March 1-5, 2009 Conference Report

Please join us March 21-25, 2010 Lake Louise, Alberta

www.acclakelouise.com

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March 1-5, 2009

T his year marks the 25th anni-versary of the Annual Cardio-vascular Conference (ACC) at Lake Louise. The concept

of this unique conference where faculty and attendees can meet friends and col-leagues, enjoy skiing during the day, and acquire the latest knowledge from out-standing faculty in cardiovascular medi-cine in the mornings and evenings, can be attributed to Dr. Peter Klinke, who founded the conference and has served as Program Director for the last 25 years. Since its first year, more than 170 dis-tinguished speakers have contributed to delivering a stellar program at the ACC Lake Louise, and many have returned on several occasions.

As the conference has grown, Drs. Wayne Warnica, Jacques Genest, and Robert Welsh have joined as Program Co-Direc-tors. To mark Dr. Klinke’s and Dr. War-nica’s final year as Program Director and Co-Director, a plaque was presented in recognition of their great contributions to the advancement of teaching and knowledge transfer in the cardiovascular sciences.

Dr. Richard Conti, who was an invited speaker at the first and several subsequent ACC Lake Louise conferences, remarked on the diversity of faculty and attendees over its history. “Every year, many top-ics are discussed, and everyone learns a lot coming to these meetings… the in-

formation presented is very current, and [attendees are] not hearing old stuff, we are talking about where cardiovascular medicine and surgery might be headed in the future.”

This conference summary report will highlight some of the key data presented by faculty during this year’s conference. By reading this report, it is hoped that attendees will have an opportunity to re-flect on the information and knowledge they gained during the conference in March, and continue to discuss impor-tant new topics in cardiovascular medi-cine with their colleagues.

Acute myocardial infarction (AMI) can be considered the iconic disease of the current generation of cardiologists –

it is the most clinically studied condition of all time. While several large random-ized controlled trials (RCTs) provide general guidelines for treatment, cardiol-ogists continue to be challenged by how best to manage individual patients.

Dr. Allan Ross, Professor Emeritus of Medicine at George Washington Uni-versity, reviewed the significant advances in the treatment of AMI over the last 50 years. Although generally considered to be a recent discovery, modern technolo-gies applied to mummies have identified the existence of coronary heart disease (CHD) as far back as 26 centuries ago. Galen correctly described the anatomy of the cardiovascular system, however,

he attributed the “pneuma” as the life force of the circulation. It was not un-til 1240 that Ibn al-Nafis discounted the existence of invisible pores in the septum and correctly identified the lungs as the location where blood is “mixed” with air before being returned to the left heart.

The discovery of the microscope in the 17th century ushered in “the beginnings of enlightenment” with the identifica-tion of the capillaries, the connection point between the veins and arteries. Symptoms of CHD were first described in the 18th century, and in the late 19th century, thrombosis or “fatty degen-eration” was attributed as the cause of CHD. Around the same time, Baumgar-ten demonstrated in animals that reper-fusion was an effective strategy for treat-ing AMI, although it was a long time before the strategy was adopted by clini-

cians. The “reperfusion era” dates back to the 1950s, when anticoagulation with heparin or dicoumarol was used to pre-vent extension of coronary thrombosis. The search for thrombolytic agents iden-tified streptokinase, which was shown to be more effective when administered early compared to later therapy. Dr. Ross remarked, “we forgot that lesson for a while, but it was eventually re-learned.”

The 1960s and early 1970s might be considered the time when cardiologists “moved from enlightenment back to confusion.” Four large studies indepen-dently concluded that thrombosis was the result – and not the cause – of AMI, and the use of reperfusion therapy was essentially abandoned until the 1980s. The prevalence of coronary thrombosis was documented during the “return to enlightenment”, when Japanese research-

Conference Overview

The Treatment of AMI: What Have We Learned in 50 Years?

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ers demonstrated that the body’s intrin-sic fibronolytic system naturally lyses the thrombus over time. Furthermore, rup-tured plaques were seen at the thrombus site in more than 90% of cases and were hypothesized to be the cause of throm-bus formation.

The body of research conducted since re-perfusion was resuscitated in the 1980s has been tremendous. Dr. Ross singled out the GISSI study as “how we came to fully understand the urgency of reperfu-sion.” More recently, cardiologists have entered the era of percutaneous inter-

ventions to restore blood flow to the in-farct-related artery. Dr. Ross concluded by referring to the many ongoing areas of research that would be the topics of further presentations at this year’s ACC Lake Louise.

Dr. Paul Armstrong, Pro-fessor of Medicine in the Division of Cardiology at the University of Alberta,

discussed the development and impact of acute coronary syndrome (ACS) guide-lines on clinical practice. According to the American Heart Association (AHA), “guidelines are systematically developed to assist practitioner and patient de-cisions for appropriate healthcare for specific circumstances.” Their goal is to improve the quality of care by bridging the gap between providers and patients. Guideline recommendations are classi-fied according to well established criteria for the usefulness of the intervention and weighted by a level of clinical evidence supporting each recommendation.

In a recent review of the 422 recom-mendations outlined in the 2004 ST el-evation myocardial infarction (STEMI) guidelines, a paradox in care emerged whereby a dominance of class I recom-mendations is supported by proportion-ately less level A evidence. Dr. Armstrong reminded the audience that “sometimes class III recommendations do not have a high level of evidence, but common sense and good judgment suggest we should pay attention to them.”

Guidelines benefit both patients and healthcare providers, despite their recog-nized potential liabilities and limitations.

In addition to guidelines, performance measures help identify aspects of care for which the failure to provide a particular process of care is judged as poor clinical performance. In essence, performance measures outline opportunities to pro-vide improved care to patients.

In answer to the question on why guide-lines are important, Dr. Armstrong noted that there exists tremendous variability in the “real world” and that “this is an ex-traordinarily important issue as it relates to the nuts and bolts care of patients.” In the CRUSADE study, a third or fewer patients received 100% of all guideline-

recommended therapies. One of the key barriers to implementing guideline rec-ommendations is that knowledge of cur-rent best care progressively declines with the number of years since graduation, “highlighting the importance of confer-ences such as the ACC Lake Louise to continue imparting current knowledge to practicing clinicians.”

Evidence suggests that adherence to guidelines is strongly correlated with improved patient outcomes. Indeed, for every 10% increase in adherence to guidelines, a 10% reduction in hospital mortality has been observed. A quality

Do ACS Guidelines Change Clinical Practice?

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March 1-5, 2009

of care cycle describes the interconnect-edness of guidelines, quality indicators, performance measures, outcomes, and clinical research that reflect the modern era of medical education. Importantly, clinicians should remember that when

it comes to individual patient care, one size does not fit all. According to Dr. Armstrong, “the art of medicine, in my view, is fundamentally aligned with im-plementing guidelines when appropri-ate, and also modifying them when ap-

propriate.” Dr. Armstrong concluded his presentation with a reminder of the “8 High C’s for guidelines”, which must be clear, concise, comprehensive, consensu-al, cost sensitive, credible, contemporary, and centred on patients.

The concept of systems of care for the treatment of patients with AMI is based largely on observations that

there is a time dependency of the benefit of fibrinolytic therapy and primary per-cutaneous intervention (PCI). According to Dr. Christopher Granger, Director of the Cardiac Care Unit at Duke Univer-sity Medical Center, “the more rapid ap-plication of fibrinolytic therapy and pri-mary PCI at this point might be much more important than some of the refine-ments that we spend much more time investigating and talking about.” Indeed, various approaches related to successful-ly applying more rapid door to balloon time or electrocardiograph (ECG) to balloon time have been shown to result in improved patient outcomes. Results from Canadian groups in both Ottawa and Edmonton have shown that field pre-activation can substantially reduce door to balloon and first ECG to balloon times compared to patient transfer from another hospital. Based on these results and others, it appears that field activa-tion based on pre-hospital ECG is a very effective way of accelerating patient care and should be more than an “optional” component of evidence-based care.

There is considerable complexity in how patients present with AMI, and differ-ent approaches are recommended based

on patient presentation. The STREAM study tests a predefined treatment and transfer strategy based on patient pre-sentation, with time since symptom onset being one of the primary consid-erations. Patients presenting < 3 hours from symptom onset are considered for treatment with fibrinolytic therapy, as further delays introduced by transfer can cause greater loss of salvage of myocar-dium. Patients presenting < 3 hours from symptom onset may derive greater ben-efit from timely provision of PCI, and so are considered for transfer to PCI centers. Achieving timely transfer of patients re-mains an ongoing challenge in the opti-mal treatment of AMI. Road conditions, traffic, equipment, and communication systems must all be taken into account. In Canada, there are substantially fewer primary PCI centres compared to the USA due to both geography and popu-lation distribution, making primary PCI difficult in some areas. Conversely, Can-ada’s emergency medical system (EMS) system is less fragmented than in the USA, and might present an opportunity to better implement pre-activation of cath labs. These factors and others make it necessary to design systems taking into account the realities within that region. To this end, Dr Grainger congratulated Canadians for their work in leading the way to reengineering the system to treat AMI and gave the examples of the work done in the WEST and Transfer AMI trials.

Dr. Granger used the metaphor of a NASCAR team approach when design-ing systems care plans for the treatment of AMI. A critical element in each is a team leader who fosters communication and teamwork to facilitate speed and good outcomes. Primary PCI hospitals have an opportunity to greatly improve patient care when senior leadership is committed to providing adequate re-sources, assigning a dedicated STEMI coordinator who works with every hos-pital and EMS group in the system, es-tablishing an experienced STEMI team, making use of guidelines and other data to reduce false activations, supporting regional EMS groups, and importantly, following evidence-based guideline rec-ommendations. Although many im-provements have already been imple-mented in systems care plans, the goal of the future should be integrated patient care, whereby systems include every hos-pital – and every STEMI patient – in North America.

Reorganizing Acute MI Care: What Next in Canada and the United States

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Dr. Peter Liu, Heart & Stroke / Polo Chair Pro-fessor of Medicine & Physiology at the Toronto

University Hospital Network, Senior Sci-entist at the Toronto General Research Institute, and Scientific Director of the Canadian Institute of Health Research (CIHR) Institute of Circulatory and Re-spiratory Health, was invited to present the Ronnie Campbell Lecture in honour of this former and frequent ACC Lake Louise distinguished speaker and partici-pant. Dr. Liu reviewed the tremendous progress that has been observed in the treatment of heart failure during the past 25 years. At the time of the first ACC Lake Louise conference in 1984, heart failure was generally treated with mor-phine and oxygen, rotating tourniquet / phlebotomy, digoxin and diuretics, ethy-crinic acid, and intravenous (IV) vasodi-lators in the intensive care unit (ICU). With the success of treatments for heart failure and the recognition of risk factors for this condition, an increasing propor-tion of patients now survive this once fatal condition. However, with the ag-ing population, the burden on the health care system in the future remains on on-going concern.

Today, heart failure is recognized as a sys-temic disease and not only isolated to the heart. In the early 1990s, the recognition that all vasodilators are not equal and, specifically, that angiotensin-converting enzyme (ACE) inhibitors can dramati-cally reduce mortality, revolutionized the treatment of heart failure. These agents, which were first recognized to reduce blood pressure, were subsequently found to attenuate heart remodeling and re-duce ventricular volume. Several large-

scale trials have confirmed these obser-vations, and the use of ACE inhibitors in left ventricular dysfunction might be considered “one of the most important bench to bedside developments in car-diology,” according to Dr. Liu. Strik-ingly, ACE inhibitors appear to change the fundamental biology of disease, as demonstrated by the continued benefit observed in 12-year survival in patients who were exposed to ACE inhibitors 9 years previously in the XSOLVD follow-up trial.

More recently, treatment strategies for heart failure have evolved to include be-ta-blockade and other hormone blockade (e.g., aldosterone). Today, beta-blockers can be considered the foundation of treatment of heart failure, offering an ex-tremely effective treatment strategy that is also cost-effective. “Beta-blockers pro-vide the best degree of reduction in ven-tricular volume…with these agents we are able to reclaim lifetime for patients

by reversing, rather than just attenuat-ing, the disease process,” opined Dr. Liu.

The newest strategies for treatment of heart failure include the addition of ARBs and epleronone to standard treat-ment that can further reduce patient mortality rates. Several other agents failed phase III trials after demonstrating encouraging results in phase II studies, including inotropic agents. Importantly, some subgroups of patients may benefit from “failed” treatments, even though benefits were not observed in the larger populations evaluated. Bucindolol might represent one of the first medications to be approved based on patient genotype and not just on disease diagnosis alone, opening the opportunity for us to per-sonalize medications in the future.

Finally, the recognition of heart failure as a chronic disease has an important impact on risk assessment and decision support tools. Importantly, late diagno-

Ronnie Campbell Lecture: Heart Failure Lost and Found – Discoveries Over 25 Years

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March 1-5, 2009

sis of any chronic disease, including heart failure, often results in poorer patient out-comes and higher costs to healthcare sys-tems. “We need to find ways to diagnose patients early, and to prevent the condition altogether. For those who already have the condition, we need to find ways to manage them in an effective fashion using multidis-ciplinary teams,” suggested Dr. Liu. Can-ada has already adopted a chronic disease model approach to the treatment of heart

failure, and while there remains room for improvement, the picture is encouraging in Canada – rates of hospitalization for heart failure and mortality rates appear to have peaked in the 1990s, and continue to fall, most probably due to changes in systems approaches and the adoption of evidence-based therapies in clinical practice.

As systems approaches continue to be re-fined across the country and elsewhere,

new treatments are being investigated not only for systolic heart failure, but now also for diastolic heart failure, an area where evidence-based treatments are lacking. Dr. Liu concluded, “we have come a long way in the treatment of heart failure and we’re now turning the clock back for our patients. We’ve seen a tremendous impact on survival in this group of unfortunate pa-tients… and I look forward to the next 25 years of impactful research in this area.”

Randomized clinical trials are now the gold standard for assessing efficacy and safety of new therapies. In the case

of statins, 15 of 20 large clinical trials have shown positive results for this class of therapy. Dr. David Waters, former Chief of Cardiology at San Francisco General Hospital and Professor Emeri-tus in the Department of Medicine at UCSF, addressed the successes and fail-ures of statins in different populations.

Statins: Where They Have SucceededSeveral large clinical trials have dem-onstrated a positive impact of statins: a 30% reduction in mortality risk (4S study), regardless of baseline low-density lipoprotein cholesterol (LDL-C) levels (Heart Protection Study). Statins are beneficial even in patients with low LDL-C levels and high-sensitivity C-reactive protein levels (hsCRP >2 mg/L) (JUPI-TER). Recently, the TNT (“Treating to New Targets”) study was designed to ad-dress whether health benefits in general increase as LDL-C levels decrease. Over a 5-year follow-up, the relative risk of cardiovascular (CV) events decreased by 22% in the group treated with 80 mg at-ovarstatin compared to 10 mg. Interest-

ingly, mortality in the 10 mg group was mostly due to non-CV events. Dr. Wa-ters pointed out the remarkable achieve-ment that, “as time has gone by, and our treatments have become better, not just with statins, but with aspirin and beta-blockers, we have driven CV mortality below the level of non-CV mortality, de-spite the fact that all of these patients had considerable history of coronary diseases at baseline.” Statin therapy has been shown to be effective in a wide spectrum of patients, including those with high LDL-C, low high-density lipoprotein cholesterol (HDL-C), hypertension, dia-betes, and high CRP levels.

Statins: Where They Have FailedStatins have failed in at least three con-ditions: heart failure, Alzheimer’s disease and aortic stenosis. Despite the theo-retical support for statin therapy in heart failure, neither the CORONA (n~5,000) nor the GISSI (n~4,500) studies demon-strated an improvement in time to first CV event or total mortality, even fol-lowing a significant decrease in LDL-C and hsCRP. Similarly, the LEADe and CLASP studies randomized patients with an early diagnosis of Alzheimer’s disease (AD) to either atorvastatin 80 mg

or placebo (LEADe) or simvastatin 40 mg or placebo (CLASP). Neither study demonstrated cognitive improvement with statin therapy. However, Dr. Waters suggested that starting therapy earlier in the course of the disease could potential-ly prevent or delay the onset of AD.

Statins have also failed to demonstrate benefit in aortic stenosis studies. In the SEAS trial, significant LDL-C lowering by ezetimibe 10 mg with simvastatin 40 mg was not associated with improve-ment in peak aortic-jet velocity, major CV events, aortic valve events, or total mortality. Importantly, this trial raised the possibility that this treatment strat-egy might have carcinogenic effects.

A substantial body of clinical trial evi-dence supports the efficacy of statins in preventing coronary and cerebrovascu-lar events in a variety of at-risk patients. However, statin therapy is not appro-priate in cases of AD, heart failure, and aortic stenosis. In the future, questions of adherence should be addressed to in-crease statin therapy effectiveness, since a recent study showed that only half of patients persist with statin therapy at 2 years after the initiation of treatment.

Newer Indications and Limitations of Statin Therapy

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Dr. A. Graham Turpie, Pro-fessor of Medicine at Mc-Master University, pre-sented a 2-part discussion

of antithrombotic therapies. His first ses-sion provided an informative overview of venous thromboembolism (VTE).

The Burden of VTEA great many patients are diagnosed with VTE. In fact, it is the third most common vascular disease. Pulmonary embolism (PE), the most dramatic pre-sentation of VTE, is the leading prevent-able cause of death in hospital. But Dr. Turpie reminds us that there are other clinically important complications of VTE. Deep vein thrombosis (DVT), the more common form of VTE, often re-sults in permanent vascular disease; in-deed, post-phlebitic syndrome occurs in about 20% of patients with symptomatic VTE. Dr. Turpie stressed the importance of risk-stratifying patients in order to ensure they receive appropriate throm-boprophylaxis. Anticoagulant therapy, the basis for prophylaxis, has been clearly demonstrated to reduce the risk of risk of DVT, PE, and mortality in both surgical and medical patients.

Antithrombotic RecommendationsIn 2008, the American College of Chest Physicians (ACCP) published its 8th consensus conference statements of an-tithrombotic guidelines; these guidelines include important changes that should impact both the prevention and treat-ment VTE. Dr. Turpie noted that one of the best models to study VTE is in or-thopedic surgery. Without prophylaxis, half of patients who undergo total hip or knee replacement are at risk of thrombo-sis. Although the majority of these cases

are asymptomatic, Dr. Turpie stressed that asymptomatic thrombi are often the source of fatal PE. Furthermore, he pointed out that this is not an in-hospital problem. The risk for VTE in these pa-tients plateaus well beyond hospital dis-charge; consequently, ACCP guidelines include recommendations for up to 1 month of prophylaxis.

Dr. Turpie stated, “there has been an evo-lution in anticoagulant therapy over the last 20 years that has resulted in dramatic improvement in the management of pa-tients who have thrombotic disorders.” He noted low molecular weight hepa-rin (LMWH) as a major breakthrough, with its substantial reduction in the risk of thrombosis in orthopedic surgery pa-tients. Fondaparinux is a more recent advancement introducing targeted in-hibition of a single coagulation factor. It demonstrated the lowest thrombosis rates recorded in this population. Both these treatments, as well as Vitamin K antagonists (VKAs), are Grade 1 recom-

mended therapies for thromboprophy-laxis in orthopedic surgery.

Importantly, our understanding of ap-propriate strategies for medical patients has also advanced. The ACCP guidelines include Grade 1A recommendations for VTE prophylaxis with LMWH, low-dose unfractionated heparin (LDUH), or fondaparinux in well-defined medi-cal patients. Similarly, the ACCP makes Grade 1A recommendations to perform VTE risk assessment for all intensive care patients, and to provide prophylaxis with LMWH or LDUH for all with a moder-ate to high risk of VTE. Dr. Turpie noted that most intensive care patients fall into this group.

How Are We DoingIn a recent multinational, cross-sectional study assessing the prevalence of VTE risk in the acute hospital setting, Cohen et al. found that about half of patients had recognized risk factors that quali-fied them for a Grade 1A recommenda-

Venous Thromboembolic Disease: Diagnosis and Treatment

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March 1-5, 2009

tion for thromboprophylaxis. However, only 42% of medical patients and 64% of surgical patients actually received this therapy. “There is an enormous care gap about what we should do and what we actually do. We can dramatically im-prove the management of patients if we apply evidence-based medicine,” Dr. Turpie commented.

DiagnosisAccording to current recommenda-tions, the diagnosis of DVT should be based on venous ultrasound because it is highly sensitive, specific, and simple to use. PE diagnosis requires the use of spi-ral computed tomography that provides good sensitivity and specificity, and oc-casionally magnetic resonance imaging. The low specificity of D-dimer testing restricts its value to ruling out DVT or PE; it should be reserved only for those patients in whom a high degree of clini-cal suspicion already exists.

Management of VTEAnticoagulant therapy is the mainstay approach to management of confirmed DVT/PE. Recommended therapies are similar to those for prophylaxis and in-clude LMWH, unfractionated heparin (UFH), and fondaparinux (Grade 1A). Guidelines for duration of therapy have been simplified and are based on the un-derlying etiology. Unfortunately, VTE recurrence rates are high (1 in 4-5 pa-tients who discontinue anticoagulants at 6 months will have a recurrence within 8 years). For patients at risk of recurrence, standard intensity warfarin (target inter-national normalized ratio [INR] 2-3) is the preferred treatment over low-intensi-ty warfarin (target INR 1.5-2).

New TherapiesFinally, Dr. Turpie commented on the new anticoagulant therapies, noting that “these new drugs have the potential to revolutionize anticoagulant therapy.”

These new agents all target a single factor in the coagulation cascade. Fondaparinux is the prototype for Factor X inhibition, and is the agent of choice for treatment of VTE in the recent ACCP guidelines. It was found to be as effective and safe as the current gold standards. Dr. Turpie noted that fondaparinux offers 2 advan-tages over UFH and LMWH:

• Practicality–onefixeddosevias/cin- jection, once a day, for all patients; and,• Averylowlikelihoodofcausinghepa- rin-induced thrombocytopenia.

In conclusion, Dr. Turpie strongly ad-vocated for risk-stratifying patients to provide adequate prophylaxis and, when possible, for the use of new prophylaxis options over heparin.

Syncopes are associated with considerable morbidity, finan-cial burden, and hospital ad-missions, most of which are

“unnecessary”, according to Dr. Bernard Gersh, Professor of Medicine at Mayo Clinic College of Medicine. The main causes of syncopes are either neurocar-diogenic or cardiac.

The Darwin Side: How Humans React Like AnimalsIn humans, the normal reflex to upright position involves peripheral venous pool-ing and pre-load reduction, reducing the stretch on cardiac mechanoreceptors that subsequently leads to the reduction of af-ferent information to the brainstem. The end result is increased sympathetic out-

put, tachycardia, and vasoconstriction. In vasovagal syncopes, this reflex becomes

maladapted. The postulated cascade, called the Von-Bezold Jarisch reflex, is

From Darwin to Tilt Table Testing: The Pathophysiology and Management of Syncope

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triggered by the left ventricular mecha-noreceptors in the heart that respond to a reduction in cardiac volume. Stimula-tion of these receptors increases traffic to the brainstem that leads to withdrawal of sympathetic tone and bradychardia. The Von-Bezold Jarisch reflex contrasts the normal response, whereby the sym-pathetic system is activated. Dr. Gersh added, “peripheral receptors must also play a role, whether with mechanical or chemical stimuli. And there is obviously the tremendous emotional impact on vasovagal syncope, whose mechanisms have yet to be defined”.

In the normal “fright and flight” reflex, elevated systolic blood pressure, tachy-cardia, and increased muscle blood flow enable us to run away from a predator. On the other hand, it is proposed that neurocardiogenic syncope occurs when there is “fright” without the “flight”. To support this claim, Dr. Gersh highlight-

ed the common features of the maladapt-ed “fright and flight” survival mechanism in humans and animals.

• It manifests as vasovagal syncope in humans and as bradycardia in some animals• Thesametrigger(emotion)evokesthe same response (hypotension and br- dycardia)• The maladapted response is more fr- quent in younger subjects, in both an- mals and humans• It isgenerallyprecededbyanacceler- tion of heart rate that is a manifest- tion of sympathetic activity

In addition, data indicate that, in tilt-induced syncope, arousal of the sym-pathetic system comes first, as in the “fright and flight” mechanism, and is subsequently withdrawn. Interestingly, one study has shown that when vagal pa-tients “fight back”, either by exercising or

reacting to painful stimuli, vagal symp-toms disappear.

When the Tilt-Table Comes Into PlayIn younger patients, most isolated va-sovagal episodes are non-pathological. However, in elderly patients, vasova-gal syncopes are often associated with a history of falls, orthostatic hypotension and/or coronary sinus hypertension. If structural heart defect has been ruled out, a combination of history, ECG, physical examinations and, possibly, a tilt-table test will help confirm the etiol-ogy of the syncope. If vasovagal syncope is confirmed, the most effective therapy is non-pharmacological, notably physi-cal maneuvers to counteract the reflex. Pharmacological options are not sup-ported by scientific evidence and are not indicated for neurocardiogenic syncopes.

Dr. Peter Liu, Senior Scien-tist at the Toronto Gen-eral Research Institute and,Scientific Director

of the CIHR Institute of Circulatory and Respiratory Health, addressed the topic of vaccines for cardiovascular dis-eases (CVD). In the future, vaccines could help medicine move away from treating advanced clinical disease to the benefit of earlier diagnosis and mainte-nance of health. There are four possible areas where cardiovascular vaccines are in clinical trial development: hypertension; smoking; influenza; and, atherosclerosis.

Antihypertensive vaccineMost hypertensive patients need three or more medications to maintain their

blood pressure below the recommend-ed target of 130/80 mmHg. According to Dr. Liu, an antihypertensive vaccine “could complement antihypertensive medications and avoid having to take many pills every day.” The most promis-ing target for a vaccine is angiotensin II (A2). A vaccine being evaluated in clini-cal trials promotes production of anti-A2 antibodies, thus reducing the concentra-tion of A2. In a small, phase IIA trial, three injections over 12 weeks in hyper-tensive patients decreased blood pressure by 9.0/4.0 mmHg, an effect comparable to current antihypertensive medications. Due to positive efficacy and safety re-sults, this vaccine is now advancing to larger (phase IIb/III) trials.

Anti-nicotine vaccineSmoking is considered to be the most prominent modifiable risk for prema-ture coronary disease. In Canada, the prevalence of smoking approaches 20%. Current cessation strategies are often in-effective, possibly due to physiological addiction processes mediated through nicotine receptors. The “anti-smoking vaccine” produces antibodies directed against nicotine receptors. Small trials have shown dose-dependent responses over a 9-month period in responders. Dr. Liu highlighted that this vaccine “could take away a lot of the physical depen-dence for smoking, but it does not ad-dress the social environment and other reinforcing factors for smoking.”

Looking Forward: Are We Ready for Cardiovascular Vaccines?

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March 1-5, 2009

Influenza vaccineIn elderly patients at high risk of CVD, administration of the influenza vaccine decreases both mortality and hospital-ization rates by 50%. Interestingly, it decreases hospital admission not only for pulmonary causes, but there is also a significant reduction in hospitalization for cardiac and cerebrovascular causes. However, this benefit is only seen in at-risk patients and the vaccine does not ap-pear to be helpful in primary prevention. Based on these data, the AHA/ACC rec-ommendations state:

• the inactivated, intramuscular form of the influenza vaccine should be part of comprehensive secondary preven- tion for all patients with coronary ar- tery disease or atherosclerotic plaque; and,

• thelive,attenuated,intranasalvaccine is not recommended for this population.

Atherosclerosis vaccineThe concept of this vaccine is to target individual molecules that activate mac-rophages and thereby prevent the athero-sclerotic cascade. One possible target is an antigen that is present on the surface of Chlamydophila pneumoniae that cross-reacts with proteins in the vascular wall, and, through mimicry, induces inflam-mation. One of these surface antigens is a heat-shock protein, hsp65, and a vac-cine targeted towards this protein has been shown to significantly decrease ath-erosclerotic plaque in animal models fed a high-cholesterol diet. Interestingly, ath-erosclerotic burden decreased even when

cholesterol intake and serum levels were high, suggesting that the vaccine could bypass the inflammatory component. Currently, Dr. Liu’s group is working to optimize the vaccine by combining the C. pneumonia surface antigen, hsp60, and possibly oxidized LDL.

Obviously, it will take time before any vaccines are ready for the clinical world, however, “these may be strategies to complement the existing pharmacologi-cal and behavioural modifications that we can use to improve outcomes for our patients,” concluded Dr. Liu.

Atrial fibrillation (AF) af-fects 2.3-5.1 million people in the USA. Its prevalence increases with age, but, in

recent years, AF rates have increased in-dependently of the aging population. In

fact, AF is considered one of the three contemporary epidemics, alongside heart failure and type 2 diabetes. These epidemics occur at a time when the rates of obesity, hypertension and ath-erosclerosis are also rising. Based on this

knowledge, Dr. Bernard Gersh, Profes-sor of Medicine at Mayo Clinic College of Medicine, hypothesized that obesity, hypertension, age, and atherosclerosis all interact together to increase arterial stiff-ness, diastolic dysfunction, left ventricu-lar hypertrophy, increased left atrium volume, and subsequently, AF.

Hypothesis Part I - ObesityObesity is a powerful determinant of AF in both men and women, although the precise mechanisms of this association remain unclear. Moreover, several dif-ferent studies have found that obesity is associated with left atrium volume and dilatation, left ventricular hypertrophy, diastolic dysfunction, elevated plasma volume, and changes in neurohormonal activity. According to Dr. Gersh, any of these factors could be the missing link between obesity and AF. In addition, there is a correlation between obstructive

Changing Epidemiology of Atrial Fibrillation: Is It a Vascular Disease?

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sleep apnea (OSA) and AF. It is unknown whether OSA is a direct cause of AF, or if the relationship is due to the coexisting conditions. Dr. Gersh hypothesized that both OSA itself and its associated inflam-mation are probably responsible for the strong correlation between OSA and AF. Obesity is also characterized by elevated concentrations of several pro-inflamma-tory molecules, and an association has been demonstrated between CRP levels and AF prevalence, recurrence after car-dioversion, and duration of AF.

Hypothesis Part II – Diastolic Dysfunc-tion and Left Atrial VolumeBoth diastolic dysfunction and left atri-um (LA) volume have been shown to be independent predictors of AF risk. Inter-estingly, body mass index (BMI) is also an independent predictor of diastolic dysfunction and LA volume. There is also a strong association between LA vol-ume and aortic stiffness, as measured by several surrogate markers.

Does AF cause thromboembolism, or is it the company it keeps?The data presented by Dr. Gersh support the link between obesity, hypertension, metabolic syndrome (and potentially OSA) with arterial stiffness, diastolic dysfunction, and increased LA volume. According to several studies, LA dilata-

tion is an independent predictor of AF, stroke, myocardial infarction, CV death, and coronary revascularization. Based on these data, Dr. Gersh supported the statement published in JACC (2003), “LA volume is the HbA1c of diastolic dysfunction and vascular disease.”

Hypertension is strongly associated with both stroke and AF, however, it is un-clear whether hypertension causes these two conditions. A meta-analysis showed that hypertension is one of many risk factors for stroke. Dr. Gersh argued that hypertension alone could be a marker of atherosclerosis. To support his hypoth-

esis, Dr. Gersh presented some of his own data from a 30-year follow-up study in AF patients with no hypertension at baseline. In this sample (n=71), stroke incidence increased based on two inde-pendent factors, age and hypertension.

There is some evidence suggesting that AF and dementia could both derive from a similar vascular pathology. Ad-ditionally, AF might be considered to be two different diseases. Patients with paroxysmal AF might have their trigger in pulmonary veins, while patients with permanent AF might have both a trigger and a diseased left atrium substrate.

Quality of life is considerably reduced in symptomatic patients with paroxysmal AF. The first strategy to

achieve rhythm control is the use of anti-arrhythmic drugs, however the efficacy of these drugs is often mod-est and/or long-term toxic effects are discouraging. Dr. Mario Talajic, a car-

diac electrophysiologist at the Montreal Heart Institute and Professor of Medi-cine at the University of Montreal, dis-cussed an alternative - pulmonary vein ablation.

Catheter Pulmonary Vein Ablation: The “How”Catheter ablation involves inducing ab-

lation lesions to electrically isolate all four pulmonary veins. The technique involves the insertion of a circular cath-eter onto the atrial side of the pulmonary vein that can then conduct sequential ablation around the veins. The end re-sult of the standard 3-hour procedure is the electrical isolation of the pulmo-nary veins so that AF in pulmonary veins

Pulmonary Vein Ablation for Atrial Fibrillation

11

March 1-5, 2009

does not spread to the atrium, resulting in maintenance of sinus rhythm. Longer history of AF or involvement of atrial substrate requires extended ablation le-sions. These more complex surgical pro-cedures are associated with lower efficacy and more frequent complications.

Catheter Pulmonary Vein Ablation: The “Why” and the “Who”Efficacy measures for pulmonary vein

isolation (PVI) are rare and come from small studies due to the recent emer-gence of this technique. Improved out-comes have been observed in younger patients with paroxysmal disease, shorter history of AF, and with no structural heart disease. During a 12-month fol-low-up, a single PVI procedure in par-oxysmal AF patients resulted in 50-60% clinical success while the success dropped to 20-40% in permanent AF. A second

procedure increased clinical success rates to 80% and 50% in paroxysmal and per-manent AF, respectively. In paroxysmal AF, studies have shown decreased recur-rence rates and improved quality of life with PVI compared to anti-arrhythmic drugs. However, there are possible com-plications associated with this invasive technique, reaching 2-4% in high-vol-ume centres. In a joint position to be published by the Canadian Cardiovas-cular Society and the Canadian Heart Rhythm Society, PVI is recommended for patients with -

• Symptomatic, paroxysmal AF and minimal heart disease refractory or in- tolerant to medical therapy (class I)• Symptomatic,persistentAFrefractory or intolerant to medical therapy (class IIa)

Dr. Talajic argued that future research should be directed towards newer imag-ing and ablation techniques and should engage different patient populations, in-cluding patients with high risk of stroke (e.g., the CABANA study), patients with coronary heart failure, and elderly patients.

Anti-arrhythmic drugs are sometimes ineffective and are often associated with side effects, whereas pulmonary

vein ablation is only successful in young patients with a short history of paroxys-mal AF. Dr. Ralph J. Damiano, Chief of Cardiac Surgery and Vice-Chairman of the Department of Surgery at Wash-ington University, presented another op-tion, surgery, which may be beneficial in a different subset of patients. Dr. Dami-

ano proposed that surgery and catheter ablation are complementary procedures because they benefit different groups of patients. In a recent expert consensus pa-per, the indications for surgery were the following -

• Patients with symptomatic AF who have failed medical therapies AND either - Have failed at least one catheter ablation

- Are not candidates for catheter ablation - Or prefer the surgical approach

Cox-Maze IV procedureDr. Damiano’s research group employs bipolar radiofrequency ablation that al-lows a rapid and focused delivery of en-ergy. This technique produces reliable transmural lesions, requires short (5-10 seconds) ablation time, and prevents col-lateral damage. In this procedure, the ab-

Surgical Treatment of Lone Atrial Fibrillation

12

lation lines are positioned to isolate the posterior left atrium from the pulmonary veins. The left atrium appendage (LAA) is amputated to reduce the risk of post-surgery stroke. With this technique, 80% of patients were free of AF without the use of medication at a 12-month fol-low-up. In a group of 234 patients (mean age: 63 ± 12 years) with a long history of AF and LA dilatation, ablation time for lone pulmonary vein isolation was 28 seconds, and cross-clamp time was de-creased to 35 minutes, a significant im-provement over older techniques.

This population was clearly different from the population indicated for cath-eter ablation as described by Dr. Talajic. Success rates reached 92% and 67% (per-centage of patients being both AF- and drug-free after one year). Additionally, contrary to catheter ablation, the proce-dure was successful for both paroxysmal and persistent AF. However, Dr. Dami-ano acknowledged that “the advantage [of this technique] is that it is the same operation for everybody …, although it is probably too much surgery for parox-ysmal patients.” Dr. Damiano suggested that pulmonary vein isolation might be better indicated for paroxysmal AF.

Surgical Pulmonary Vein IsolationDr. Damiano’s team performs video-as-sisted surgical PVI with bipolar clamps, often with amputation of the LAA. The success of surgical PVI is similar to cathe-ter ablation, with 74% of paroxysmal AF patients being symptom-free and drug-free after the procedure. However, only 39% of permanent AF patients achieve the same success, which is “not good enough for a surgical procedure”, accord-ing to Dr. Damiano. In summary, “to no great surprise considering the results of

catheter ablation, PVI is not enough in some patients, particularly those with large left atria and long-standing AF.”

Dr. Damiano emphasized the need for a surgical approach with a more pre-dictable success rate. “The real future is probably taking some of our surgical procedures down to the electrophysio-logical lab and working together”. In the long term, this hybrid approach could improve the management and success of patients with symptomatic AF.

Half of patients with class IV congestive heart fail-ure (CHF) have AF, and the more severe the heart

failure, the more prevalent AF becomes. Moreover, co-occurrence of AF and CHF generally predicts worse outcomes than CHF alone. According to Dr. Ma-rio Talajic, management of this popula-tion can be challenging since AF and CHF can induce each other.

AF/CHF Management: The First StepsFirst, AF should be ruled out as a pos-sible cause of CHF. Indeed, tachycardio-myopathy is a reversible cause of CHF and should be suspected when patients present with non-ischemic cardiomy-opathy, there is simultaneous occurrence of AF and CHF, patients do not com-plain of palpitations, and have modest left ventricular dilatation. Moreover, the prevalence of tachycardiomyopathy

may be more common than previously believed, reaching 14% in patients ad-mitted to hospital with AF/CHF accord-ing to a recent study. Second, Dr. Talajic argued that many AF/CHF patients also have elevated risk for stroke, hence anti-coagulation is desirable. For patients at low risk for stroke, the American College of Cardiology (ACC) guidelines support the use of either aspirin or warfarin.

Management of Atrial Fibrillation in Congestive Heart Failure

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March 1-5, 2009

In the last 10 years, studies have shown that inflammation is as predictive of atherosclerosis as lipid levels. Most research has

targeted C-reactive protein (CRP) as a marker of inflammation, but any mol-ecule involved in the complex inflamma-tion cascade (e.g., IL-6, leptin) will have some predictive power. Dr. Paul Ridker, Professor of Medicine at Harvard Medi-cal School, advocated that inflammation causes atherosclerosis; hence, inhibition of inflammation may have considerable benefits for patients at risk of CVD.

Dr. Ridker supports the use of the Reyn-olds Risk Score for assessing CV risk. This scale takes into account all major CV risk factors - smoking status, HDL-C, family history, age, diabetes, and hsCRP. Notably, due to the inclusion of inflammatory markers, the Reynolds Risk Score provides an accurate estimate of CV risks for several types of patients. In fact, when comparing 10-year pre-dicted risk and observed CV events, the Reynolds Risk Score was accurate in al-most all patient subgroups evaluated.

Can we target inflammation for CV pri-mary prevention?

Dr. Ridker posed the hypothesis that if inflammation is a predictor of CV risk, then drugs inhibiting inflammation should be associated with improved out-comes. He argued that 25% of North American adults have normal LDL-C, but elevated hsCRP. According to previ-ous guidelines, these patients should not be treated with statins. However, accord-ing to the Reynolds Risk Score, they may be at high risk of CVD. Statins are good candidates for primary prevention thera-py. Independent of their LDL-lowering effects, they also have anti-inflammatory effects. In fact, the first statin studies ob-served reduced hsCRP levels in a variety in patients. In addition, statin treatment was associated with positive outcomes even in patients with low LDL at base-line, probably due to a reduction in in-flammation. Subsequently, many trials (PROVE-IT, REVERSAL, A to Z, and TexCAPS/AFCAPS) suggested that low-ering both LDL-C and hsCRP would optimize benefits.

These observations constituted the basis of the JUPITER study that investigated statin therapy as primary prevention in patients with LDL-C ≤ 3.36 mmol/L

and hsCRP ≥ 2 mg/L (i.e., patients who would not qualify for preventative ther-apy based on current guideline recom-mendations). Subjects were randomized to rosuvastatin 20 mg or placebo. Statis-tically significant effects were observed across all endpoints, including a 44% reduction in the primary endpoint, time to first CV event. A 20% risk reduction in all cause mortality was also observed, driven almost entirely by reduction in vascular events. Dr. Ridker commented, “we now have hard evidence that when we target inflammation and give a statin, we lower mortality, as well as heart at-tack, stroke, bypass, and angioplasty.” Importantly, these results hold true for every subgroup evaluated in the JUPI-TER study, including women and ethnic groups. Interestingly, subgroup analysis also revealed that family history of pre-mature CVD is a major determinant of both CV risk and of therapeutic benefit. Overall, data from JUPITER showed greater benefits than anticipated, suggest-ing that rosuvastatin may have clinically important effects beyond LDL-lowering, and probably beyond hsCRP-lowering. Data to be published soon will uncover whether both should be targeted (i.e.,

Targeting Inflammation As a Predictor of Risk

AF/CHF Management: Rhythm or Rate?In AF patients, physiological arguments favour rhythm control while rate control is simpler and achievable in all patients. However, the expected superiority of rhythm control has not been demon-strated in large RCTs in AF patients and AF/CHF patients. The AF-CHF study did not show any improvement in car-diovascular mortality during a 37-month follow-up. However, the rate of hospital-ization for AF management was higher in the rhythm control group. An obser-

vation from the AFFIRM study led to the hypothesis that the end result, i.e. sinus rhythm, may be more important than the choice of therapy. This potential benefit was not observed in the AF-CHF study. Dr. Talajic commented that “rate control should be the initial strategy and, if symptoms persist, rhythm-control may then be considered”.

In the subset of patients where sinus-rhythm is the goal, the 2006 ACC guidelines recommend amiodarone or

dofetilide1 as anti-arrhythmic drugs, with catheter ablation as a later alterna-tive. Finally, AF ablation in AF/CHF pa-tients is a promising strategy. One study demonstrated that PVI improved exer-cise function, quality of life, and ejec-tion fraction. However, data are available only from four small studies. Larger trials are needed before strong support can be given to this technique in the AF/CHF population.

1 In Canada, dofetilide is only available through special request to Health Canada.

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LDL-C and hsCRP) to optimize benefits.

Diet, exercise, and other therapies can also reduce inflammation. Dr. Ridker argued that atherosclerosis shares etiol-ogy with rheumatoid arthritis and pso-riasis. Consequently, drugs such as IL-6, TNF-α inhibitors, and methothrexate could potentially reduce vascular risk as well. A trial is ongoing with CV patients randomized to placebo or methothrex-ate to determine whether an approach targeting solely inflammation could be beneficial. In conclusion, Dr. Ridker acknowledged the open-mindedness of patients and physicians that made JU-PITER possible and added, “I think we must have that open-mindedness as we move into guidelines and move forward in preventing diseases.”

Post Script: Results from 2 Jupiter sub-studies were presented at the American Heart Association meeting; they are summarized below.

Jupiter: Dual Target Analysis: Patients

who achieved a dual treatment target of LDL-C< 1.8mmol/L and hsCRP< 2mg/L with rosuvastatin achieved a greater reduction in CV events com-pared to placebo than those who did not (65% vs. 36%, p=0.033). Ridker PM et al. Lancet 2009; 373:1175-82.

Jupiter: Venous Thromboembolism Analysis: Rosuvastatin 20mg significant-ly cut the risk of venous thromboembo-lism (VTE) by 43% (p=0.007) compared to placebo. Glynn RJ et al. NEJM 2009; 360:1851-61.

The American Heart Asso-ciation (AHA) published their first guidelines on antibiotic prophylaxis in

1955 after associations between dental procedures, bacteremia, and infectious endocarditis (IE) were observed. Dr. Heidi Connolly, Professor of Medicine at the Mayo Clinic, reviewed recent chang-es to AHA guidelines and the evidence that supports these modifications.

Different dental procedures may cause bacteremia that can subsequently lead to endocarditis. The frequency of bacte-remia ranges from 8-100%, depending

on the nature of the procedure. Simi-larly, many daily activities, such as teeth brushing, flossing, and chewing, can also cause bacteremia. Dr. Connolly quoted Dr. Roberts (1999), “it is far more likely that everyday procedures cause bacterial endocarditis because the cumulative ex-posure is often hundreds, thousands, or even millions of times greater than that occurring following surgical procedures. The value of antibiotic prophylaxis prior to dental procedures is questionable.” Importantly, studies have shown that good oral hygiene significantly decreases the risk of bacteremia resulting from both dental procedures and everyday activities.

Recent studies on the efficacy of pro-phylaxis in preventing bacteremia have yielded conflicting findings. In addition, studies investigating prophylaxis of IE showed that dental procedures are sel-dom responsible for IE. Therefore, pro-phylaxis would only prevent a few cases of IE. Nonetheless, cardiovascular diseas-es constitute an additional risk of IE. On the other hand, the use of antibiotics car-ries some risks and raises drug resistance issues. Dr. Connolly argued, “we need to weigh the potential risks versus the ben-efits [of prophylaxis] in each individual patient.”

Update on Infectious Endocarditis Prophylaxis

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March 1-5, 2009

In this second of a 2-part discus-sion, Dr. A. Graham Turpie, Pro-fessor of Medicine at McMaster University, discussed recent ad-

vances in antithrombotic therapy. Dr. Turpie opened his talk by pointing out that despite many advances in parenteral antithrombotic therapy over the past 20 years, warfarin is still the only option available for oral anticoagulation. His discussion of the development of new antithrombotic agents focused on the prevention of VTE in orthopedic sur-gery, which is the standard setting for the early evaluation of new anticoagu-lants, and in AF, where “we have a very marked, unmet need for new anticoagu-lant therapy”.

Anticoagulation in Atrial Fibrillation AF represents the most common serious dysrhythmia faced by clinicians. Its prev-alence increases markedly with age, and is increasing over time. Notably, an esti-mated 5.6 million patients in the United States will have AF in 2050. Dr. Turpie stressed that this is important because AF increases the risk of stroke 5-fold, ac-counting for 15-20% of all strokes. War-farin has been clearly shown to reduce stroke risk by 64% in patients with AF. Significantly, it is far superior to ASA. As a result, current guidelines recommend VKA therapy for all AF patients with

CHADS2 score ≥2. Dr. Turpie points out that “about 80% of the AF patients that we see have a CHADS2 score ≥2, and so should receive oral anticoagulants.”

However, underutilization of anticoagu-lation therapy in AF is a very real con-cern. According to Dr. Turpie, “only about half of the patients with AF who should get oral anticoagulants actually receive it. And we’ve done no better in recent years.” He suggested that the per-ceived risk of bleeding, lifestyle implica-tions with VKA treatment, and the lack of resources for outpatient anticoagulant

monitoring all contribute to this under-utilization. As a result, “there are a mil-lion strokes every year that could be pre-vented, but are not.”

New Agents in DevelopmentWarfarin’s limitations have spurred the development of new anticoagulants. Dr. Turpie discussed those agents in the later stages of clinical development. Dabi-gatran is the only oral direct thrombin inhibitor. It is administered once daily, with a highly predictable response and no requirement for anticoagulant moni-toring. Dabigatran has a large clinical

Novel Anticoagulants: Goodbye, Warfarin!

Who should receive antibiotic prophylaxis? In the general population, the lifetime risk of IE is 5/100,000 patient-years, but this risk increases with the presence of CVD and past history of IE. Due to the conflicting evidence, prophylaxis should be reserved for patients with the highest risk of adverse outcomes, i.e. patients with:

• prostheticcardiacvalve;• previousinfectiveendocarditis;• cardiactransplantrecipientswithcar- diac valvulopathy; and,• congenital heart failure, shortly after surgery or those with residual defects.

In these patients, the AHA recommends 2 g of amoxicillin for all dental proce-

dures and events that involve manipula-tion of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. Dr. Connolly concluded with a reminder that adequate oral hygiene is more important than antibiotic pro-phylaxis to reduce the risk of IE for most patients.

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trial program across the spectrum of thrombosis. The component addressing VTE prevention in orthopedic surgery has been completed. Results from the pre-specified pooled analysis of the 3 trials within this component have been published. According to Dr. Turpie, these results demonstrate dabigatran’s equivalence to enoxaparin, the current gold standard, in both primary and sec-ondary efficacy outcomes. Importantly, this benefit was achieved without an in-creased risk of bleeding.

Dr. Turpie observed, “dabigatran pro-vides us with a balance between efficacy and safety, without the need for coagula-tion monitoring, in a simple regimen.” Based on these results, dabigatran is approved in Canada and the European Union for this indication.

A large trial studying dabigatran for the prevention of stroke in patients with AF, called RE-LY, has recently been com-pleted. Final results from RE-LY will be presented this year. In Dr. Turpie’s view,

dabigatran will likely meet its non-inferi-ority margin. He sees “very exciting po-tential this year for a change in the way that we manage patients with AF.”

Factor X is a target for many novel anticoagulants. Rivaroxaban and apixaban are the most advanced oral di-rect inhibitors of Factor Xa. Like dabi-gatran, they do not require anticoagu-lant monitoring and are being studied in large clinical trial programs covering a spectrum of thrombosis. Apixaban showed promising results in Phase II studies for VTE prevention after ortho-pedic surgery compared to enoxaparin. The first Phase III trial in this popula-tion, ADVANCE-1, failed to meet its pre-specified non-inferiority criteria; Dr. Turpie pointed out that results from 2 other Phase III orthopedic trials are awaited. In addition, two studies , ARIS-TOTLE and AVERROES, are currently ongoing in AF patients. They are com-paring apixaban with warfarin and aspi-rin, respectively.

Rivaroxaban was compared to enoxapa-

rin in an orthopedic population in the RECORD trial program. Dr. Turpie re-viewed the results from a pre-specified pooled analysis of the 4 component trials that demonstrated that the primary ef-ficacy outcome was significantly reduced with rivaroxaban treatment. There was no statistically significant difference in the incidence of major bleeding. Based on these results, rivaroxaban has been approved in Canada and the European Union for orthopedic surgery patients. The ROCKET trial, investigating the efficacy and safety of rivaroxaban in the prevention of stroke in AF patients with a CHADS score ≥2, is ongoing.

Improved OutcomesIn conclusion, data already available on the new oral anticoagulants show very promising potential for stroke preven-tion in patients with AF. Dr. Turpie con-cludes, “this year, we’ll see the dabigatran data that I think will prove positive, and will allow us to change that figure of 1 million strokes that should have been prevented and weren’t.”

Cardiac masses most often involve the left atrium and have varied pathol-ogy, including thrombus,

vegetation, and primary and metastatic tumours. Initial symptoms can be car-diovascular (embolism, arrhythmias), systemic (fever, fatigue), obstructive (chamber, valve, or venous) or cardiac compression. Dr. Heidi Connolly, Pro-fessor of Medicine at the Mayo Clinic, discussed the evaluation and diagnosis of cardiac masses.

In recent years, advances in imaging technology have improved diagnoses

of cardiac masses. Widely available, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) provide anatomical, location, size and mobility information. Computed tomography (CT) and cardiac magnetic resonance imaging (CMR) are comple-mentary to echocardiography and help confirm the diagnosis.

Primary cardiac tumours are benign in 94% of cases, with myxoma representing the most common benign cardiac neo-plasm (41% of cases). It is primarily situ-ated in the left atrium. Symptoms include embolism, obstruction, arrhythmias,

and systemic manifestations. Myxoma-induced embolism is related to mobil-ity – and not size – of the mass. Surgery is usually indicated. Myxoma syndrome describes an autosomal dominant condi-tion that should be suspected in patients who present with atypical location, mul-tiple, or family history of myxoma. Con-versely, papillary fibroelastomas, Lambl’s excrescences, fenestration of the aortic valve, fibromas, and rhabdomyomas all affect cardiac valves. Papillary fibroelas-tomas have embolic potential and shave excision is often sufficient to manage the condition. Lambl’s excrescences and fen-estration of the aortic valve are degenera-

Evaluation of Cardiac Masses

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March 1-5, 2009

The debate between surgeons and interventionalists on choosing between coronary artery bypass graft (CABG)

or percutaneous coronary intervention (PCI) continued at this year’s ACC Lake Louise meeting. Dr. Ralph Damiano, Chief of Cardiac Surgery at the Wash-ington University School of Medicine, argued in favour of surgical treatment for left main and three-vessel coronary artery disease (CAD). According to nu-merous international societies, the issue is not even a matter of debate. Indeed, the ACC/AHA/SCAI 2005 guidelines for PCI in the treatment of left main dis-ease suggest that PCI is a class III therapy and is “generally not effective and may even be harmful.” Even major societies favour the appropriateness of surgery for left main disease with or without addi-tional CAD over PCI. Dr. Erick Scham-paert, Associate Professor and Head of the Division of Cardiology at the Uni-versité de Montréal, presented the in-terventionalist’s perspective in favour of PCI for the treatment of unprotected left main disease.

Although PCI may be attractive for ana-tomic and economic reasons, Dr. Dami-ano cautioned that there remains a real

possibility for incomplete revasculariza-tion with PCI procedures. Furthermore, late stent thrombosis remains a clinical reality. He cited several placebo-con-trolled RCTs that have demonstrated a survival benefit of CABG over medical therapy. On the other hand, based on results from a recent large meta-analysis, Dr. Schampaert argued that in-hospital mortality rates for PCI are similar to those observed with CABG. Further-more, the low mortality rates observed for CABG in the general population may not be representative of those in the sub-population of patients with unprotected left main disease. Dr. Schampaert coun-tered Dr. Damiano’s argument regarding incomplete revascularization by stating that rates are <1% in patients with Ostial lesions managed with drug-eluting stents.

The SYNTAX trial, published in Feb-ruary 2009, is arguably the best trial directly comparing CABG versus PCI. Both debaters used data from this trial to support their respective positions. Dr. Damiano pointed to the significant dif-ferences in favour of CABG versus PCI in the overall SYNTAX patient popula-tion. Based on the robust results, CABG should remain the standard of care for left main and three-vessel disease. Dr.

Damiano concluded by stating that “un-til the problem of late stent thrombosis is solved, the evidence available to date strongly favours CABG.” Dr. Scham-paert argued that while the primary endpoint significantly favoured CABG, the difference was driven by the higher revascularization rates with PCI, which can generally be managed by repeat PCI. Furthermore, the results should be con-sidered in the context of the significantly higher risk of stroke in the CABG group. Finally, when patients were stratified by a syntax score that evaluates lesion com-plexity, there was no difference between CABG and PCI in patients with low syn-tax scores.

Dr. Schampaert concluded that the only way to definitively answer the question under debate is to conduct a proper RCT. “In the meantime, I strongly be-lieve that a collaborative evaluation of each patient with unprotected left main disease is warranted… We should inte-grate the use of syntax scores into clini-cal practice, consider lesion location, and stroke risk should not be neglected.”

CABG vs. PCI for Left Main and Three-Vessel Coronary Artery Disease: The Great Debate

tive conditions while rhabdomyoma is the most common cardiac tumour ob-served in the pediatric population.

Masses most often found in the atrioven-tricular (AV) groove include pericardial cyst, pheochromocytoma, coronary ar-tery aneurysm, lipomatous hypertrophy, lipoma, and blood cyst. Most of these conditions can be seen on an echocar-diography, but CT or CMR scans are

necessary to confirm the diagnosis. In the case of coronary artery aneurysm, an angiogram may be indicated. Finally, blood cyst should be suspected in pa-tients younger than 2 years old. Several other masses or pseudomasses can occur in the heart (e.g., Eustachian valve, Chi-ari network, fat in the AV groove, calci-fied amorphous tumour, hydatid cyst, Q-tip, hiatal hernia, and vegetations). Dr. Connelly commented, “be careful not to

miss the opportunity to make the diag-nosis of a benign abnormality.” In fact, primary malignant cardiac neoplasms are rare with sarcomas accounting for most of the primary cardiac malignant masses. Pericardial effusion strongly suggests ma-lignancy. Conversely, metastatic cardiac tumours are more common and most often derive from melanomas (46%), breast (17%), or lung (17%) tumours.

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Over the last 20 years, deaths from coronary heart disease (CHD) have diminished sub-

stantially (approximately 40%). This has been largely due to the application of treatments that have been proven by clinical trials to be effective interven-tions. Dr. Christopher Granger, from the Duke Clinical Research Institute, stated, “the list of treatments we have proven through clinical trials to reduce mortality is relatively short.” He noted, “with the results from the Jupiter trial, statins for primary prevention can be added to this list.” Furthermore, “we need to be sys-tematically applying these treatments to all eligible patients and working on ad-herence to ensure patients are getting the benefits of these therapies.” Dr. Granger went on to observe that “large RCTs are recognized as having the best strength of evidence to demonstrate modest benefits on clinical outcomes and serve as the foundation for assessing a treatment’s ef-fectiveness.”

Why, then, do large clinical trials some-times fail to meet our expectations? Dr. Granger suggested several reasons for this phenomenon. First, large RCTs are often based on findings from smaller positive studies that are limited by sample size. In-deed, trials with 150 events or less are gen-erally underpowered and probably inad-equate for determining treatment effects. “When unexpected findings are reported in small studies, we need to be very skepti-cal about whether or not the findings will hold up when larger, definitive trials are conducted,” explained Dr. Granger.

Second, the positive results observed in observational studies are not always

replicated when larger RCTs with rigor-ous inclusion and exclusion criteria are conducted. Often, patients at the high-est risk of events (and of adverse effects) are excluded from RCTs. This highlights one of the weaknesses of large RCTs, whereby the results might not be gen-

eralizable to the broader patient popu-lation. The GUSTO trial was probably one of the most successful studies in terms of recruiting a wide spectrum of patients, making its results more appli-cable to clinical practice.

Clinical Trials: Why They Fail to Meet Expectations

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March 1-5, 2009

Finally, Dr. Granger cautioned that RCTs that are stopped early when they meet a pre-defined number of events prob-ably overestimate treatment effects. “We should discount treatment effects at least slightly when trials are stopped early, particularly with relatively few events.” For example, early interim results of the CHARM trial demonstrated a highly significant reduction in mortality, but, over time, the treatment effects dimin-ished and by the time the study met its pre-defined stopping criteria, the benefit was no longer statistically significant.

One of the greatest challenges remains reliably assessing drug safety that requires longer-term exposures than typically evaluated in RCTs and the inclusion of higher-risk cohorts. Two options for im-proving the detection of adverse drug effects are 1) to increase the numbers of patients enrolled in pre-registration clinical trials, and 2) to improve post-marketing safety evaluation (phase IV) trials. According to Dr. Granger, “there needs to be a balance of these so that we don’t overly prohibit the development of new treatments, while ensuring adequate

safety surveillance.”

In closing, Dr. Granger stressed the im-portance of replicating clinical trials to increase our confidence in their findings and challenged the idea that a single trial can produce definitive answers. “Clinical trials have major challenges, but are still the best we have. We need to continue to work on improving their applicability in clinical practice.”

Dr. Erick Schampaert, As-sociate Professor and Head of the Division of Cardiology at the Uni-

versité de Montréal, reviewed evidence supporting the use of antithrombotic regimens in patients post-PCI. Guide-lines and clinical practice have moved towards the use of dual antiplatelet ther-apy (DAPT) to reduce the risk of plaque rupture, stent thrombosis, and throm-boembolic events. When choosing the antiplatelet regimen and the duration of treatment, the potential benefits of DAPT must be balanced against the risk of bleeding.

Evidence supports the use of aspirin at a dose of 75-150 mg to protect against thrombotic events and is associated with significantly less bleeding than higher doses. The PCI-CURE and CREDO tri-als support the benefit of adding clopido-grel (using both a loading dose pre-PCI and maintenance treatment post-PCI) to aspirin for long-term protection against CV events. More recently, the TRITON-TIMI 38 trial suggested that DAPT with

prasugrel was more effective than clopi-dogrel both early and over time. This additional protection was achieved at the expense of statistically significantly higher bleeding complications including major, life threatening, and fatal bleeds compared to clopidogrel. Dr. Schampaert advised that limitations of the study design should be considered when interpreting these re-

sults. For instance, the clopidogrel load-ing dose (300 mg) was given immediately prior to PCI, even though studies have demonstrated that it takes up to 15 hours to take effect, whereas prasugrel is faster-acting. Furthermore, there is considerable heterogeneity in patient response to clopi-dogrel, and higher loading doses may be required in patients who are poor drug me-

Antithrombotics in Post-PCI Care

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tabolizers (i.e., those with CYP2C19 poly-morphisms). Additionally, recent studies have suggested that proton pump inhibi-tors (PPIs) may negatively influence the antiplatelet action of clopidogrel. Despite this observation, guidelines recommend that patients at increased risk of gastroin-testinal bleeding – including those receiv-ing DAPT – should be treated with PPIs. “This is potentially the opposite of what we should be doing if we want to protect

our patients against ischemic events,” cau-tioned Dr. Schampaert.

For the prevention of stent thrombosis, both the type of stent and the antiplate-let regimen impact outcomes. RCTs, reg-istries, and meta-analyses all support the superiority of drug-eluting stents (DES) over bare metal stents (BMS) for reduc-ing the need for target vessel revasculariza-tion and suggest a trend towards benefits

on hard endpoints such as MI and death. The TRITON-TIMI 38 study demon-strated that prasugrel is associated with a significantly lower risk of early or late stent thrombosis (using any type of stent) com-pared to clopidogrel, but at the cost of a higher risk of major bleeding. The optimal duration of DAPT to prevent stent throm-bosis remains unclear, although guidelines currently recommend 1 year in patients at low risk of bleeding.

The Metabolic Syndrome: What Every Cardiologist Should Know

The definition – and the ex-istence – of the metabolic syndrome are controversial. The Adult Treatment Panel

III (ATP III) defines metabolic syndrome as the co-occurrence of at least three of the following five criteria: increased waist cir-cumference, high triglycerides, low HDL-C, high blood pressure, or impaired fasting glucose. Dr. David Waters, Chief of Car-diology at San Francisco General Hospital, discussed the metabolic syndrome in the context of cardiovascular disease.

What is the link between the metabolic syndrome and cardiovascular risk factors?Due to the ongoing debate about an ad-equate definition of the metabolic syn-drome, Dr. Waters presented a simplified diagnostic measure. A waist circumference >90 cm and triacylglycerol (TAG) levels >2.0 mmol/L were found to be accurate screening tools for insulin resistance, el-evated apoB levels, and presence of small, dense LDL particles: all factors that are implicated in the metabolic syndrome. Indeed, 83% of patients with both large waist circumference and high TAG levels met criteria for metabolic syndrome. Dr. Waters also argued that abdominal obesity is a key component of the metabolic syn-drome. In fact, elevated abdominal visceral

fat is associated with impaired insulin sen-sitivity and hypertension. It is commonly accepted that rising obesity rates promote the development of the metabolic syn-drome. A large-scale study showed that obesity was associated with mortality risks similar to smoking. Along with the obesity epidemic, type 2 diabetes is becoming a worldwide problem, affecting several eth-nic groups. For instance, Asian populations are at risk for diabetes and CVD at lower BMI and waist circumference compared to Caucasians. For this reason, ethnic-specific cutpoints for BMI and waist circumference are now available.

Treatment Options for Patients With Meta-bolic Syndrome: What are our good options?In a typical patient with metabolic syn-drome, the CV risk is relatively low accord-ing to Framingham risk scoring because it only considers the individual’s 10-year risk. Dr. Waters argued that lifetime risk is a much better indicator. In patients with metabolic syndrome, the best therapeutic option to prevent type 2 diabetes mellitus (T2DM) is diet and exercise. In fact, a small weight loss (4.2 kg in a year) reduced the prevalence of T2DM by 58% compared to a control group. For many patients who struggle with lifestyle management, statins constitute a good pharmacological option.

Due to their effects on LDL-C and inflam-mation, statins are effective at preventing CV events in a variety of at-risk popula-tions, including patients with low HDL-C, diabetes, and hypertension. The Treating to New Target (TNT study) specifically found a 29% CV event rate reduction in patients with metabolic syndrome when treated with atorvastatin 80 mg compared to 10 mg. Dr. Waters further supported the use of statins by noting, “when you look at the laboratory report of somebody with the metabolic syndrome, we are struck by the high TAG and the low HDL-C and we think about treating those. The LDL-C levels are not that abnormal, but these patients have small dense LDL with endo-thelial dysfunction, they have a very ath-erogenic, prothrombotic milieu. So statins can offer many benefits.”

Studies have also shown that metformin is more effective than placebo, but not as good as lifestyle intervention, in preventing new onset diabetes in patients with meta-bolic syndrome. Finally, rosiglitazone and pioglitazone can both reduce diabetes in-cidence, but pioglitazone may be preferred due to its more favourable safety profile. Fi-nally, bariatric surgery has yielded impres-sive results in terms of weight loss, LDL-C, triglycerides, and HbA1c levels.

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March 1-5, 2009

Dr. Jacques Genest, Di-rector of the Division of Cardiology at McGill University Health Cen-

tre, presented proposed changes to the Canadian guidelines for lipid manage-ment. Importantly, the information he presented had not yet been approved by the Canadian Cardiovascular Society at the time of the ACC Lake Louise meet-ing, and should be treated accordingly. The major changes for management of dyslipidemia include high-risk strategy, end-stage disease, primary prevention, and simplified targets.

First, screening would be recommended

for patients above the age of 40 (men) or 50 (women), for patients with hyper-tension, diabetes, family history of CAD, obesity, inflammatory diseases, or HIV. According to Dr. Genest, the roles of obesity and stress in mediating risks of myocardial infarction have been under-estimated in recent years. Notably, CV events in at-risk patients dropped from 28% in 1997 (4S study) to 7% in the recent TNT trial. Dr. Genest noted that, “over a 20-year period, we have come a very long way in high-risk reduction, not just because of lipid lowering, but because of all the preventive strategies.” Dr. Genest strongly supported the use of

primary prevention strategies, including smoking cessation, diet changes, exer-cise, and stress management.

The only target for dyslipidemia that is strongly supported by evidence is LDL-C (or apolipoprotein B). There are no clinical trial data to support the use of treatment to correct other parameters of dyslipidemia once LDL-C targets are achieved. At this point, the belief that lowering hsCRP, or adjusting the total cholesterol/HDL-C ratio, decreases CV risks is solely based on expert opinion.

The updated guidelines are expected to be available later this year.

D r. Fedak, clinical cardiac surgeon at the University of Calgary, discussed nov-el surgical approaches to

treat patients with congestive heart failure (CHF). His talk focused on the Heart-NetTM device, the most recent approach to cardiac restraint therapy.

CHF is an important clinical problem that is preceded by structural modifica-tions, namely ventricular remodeling and dilatation. Dr. Fedak argued that once ven-tricular remodeling has started, it triggers additional remodeling, and increases ven-tricular dilatation. This vicious cycle seems to be mediated, at least in part, through increased cardiac wall stress. The concept of cardiac restraint therapy is to intervene in this cycle to prevent further damage to the ventricles. The hypothesis is that reduc-ing LV size could decrease CHF symptoms and lead to improved outcomes for pa-tients. Interestingly, this type of approach could benefit patients in stage C of the

disease who are traditionally treated with medical therapies and cardiac resynchroni-zation therapy (CRT).

Cardiac restraint therapy originally re-quired invasive surgery, but the Heart-NetTM device is less invasive, requires a shorter procedure (~60 min), and involves less scarring. The proposed mechanism involves increasing epicardial pressure through the use of the elastic HeartNetTM, hence decreasing transmural pressure. The alleged results are considerable reductions in both wall stress and ventricular remod-eling. A recent study showed that pressure in the range of 1.5-3 mmHg is optimal for cardiac restraint devices. However, with traditional devices, the pressure and the ef-fects of the therapy tend to lessen as the ventricle size diminishes. The HeartNetTM elastic properties may provide a self-adjust-ing device that continues to deliver pres-sure even after reversal of cardiac remodel-ing. Dr. Fedak’s research group conducted an animal study to measure HeartNetTM

effects in vivo. His data showed linear compliance of the device, its capacity to deliver 1.5-3 mmHg of epicardial pres-sure over a wide range of stretch, and its efficacy at reducing myocardial stress. Dr. Fedak believes that “We now have direct data to suggest that this device can, in fact, reduce transmural pressure and diastolic stress. We also know that this device can provide an optimal support level.” Howev-er, questions remain whether the device is self-adjusting or whether it can provide full cycle support and what its effects would be during systole.

Implantation of the HeartNetTM device is indicated for stage C, non-ischemic car-diomyopathic patients who will not need revascularization. A feasibility and safety study showed strong evidence of structural remodeling and improvement in exercise capacity and quality of life. A randomized, controlled trial is now ongoing and should provide further information about the ben-efits and safety of this surgical procedure.

Canadian Prevention Guidelines

Bigger Is Not Better: How to Shrink a Failing Heart

For more information about this Conference Report, contact us at: info@evidencebasedmarketing.ca or (905) 607-4201