now in its 28th year, the annual cardiovascular confer-are very common in patients with chronic...

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Now in its 28th year, the Annual Cardiovascular Confer-ence in the Rockies (ACC Rockies, formerly ACC Lake Louise) Organizing Committee continued its tradition of serving as Canada’s premier cardiovascular CME. An esteemed faculty of national and international experts was invited to share clinical and research experience with attending clinicians from across Canada. The scientific agenda offered attendees a broad-based program with topics covering the latest diagnostic, therapeutic, and preventative approaches to heart health and disease. Ple-nary sessions and interactive case discussions highlighted ground-breaking clinical trials, updated national guide-lines, and strategies to overcome common clinical chal-lenges. As part of its ongoing collaboration with the ACC Rockies, the Canadian Cardiovascular Society (CCS) pre-sented two interactive workshops to review and discuss

the clinical implications of some of its newest evidence-based guidelines, focused on the management of atrial fibrillation and heart failure.

The ACC Rockies continues to offer valuable opportuni-ties for sharing best practices among clinicians practicing in cardiovascular medicine, drawing together collective knowledge, efforts, and innovative strategies to improve patient outcomes and care. In an effort to enhance the knowledge translation and educational opportunities at the meeting, this conference report will provide a brief summary of topics selected by the Organizing Commit-tee. Readers are encouraged to visit the conference website at www.accrockies.com to view featured presentations and speaker interviews as well as download slidesets.

Conference Overview

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the express written permission of EBM Consulting Inc.

Non-communicable diseases were once segregated to the Western world, but today they constitute a global concern. Indeed, 80% of worldwide cardiovascular (CV) mortal-ity occurs in developing countries. Moreover, in low- and middle-income countries (LMIC), the absolute number of CV deaths is more than 3 times higher than deaths attrib-utable to HIV, tuberculosis and malaria combined. Yet the World Health Organization continues to focus the bulk of its activities and resources in developing countries towards communicable diseases. According to Dr. Bernard Gersh from the Mayo Clinic, our efforts in addressing CV disease should be el-evated to a higher level based on its increasing prevalence and burden.

The interaction between socioeconomic status (SES), economic factors, and CV risk has been well established. Most LMIC are in an epide-miologic transition stage characterized by rapid and profound changes in environmental risk factors such as tobacco use and caloric and lipid intake. In this stage, risk factors and CV disease are more prevalent in higher SES classes and tend to affect adults of working age. This contrasts with the situation in high-income countries, where individuals with low SES have a higher prevalence of risk factors and CV disease. It is expected that high-income countries will soon reach the

next epidemiologic stage characterized by a worsening of CV mortality due to the growing prevalence of diabetes and childhood obesity.

The risk factors associated with CV disease are well-known and constitute a “perfect storm” brewing in LIMC: smoking, diabetes, hypertension, abdominal obesity, ApoB:ApoA1 ratio, psycho-social index, low intake of fruits and vegetables, lack of exercise, and alcohol consumption. Taken together, these 9 modifiable risk factors account for

90% of the population-attributable risk in LMIC, a figure very similar to that in high-income countries. However, the situation in LMIC may be complicated by factors that are specific to their economic and so-cial circumstances, such as urban migration, exposure to second-hand smoke, a positive culture of obe-sity, aging societies, lack of infrastructure, a possible “thrifty-gene phenotype”, etc. LMIC are likely to face

similar obstacles as those that continue to plague high-income countries in their efforts to reduce CV morbid-ity and mortality, including physical environments, public health policies, food labeling, and other issues that will require support from both the public and private sectors.

“The human race has had long experience and fine tradition in surviving adversity; but we now face a task for which we have little experience, the task of surviving prosperity.” Alan Gregg, 1890-1957, Rockefeller Foundation

Cardiovascular Disease Prevention

Global Burden of Cardiovascular Health


Premature mortality and cardiovascular disease (CVD) are very common in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Can the demonstrated benefits of treatment with statins to prevent CV events in at-risk populations be extended to patients with CKD and/or ESRD? According to Dr. Marcello Tonelli, a nephrologist at the University of Alberta, the answer depends on intrinsic differences between CVD in patients with or without comorbid CKD as well as the heterogeneity within the CKD population itself.

First, while the rate of CVD mortality is only slightly higher in patients with ESRD (42%) compared to the general population (31%), the nature of CVD events is strikingly different: CVD mortality in ESRD is mostly attribut-ed to arrhythmias and sudden cardiac arrest (61% of total CVD mortality), while the majority of CVD mortality in the general population is attributed to acute myocardial infarction (AMI; 51%). Furthermore, LDL-cholesterol (LDL-C) does not predict CV risk in patients with ESRD or advanced CKD in the same way that it does in the general population. LDL-C levels vary based on intrinsic characteristics of CKD, including diabetes mellitus comorbidity, proteinuria, and glo-merular filtration rate (GFR). As GFR decreases, LDL-C levels also decrease. The predictive association between fasting LDL-C and risk of AMI is therefore greatly attenu-ated in the later stages of CKD, and LDL-C targets for the general population may not be appropriate for CKD patients.

Despite these differences, can statins still be used effective-ly in patients with CKD to prevent CV events? The rela-tive benefits of statins appear to be similar in patients with stage 1-3 CKD to those without CKD. In fact, studies report a relative risk reduction of 20-25% for CV events and 15-20% for CV mortality in stage 1-3 CKD patients.

However, no randomized controlled trial (RCT) has, to this point, demonstrated the efficacy of statins alone or in combination for dialysis patients.

Dr. Tonelli suggests that stage 1-4 CKD could be con-sidered as a CVD risk factor itself, equivalent to the risk attributed to diabetes. This is based on data showing that AMI rates in patients with diabetes are similar to those of patients with stage 1-3 CKD and that risks associated with higher levels of CKD supersede those of diabetes.

The question of whether statins could be beneficial in di-alysis patients remains to be addressed by RCTs. Accord-ing to Dr. Tonelli, the benefits are “likely, but uncertain” and he advocates for more RCTs to specifically address this issue. From a clinical perspective, he recommends early identification and treatment of CKD patients at risk of CV events and use of statins at doses evaluated in RCTs (e.g., pravastatin 40 mg, simvastatin 40 mg, atorvastatin 20 mg, simvastatin 20 mg + ezetimibe 10 mg). He con-cluded with a reminder to the audience that patients with CKD present additional clinical challenges, including a higher potential for drug interactions, drug toxicity due to reduced clearance, and low adherence rates.

Management of Lipids in Patients with Chronic Kidney Disease



Recent advances have resulted in a dramatic reduction in the proportion of deaths due to CVD in Canada from 32.4% in 2000 to 27.4% 2007. Dr. Jacques Genest from McGill University reviewed three novel targets that could potentially reduce CV mortality and morbidity even fur-ther: phospholipase A2 (Lp-PLA2), HDL-cholesterol (HDL-C), and PCSK9.

Several lines of evidence support Lp-PLA2 inhibition, a marker of vascular inflammation, as a target for the treat-ment and prevention of CVD. Lp-PLA2 is more specific to vascular inflammation than traditional markers such as C-reactive protein (CRP). Ruptured or “rupture-prone” plaques show increased Lp-PLA2 content. Selective in-hibition of Lp-PLA2 with darapladib has been shown to reduce the development and complexity of coronary atherosclerotic plaque in a swine model. Based on these encouraging results, two clinical trials are currently un-derway to test the effects of darapladib on CV death, nonfatal MI, and nonfatal stroke in at-risk populations. Limitations to this approach must also be acknowledged, including redundancy of the human proteome. Further-more, loss-of-function mutation in the gene encoding for Lp-PLA2 that is common in East Asian populations has been shown to abolish its activity without decreasing vascular risk.

Increasing HDL-C is another therapeutic approach that has received considerable attention over the last years. The epidemiological data are strong and coherent showing a graded and continuous relationship between increasing HDL-C and a reduction in the risk of coronary artery disease (CAD) and, although less robustly, the risk of

ischemic stroke. One of the main physiological effects of HDL-C is its ability to promote cholesterol efflux from lipid-loaded macrophages and foam cells and to subse-quently promote its excretion in bile acids via the liver (the reverse cholesterol transport pathway). While one of the first important trials looking at HDL-C-elevating strategies was terminated early due to null results, two other trials are currently underway, evaluating the effects of evacetrapib or anacetrapib (REVEAL trial) on CV mortality. Preliminary data already show strong increases in HDL-C levels, but the question remains whether this will translate into positive outcomes when hard mortal-ity endpoints are evaluated.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that, upon autocleavage and activation, trig-gers lysosomal degradation of the LDL receptor, thus causing hypercholesterolemia. A single nucleotide poly-morphism (SNP) in the PCSK9 gene associated with a loss of function results in lifelong decreased LDL-C lev-els and a near 90% reduction in coronary heart disease (CHD) risk. This observation has prompted no fewer than 8 companies to initiate trials testing monoclonal antibodies to prevent the interaction of PCSK9 with the LDL receptor. Phase I and II trials published to date have consistently shown a 60-70% decrease in LDL-C com-pared to placebo.

Dr. Genest predicted that biologic medicines, despite their higher cost relative to pharmaceuticals, will soon be added to the armamentarium for the treatment of hyper-cholesterolemia.

Novel HDL Therapies – A Promising Future?


Weight reduction and management in overweight and obese populations is an ongoing clinical challenge. Dr. David Lau from the University of Calgary suggests 5 prin-ciples for clinical weight management in obese patients.

1. Obesity is a chronic condition: As such, it requires long-term treatment to prevent weight regain. Suc- cessful weight management requires the understanding from both physicians and patients that “quick-fix” solutions are not beneficial in the long-term.

2. Successful obesity management is about improving health and well- being: Due to the normal course of weight gain, weight maintenance should be regarded as a success. Even modest weight loss (1.2% as seen in the Diabetes Prevention Pro- gram) is associated with considerable health benefits including improvement in CVD risk, blood pressure, lipid profile, and glycemic control. Maintenance of weight loss is challenging because the body adapts by reducing resting metabolic rate and changes in body composition. Dr. Lau emphasized the importance of mindful eating and incorporating exercise (30 min of moderate intensity exercise 5 times a week), especially in the weight maintenance phase.

3. Early intervention means addressing root causes and removing barriers: Obesity due to genetic causes is rare and it is more likely attributable to social, emotional, and/or biomedical factors that are the major root causes of obesity. Identifying and removing barriers to health behavior changes will facilitate weight loss and maintenance.

4. Success is different for every individual: Patients vary considerably in their readiness to change and underlying physiological mechanisms contribute to large inter- individual variability in response to weight loss strategies. For example, men are more likely to be successful in weight management than women, due, at least in part, to the faster decrease in resting metabolic rate in women following weight loss.

5. A person’s best weight may never be an ideal weight: For some patients, a ‘healthy’ body mass index (BMI; 20-25 kg/m2) may not be achievable and targeting this goal may set patients up for failure.

Treatment of obesity consists of 3 main types of inter-ventions: lifestyle modification, especially for overweight patients (BMI ≥25); pharmacotherapy (options are very

limited and are associated with side effects); and bariat-ric surgery (reserved to patients with class 3 obesity [BMI ≥40] or with class 2 obesity [BMI ≥35] with comorbidi-ties, particularly diabetes). Gastric bypass is the most ef-fective bariatric surgery routinely used and has been as-sociated with striking weight reduction (10%), as well as improvements in metabolic and glycemic control inde-pendent of weight loss.

Dr. Lau encouraged all physicians to routinely assess obesi-ty in all patients by first evaluating BMI and waist circum-ference, which he considers “a new vital sign”, together with appropriate history, physical examination, and labo-ratory tests to diagnose obesity-related health problems.

Practical Approaches to the Treatment of Obesity



The inaugural ACC Rockies Lecture, delivered by Dr. Duncan Stewart, CEO and Scientific Director of the Ottawa Hospital, highlighted the promise – and the chal-lenge – of stem cell therapies in cardiovascular medicine. A large proportion of patients who suffer a myocardial in-farction (MI) are left with considerable cardiac injury even after treatment, which contributes to reduced left ventricu-lar ejection fraction (LVEF). Molecular and cellular thera-pies offer the potential to enhance repair processes and per-haps even promote regeneration of damaged myocardium.

Stem cell therapies have been a popular topic in the field of CV research for many years. The first stems cells that were shown to enhance cardiac repair were the blood-derived endothelial progenitor cells (EPCs). While EPCs can be isolated from blood or bone marrow mononuclear cells (MNCs) using surface markers, there is no agree-ment about which markers to use and it is difficult to iso-late enough of these cells to be effec-tive when delivered to the infarct area. When circulating MNCs are cultured for 3-7 days in the presence of matrix and endothelial growth factors, they yield a population of early outgrowth EPCs, also called circulating angio-genic cells, that decrease by 10-fold the required number of injected cells to achieve the roughly equivalent ac-tivity. These culture-derived EPCs are nonproliferative, highly angiogenic, and can be injected directly into the coronary artery.

Systematic reviews of clinical trials us-ing bone marrow-derived stem cells for acute myocardial infarction (AMI) have yielded consistently positive results, showing a 2-3% improvement in LVEF compared to placebo. This improve-ment has been reported after short-term and long-term (12-61 months) follow-up in several trials, with the greatest ef-fect observed in patients with lower baseline LVEF. Despite these consistent results, Dr. Stewart raised some important

questions: is a 2-3% improvement in LVEF “good enough”? Could the process be improved upon by using cell enhance-ment strategies?

One of the major issues limiting the efficacy of autologous EPC therapy for AMI is the deleterious effect of host car-diac risk factors, such as age, diabetes and hyperlipidemia, which all reduce the expression or activity of endothelial nitric oxide (eNOS). Dr. Stewart’s group examined wheth-er increasing the expression of eNOS in EPCs through a genetic engineering approach could improve outcomes of stem cell therapy. Using a mouse ischemic limb model, Dr. Stewart’s group showed that eNOS-transfected EPCs significantly increased perfusion recovery compared with placebo and non-transfected EPCs. A Canadian Phase II trial called EnACT-AMI will be the first trial worldwide to evaluate the safety and efficacy of this strategy in a clini-cal population; the trial is scheduled to start this summer.

While investigations with blood- and bone marrow-de-rived stem cells are encouraging, these cells do not appear to directly give rise to new cardiac cells and work mostly through paracrine and immunomodulatory mechanisms,

ACC Rockies Lecture: Translating Molecular Insights into New Cellular Therapies for Cardiovascular Disease


which enhance repair processes but do not regenerate myocardium in animals or humans. There remains strong interest in identifying cells that have the ability to regener-ate cardiac cells. The adult heart contains small reservoirs of cardiac progenitor cells, which can be isolated from a cardiac biopsy. The cells can be cultured to expand the population to clinical doses, a process that can take be-tween 1-4 months. Two small, open-label trials have exam-ined the effects of resident cardiac stem cells on LVEF in post-MI patients. The CADUSEUS trial (n=25 patients; 8 controls) reported decreased scarring and increased vi-able mass on magnetic resonance imaging (MRI); howev-

er, these effects were not associated with improved LVEF. The SCIPIO trial (n=23 patients; 7 controls) reported de-creased infarct size and a 5% increase in LVEF.

Dr. Stewart predicted that stem cells may one day be an important adjunct therapy for patients with cardiac dys-function post-MI. Blood-derived cell therapies are prom-ising but “enhancement” may be needed to improve ef-ficacy. Resident cardiac stem cell therapies require larger Phase II trials to assess their relative benefits compared to blood marrow and blood-derived stem cells, and results of such trials are eagerly awaited.

Clinicians often find themselves in a difficult balancing act when managing patients with acute coronary syn-drome (ACS): aggressive antiplatelet and antithrombotic therapy is indicated to reduce the risk of ischemic events, but this protection comes at the cost of an increased risk of major bleeding, which itself is associated with increased mortality and recurrent ischemic events. Dr. Stefan James, Head of Interventional Cardiology at Uppsala Clinical Research Center University Hospital in Uppsala, Sweden, suggests that patient outcomes could be significantly im-proved if physicians were better able to “hit the optimal therapeutic window for antiplatelet drugs.” This is contingent on identify-ing ACS patients with increased risk of ischemic events and/or bleeding and then selecting the best treatment agent and dose that minimizes the risk of either event. The GRACE risk score and CRUSADE bleeding score can be used to categorize patients by risk of ischemic and bleeding events, respectively.

Dr. James summarized the net benefit/risk of some of the newer antiplatelet and anticoagulant strategies that have been evaluated in recent clinical trials:

•The OASIS-5 study showed that fondaparinux was non-inferior to

enoxaparin in reducing the risk of death/MI/ischemia but significantly reduced the risk of major bleeding (50%) and death (17%). Dr. James opined that the dose of enoxaparin was probably too high and may have accounted for the difference in bleeding.

•TheHORIZONSAMIstudyshowedthatbivalirudin + unfractionated heparin (UFH) significantly reduced the rates of death and major bleeds at 30 days versus heparin + a GPIIb/IIIa inhibitor, with no difference in major adverse CV events.

Acute Coronary Syndrome

Walking the Tight Rope in ACS: Balancing Safety and Efficacy



•ThePLATOstudyshowedthatticagrelorsignificantly reduced CV death compared with clopidogrel with no difference in major bleeds in coronary artery bypass graft (CABG) and non-CABG patients. It offers a faster onset of action and consistent efficacy across patient subgroups.

•TheTRITON-TIMI38studyshowedthatprasugrel significantly reduced a composite primary endpoint of CV death/MI/stroke but at the cost of increased major non-CABG bleeds. Net clinical benefit was not consistent across subgroups, making this agent more complex to use in the clinical setting.

Antithrombotic and antiplatelet therapies such as warfa-rin and clopidogrel, alone or in combination with aspirin, have been shown to reduce ischemic events and CV mor-tality in ACS patients. However, there remains an event rate of approximately 10%, suggesting a gap in terms of optimizing anti-ischemic therapy. Studies evaluating triple therapy with clopidogrel, warfarin, and aspirin showed no additional anti-ischemic benefit and an unacceptable in-crease in bleeding complications. Could new antithrom-botic agents be beneficial as adjuncts to standard ACS

therapy? Dr. James summarized the available evidence for two new antithrombotic agents assessed in triple therapy:

• APPRAISE-2 showed that apixabanwasnon-inferior to placebo on a primary endpoint of CV death/MI ischemic stroke and was associated with increased risk of major bleeds; there was a trend towards reduced risk of stent thrombosis.

•TheATLAS-ACS-2TIMI51studyshowedthatriva- roxaban significantly reduced ischemic event rates and stent thrombosis but increased the risk of major bleeds. CV death was significantly reduced with the 2.5 mg, but not the 5 mg, dose.

Taken together, Dr. James concluded that there remains a need to improve patient selection concerning both the risk of new ischemic events and of bleeding complica-tions. Furthermore, new drugs and/or combinations of antiplatelets and anticoagulants are needed that improve efficacy with an acceptable bleeding risk. Finally, clinical management of bleeding complications needs to be fur-ther refined so that when bleeding occurs, it is associated with lower patient morbidity and mortality.

According to Dr. Paul Armstrong from the University of Alberta, the electrocardiogram (ECG) is a “renaissance tool that is grossly underappreciated… and a very impres-sive bioassay.” He discussed how prognostically powerful and clinically insightful the ECG can be, particularly in assessing the efficacy of early pharmacological interven-tions for reperfusion.

Dr. Armstrong has compared over ¼ million ECGs from several clinical trials and concluded that baseline area un-der the curve of ST segment abnormality (elevation and depression) are important predictors of patient outcomes. Notably, survival rate decreases as the magnitude of ST de-viation at baseline increases. This is true both for patients who achieve reperfusion (defined as ≥50% resolution in ST deviation) as well as those who do not, highlighting that it’s not just the extent of resolution that’s important from a prognostic perspective, but also the extent of ST segment abnormality at baseline.

Similarly, there is a striking effect of the extent of ST de-pression on outcome in NSTEMI patients, with increas-ing ST depression associated with increased mortality. Further, a strong interaction exists between the extent of ST depression and the level of NT pro-BNP, a neurohor-monal marker of left ventricular performance, on mortal-ity. Finally, persistence of ST depression at discharge in NSTEMI patients is also predictive of increased mortality risk at 180 days.

When using ECG to guide treatment decisions, Dr. Arm-strong warned clinicians to beware of “infarct masquerad-ers” that can result in unnecessary trips to the cath lab. Other abnormalities such as ventricular aneurism, peri-carditis, and other pathologies may account for abnormal ECG findings.

The Q wave can provide important insights regarding the time of MI symptom onset as it relates to outcome. Pres-

New Role For an Old Friend: Contemporary Insights From the ECG


ence of a baseline Q wave significantly increases risk of death/CHF/shock over 90 days and is a better predictor of this outcome than time from symptom onset to percutane-ous coronary intervention (PCI), particularly in women.

ECG is promptly responsive to phar-macological interventions and is a powerful tool to assess reperfusion in STEMI patients. ST segment resolu-tion within 60 minutes of treatment indicates an aborted MI, whereas ST deviation that does not improve 90 minutes post-treatment signifies failure of reperfusion therapy. Dr. Armstrong suggested that aborted MI could serve as a new therapeutic target as patients are treated earlier and with better drugs. The extent of ST resolution post-PCI in STEMI patients is strongly associat-ed with outcome. This measure can be readily calculated in the clinical setting by identifying the worst lead pre-PCI and then measuring the residual devia-tion in that lead post-PCI, providing an important prognostic tool. Importantly, approximately 1 in 4 STEMI patients present with ST depression. Valu-able prognostic insights can be afforded by assessing the extent of resolution of both ST elevation and depression, with failure to resolve either characteristic associated with the worst outcome.

The value of the ECG in providing insights into new treat-ment mechanisms can be illustrated with the ECG Sub-study of the PLATO trial. Among STEMI patients who achieved reperfusion (i.e., ≥50% ST resolution), survival

was improved in those treated with ticagrelor compared with clopidogrel. Survival was lowest in patients who did not achieve reperfusion, irrespective of treatment group. There was no difference between treatments in the rate of

reperfusion. These hypothesis generating findings suggest the potential impact of a later and more powerful platelet inhibiting effect with ticagrelor compared with clopido-grel, an effect that did not come into play in patients who did not achieve reperfusion.

Dr. Armstrong concluded that “There are new tricks from old dogs” and that the ECG is a prognostically powerful, underappreciated bioassay that offers unique insights into the “state of evolution” in AMI.



Canada is recognized as a leader in enhancing systems of care to improve time to treatment and outcomes for STEMI patients. Dr. Robert Welsh, from the University of Alberta, shared key insights and lessons learned about regional STEMI networks based on his experience with the Vital Heart Response (VHR) reperfusion protocol in Edmonton and surrounding area. These were summarized into 3 main insights:

1. Knowledge is key. Regional STEMI networks benefit from “hub and spoke” systems with collaboration between regional referral hospitals without primary PCI (PPCI) capacity and experienced PPCI centres. To function optimally, these networks must acknowledge and incorporate geographic re- alities of the region. Common approaches to regional STEMI networks include pre-hospital diagnosis and triage of STE- MI, optimizing timely PPCI, and appropriate activation of the catheterization lab. The focus of regional STEMI networks on PPCI as the dominant strategy has led to both positive and negative consequences, namely the “reperfusion paradox.” Delays in accessing timely PPCI persist in most patients presenting to non-PCI hospitals, and at the same time, there has been a decline in the ability to provide “state-of-the-art” fibrinolytic management, which is known to be particularly beneficial in early presenting patients.

2. Importance of “on line” medical oversight. The VHR system is focused on initiating patient care at the first point of patient contact. To facilitate this, the system utilizes a single phone number for paramedic teams and referral physicians giving them access to a dedicated “on call” team of specialists capable of receiving and interpreting ECGs in real time, assessing individual patient risk profiles, and immedi- ately assigning patients to a reperfusion strategy based on either PPCI or fibrinolysis, depending on patient characteristics and temporal parameters. Importantly, this system allows the expansion of protocols to rural patients, who account for 45% of STEMI cases in the VHR region. Notably, 72% of rural patients are treated with a pharmacoinvasive strategy and benefit from significantly better outcomes in terms of death and re-MI compared to patients treated with PPCI in urban

centres. Benefits of on line oversight include avoidance of in- appropriate cath lab activation (<5% in the VHR system) and enhanced administration of timely reperfusion, including fibrinolysis in pre-hospital and rural settings.

3. Importance of comprehensive quality improvement. The VHR program tracks response data in an effort to continually improve the system and patient outcomes. Dr. Welsh candidly acknowledged that “You get a sense of just how challenging this is when you track your outcomes.” In an analysis of all STEMI patients treated in the Edmonton region in 2010, median time from first medical contact to PPCI was 128 minutes and fibrinolysis was 47 minutes. Patients who were managed through the VHR system had substantially faster times to PPCI (99 min in 2010, 94 min in 2011) and fibrinolysis (37 minutes in 2010 and 33 minutes in 2011).

Dr. Welsh concluded that “Regional systems of care need to ad-dress multiple levels, but the focus has to be on the patient.” Administrative input and support is essential, as is system-wide integration and governmental support, including the ability to track outcomes through a quality assurance program.

STEMI Management in 2012: Facilitating Timely Reperfusion Therapy for Urban and Rural Patients


Dr. Erick Schampaert, from the Université de Montréal, was assigned the daunting task of presenting important up-dates to the field of interventional cardiology. He catego-rized the selected topics into 3 groups, summarized below.

• Vascular access. The majority of bleeding complications in patients with ACS who undergo PCI relate to vascular access, making this an important area in which patient care could be improved. Real-time ultrasound has been shown to facilitate proper puncture positioning and to reduce vascular complications. Evidence from small RCTs and meta-analyses show equivocal results for vascular closure devices, suggesting that these should not be used in the overall cath lab population until large RCTs have confirmed their efficacy and safety. Radial access has been shown to be as effective and safe as femoral access for PCI, with a lower rate of local vascular complications. Studies are ongoing to determine if radial access reduces CV events and bleeding in the subpopula- tion of STEMI patients.

• Antithrombotics in the cath lab. Bivalirudin could become the dominant anticoagulation strategy in STEMI patientsbasedontheHORIZONAMIstudy.Thistrial showed a significant benefit with bivalirudin versus UFH with a GIIb/IIIa inhibitor in terms of both major bleeding and mortality at 1 year; an extension study showed that this benefit was maintained at 3 years. Other studies have shown that bivalirudin is associated with a reduction in mortality when major bleeding occurs, whether related to access or non-access sites, in both STEMI and non-STEMI patients. In terms of antiplatelets, prasugrel has been shown to reduce the risk of death/ MI/stroke and stent thrombosis without increasing major bleeding versus clopidogrel in patients who were not pre-treated with clopidogrel and whose coronary anatomy was known and were indicated for PCI or were undergoing primary PCI for STEMI. Ticagrelor has been demonstrated to reduce MI, cardiovascular death, and stent thrombosis versus clopidogrel in all ACS patients, whether or not pre-treated with clopidogrel.

• Adjunctive modalities. Fractional flow reserve (FFR), a means to assess the physiological significance of a lesion’s

severity in the lab, is a measure of the extent to which a vessel’s maximal myocardial flow is limited by the stenosis. FFR has demonstrated significant benefit over angi- ography for guiding PCI in patients with multivessel CAD with respect to death/MI after 2 years and a strong trend for 2 year survival free of repeat revascularization. There was no signal suggesting that deferred lesions were likely to be responsible for late MIs or to progress and require repeat revascularizations. The instantaneous wave-free ratio (iFR) is a new concept that is a measure of the instantaneous pressure ratio across a stenosis at a specific point in diastole when resistance is minimal, thus not requiring IV adenosine to be administered. iFR appears to have a diagnostic accuracy that is similar to the FFR for identifying the severity of lesions; this approach remains to be validated in larger studies. New technologies are providing improved identification and charac- terization of lesions, including high-definition intra- vascular ultrasound (HD-IVUS) and optical coherence tomography (OCT), which uses light instead of sound waves. These technologies continue to be evaluated and refined in the research setting.

• Stents. New generation drug-eluting stents (DES) have been shown to afford a lower rate of definite and proba- ble stent thrombosis compared with first generation stents, and could potentially allow for a shorter duration of use of antiplatelet therapy (3 to 6 months vs. 12 months). Stents made of biodegradable polymers are showing promising preliminary results in large RCTs. Bioabsorbable stents made of materials that are com- pletely resorbed over the course of 2 years, offering the potential to leave patients with more “normal” vessel physiology and function, are currently being evaluated in Phase III trials.

Dr. Schampaert’s presentation provided a succinct summa-ry of the topics that he considers to be significant changes in terms of clinical practice or that have the potential for be-coming innovations in interventional cardiology in general.

Update in Interventional Cardiology



Microvascular angina is a significant and diagnosable con-dition that affects up to 40% of women and 20% of men with atypical chest pain syndromes and minimal CAD. The condition affects a heterogeneous group of patients with variable presentation, and tends to be more common in patients with metabolic syndrome, fibromyalgia and chronic fatigue syndrome.

Dr. Todd Anderson, from the Univer-sity of Calgary, reviewed the patho-physiology of microvascular angina, a condition that is not yet fully under-stood. He described 5 hypotheses: 1) abnormalities in vasomotion or the in-ability of the microvasculature within the myocardium to dilate properly, 2) diffuse minor atherosclerosis that is not easily visualized, except with IVUS, 3) metabolic abnormalities that result in ischemia (approximately half of patients have been shown to have documented ischemia by MR-spectroscopy), 4) abnormal cardiac adrenergic function whereby patients perceive pain in response to a stimulus where others would not, and 5) meta-bolic syndromes, which have a pathophysiologic overlap whereby patients with insulin resistance (whether obese, overweight or normal weight) experience more events than non-dysmetabolic patients.

Although there is no gold standard for diagnosis of micro-vascular angina, an angiogram with an acetylcholine chal-lenge can produce diffuse vasospasm and induce chest pain in ~50% of patients with cardiac chest pain and minimal CAD. The role of non-invasive testing is promising but re-mains to be elucidated. A research group at the Libin Car-diovascular Institute has shown that measures of peripheral vascular function may be used to risk stratify patients with atypical cardiac pain; while the results are encouraging, larger scale studies are needed to validate this approach.

Diagnosis is important because these patients tend to be highly symptomatic, use considerable resources (estimat-ed at $750K per patient over their lifetime) because they often receive repeat testing procedures, multiple visits to

the cath lab, and repeat hospitalizations, and they have a worse prognosis than those without vasomotor abnormal-ities (1-2% event rate per year). Moreover, diagnosis can be reassuring to patients. Often, these patients develop epicardial disease that warrants treatment of risk factors for primary prevention of atherosclerosis and metabolic

risk factors (e.g., aspirin, statins, ACE inhibitors); howev-er, there is a lack of good quality evidence to support such treatment strategies. Dr. Anderson noted that exercise can be effective; therefore, referral to cardiac rehabilitation for consultation with an exercise physiologist can be benefi-cial. Some patients also benefit from psychotherapy.

Dr. Anderson encouraged the audience to keep an open mind when they encounter patients with chest pain and minimal CAD. Non-cardiac diagnoses may contribute to their chest pain (e.g., musculoskeletal or gastrointestinal conditions, fibromyalgia, anxiety) and these should be investigated. “These are amongst the most difficult pa-tients that we deal with.” In his practice, Dr. Anderson concentrates on the chest pain syndrome and reassures pa-tients that they have a real diagnosis from a cardiac point of view. Further research is needed to determine the best treatment and monitoring strategies for progression of CAD or abrupt events.

Microvascular Angina’s Current Relevance to Clinical Practice


With the introduction of several new and more potent an-tithrombotic agents in recent years, the treatment of ACS has become very complicated. Indeed, the availability of 11 antithrombotics generates 384 possible treatment com-binations. Dr. Stefan James, from the University Hospital in Uppsala, Sweden, provided practical insights on how to integrate some of the most recent clinical trial findings of newer antithrombotic agents that are poised to change the clinical management of ACS.

New developments in antiplatelet therapy are leading the way in improving primary and secondary outcomes for patients with ACS:

• Clopidogrelcontinuestobearecommendedantiplate- let agent and is an important option for patients who have contraindications to newer and more potent agents such as prasugrel or ticagrelor. Recent evidence supports the use of a 600 mg loading dose of clopidogrel in patients undergoing planned PCI; however, there is limited evidence to support a higher maintenance dose.

• Prasugrelandticagrelorhavefasteronsetandhigherpo- tency than clopidogrel and have both shown superiority over clopidogrel in Phase III clinical trials. Dr. James recommends that prasugrel is best reserved for patients with ACS and planned PCI who are at lower risk of bleeding (i.e., younger than 75 years of age, are not un- derweight [<65 kg], and have no history of stroke or transient ischemic attack). Moreover, Dr. James advised that “Prasugrel should probably not be given pre-hospital.” The net clinical benefit appears to be greatest for patients with STEMI or diabetes mellitus whose coronary anatomy is known.

• DatafromthePLATOstudyconclusivelydemonstrate reduced CV death/MI/stroke with ticagrelor at the cost of an increase in TIMI major non-CABG bleeding; adjunctive use of proton pump inhibitors (PPI) should be considered to reduce the risk of major GI bleeds. Ti- cagrelor has been shown to reduce stent thrombosis and all-cause mortality with an impressive absolute risk reduction of ~1-2% in both invasive and non-invasive treatments strategies compared with clopidogrel, even in patients with a history of prior stroke or transient ischemic attack (TIA). Ticagrelor has not been evaluat-

ed in patients who have been pre-treated with fibrolyt- ics. Although guidelines recommend stopping the drug 5 to 7 days prior to surgery or CABG, Dr. James suggested that 3 to 5 days might be more reasonable. There is no apparent association between dyspnea and adverse outcomes, therefore Dr. James advises his patients that this adverse effect is usually temporary and the drug should be continued if tolerable.

There have also been important advancements in anticoagulation:

• Bivalirudin is associatedwith significantly lower rates of major bleeding compared with UFH plus a GPIIb/ IIIa inhibitor in STEMI patients. Data from the SCAAR trial suggest that bivalirudin should probably always be combined with a low dose of UFH for patients undergoing PPCI, since this combination was associated with a significantly lower rate of stent thrombosis.

•The additionof rivaroxabanor apixaban todual antiplatelet therapy is unlikely to be adopted into clinical practice due to the considerable increase in risk of major bleeding. Dr. James predicts that using a higher potency antiplatelet agent such as prasugrel or ticagrelor will be a preferred treatment approach in ACS patients.

Dr. James concluded his presentation by sharing some re-cent data from the Swedish SWEDEHEART online car-diac patient registry. Notably, there was a marked decrease in the use of warfarin and acetylsalicylic acid (ASA) in both STEMI and NSTEMI patients from 1995 to 2008, with a concomitant rise in the use of clopidogrel plus ASA. This was paralleled by increasing rates of PPCI and reduced use of fibrinolytics, although these continue to be used in more remote areas. Strikingly, mortality has been reduced by almost 50% in this time frame, with increases in survival of 2.6 years in STEMI patients and 1.7 years in NSTEMI patients. Dr. James anticipates that mortality will be even further reduced with the introduction of new and more potent antithrombotic agents that offer a more favourable balance between efficacy and safety.

Practical Applications of New Developments in Antithrombotic and Antiplatelet Therapy in ACS



Transaortic valvular implantation (TAVI) is now con-sidered a standard of care for carefully selected patients with symptomatic aortic stenosis who are not suitable for surgery. This recommendation by the CCS guidelines is based in large part on data for the SAPIEN valve, which was shown in the large PARTNER A/B trials to signifi-cantly reduce all-cause mortality, CV mortality, and repeat hospitalization and to improve quality of life compared to standard treatment in patients with se-vere high-risk or inoperable symptom-atic aortic stenosis. According to Dr. Robert Welsh from the University of Alberta, the data translate into impres-sive number-needed-to-treat (NNT) values ranging from 2.7 to 4.1, with a particularly strong effect observed for reduction in CV mortality. These benefits were offset by a higher risk of stroke and a 30-day mortality rate of 6.4%, suggesting that TAVI is not a benign procedure. Reassuringly, there were no apparent adverse effects of paravalvular leakage.

The PARTNER studies also addressed the question of whether transfemo-ral or transapical TAVI was superior to surgical aortic valve replacement (SAVR). There was an early apparent advantage of TAVI in reducing all-cause mortality at 6 months, but this dif-ference was lost at 1 and 2 years of follow-up, suggesting that long-term outcomes of TAVI are similar to SAVR. Likewise, early benefits in quality of life also disappeared after 6 months. Although the study was not designed to directly compare transfemoral versus transapical ap-proaches, there was an apparent advantage for the trans-femoral approach.

The cost of TAVI is substantial and estimated at ~$50,000 per life-year gained. Therefore, careful patient selection is important. The CCS guidelines strongly endorse transfem-oral TAVI in patients for whom the risk of open heart sur-gery is prohibitive, who are expected to derive significant improvement in duration and/or quality of life, and whose

life expectancy with treatment is expected to exceed 1 to 2 years. Traditional surgical approaches are recommended for patients who are considered to be at intermediate or low surgical risk and for non-high risk patients with fail-ure of bioprosthetic surgical valves. Dr. Welsh predicts that “We will eventually see patients coming back with failed TAVI valves” and repeat TAVI may be reasonable in care-fully selected patients with transcatheter valve failure.

Appropriate patient selection for TAVI requires an exten-sive work-up and successful procedures rely on an expe-rienced multidisciplinary team that is involved in screen-ing, the peri-procedural period, and follow-up. Individual TAVI team members must perform at least 25 procedures annually to maintain competency.

TAVI devices continue to be refined with smaller diam-eters that are easier to implant and other enhancements that may reduce the frequency of procedural complica-tions. Stay tuned for the results of two ongoing random-ized trials evaluating the Edwards and CoreValve devices in intermediate- to high-risk patients.

Structural Heart Disease

Percutaneous Aortic Valves – The Canadian Perspective


Randomized trials of surgical (CABG) versus medical therapy in patients with congestive heart failure (CHF) suggest that the sicker the patient, the greater the long-term survival benefit of CABG over medical therapy. Dr. Bernard Gersh discussed this revascularization paradox in the context of the 5-year results of the landmark STICH trial, and provided his interpretation of what the study tells us about surgical treatment of patients with CHF and coronary disease.

Contrary to other trials, the STICH study showed no significant difference in the primary endpoint of all-cause mortality at 1 year between medical therapy and CABG; however, there was a significant reduc-tion in CV death and CHF hospital-ization favouring CABG over medi-cal therapy over 6 years of follow-up, suggesting that CABG is the better option in the long term. Dr. Gersh recommends that all patients with left ventricular (LV) dysfunction should be evaluated for CAD, and patients with the best chance of revasculariza-tion should probably receive CABG over medical therapy.

Meta-analysis of nonrandomized trials and results of a STICH substudy sug-gest that viability testing might not be as important in the decision-making process as once thought. However, Dr. Gersh noted that the STICH sub-study had several limitations that must be taken into consideration when in-terpreting the results. He suggested that viability testing may be helpful in patients with severe LV dysfunction, extensive LV remodeling, multiple comorbidities, or in-complete revascularization, whereas it may not be essen-tial in patients with significant angina, good distal vessels, ECG with no Q waves and preserved voltage, and those who present a reasonable surgical risk.

The STICH trial also evaluated the efficacy and safety of surgical ventricular reconstruction (SVR) in patients un-dergoing CABG. There was no significant difference in mortality between CABG with or without SVR, which contrasts with previous studies that showed very significant reductions in mortality for CABG plus SVR. Inadequate volume reduction may have accounted for this negative finding in the STICH trial. Other surgical therapies for heart failure include LV-assist devices (LVAD), which have been shown to improve symptoms in patients with dilated but not ischemic cardiomyopathy. By unloading the heart, Dr. Gersh hypothesized that LVAD may allow the heart to rest enough to allow cellular, structural, and functional re-

covery. LV-assist devices may be a key tool for understand-ing the molecular mechanisms of cellular repair and for identifying new therapeutic targets. Dr. Gersh predicted that the future of CHF therapy will most likely be driven by “unraveling the molecular web” that controls contrac-tion and relaxation of sarcomeres, signaling, calcium trans-port and energetics, as well as pharmacogenomic profiling.

Surgical Approaches to CHF: Implications of STICH and the VAD



Dr. Peter Liu from the University Health Network in Toronto, Ontario presented an “advanced heart failure” review that focused on two key challenges facing cardiolo-gists in the management of acute HF: hyponatremia and prevention of thromboembolic events.

Hyponatremia (defined as serum [Na+] < 134 mmol/L) is frequent at the time of hospitalization and is recognized as an important predictor of mortality in patients with acute-ly decompensated HF. Whereas there are many evidence-based treatments and devices available for the management of chronic HF, evidence-based treatment algorithms for acute HF are more limited. Patients with volume overload should have fluids withheld and IV diuretics should be commenced using either bolus or continuous infusion, followed by step-down to oral diuret-ics. Evidence from the NHLBI DOSE study suggests that high intensification (2.5 x oral dose) was associated with trends towards greater improvement in several domains including symptom relief, weight and net volume loss, re-duction in NT-proBNP levels, and a greater chance of being free from signs of congestion.

An increasing number of centres are offering ultrafiltration for acute HF patients who are resistant to traditional IV diuretics and who meet criteria of significant volume overload, adequate blood pressure and perfusion, reason-able renal function, and who can tolerate full anticoagula-tion. The UNLOAD trial showed that ultrafiltration im-proved weight and net fluid loss, and was associated with less need for vasoactive drugs; however, ultrafiltration did not improve dyspnea compared to IV diuretics.

Vasopressin antagonists are a new class of drug that has recently become available in Canada. These agents work by opening water channels in renal tubules resulting in aquauresis (loss of water but not solutes). Tolvaptan was evaluated in the EVEREST study, which showed no ef-

fect on all-cause mortality or a combined endpoint of CV mortality or hospitalization for worsening HF. However, a post hoc subgroup analysis of patients with hyponatremia showed improvements in serum sodium concentration, dyspnea, and survival, and a trend towards shorter length of hospital stay. Dr. Liu predicted that patients with acute HF and hyponatremia are the most likely to benefit from vaso-pressin antagonists since they cause aquauresis rather than diuresis, allowing rapid correction of serum sodium levels.

Thromboembolic complications continue to be a chal-lenge in the management of HF patients, with an inci-dence of 2-3% per year. While warfarin has tradition-

ally been recommended in this patient group to prevent thromboembolism, the WARCEF study suggests that ASA is associated with a significantly lower risk of isch-emic stroke than warfarin, whereas both agents offer equivalent efficacy against death, stroke or intracranial bleed. Guidelines for anticoagulation in HF are likely to continue to recommend individualization of anticoagula-tion treatment based on patients’ presenting risk factors.

Current Challenges in HF Care – Impact of Hyponatremia & Thromboem-bolic Complications


Supraventricular tachycardia (SVT) is less common than ventricular arrhythmias, but must be correctly identified to make appropriate treatment decisions. The three most common types of SVTs are AV node reentry (AVNRT), AV reentry (AVRT) and atrial tachycardia (AT); however, other conditions should be considered in the differential diagnosis, including inap-propriate sinus tachycardia and postural orthostatic tachycardia syndrome. Per-manent junctional reciprocating tachy-cardia, junctional ectopic tachycardia and Mahaim tachycardia are more common in children than in adults. Dr. Derek Exner, an electrophysiolo-gist from the University of Calgary, re-viewed 9 key steps to unraveling SVT and arriving at a correct diagnosis:

1. Evaluate QRS width and regularity of the tachycardia2. Look for evidence of atrial activity3. Look for P waves 4. Evaluate P wave morphology if flutter waves are seen or suspected5. If there are no P waves, consider irregular and non-iso- electric / pseudo R, suggestive of atrial fibrillation and AV node reentry, respectively6. Assess underlying atrial and ventricular rates7. Assess initiation and termination8. Evaluate response to adenosine9. Assess change in rate (cycle length) with and without bundle branch block (BBB)

Patient history and QRS width and regularity can provide many clues to the correct diagnosis. Irregular tachycardia is almost always atrial fibrillation or flutter, whereas evidence suggests that 98% of patients with wide complex tachycar-dia (WCT) with a prior history of MI have a ventricular tachycardia (VT). Assessing QRS morphology offers higher sensitivity and specificity than the commonly used Brugada criteria. Dr. Exner recommends looking for a notch in leads V1 and V2, which also favours a diagnosis of VT over SVT. When SVT is suspected, pharmacological interventions can be used to assist in diagnosis, for example, by evaluating if

and how the tachycardia is terminated after adenosine ad-ministration. Dr. Exner advised that adequate data using a 12-lead ECG is needed to correctly distinguish between narrow complex tachycardia and WCT.

SVT can be discriminated from sinus tachycardia by chang-es in P-wave morphology. Dr. Exner suggests looking for P waves in leads where the QRS interval is either the smallest or the narrowest, and to pick a lead and focus on it.

Changes in QRS rate also provide clues for diagnosis of SVT. The presence of a right BBB results in no change in cycle length or rate, whereas a left BBB results in a slower rate. Therefore, rate changes indicate whether or not bun-dles are part of the pathway, help to distinguish SVT from VT, and indicate on which side of the heart the accessory pathway can be found.

Dr. Exner concluded by reminding the audience that SVT does not always rule out other problems such as MI. Referral to an electrophysiologist should be considered for patients with wide QRS tachycardia, SVT with severe symptoms who are drug-resistant or -intolerant, with certain occupa-tions, when a non-pharmacologic approach is preferred, and when pre-excitation is present.

Arrhythmia Management

Supraventricular Arrhythmias – Bread and Butter or Toast and Jam?



Dr. Brent Mitchell from the University of Calgary provid-ed his clinical viewpoints on current implantable cardio-verter defibrillator (ICD) and cardiac resynchronization therapy (CRT) device usage. He outlined the evidence supporting the 4 available platforms for treatment of pa-tients with ventricular tachyarrhythmias: medical therapy, ICD, CRT, and CRT defibrillator (CRT-D). According to the literature Dr. Mitchell reviewed, there is “an ap-proximate 30% reduction in the risk of all-cause mortal-ity as we step up the ladder of complexity of these im-plantable devices.” Indeed, meta-analyses strongly support benefits of ICD, CRT, and CRT-D over standard medical therapy, and there was a trend for a benefit of CRT-D over CRT alone. Two recently published large studies, MADIT-CRT and RAFT, support a benefit of CRT-D over ICD alone in appropriately selected patients.

While devices offer the potential to address underlying structural disease and improve outcomes, Dr. Mitchell stressed that patients must be selected appropriately for these devices. He provided the following guidance on pa-tient selection:

• ICDsareappropriate forpatientswithahighriskof sudden cardiac death (more than ~3%/year)

• CRT is appropriate for patients with symptomatic CHF with low LVEF (<35%) and evidence of electri- cal and/or contractile dyssynchrony. Although only about two thirds of patients respond, CRT is nonethe- less often associated with reversal of adverse LV remodeling in these patients.

• CRT-Disrecommendedinthesamepatientpopula- tion as CRT in patients whose annual risk of sudden cardiac death exceeds the hazard of having an ICD.

• ICDs,CRT,andCRT-Dshouldpreferablybeusedin scenarios where use of these devices has been proven effective in a RCT.

• In the absence of a current or anticipated indication for brady pacing, ICD only patients are best treated with single chamber (VVI) pacing.

• AVresynchronizationisanimportantpartofcardiacre- synchronization; CRT only and CRT-D patients are best treated with atrio-biventricular pacing.

Patients should be made aware that the goal of an ICD is to reduce the risk of sudden cardiac death and that symp-tomatic improvement is not expected. Furthermore, there is no demonstrable benefit of devices implanted in the acute setting; Dr. Mitchell recommends waiting 1 month after an acute procedure such as CABG or after an acute MI. He also recommends a 3-month trial of intensive medical therapy and reassessing candidacy for a defibril-lator after that passage of time, since some patients, espe-cially those with new onset congestive cardiomyopathy, dramatically respond to medical therapy and may not re-quire implantation of a device.

Living Better Electrically: Which ICD and/or CRT Device for Which Patients and When


Dr. Anthony Tang from the University of British Colum-bia reviewed some of the most recent evidence for CRT in patients with complex presentations who do not “fit” traditional indications for devices but who might none-theless benefit from these therapies. Meta-analyses of case control studies suggest some benefit of CRT in HF patients with permanent AF, although they tend to have a lower response rate and derive less benefit in terms of re-modeling and morbidity and mortal-ity outcomes compared to patients in sinus rhythm. Importantly, AV nodal ablation predicts survival and better LVEF outcomes compared to no abla-tion or to medical therapy alone.

The RAFT study, which provides the best RCT evidence to date in this pa-tient population, stratified 229 HF pa-tients with permanent AF at random-ization. In a secondary analysis, there were non-significant trends suggesting poorer outcomes in patients with AF who received CRT-D compared to those without AF. Dr. Tang noted that failure to achieve adequate pacing may have accounted, at least in part, for the negative findings. Although the protocol stipulated strict rate control, only 1 out of 114 patients randomized to CRT-D received AV nodal ablation within 6 months of randomization, sug-gesting that investigators believed the majority of patients were adequately paced using medical therapy alone. Yet the data show that only 34% achieved 95% pacing on a daily basis. This is important because data from a recent large patient series suggest that even incremental improve-ments in percentage pacing are associated with improved

survival over a 3-year follow-up. A large RCT is currently being planned to more definitively assess the efficacy and safety of CRT with AV nodal ablation in HF patients with permanent AF.

Another complex patient presentation is HF with sinus rhythm but wide QRS and bundle branch block (BBB) morphology. Evidence from the MADIT-CRT and RAFT studies suggests that patients with left BBB derive more benefit from CRT-D than those with non-left BBB morphology. Furthermore, the RAFT data suggest that al-though all patients with left BBB in sinus rhythm benefit from CRT-D, the wider the QRS interval, the greater the benefit. In contrast, patients with non-left BBB in sinus rhythm only benefit from CRT-D when the QRS interval is ≥160 ms.

The Current Status of Cardiac Resynchronization



The association between AF and stroke has been recognized for more than 100 years. Today, we know that AF increases the relative risk of stroke by approximately 5-fold and ac-counts for 15-20% of all strokes. Unfortunately, in a third of stroke patients, AF is not diagnosed until after the event.

Dr. Brent Mitchell, from the Libin Institute at the Univer-sity of Calgary, reviewed recent changes in the evidence-based management of AF for stroke prevention. A meta-analysis by Hart et al. showed that in untreated patients with AF, the annual risk of stroke was approximately 6% and the annual risk of major bleeding was approximately 1%. Treatment with ASA reduces the risk of stroke (rela-tive risk reduction 19%) and increases risk of major bleeding (relative risk increase 130%). Warfarin reduces the risk of stroke dramatically (relative risk reduction 64%) but also significantly increases the risk of major bleed-ing (relative risk increase 180%). Dr. Mitchell summarized that “We want to use ASA for its safety, but we should use an anticoagulant for efficacy.” De-spite its recognized efficacy, evidence suggests that warfarin is under-utilized for stroke prophylaxis. Indeed, among patients who would be candidates for warfarin treatment, only about half are prescribed the drug, and only half of those are therapeutically dosed. Sev-eral reasons account for this under-treatment, including warfarin’s narrow therapeutic window, substantial het-erogeneity in individual sensitivity, and multiple interac-tions with other drugs. Therefore, there remains a con-siderable opportunity to improve patient outcomes with more efficacious and more convenient treatments.

Three new oral anticoagulants – dabigatran, rivaroxaban, and apixaban – have been evaluated for the prevention of stroke in patients with AF and results of their regis-tration trials have been reported within the last 2 years. The positive findings are reflected in the recently updated

CCS guidelines for the management of AF, which recom-mend these new agents over warfarin in most patients who are candidates for oral anticoagulation (see the CCS AF Workshop for a summary of changes to the guideline rec-ommendations). Dr. Mitchell summarized the evidence for efficacy and safety of each of the 3 new oral anticoagulants and provided his clinical perspectives on how to choose amongst them.

One of the key findings from the RE-LY trial of dabiga-tran is that both doses dramatically reduce the incidence of hemorrhagic stroke, a limiting factor with the use of warfarin. Moreover, dabigatran 150 mg bid significantly

reduced the rate of ischemic stroke compared to warfarin. The 110 mg bid dose of dabigatran reduced the risk of major bleeding compared to warfarin; the 150 mg dose was associated with a similar bleeding risk as warfarin but with an increased risk of gastrointestinal bleeding. Among the new oral anticoagulants, dabigatran 150 mg bid showed the greatest magnitude of benefit in terms the primary endpoint of stroke/thromboembolism, as well as hemorraghic stroke and mortality.

Anticoagulation for Stroke Prevention in Atrial Fibrillation: A Changing Landscape


The ROCKET-AF study of rivaroxaban demonstrated non-inferiority to warfarin and was associated with a simi-lar incidence of major bleeding. Rivaroxaban was dosed once-daily in this study.

The ARISTOTLE trial demonstrated the superiority of apixaban over warfarin for prophylaxis of stroke/throm-boembolism and was associated with a significantly lower risk of major bleeding. Like dabigatran, apixaban was dosed twice daily.

Given that the CCS guidelines recommend the new oral anticoagulants over warfarin in most patients, how should clinicians choose which agent to use? Currently, only dabi-gatran and rivaroxaban are approved by Health Canada for stroke prophylaxis in patients with AF. All 3 agents result in effective anticoagulation after administration of the sec-ond dose. Although no reversal agents are available yet for these agents, Dr. Mitchell noted that no apparent excess of problems in emergency situations resulting from lack of reversal agents has occurred. As all the new agents are excreted by the kidneys to varying de-grees, none are recommended for use in patients with creatinine clearance

<25-30 mL/min. Notably, anticoagulation monitoring is not required for the new oral anticoagulants, representing a benefit in terms of convenience and cost of administra-tion over warfarin. None of the new agents were publicly reimbursed at the time of the ACC Rockies meeting, with an approximate cost of $120/month for the AF indica-tion. [Post-meeting note: dabigatran is now publicly reim-bursed in most provinces.] Given the substantial burden to patients and the healthcare system in terms of stroke-relat-ed morbidity and mortality, it is expected that these new agents will show cost-effectiveness relative to warfarin.

In the absence of head-to-head studies directly compar-ing the new oral anticoagulants, Dr. Mitchell proposed his personal viewpoint on differentiating these agents in clinical practice.



The concept of personalized medicine is appealing for a variety of reasons, notably the variable response to CV drugs, adverse drug reactions that are associated with sub-stantial burden in terms of morbidity, mortality and cost, and the fact that Canadians spend more than $5 billion annual on CV medications. Personalized medicine has the potential to reduce this burden by both identifying poten-tial non-responders to drugs as well as predicting patients who are predisposed to drug toxicity so that alternative doses or agents can be used in these patients. Dr. Simon de Denus, a pharmacist at the Montreal Heart Institute and the Université de Montréal Beaulieu-Saucier Chair of Pharmacogenomics, reviewed the state-of-the-art evi-dence for pharmacogenomics in CV medicine, with a fo-cus on warfarin and clopidogrel.

Cytochrome P450 isozyme 2C9 (CYP2C9) is a major factor in maintenance dosing with warfarin. Individu-als who carry variant alleles for CYP2C9 require a 3-fold lower maintenance dose than those with wild-type al-leles. The VKORC1 gene variants have shown similar effects on warfarin dosing. Taken together, genetic infor-mation and other factors such as age account for approximately 50 to 60% of dose variability with warfarin. No-mograms are available to clinicians to assist in personalizing warfarin dosing; however, there is limited evidence of benefit of a personalized approach to warfarin dosing to date.

Clopidogrel is a pro-drug that requires a 2-step conversion for activation. Sev-eral cytochrome P450 isoenzymes are involved in the activation of clopido-grel, including CYP2C19. Individuals who carry CYP2C19 loss-of-function polymorphisms have a reduced re-sponse to the drug. Moreover, these CYP2C19 polymorphisms are also associated with worse cardiac outcomes (e.g., higher risk of stent thrombosis) in patients treated with clopidogrel. Emerging data indi-cate that higher dosing of clopidogrel may be effective in individuals who are heterozygotes for CYP2C19*2 poly-morphisms, but in homozygotes, clopidogrel cannot be

activated at any dose. For patients who carry CYP2C19 loss-of-function polymorphisms, treatment with prasug-rel or ticagrelor should be considered since these drugs are independent of CYP2C19 activity. The question remains whether there is benefit to genotype-guided use of these new agents compared to unselected use in the general population of patients who require antiplatelet therapy.

Dr. de Denus remarked that there is considerable vari-ability in how pharmacogenomic evidence is evaluated. For example, the American Heart Association requires evidence from RCTs before making recommendations for patient genotyping, whereas the Clinical Pharmacoge-nomics Implementation Consortium of the National In-stitute of Health’s Pharmacogenomics Research Network requires only consistent results from well-designed, well-conducted genotyping studies. Dr. de Denus surmised that genetic profiling in ACS/PCI patients is probably not done routinely based on the cost of testing.

Dr. de Denus argued that RCTs may not always be neces-sary to demonstrate the effectiveness of pharmacogenomic markers. He predicted that the use of pharmacogenomics in the clinical assessment of patients in the future will depend on the affordability of testing entire personal genomes.

Pharmacogenomics in Cardiovascular Diseases: Ready For Prime Time?


Dr. John Cairns, from the University of British Columbia, and Dr. Brent Mitchell, from the University of Calgary, led this highly interactive CCS workshop that highlighted some of the key changes to the recently updated guide-lines on the management of AF. These latest changes were largely the result of new evidence relating to antithrom-botic agents and to dronedarone. Key changes are briefly summarized below; readers are encouraged to visit www.ccs.ca for a full presentation of the 2012 AF guidelines.

GRADE approach – strength of recom-mendations is now graded as strong or conditional/weak, based on 4 catego-ries of quality of evidence (high, mod-erate, low or very low).

Rate control – dronedarone is no longer recommended as a rate control agent.

Rhythm control – dronedarone is no longer recommended for rhythm control in patients with abnormal LV function or those with persistent atrial fibrillation.

Stroke prevention

• The CHADS2 score continues to be preferred to assess thromboembolic risk; if score is zero, additional risk factors should be considered (i.e., age, vascular disease, and gender).

• New oral anticoagulants are preferred over warfarin based on superior efficacy, greater convenience, and similar or reduced risk of major bleeding compared to warfarin.

• Warfarinisnolongerpreferredover new oral anticoagulants in patients with CAD, since the net clinical benefit continues to favour new agents even accounting for a trend to a numerically higher incidence of MI with dabigatran.

• PatientswithCKDwithestimatedGFR≥30mL/min may be treated with newer oral anticoagulants with rou- tine monitoring of renal function; for GFR 15-30 mL/ min, warfarin is preferred; whereas a nephrologist should be consulted for patients with GFR <15 mL/ min or those who are on dialysis.

CCS Interactive Workshop: Atrial Fibrillation Guidelines



Pulmonary hypertension remains a difficult disease to manage and is associated with poor prognosis despite the many treat-ments available. The reasons for this include poor response rates to first-line therapies, suboptimal response rates to second-line treatments, loss of response, and limited availability of organs available for transplantation. Moreover, RCT evidence support-ing outcome measures are limited for currently available treat-ments and meta-analyses suggest no survival benefit with the use of medications such as prostaglandins, endothelin receptor antagonists, and phoshodiesterase inhibitors. According to Dr. Duncan Stewart, from the University of Ottawa, it is therefore important to better understand the mechanisms of the disease so that more targeted therapies can be developed to fill this consid-erable treatment gap. He reviewed the pathogenesis and current approach to the work-up and management of pulmonary arte-rial hypertension (PAH) and shared some of his own research experience investigating next generation stem cell therapies.

Current understanding of the pathophysiology of PAH is in-complete. Several distinct processes appear to be involved at the microvascular level, including hyperproliferative abnormalities, innate or adaptive inflammatory response, and degenerative loss of functional arterioles. Dr. Duncan noted that these 3 processes are not mutually exclusive. For example, recent findings from animal studies support increased lung vascular endothelial cell apoptosis as a trigger for PAH leading to reactive vascular cell proliferation and inflammation. This mechanism is also sup-ported by observations from genetic studies of familial PAH. Indeed, loss of function mutations in the BMPR2 gene have been shown to induce smooth muscle cell (SMC) growth and prevent normal apoptosis in endothelial cells. Approximately 70% of patients with familial and up to 25% of sporadic PAH

patients carry such loss of function mutations. BMPR2 is also important in cell survival pathways of endothelial cells and the loss of function mutation increases susceptibility for endothelial cell apoptosis and the development of PAH.

Since current treatments for PAH target only a single process involved in the pathogenesis of the disease, Dr. Duncan is not surprised that they are not very effective in the majority of pa-tients. Even antiproliferative drugs that target SMC hyperplasia or vascular cell proliferation, such as imatinib and sorafenib, re-spectively, have shown mixed results in clinical trials of PAH. New strategies that enhance the repair of endothelial cells using progenitor cell therapy may hold promise for repair and regen-eration of pulmonary microcirculation in PAH. Both preclini-cal and early clinical data support the importance of eNOS-enhanced cell therapy in the reversal of established PAH.

Preliminary data from a human trial led by Dr. Duncan’s re-search group called the Pulmonary Hypertension And Cell Therapy (PHACeT) trial showed benefit in patients with treat-ment-refractory PAH who received eNOS-transfected autolo-gous delivery of early growth EPCs. Specifically, pulmonary vas-cular resistance declined after 3 days and there was a cumulative reduction in total peripheral vascular resistance. Hemodynamic effects were enhanced in patients who were receiving sildenafil and there was an apparent improvement in the 6-minute walk test. These positive results have lead Dr. Duncan’s group to be-gin planning the PHACeT-2 study, a double-blind RCT com-paring eNOS-transfected EPCs and placebo. Stay tuned for the PHACeT-2 study results as this promising strategy for the treat-ment of PAH continues to evolve.

General Cardiology

Update on Current Concepts and Treatment of Pulmonary Hypertension


Existing guidelines define severe hypertension as blood pressure >180/120 mmHg with evidence of critical vas-cular damage to vital organs. However, Dr. Robert Her-man, an Internal Medicine specialist from the University of Calgary, suggests that this definition is backwards. He proposes the definition of severe hypertension should be primarily based on critical organ damage, since some pa-tients have target organ damage without having severely elevated blood pressure.

Dr. Herman proposed that severe hypertension may be conceptualized as a problem of the microcirculation. He used a case of hypertensive posterior reversible encepha-lopathy syndrome (PRES) causing repeated seizures to exemplify this concept. Consistently high pressure and other stresses to the microcirculation – such as increased blood volume and increased capillary blood flow – result in a re-setting of cerebral autoregulation over time, as well as structural changes (e.g., hypertrophy of vessel walls), in order to accommodate changes in blood pressure and flow. When blood pressure changes too rapidly, the mi-crocirculation is unable to adapt sufficiently and hyper-perfusion and edema result.

Dr. Herman conducted an extensive systematic review of all cohort studies and case reports of PRES from 2005 to 2010. He found that the change in blood pressure from normal baseline values was more important than the abso-lute blood pressure, with considerable variability between patients in terms of the magnitude of the change that was required to trigger events. Dr. Herman proposed that a better definition for a potentially severe elevation in blood pressure would be a persistent rise in mean arterial pressure

(MAP) of >30-45 mmHg over baseline developing over the course of several hours to days, or a rise in MAP of 40-60 mmHg lasting greater than 1 hour. If baseline MAP is not known, a MAP >90 mmHg should be used. In pa-tients with sepsis / systemic inflammatory response syn-drome (SIRS) or those receiving immune modulating or cytotoxic chemotherapy, which potentially impair cerebral autoregulation and/or vascular permeability, blood pres-sure elevations less than these levels may similarly cause a hypertensive emergency. Finally, patients with poorly con-trolled hypertension or blood pressure >180/120 mmHg for longer than 3 to 6 months are likely to possess adaptive structural changes in their heart and systemic vasculature that support a higher blood pressure; these people are at particularly high risk of ischemic injury if blood pressure is rapidly lowered below autoregulatory limits. Thus, severe, poorly controlled hypertension can also be considered a hypertensive emergency and blood pressure in these indi-viduals should be lowered over many months with moni-toring of end-organ (i.e., the kidney) function.

Evidence suggests that hypertensive microvascular events are associated with poor long-term outcomes, including increased risk of subsequent MI, stroke, thromboembo-lism, and higher overall and CV mortality, underscoring the importance of proper identification and appropriate management of severe hypertension.

Reassessing the Definition and Treatment of Severe Hypertension



Key Cardiovascular Late-Breaking Trials 2011-12

Drs. Todd Anderson and Jacques Genest were tasked with reviewing some of the most relevant late-breaking trials that have been reported since the 2011 meeting. Although some of these trials were addressed by other speakers, the most salient points are worthy of reviewing and are sum-marized below.

ARISTOTLE

This large trial conducted in >18,000 patients with AF showed that apixaban was superior to warfarin for a pri-mary composite endpoint of stroke/systemic embolism. Notably, apixaban was associated with a significantly lower risk of major bleeding than warfarin. Dr. Anderson placed the ARISTOTLE results in the context of findings from other trials for novel anticoagulants (RE-LY for dab-igatran and ROCKET-AF for rivaroxaban). He predicted that these 3 new agents will probably replace warfarin, depending on when they are approved and reimbursed. He summarized by stating that “This is the third of the large trials to show us the first 3 novel anticoagulants re-ally provide very good results for our patients with great safety.”

ATLAS-TIMI 51

The ATLAS-TIMI 51 study random-ized >15,000 patients with ACS to ri-varoxaban 2.5 or 5 mg bid or placebo on a background of dual antiplatelet therapy (ASA plus clopidogrel). The primary composite endpoint of CV death/MI/stroke was significantly reduced by 16% with rivaroxaban (both doses combined) versus placebo. This benefit was offset by a higher rate of bleeding in the triple therapy group. These results contrast with the AP-PRAISE-2 study, which did not show a significant dif-ference when apixaban was added to dual antiplatelet therapy in a higher-risk population of patients with ACS. Given these equivocal results, it remains to be determined if and how clinical practice and guideline recommenda-tions will change in this patient population.

TAC-HFT

This proof of concept study was rated by the journal Cir-culation as one of the top 10 trials of 2011. In the TAC-HFT trial, 8 subjects received transendocardial injections of autologous bone marrow or mesenchymal stem cells directly into ischemic scar tissue using a specialized cath-eter. This differentiates the TAC-HFT study from previ-ous trials, which generally administered stem cells soon after an ischemic event and before substantial remodeling had taken place. Cardiac MR imaging showed significant improvements in both end-systolic and end-diastolic vol-umes as well as significant reductions in the size of scar tissue. In other words, patients benefited from a reduction in heart size that was paralleled by reductions in nonvi-able tissue, even though there was no significant effect on ejection fractions. Dr. Anderson predicted that stem cell

therapies will continue to be a hot topic at the ACC Rock-ies meeting in future years, as new developments from Ca-nadian and international research groups contribute to a rapidly growing body of evidence.


AIM-HIGH

This RCT comparing niacin to placebo as adjunctive treatment to a statin in patients with atherogenic dyslip-idemia despite statin treatment failed to meet its primary endpoint of CV death/MI/stroke/ACS despite a fairly robust increase in HDL-C and decrease in LDL-C. Dr. Genest noted that the study was grossly underpowered due to a lower on-trial event rate than predicted. The trial was stopped early due to lack of effica-cy and an apparent increase in the risk of stroke. The ongoing HPS-2 trial in >25,000 patients should provide more definitive answers regarding the effica-cy and safety of adding niacin to statin treatment in patients with atherogenic dyslipidemia; results are expected to be reported within the next year.

SATURN

This study compared two intensive statin regimens in terms of progression of atherogenesis as assessed by IVUS. About 1400 patients were randomized to maximal doses of either atorvastatin (80 mg) or rosuvastatin (40 mg) for 24 months. Among the 75% of patients who completed a follow-up imaging assessment, there was equivalent regression of atheroma volume, suggesting that both treatments are equally effec-tive at prevention progression of atheroclerosis. This was observed despite significantly lower LDL-C and higher HDL-C achieved in the rosuvastatin group. Some sec-ondary endpoints reached statistical significance; however, Dr. Genest noted that the associations were only weakly positive.

SHARP

The results of this trial were presented in detail by Dr. Marcello Tonelli. Dr. Genest reiterated that the findings should have an impact on Canadian guidelines and that CKD patients who are not on dialysis stand to benefit from lipid lowering treatment. Furthermore, he support-ed the notion that “a GFR [glomerular filtration rate] of 30 mL/min or less should probably be considered as a CHD risk equivalent.”

CTT Meta-analysis

In this second cycle of the Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis, very strong results favoured optimized statin treatment for LDL-C reduc-tion with a 22% overall risk reduction for any major CV event. One remarkable observation from this analysis is that patients with baseline LDL-C levels <2 mmol/L had significantly fewer events and derived significant ben-

efit with higher dose statin treatment. There was an im-pressive 10% risk reduction in overall death, which was mostly driven by reduction in CHD and other cardiac deaths. Reassuringly, there was no increased risk of inci-dent cancer with statin treatment, laying to rest concerns that had been previously raised by some smaller studies. Dr. Genest’s overall conclusion from this meta-analysis is that optimization of statin treatment can significantly lower LDL-C with a proportional reduction in the risk of major CV events, with the greatest benefits achieved in patients who are able to tolerate maximal doses.

Statins and risk of incident diabetes: Meta-analyses

One of the pitfalls of LDL-C reduction is an apparent in-crease in the risk of diabetes, a concern that was first raised based on the JUPITER trial. Since then, meta-analyses have addressed the issue of whether or not statins protect against – or increase the risk of – incident diabetes. In the Ameri-



can Diabetes Association meta-analysis of 6 RCTs, only 1 evaluated diabetes incidence in a pre hoc design. That study, the West of Scotland WOSCOPS trial, showed a benefit for statin treatment. However, when the WOSCOPS study was removed from the meta-analysis, there was a significantly in-creased risk of incident diabetes. A more recent meta-analy-sis based on 5 RCTs comparing moderate- to intensive-dose statin therapy showed a 12% increase in diabetes that was statistically significant. This risk should be considered in the context of the recognized benefits of statin therapy for coro-nary risk reduction. Dr. Genest concluded that the risk of diabetes must be taken seriously, since there is a consistent – albeit small – signal from meta-analyses of large statin trials.

COURAGE

The COURAGE trial compared initial coronary stent im-plantation with medical therapy against medical therapy alone for the treatment of patients with stable CAD. The findings showed that initial treatment with PCI offered no benefit compared with initial medical therapy for pre-vention of death, nonfatal MI, unplanned revasculariza-tion, or angina. Dr. Genest summarized that patients with chronic stable CAD should initially be treated medically.

now in its 28th year, the annual cardiovascular confer-are very common in patients with chronic...

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