The Canadian Cardiac Chronicle Winter 2014
Volume 18, No. 4 Canadian Clinical Trial Performance: Embarking on an ODYSSEY to further IMPROVE-IT I recently returned from the cold and windy city of Chicago-to the cold and windy city of Toronto--where I attended the 2014 American Heart Association Scientific Sessions. During my flight home, I read an article in the Wall Street Journal highlighting the long-awaited results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVEIT). Nine years after this important global randomized clinical trial started, the preliminary findings from 18,144 post-acute coronary syndrome patients had finally been presented from the Late Breaking Clinical Trials podium and were now in the public domain. The Journal headline described the addition of ezetimibe to simvastatin therapy as showing a “…modest benefit in reducing heart attacks…”. However, the subtitle of the article more appropriately captured the spirit of this enormous undertaking by physicians, study coordinators, and academic research organizations: “Trial Marks a Milestone in Battle to Fight Cardiovascular Disease by Lowering Cholesterol”. Indeed, the IMPROVE-IT trial represents the first time that adding a non-statin lipid modifying agent to patients’ secondary prevention regimen not only resulted in even lower LDL cholesterol levels, but led to a significant reduction in subsequent cardiovascular events. Canadian contribution to this trial was substantial--we were the 3rd highest enrolling country (of 39) in the world with 1,106 patients from 64 sites! The IMPROVE-IT trial, consistent with the vision of the Canadian VIGOUR Centre (CVC) “…to generate, translate and disseminate knowledge on novel… therapeutics strategies in cardiovascular medicine acquired through collaborative research to enhance the health of the citizens of…Canada, and the world” embodied our core values of quality, collaboration, integrity, and respect. Indeed, one measure of the outstanding Canadian effort was the fact that only 5 patients (<1%) were lost to follow-up at sites collaborating with the CVC. This is a remarkably low rate in the context of a trial that identified >5,300 primary endpoints during almost 100,000 total patient-years of follow-up. The CVC is proud to be a University of Alberta Centre
In This Issue: Letter - Shaun Goodman Trial Updates Monitoring CVC News Publications
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Of course, to get to the finish line, one has to first enroll the “right” patient from the start. Even after careful identification of potentially eligible patients, recruitment requires a discussion with the patient (and often their family member[s]) as part of the informed consent process, including the importance of maintaining study drug and regular follow-up assessments. As in most trials like IMPROVE-IT, participants are analyzed according to their allocated treatment (i.e., intention-to-treat) even if they temporarily or permanently discontinue study drug. The potential treatment effect may be diluted or even nullified if we aren’t able to keep our patients on the assigned study drug. This critical issue was brought to the forefront midway through the trial when negative publicity regarding ezetimibe required the IMPROVE-IT leadership to provide compelling arguments that the study needed to continue. We still didn’t have the answer to whether ezetimibe could improve clinical outcomes. Indeed, continued enrollment and adherence to study drug treatment in the trial was both ethical and vital. However, despite the global challenge of keeping patients on study drug, particularly in such a long-term trial with negative press, Canada’s rate of study drug continuation was above the trial average, representing yet another indication of the high quality of Canadian investigator and coordinator engagement in order to maintain high intensity patient participation. In addition to demonstrating the safety and efficacy of ezetimibe, the IMPROVE-IT investigators were able to reaffirm the LDL hypothesis—that lowering LDL (even with a non-statin agent) prevented cardiovascular events. Furthermore, the axiom that “even lower is better” was confirmed: patients on statin therapy alone achieved mean LDL cholesterol levels