Clinical Management Teams: The Ottawa-FIVE Substudy of the PARR 2 Trial J Nucl Med 2010; 51:567–574
• Paterson I, Mielniczuk LM, O'Meara E, So A, White JA. Imaging heart failure: current and future applications. Can J Cardiol. 2013;29(3):317-28.
• Paterson I, OMeara E, Chow B, Ukkonen H, Beanlands RS. Recent Advances in Cardiac Imaging for Patients with Heart Failure. Curr Opin Cardiol. 2011;26(2):132-43.

Under the leadership of Andrew Pipe, MD and Robert Reid, PhD, the Heart Institute has conducted many clinical trials in the area of smoking cessation, resulting in a strong body of evidence that is recognized both nationally and internationally. This research has led to the development of the Ottawa Model for Smoking Cessation (OMSC), which delivers novel, evidence-based smoking cessation interventions which are now used in clinical practice across Canada. Implementation of the OMSC uses an array of state-of-the art strategies, including needs assessment, facilitating technologies, health care professional training, standardized patient tools, reminders, and continuous quality improvement processes. Research at UOHI has shown that the OMSC, compared to standard care, improves long-term quit rates by an absolute 11%-15%. In addition, UOHI has recently shown that the model translates into 30% fewer patients smoking, reduced rates of death and re-hospitalization, and a cost saving to the Canadian healthcare system.

Following dissemination of initial OMSC research results in 2006, a highly effective partnership was formed linking researchers, knowledge users, opinion leaders, hospitals, primary care and specialty clinics, regional health authorities, provincial ministries of health, Health Canada, the Public Health Agency of Canada, the Heart and Stroke Foundation of Canada and private sector partners (Pfizer Canada Inc, TelAsk). This partnership enables research and broad knowledge dissemination. As a result, over 300 healthcare sites across nine provinces are now using the OMSC approach and, subsequently 200,000 smokers have been reached with evidence-based cessation treatment. 

Positive patient impacts from the OMSC include:

• Improved quit rates by an absolute 11% in general hospital patients and 15% in tertiary care cardiac patients
• 30% of patients (~10,000) quit smoking each year across OMSC programs
• Removal of barriers to ongoing smoking cessation support by seamlessly linking patients from hospital to supportive cessation services in the community, including counseling services and resources to access cost-free quit smoking medications (financial cost of medications has been identified as the main barrier to quitting among patients).

Related Publications

• Mullen KA, Coyle D, Manuel D, Nguyen HV, Pham B, Pipe AL, Reid RD. Economic Evaluation of a hospital-initiated intervention for smokers with chronic disease, in Ontario, Canada. Tobacco Control. 2014 Jun 16
• Reid R, Mullen KA, Pipe A. Hospital-Initiated Smoking Cessation: The Ottawa Model for Smoking Cessation. In: Disease Interrupted: Tobacco Reduction and Cessation. Els C, Kunyk D, Selby P (Eds.). Charleston, SC: CreateSpace, 2012.
• Reid RD, Mullen KA, Pipe AL. Systematic approaches to smoking cessation in the cardiac setting. Current Opinion in Cardiology. 2011, Sep;26(5):443-448.
• Campbell S, Pieters K, Mullen KA, Reece R, Reid RD. Examining sustainability in a hospital setting: Case of smoking cessation. Implementation Science. 2011, 6:108 

This clinical trial was a physician-initiated study conducted at the Heart Institute, with funding from an industry partner, Spartan Biosciences. The study enrolled 200 patients and was led by Derek So, MD.

Following a percutaneous coronary intervention (PCI) (a procedure for opening up blockages in coronary arteries with balloons and stents (wire meshes)), patients must be treated with an antiplatelet agent to prevent clotting of stents and to prevent future heart attacks. The standard therapy is a medication called clopidogrel. It is known that a very common variant of a gene, called the CYP2C19*2 allele, is associated with increased complication rates in individuals given clopidogrel after PCI. Essentially, for carriers of the gene variant, clopidogrel doesn’t work as it should and patients have an under-responsiveness to the drug. However, other antiplatelet drugs such as prasugrel or ticagrelor, are known to be effective in these individuals. The disadvantage of giving prasugrel or ticagrelor to all patients is the increased risk for bleeding complications associated with these drugs. Until the RAPID GENE study, there was no means available to quickly test for the gene variant, and almost all patients were given clopidogrel as the default standard drug.

This study involved the co-development of the first bedside genetic test in clinical medicine. The study was a proof of concept study, using a novel point-of-care (at the bedside) genetic test to identify carriers of the CYP2C19*2 allele and aimed to assess a personalized approach to antiplatelet treatment after PCI. Patients undergoing PCI were randomly assigned to rapid point-of-care genotyping or to standard treatment. Individuals in the rapid genotyping group were screened for the CYP2C19*2 allele, and carriers of the gene were given 10 mg prasugrel daily, and non-carriers and patients in the standard treatment group were given 75 mg clopidogrel daily.

Results

This trial demonstrated that the point-of-care genetic testing can be done effectively at the bedside, (with a simple swab of the lining of the mouth) and treatment of identified CYP2C19*2 carriers with prasugrel can improve response of the platelet cell to drugs. This was the first point-of-care genetic testing technology in medicine.

The results of this study were presented as a late-breaking trial at TCT 2011 (the world’s largest interventional cardiology conference) and published in The Lancet. The point-of-care genetic testing machines are now licensed and available for sale in Canada and the US. This will significantly impact the safe treatment of patients requiring antiplatelet therapy, for any reason.

What Next

Three new clinical trials are currently underway at the UOHI, utilizing the point-of-care genetic test. The new studies are assessing the effectiveness and benefits of personalizing medical therapy based on the genetic results.

Related Publication

• Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, Dick A, Marquis JF, O'Brien E, Goncalves S, Druce I, Stewart A,Gollob MH, So DY. Point-of-care genetic testing for personalization of antiplatelet treatment (RAPID GENE) aprospective randomized proof-of-concept trial. Lancet. 2012 May 5; 379(9827):1705-11

This clinical trial was funded by the Canadian Institutes of Health Research (CIHR) University-Industry (Medtronic) Program. This was a large multi-centre international trial involving 1,798 patients at 24 centres in Canada, eight centres in Europe and Turkey, and two centres in Australia. The project was coordinated by the University of Ottawa Heart Institute (UOHI), led globally by George Wells, PhD (UOHI) and Anthony Tang, MD; and David Birnie, MD was lead for the UOHI site.

The RAFT trial tested implantation of a basic implantable cardioverter defibrillator (ICD) alone versus implantation of an ICD plus a Cardiac Resynchronization Therapy (CRT) device in patients with symptoms of mild to moderate heart failure that were indicated to receive an ICD. An ICD is similar to a pacemaker but can deliver an electrical shock to restore normal heart rhythms when needed. A CRT device delivers electrical impulses to the heart through insulated wires called leads that are connected to the heart tissue. These impulses do not “restart” the heart’s electrical signalling like an ICD but stimulate and coordinate both lower chambers of the heart to beat in synchronization, as they should.

RAFT sought to determine whether pairing cardiac resynchronization therapy (CRT) with the standard implantable cardioverter defibrillator (ICD) therapy in patients with mild to moderate heart failure could reduce death and the rate of hospitalization for heart failure. At the time, CRT was only being used for patients with advanced heart failure. In Canada alone, roughly 600,000 people live with heart failure and the numbers are expected to increase.

Results

The addition of CRT to the standard ICD therapy, among patients with mild to moderate heart failure, reduces:

• Death or hospitalization for heart failure: 25% relative risk reduction
• All-cause death: 25% relative risk reduction; absolute reduction of 6% over a treatment period of 5 years; for every 14 patients treated for 5 years, 1 death is prevented
• Hospitalization for heart failure: 32% relative risk reduction; for every 11 patients treated for 5 years, 1 hospitalization for heart failure is prevented.

This knowledge translated to a change in the practice guidelines and the adoption of CRT into usual clinical practice, benefitting many HF patients. CRT is now an important state-of-the-art therapy for HF patients.

To underline the significance of the RAFT findings, the following honours have been bestowed on the trial and the Principal Investigators:

• CIHR-CMAJ Top Achievements in Health Research Award in 2011
• Named among the top 10 research advances in heart disease in 2010 by both the American Heart Association and the American Stroke Association
• Called “the tipping point” in favour of CRT for heart failure treatment by theheart.org
• To date there have been 11 publications directly related to the RAFT trial.

What Next

RAFT led directly to another multicentre, randomized controlled trial known as RAFT-PermAF, which is currently recruiting patients. This study is similar to RAFT but is concerned with patients that have permanent atrial fibrillation.

Related Publications

• David H Birnie, Andrew Ha, Lyall Higginson, Kiran Sidhu, Martin Green, Francois Phillipon, Bernard Thibault, George Wells, Anthony Tang. Impact of QRS Morphology and Duration on Outcomes Following Cardiac Resynchronization Thearpy: Results from the Resynchronization-Debribrillaton of ambulatory Heart Failur Trial (RAFT). Circulation: Heart Fail. 2013 Nov:6(6): 1190-8.
• Gillis AM,Kerr CR, Filippon F, Newton G, Talajic M, Froeschl M, Froeschl S, Swiggum E, Wells GA, Tang AS, Impact of Cardiac Resynchronization Therapy on Hospitalizations in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial. Circulation 2013.
• Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. New England Journal of Medicine. 2010 Dec 16;363(25):2385-95.
• Wells G, Parkash R, Healey JS, Talajic M, Arnold JM, Sullivan S, Peterson J, Yetisir E, Theoret-Patrick P, Luce M, Tang AS. Cardiac resynchronization therapy: a meta-analysis of randomized controlled trials. Canadian Medical Association Journal. 2011 Mar 8;183(4):421-9.