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ACC 2007 ANNUAL SESSION HIGHLIGHT

ACC.07 and i2 Summit Highlights: A Conversation With the Experts

Abbreviations and Acronyms   ACHD = adult congenital heart disease   ACS = acute coronary syndrome   ADHF = acute decompensated heart failure   AF = atrial fibrillation   AMI = acute myocardial infarction   AS = aortic stenosis   BMS = bare-metal stent(s)   CAD = coronary artery disease   CHD = coronary heart disease   CI = confidence interval   CIMT = carotid intima-media thickness   CMR = cardiac magnetic resonance   CRT = cardiac resynchronization therapy   CT = computed tomography   CTA = computed tomography angiography   DES = drug-eluting stent(s)   FDG = fluorodeoxyglucose   HDL = high-density lipoprotein   ICD = implantable cardioverter-defibrillator   LDL = low-density lipoprotein   LV = left ventricular   LVAD = left ventricular assist device   LVEF = left ventricular ejection fraction   MACE = major adverse cardiac events   MI = myocardial infarction   MPI = myocardial perfusion imaging   MR = mitral regurgitation   MV = mitral valve   MVR = mitral valve replacement   NNT = number needed to treat   NYHA = New York Heart Association   ox-LDL = oxidized low-density lipoprotein   PCI = percutaneous coronary intervention   PET = positron emission tomography   PHV = percutaneous heart valve   PPAR = peroxisome proliferator-activated receptors   PPM = patient prosthesis mismatch   PVAD = percutaneously placed continuous-flow left ventricular assist device   SES = sirolimus-eluting stent(s)   STEMI = ST-segment elevation myocardial infarction   TIMI = Thrombolysis In Myocardial Infarction   TRA = thrombin receptor antagonist   TWA = T-wave alternans

	Introduction

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

As part of the effort to make new information applicable to the day-to-day problems of cardiologists, there was a change in the format of the closing symposium that reviews the meeting’s most important and interesting presentations. This supplement to the Journal of the American College of Cardiology (JACC) presents the Highlights of the Annual Scientific Session, which for the first time were presented as a Conversation With the Experts. Rather than a comprehensive examination of all major presentations, short summaries of individual presentations were reviewed in an effort to provide the most important insights and bullet points of the meeting, followed by a spirited discussion from a panel of experts.

The Highlights Session was chaired by E. Murat Tuzcu, MD, FACC, Chair of the 2007 Annual Scientific Session Program Committee. He was joined on the panel by his committee co-chairs, Randall C. Starling, MD, MPH, FACC, and James D. Thomas, MD, FACC. Summaries of original research and structured sessions were prepared and presented by the coordinators of the topic working groups from the Program Planning Committee.

James H. Stein, MD, FACC, led off the ACC.07 and i2 Summit Highlights covering Vascular Disease, Hypertension, and Prevention. This topic attracted 22.2% of the abstract submissions for ACC.07, which was the highest percentage of overall submissions for any topic in more than a decade. Robert A. Harrington, MD, FACC, was the topic coordinator who summarized key themes and important messages to emerge from the sessions on Myocardial Ischemia and Infarction. William D. Knopf, MD, FACC, prepared the highlights of the Innovation in Intervention: i2 Summit, along with his co-chairs, David Holmes, Jr., MD, FACC, FSCAI, and Barry Uretsky, MD, FACC, FSCAI. Valvular Heart Disease was addressed by Samir R. Kapadia, MD, FACC, and highlights relating to Cardiac Function and Heart Failure were summarized by Lynne E. Wagoner, MD, FACC. Steven Markowitz, MD, FACC, reviewed Cardiac Arrhythmias and Flordeliza Villanueva, MD, FACC, presented the highlights related to Imaging and Diagnostic Testing. According to Dr. Tuzcu, John Rhodes, Jr., MD, FACC, probably created the largest, most diverse congenital heart disease track of any previous ACC sessions, and he presented highlights in Pediatric Cardiology and Adult Congenital Heart Disease. JoAnne Foody, MD, FACC, had 1 of the toughest tasks because Special Topics encompasses a broad range of investigations that may be hard to classify but are of great importance. Special Topics include subjects as diverse as assessing and improving cardiovascular health care quality and the measurement of the impact of cardiovascular informatics. Finally, the discussants included 2 of the College’s leading editors: Anthony N. DeMaria, MD, FACC, Editor-in-Chief of JACC, and C. Richard Conti, MD, MACC, Editor-in-Chief of ACCEL.

This supplement to JACC presents the highlights of this Conversation With the Experts and features more detailed summaries of the individual presentations covered during the final session; plus, there is additional artwork and references that can be used to find the many sessions with full audio and video that are available online at ACC’s Cardiosource. After the session highlights are summarized, the panelists provide important perspectives on the topics discussed and help discern what the data mean for clinical practice.

	Vascular Disease, Hypertension, and Prevention

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
There were 424 presentations related to vascular disease, hypertension, and prevention at the ACC.07 Scientific Session, including disappointing results from trials targeting high-density lipoprotein (HDL) cholesterol. However, the news was decidedly better for drugs that lower low-density lipoprotein (LDL) cholesterol and for studies evaluating screening tests used to assess cardiac risk. These presentations were selected from a total of 1,181 abstracts on these specific topics that were submitted to the Program Planning Committee.

High-density lipoprotein cholesterol is an attractive target for reducing cardiovascular risk because of epidemiologic evidence demonstrating a strong inverse relationship between HDL cholesterol levels and cardiovascular risk. The rationale for increasing HDL cholesterol levels as a therapeutic strategy is further supported by evidence of the lipoprotein’s anti-inflammatory properties, antioxidant effects, and ability to promote reverse cholesterol transport. Dr. Stein began by noting the abundance of bad news relating to drugs in development for raising HDL cholesterol levels. Torcetrapib, a cholesterol-ester transfer protein inhibitor, was tested versus atorvastatin in the ILLUSTRATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) trial (1) and the RADIANCE 1 and RADIANCE 2 (Rating Atherosclerotic Disease Change by Imaging with a New Cholesteryl Ester Transfer Protein [CETP] Inhibitor) trials (2–4). In these studies, there were large increases in HDL cholesterol levels (60%) and a substantial decrease in levels of LDL cholesterol (20%) (Table 1), yet there was no significant decrease in the progression of coronary atherosclerosis. Indeed, one secondary end point of RADIANCE 1 suggested progression of disease in torcetrapib-treated patients based on measurement of carotid intima-media thickness (CIMT) studies.

In the ERASE (Effects of Reconstituted HDL on Atherosclerosis) trial, treatment with CSL-111, which chemically and biologically resembles native HDL, was not superior to placebo in the primary efficacy end point of percent change in coronary atheroma volume (7). However, CSL-111 did lead to significant differences in 3 secondary efficacy end points: change in atheroma volume versus baseline, change in plaque characterization indexes, and change in coronary score on quantitative coronary angiography.

Another approach under study uses peroxisome proliferator-activated receptors (PPARs). Although the results of early trials were disappointing, a series of PPAR agonists have been described, leading to the discovery of LY518674, a highly potent and selective PPAR agonist. However, in data presented at ACC.07, LY518674 proved to be no better than fenofibrate (Table 2); plus, it increased the level of serum creatinine compared with placebo (p < 0.001), with many patients experiencing serum creatinine values exceeding the upper limits of normal (8). Also, the PPAR agonist was associated with what Dr. Stein called "a very odd dose response." Specifically, there were unusual dose-response curves; for example, the greatest elevation of HDL was found with the intermediate LY518674 dose (25 µg), whereas the 100-µg dose produced almost no effect on these lipids. Furthermore, the study drug had a significantly unfavorable effect on LDL compared with fenofibrate, increasing LDL by 18.3% (50 µg) and 19.5% (100 µg), versus 2.3% with fenofibrate (p = 0.002 for both comparisons). The results of this study were published simultaneously in JAMA (9). "Overall there was not very good news for raising HDL cholesterol at this meeting," said Dr. Stein, "but we have to remember that we have an excellent HDL cholesterol-raising drug already available, which is niacin."

The METEOR trial was not the only one presented at ACC.07 suggesting value to using imaging as screening tests. The measurement of CIMT has been used mostly as a research tool and only as a clinical tool at selected centers because it is difficult to perform. However, data by Gepner et al. (14) showed that an abbreviated CIMT screening protocol, focusing on plaque at the common carotid artery, was just as good as a more complicated research protocol (area under the curve 0.848, p < 0.001).

More good news for screening tests emerged from an analysis of asymptomatic participants of the MESA (Multi-Ethnic Study of Atherosclerosis) study (15). There is a consensus that coronary calcified plaque measured by cardiac computed tomography (CT) predicts incident coronary heart disease (CHD) and that the prevalence of calcified plaque varies by race in the U.S. However, few studies have been undertaken related to the prediction of cardiac-related events in American minority groups. The MESA investigators evaluated the impact of coronary artery calcium score as it relates to future cardiac events in 4 major U.S. ethnic groups: Caucasians, Asian Americans, African Americans, and Hispanics. A total of 6,726 individuals without CHD at study entry underwent coronary risk factor evaluation, cardiac CT scanning for coronary artery calcium measurement, and clinical follow-up for 35.4 months. Cox regression of coronary artery calcium and Framingham risk score as predictors of CHD events in the 4 ethnic groups resulted in hazard ratios for calcium (per unit change in log transformed calcium score) of 1.4 for Caucasians, 1.8 for Chinese, 1.7 for African Americans, and 1.4 for Hispanics (all p < 0.001). Dr. Stein said, "That was a major gap in the literature. We didn’t have data on a large, relatively unselected group of people. This really helps fill that gap."

Finally, just how large is the low-risk population evaluated in the METEOR trial? Dr. Stein said that a sense of the size of this population can be seen in results of the Dallas Heart Study presented at ACC.07 (16). Fully 27% to 33% of participants in the Dallas Heart Study with calcium scores >400 had low Framingham risk scores.

Question and Answer
Dr. Thomas: I chaired the late-breaking clinical trial session featuring the ILLUSTRATE and RADIANCE trials. It was really striking how negative they were. There was a concern about increased blood pressure with torcetrapib as the possible fly in the ointment that prevented this approach from being more useful. I was very interested in the comments by Daniel J. Rader, MD, one of our panelists and the presenter of this year’s Louis F. Bishop lecture, which was a wonderful basic summary of where we are with HDL raising and where we may be able to go from there. He showed some data from preclinical studies of another cholesteryl ester transfer protein inhibitor that appears to have no associated blood pressure problem. So, the ILLUSTRATE and RADIANCE data may not be a class effect but rather a molecule effect with this particular drug.

Dr. DeMaria: One of the most intriguing aspects of these presentations was the implication regarding surrogate end points. As you know, there has been a major debate: can we look at CIMT or intravascular ultrasound and predict how a drug will behave? Given the progression of disease that was reported, it suggests that the surrogates may still provide a basic first step, a relatively inexpensive way to screen drugs.

Dr. Stein: That’s definitely my take on it. In fact, it has been said that by conducting morbidity and mortality trials in conjunction with imaging trials, the imaging trials serve as a data and safety monitoring referendum about the safety of these trials and these medications. If you have a medication that does not slow atherosclerosis, it really closes the door on proving that the drug will eventually reduce cardiac events.

Dr. Starling: Jim, help me interpret the data. Where are we headed with statin therapy in the context of "apparently low-risk patients"?

Dr. Stein: I certainly don’t think we can take a total population approach and just say, "Everyone needs to be on a statin." But we do need to be smarter about identifying who among those low-risk patients needs to be treated. After all, most heart attacks occur in people who are at low risk. It’s just that this is such a large group of people and maybe noninvasive imaging or, perhaps, some new biomarkers can help us be smarter about who we treat rather than just treating more people.

Dr. Tuzcu: Jim, the authors of the Dallas Heart Study found that in the intermediate-risk group, calcium screening did not add much. The data suggested that you would have to scan 100 women and about 60 men to get 1 benefit as far as risk assessment. We have previously thought that screening was going to be important in the intermediate-risk group. So what’s going on?

Dr. Stein: The intermediate-risk group of patients in the U.S. is quite small; it’s between 5% and 15% of the U.S. population. The majority of people who have advanced subclinical atherosclerosis are in the low-risk group; therefore, we need to be smarter about finding those people and that’s what explains that difference.

Dr. Conti: Jim, I’m all for doing CT. Principally, I like CT angiography, but CT calcium screening is here to stay. What do you do with that information if you don’t have the traditional risk factors? How do you handle an elevated coronary calcium score in these patients?

Dr. Stein: That’s a critical point. None of these tests have any value in isolation. In fact, you really shouldn’t make your way to any one of these tests unless you’ve looked at risk factors. And by no means should people take these studies to mean that risk factors don’t predict anything and they’re not useful. They are useful; they get us on a starting page and tell us what should be the target of treatment if something is wrong.

	Myocardial Ischemia and Infarction

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
There were 274 abstracts related to myocardial ischemia and infarction that were accepted for presentation at the ACC.07 Scientific Session, including the 1-year results of the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, which evaluated bivalirudin for acute coronary syndrome (ACS); MERLIN-TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes–Thrombolysis In Myocardial Infarction 36), providing long-term safety data on ranolazine in a high-risk population of patients; and the effects of a novel antioxidant/anti-inflammatory agent to reduce ACS-related events. Plus, a number of papers evaluated new approaches to reduce complications or better discriminate high-risk patients. These presentations were selected from a total of 796 abstracts on these topics that were submitted to the Program Committee.

In summarizing key themes and identifying important areas of research in myocardial ischemia and infarction, Dr. Harrington began with the category of non–ST-segment elevation ACS. He noted there was a wealth of clinical trial data presented at ACC.07 and the i2 Summit.

One-year follow-up was presented from the ACUITY trial (17). Patients (n = 13,819) with moderate- and high-risk ACS were randomized to heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition, bivalirudin plus glycoprotein IIb/IIIa inhibition, or bivalirudin monotherapy (plus provisional glycoprotein IIb/IIIa inhibition). Stone et al. (17) showed that bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin. Moreover, major bleeding complications had a significant, independent, adverse impact on 30-day outcomes, including mortality, and treatment with bivalirudin was an independent predictor of freedom from major bleeding (18).

At 1 year, approximately 98% of all ACUITY patients were available for follow-up, and investigators looked at the adjudicated end points of composite ischemia and stent thrombosis (19). There was no significant difference among the arms in terms of the composite ischemia end point (Table 4); however, interestingly, the lowest number of deaths were in the bivalirudin-alone arm and there appeared to be a slight separation of the curves at 1 year, trending in favor of bivalirudin monotherapy. The results suggest a relationship between iatrogenic bleeding complications and subsequent mortality in patients with ACS. Calling this an "important message," Dr. Harrington said preventing bleeding early on in the setting of ACS "may carry important prognostic implications."

Although the MERLIN-TIMI 36 study did not meet its primary end point of reducing cardiovascular death, myocardial infarction (MI), or recurrent ischemia compared with placebo, there was a significant reduction in recurrent ischemia (p = 0.03) as well as a reduction in the percentage of patients with worsening angina at 12 months in the ranolazine group compared with the placebo arm (p = 0.023) (Fig 1). The evidence suggests antianginal efficacy of ranolazine in a much broader population than ever studied before with this agent.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Assessment of Antianginal Effects in the MERLIN-TIMI 36 Trial Selected efficacy end points in the MERLIN-TIMI 36 trial. Based on Kaplan-Meier cumulative incidence (%) at 12 months. Primary end point: cardiovascular (CV) death/myocardial infarction (MI)/recurrent ischemia (RI). *p = 0.11; p = 0.03; p = 0.023. Blue bars = ranolazine (n = 3,279); yellow bars = placebo (n = 3,281).

In discussing the ARISE (Aggressive Reduction of Inflammation Stops Events) trial, Dr. Harrington called the results "a big disappointment" (21). It was a double-blind, placebo-controlled trial of 6,145 high-risk patients with a recent ACS. Patients were randomized to receive a probucol analog (succinobucol or AGI-1067) or placebo in addition to standard care. The primary end point was time to first incidence of any centrally adjudicated events: cardiovascular mortality, resuscitated cardiac arrest, MI, stroke, use of coronary revascularization, or hospitalization for unstable angina.

Because of the agent’s antioxidant/anti-inflammatory effects, it was hoped that by focusing on inflammation the drug might "really change the paradigm of treating the acute ischemic heart," said Dr. Harrington. However, there was no difference in the primary end point (17.2% vs. 17.3% for placebo; p = 0.985). Although there were some benefits in the treatment group, such as a significant reduction in new-onset diabetes mellitus (p < 0.0001) and improved fasting glucose (p < 0.0001), some individual components of the ARISE primary end point favored placebo, such as incidence of unstable angina and revascularization. Moreover, LDL increased and HDL decreased with active therapy.

Despite the availability of numerous antithrombotic therapies, adverse events after percutaneous coronary intervention (PCI), such as late stent thrombosis, are still a major concern. Researchers at the University of Kentucky, Gill Heart Institute, and Duke Clinical Research Institute led a phase II, randomized, double-blind, placebo-controlled trial to evaluate a potent new oral thrombin receptor antagonist (TRA), SCH 530348, for reducing PCI complications (22).

The TRA-PCI study randomized 1,030 patients in a 3:1 ratio to a 10-, 20-, or 40-mg loading dose of SCH 530348 or placebo. Of the total patient population, 573 underwent PCI (primary cohort) whereas 75 underwent coronary artery bypass graft surgery and 382 were managed medically. Patients undergoing PCI (primary cohort) were further randomized to a 0.5-, 1.0-, or 2.5-mg daily maintenance dose of SCH 530348 or placebo (depending on loading therapy) for 60 days. Patients also received other standard therapies, including aspirin, clopidogrel, and an antithrombin. The primary safety end point was Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding at 60 days in the PCI cohort. Secondary end points included the composite of death and major adverse cardiac events (MACE) at 60 days, again in the PCI cohort.

Overall, TRA treatment reduced adverse event rates in the study population without an increase in bleeding risk (Table 5). Major TIMI bleeding was reduced in the low-dose cohorts of TRA patients as compared with placebo (1.6% vs. 3.3%). The highest-dose TRA-treated populations fared best in overall death or major adverse events compared with placebo (4.6% vs. 8.6%) as well as heart attack risk (3.5% vs. 7.3%). Although not statistically significant, this new TRA led to a 32% overall reduction in death/MACE and a 41% overall reduction in MI.

An expanding body of evidence continues to build on the relationship between bleeding and outcome. Dr. Steve Steinhubl and others have shown that inflammatory markers may be the pivotal link (23,24). At ACC.07, Jozic et al. (25) presented results from the ACUITY inflammatory biomarker substudy. They found that major bleeding events in patients experiencing an ACS are associated with striking increases in inflammation as measured by change in high-sensitivity C-reactive protein from admission to discharge. The heightened inflammatory response with bleeding may help explain increases in long-term thrombotic events in this population.

In concluding the non–ST-segment elevation ACS highlights, Dr. Harrington said, "Finally, a really interesting theme throughout the last few days: monocyte activation as perhaps one of the key pathogenic underpinnings of acute coronary syndromes."

Question and Answer.   Dr. Tuzcu: This meeting had more studies than ever, I think, presenting so-called negative results or results that did not meet the primary end point. Having said that, even the ARISE study results suggest some hope that researchers continue investigating this approach. Certainly the ARISE data were far from conclusive; there were a lot of conflicting data. In ARISE, they had an increase in LDL and a lowering of HDL, but despite that they did not have increased hard end points.

Dr. Harrington: ARISE is a tough trial to interpret. Overall, it did not meet its primary end points, but clearly it is critically important in this format to talk about trials that are neutral or negative. We do learn a lot.

What troubles me about ARISE is maybe there is a hypothesis there that some of the events were more favorable with treatment, but at the same time there were a fair number of events, such as heart failure, revascularization, and recurrent ischemia, that did not look so favorable for the study drug. This split between improvement in glucose and the deleterious effect on LDL all seems to me to kind of wash to the middle of not working.

Dr. Stein: You can’t pick and choose the effects that come from this drug (succinobucol).

Dr. Harrington: Jim, that’s a good way to look at it. There were some good effects and bad effects. As Murat suggested, do I think there is enough there for a hypothesis if the investigators wanted to go forward? Sure, but we have to interpret it with what we have right now.

Dr. DeMaria: With some exceptions, the negative trials don’t seem to get simultaneous publication. They dwindle away a bit more, don’t they?

Dr. Harrington: That’s probably an issue for the journals as well as for the investigators. All of us, perhaps at times, lose a little interest when a study is not positive, but your message is that it’s critically important that we get this information out because there is an enormous amount to learn, probably more to learn from a failed trial than there is to a positive trial.

Dr. Conti: The important message I take from MERLIN is that it was given to the sickest of our patients, those with ACS. It was given intravenously in fairly high doses, but it didn’t produce any of the problems we were concerned about: the QT prolongation, arrhythmias, and so forth.

The other point that I took from that trial, granted it’s a subanalysis, but if anyone wants to continue looking at this drug in acute coronary syndromes, you want to pick the individuals who are TIMI risk score 4 and greater because that particular group seemed to do much better in terms of decreased end points than those who were less than TIMI 4.

Dr. Harrington: Your first point is incredibly important. Here was a drug from one of the first new classes of agents to treat angina in many, many years. A lot of us were quite concerned about this issue of QT prolongation. In MERLIN, as you say, if we gave it to the sickest group of patients, first intravenously, then orally, and we follow them very carefully and use Holter monitoring—we were very rigorous about this—that might be worth studying. To me, that was one of the most important findings to come out of that particular trial; this QT issue seems to be largely resolved.

ST-Segment Elevation Myocardial Infarction (STEMI).   Myocardial damage caused by ischemia and reperfusion limits current reperfusion strategies for patients with acute STEMI, and reducing infarct size remains an elusive target. At the i2 Summit, investigators presented data on a novel protein kinase C inhibitor (KAI-9803), which has been shown in animal models to reduce infarct size, enhance recovery of left ventricular (LV) contractility, and improve microvascular function when administered before reperfusion (26,27). In an exploratory, first-in-human study, the agent demonstrated a favorable impact on multiple biomarkers of reperfusion success, including creatine kinase-myocardial band area under the curve and ST-segment recovery area under the curve.

Stem cells remain a big news item, although many of the current studies are returning to the basics, trying to understand the implications of the electrical abnormalities of what happens when you try to implant cells in the infarcted myocardium.

Quality of care clearly remains an important issue and a key initiative of the American College of Cardiology. In an i2 Summit session on the National Cardiovascular Data Registry (NCDR), Ralph Brindis, MD, FACC, Chief Medical Officer of the ACC-NCDR, and a panel of experts summarized current trends for clinical practice and patient outcomes. The CathPCI Registry now has 890 participants and 4.5 million patient records. There have been 19 published manuscripts: 2 are in press and 17 are in development. (Six abstracts were presented at ACC.07.)

Nearly 1 decade after initiating the CathPCI registry, the College has 3 new projects that were launched in the last year: an implantable cardioverter-defibrillator (ICD) registry (1,450 hospitals are enrolled with 120,000 patient records now in the registry), the CARE registry (with more than 85 participating centers) for carotid stenting and carotid endarterectomy data, and the ACTION registry (already with more than 100 participating centers and another 450 centers expressing interest), which is an ACS registry representing the merging of 2 drug company registries. In the near future there will be an ambulatory care registry related to CHD, the IC3 coronary artery disease (CAD) registry, and a longitudinal ICD registry; plus, the ACC Foundation is looking for funding to develop a long-term registry looking at PCI outcomes (the Achieve Registry). In feasibility and business model planning there are 2 other possible projects: an imaging registry and a congenital heart disease registry.

Door-to-balloon times were highlighted during the week, and important progress is being made. Among the 580 NCDR participating hospitals, there was a marked nationwide improvement in door-to-balloon time in 2004 with continued modest improvement through the first quarter of 2007 (Fig. 2). Two external influences may have positively affected this performance metric in 2004. The first was the publication of updated STEMI guidelines (28). Recommended door-to-balloon time in the 1999 guidelines was 90 ± 30 min; in the updated document, chaired by Elliot Antman, MD, FACC, the recommendation was tightened to 0 to 90 min based on overwhelming evidence favoring a door-to-balloon time of 90 min or less. The second external force that could have influenced the marked improvement in door-to-balloon time in 2004 among NCDR participating centers was public reporting of quality data relating to the Joint Commission on Accreditation of Healthcare Organizations and the Centers for Medicare & Medicaid Services announcement of using door-to-balloon time as a core measure of quality. Said Dr. Harrington, "As public reporting of these data were announced, in fact, our door-to-balloon time started to get better." In the last quarter of 2006, there was a more modest increase in slope to this performance metric that corresponded to the release of the alliance door-to-balloon initiative. It will be interesting to continue tracking these numbers now that there are more than 800 centers participating in the door-to-balloon initiative.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Trend for DBT for 586 National Cardiovascular Data Registry Hospitals Data are based on the hospital’s ability to perform percutaneous coronary intervention (PCI) in their composite patients in <90 min. DBT = door-to-balloon time.

Experimental data suggest that high levels of nitric oxide may play a role in the genesis and persistence of cardiogenic shock. The TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients with Cardiogenic Shock) trial tested the effect of nitric oxide synthase inhibition with tilarginine on mortality attributable to persistent cardiogenic shock complicating MI despite an open infarct artery (30). In this international study of nearly 400 patients, tilarginine, 1-mg/kg bolus and 5-h infusion, did not reduce mortality rates (31). (This was a negative trial that was published simultaneously.)

In a small study from the Texas Heart Institute, investigators evaluated the TandemHeart, a percutaneously placed continuous-flow left ventricular assist device (PVAD) capable of complete hemodynamic support (32). At ACC.07, they presented 1-year outcomes in cardiogenic shock patients receiving PVAD assistance after failure of intra-aortic balloon counterpulsation and pressor support. The PVAD reversed the terminal hemodynamic compromise in patients with severe refractory cardiogenic shock, even in patients undergoing active resuscitation; 1-year mortality was 56%. "Even amongst patients who were being resuscitated, again the message is that if you survive that initial insult, there is reasonable 1-year mortality," said Dr. Harrington.

In wrapping up the STEMI highlights, Dr. Harrington reviewed the results of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, which enrolled 2,287 patients with stable CAD who were randomized to PCI plus optimal medical therapy (n = 1,149) or optimal medical therapy alone (n = 1,138) (33). Both groups received intensive lifestyle intervention. The primary end point was death or nonfatal MI during a mean follow-up of 4.6 years. All patients had single or multivessel disease, defined as at least 70% visual proximal stenosis of a major epicardial coronary, and Canadian Cardiovascular Society class I to III angina, as well as objective evidence of ischemia at baseline.

For both groups, optimal medical therapy was "intensive, guideline-driven" therapy, including aspirin and/or clopidogrel; a statin; angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; beta-blocker; calcium channel blocker; and a nitrate. Lifestyle interventions involved smoking cessation, exercise programs, nutrition counseling, and weight control where needed.

The addition of PCI to optimal medical therapy (OMT) did not significantly improve any end points measured in the COURAGE trial, including the primary end point of death or MI (19.0% for PCI vs. 18.5% for OMT; p = 0.62). Unexpectedly, angina improved almost as much in the OMT group as it did in the PCI group, and although there was a significant difference in favor of PCI at 1 and 3 years (p < 0.001 and p = 0.02, respectively), this difference dissipated by 5 years (Table 6). The findings reinforce current guidelines that recommend deferring PCI in stable angina patients treated with intensive OMT.

"My back-of-the-envelope estimation, although I’d like to see more research done on this, is probably half or so of those nonurgent interventions might meet the COURAGE criteria."

Question and Answer
Dr. Knopf: It’s encouraging that patients who have chronic stable angina can be treated medically, but you do have to preface that with the fact that all of these patients underwent cardiac catheterization before randomization. That’s a very important point that needs to be highlighted. So, these patients were a little more stable and did not have high-risk anatomy that would warrant interventions.

If you look at the total patients who were screened, about 7% of this population was enrolled. Certainly angioplasty is appropriate for primary intervention, certainly appropriate for acute coronary syndromes, and that is still the majority of the patients that we take care of in the interventional world.

Dr. Starling: I’m not an interventional cardiologist; I’m a clinical heart failure cardiologist. Help me with the patient with chronic stable angina who maybe underwent catheterization 5 or 6 years ago or who presents now without an acute coronary syndrome. How are we going to stratify these patients and make decisions? Are you suggesting, Bill, that they all need to undergo angiography? How are we going to put that in balance with the findings from COURAGE?

Dr. Knopf: Clearly, if you follow the COURAGE protocol, they would all undergo cardiac catheterization, but I’m not advocating that. In the general patient population, patients with chronic symptoms and with a reasonable quality of life are perfectly fine on medical therapy. Those patients can be stratified as you would normally and as the COURAGE investigators did. They excluded those patients who had markedly abnormal stress tests, 1 or more millimeters’ ST-segment deviation on electrocardiogram, early positive stress tests, hypotension, things of that nature. Those patients were not included in the trial, so there are numerous patients you could restratify based on stress test results.

Dr. Harrington: The key message here is the same one addressed in the chronic stable angina guidelines: you can go to catheterization if the patient has refractory symptoms, a high-risk stress test, you’re uncertain of the diagnosis, or there is evidence of heart failure or hemodynamic instability. What COURAGE really tells us is this: if you’re being managed well with medical therapy, you’re being managed well.

I don’t think the COURAGE investigators are telling us that these are two competing strategies. They’re complementary strategies and what the COURAGE results ought to get us to do is talk to the patients. Make sure we’re considering their values, their preferences; what’s the strategy for that particular patient that’s going to fit the best with what they want to do?

Dr. DeMaria: The COURAGE trial has the limitations of every randomized clinical trial: you can’t get everybody into the trial. You need a registry for that kind of thing. Also, it’s an intention-to-treat analysis, so there were several crossovers to the other therapy; but, to be fair, there also were several re-do’s of revascularizations. The strength of this trial in my view is the medical management. As far as I know, this is the only protocol-driven trial with optimum medical management in both arms, and we have to look at that aspect of it.

Dr. Harrington: I think COURAGE was a terrific clinical trial and the investigators should be complimented. They did a superb job, and the medical therapy in this trial is truly optimal. I don’t think what they’re saying is that we should be going down one path or another. It’s how do we use these approaches? But the pivotal underpinning here is OMT, and they did a superb job.

Dr. DeMaria: We need some controversy here, so I’m going to disagree a little. The ascertainment bias is an important question. You enroll at 50 centers for 5 years to get 3,000 patients; there are a whole lot of unenrolled patients out there. I do stand in awe of their ability to do maximal medical therapy. Their compliance rate was extraordinary. I’m not sure how successful I’d be.

That being said, extrapolating on the findings here is the idea that patients who ought to be considered for intervention should have failed maximum medical therapy. I don’t believe, by and large, that’s the practice in the U.S. today. More often, patients get some medical therapy. If you know they can’t alpine ski because they get a little bit of angina, even if it’s single-vessel disease, they’re apt to be treated interventionally. I do think the COURAGE results will have an impact to some extent and reduce the number of interventions being done.

	Innovation in Intervention: i2 Summit

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
In its second year, the Innovation and Intervention or i2 Summit continued to build on its success with excellent programming involving some of the world’s leading interventionalists. There were 789 abstract submissions to the 2007 i2 Summit, including 17 late-breaking clinical trials (of 29 submitted) and 225 other accepted abstracts for presentations.

A highlight of the i2 meeting is live cases, and in 2007 these real-time demonstrations included more international activity. The cases were transmitted to New Orleans from 8 sites, including Japan, the Netherlands, Canada, and several U.S. sites. It was a great opportunity to see master interventionalists work live on complex, everyday practical issues in interventional cardiology. Moreover, rather than showing a set way to manage a case, the live presentations demonstrated how the physician thinks through a procedure and how strategy changes when a problem is encountered.

For example, in 1 live demonstration, a stent became stuck and the interventional cardiologists had to decide immediately which technique to use to engage the guiding catheter to force the stent down. The session moderator, Alan Yeung, MD, FACC, Director of Interventional Cardiology and Division Chief at Stanford University Medical Center, noted that the ad-hoc aspect of the case would likely not be mentioned in a publication describing the procedure.

Dr. Knopf co-chaired the i2 Summit with Barry F. Uretsky, MD, FACC, and David R. Holmes, Jr., MD, FACC. The 2007 sessions were in the heart of the convention center and in the heart of the ACC meeting. In a Saturday morning session before the opening of ACC.07, the i2 Summit highlighted issues germane to general cardiologists as well as interventionalists, dealing with topics such as late stent thrombosis, carotid stenting versus surgery, multivessel disease in diabetics, and more, which engendered interesting debate and cross-discipline discussion with colleagues in cardiovascular surgery and vascular surgery.

This year’s demonstrations included new or improved techniques for chronic total occlusion angioplasty from Japanese investigators who are masters at this type of technique. Dr. Holmes demonstrated how to do a closure of a paravalvular mitral prothesis. Complex interventional cases included left main and peripheral vascular interventions.

An emerging technologies track emphasized the early nature of the data presented, making it clear, in some cases, that the science is not necessarily ready for even phase I trials yet. One presentation featured preliminary results of European and U.S. trials of the Rheos Baroreflex (CVRx, Maple Grove, Minnesota), an implantable device for the treatment of resistant hypertension (34). By modulating the baroreceptors in the carotid sinus, the brain perceives increased afferent signaling as an increase in blood pressure that needs to be corrected. In early trials, the Rheos device significantly reduced both systolic and diastolic blood pressure. In an evaluation of long-term effectiveness, the device seems to have had a profound and durable effect in the 49 patients implanted worldwide (as of March 2007) with 822 patient-months of follow-up.

Another first-in-human study evaluated a new absorbable stent. Currently available drug-eluting stents (DES) dramatically reduce restenosis rates after PCI compared with bare-metal stents (BMS), but there are drawbacks to both types of stents. Any permanent metallic implant may impair coronary imaging with magnetic resonance imaging or CT, can hinder surgical revascularization, prevent positive remodeling, and (in the case of DES placement) predispose the vessel to late stent thrombosis. At the 2007 i2 Summit, Serruys et al. (35) reported the results of a study using a novel absorbable stent with controlled-release drug delivery. Once the stent degrades completely, only the healed natural vessel remains.

According to principal investigator Patrick W. Serruys, MD, FACC, the scaffolding effect of any stent is needed for only 3 to 6 months to prevent constrictive vascular remodeling after dilation. But the traditional metal cage, which is how he describes metal stents, remains long after this period. The bioabsorptive properties of the new stent appear to allow late expansive luminal and vessel remodeling that is not hindered as it is now with metal stents. The newer coating used on the stent also may minimize chronic inflammation seen with current agents and may reduce the need for long-term dual antiplatelet therapy.

The biodegradable stent was placed in a single de novo coronary artery lesion in 30 patients. At 30 days, device success was 93.5%, and procedural success was 100% with no MACE or stent thrombosis. At 6 months, rates of MACE continued to be low: 1 patient (3.3%) had a non–Q-wave MI. Angiographic results, available for 26 patients at the time of the ACC meeting, showed good results (Table 7) with late loss (0.44 mm) in between that reported in standard DES trials and BMS studies. Although neointimal hyperplasia was very much under control, some late recoil of the stent was evident, which may be due in part to stent design. According to Dr. Serruys, a second iteration of the stent appears to be much stronger in terms of radial force and scaffolding properties.

The data from the MATRIX trial was particularly encouraging. It is a prospective, single-arm study, initiated in 2004, to evaluate the impact of sirolimus-eluting stents (SES) in a consecutive "real-world" population. The late stent thrombosis rate at 2 years was 1.1% after off-label use of the stents (36). In 12,395 patients from western Denmark receiving either a DES or BMS, there was no significant difference in mortality at approximately 15-month follow-up (p = 0.29) and a similar low rate of late stent thrombosis at 12 months (0.6% annually) (37). However, between 12 and 15 months, there was a small but significant excess of definite stent thrombosis and MI in the DES group (Fig. 3).

View larger version (45K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Definite ST and MI After Implantation of DES or BMS in Western Denmark (A) Definite stent thrombosis (ST) and (B) myocardial infarction (MI). BMS = bare-metal stent(s); DES = drug-eluting stent(s); RR = risk ratio.

View larger version (47K): [in this window] [in a new window] [Download PPT slide]   Figure 4 In-Segment Late Loss at 8 Months* (Primary End Point) of the SPIRIT III Trial *Follow-up window ± 28 days.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 5 MACE and TLR Through 270 (± 14) Days in the SPIRIT III Trial Blue bars = XIENCE V (n = 658); yellow bars = TAXUS (n = 322). ID = ischemia-driven; MACE = major adverse cardiac events; NID = nonischemia-driven; TLR = target lesion revascularization.

Dr. Knopf: They have 26 patients and only 6 months’ follow-up, but the encouraging news was the low rate of target lesion revascularization at 6 months and no stent thrombosis, suggesting that it’s certainly safe and well tolerated. The late loss of 0.44 mm means there seems to be appropriate healing of the vessel, which is important. There was some late-acquired stent apposition observed with intravascular ultrasound and that is of some concern, but intuitively if you can design something that is completely bioabsorbable there is certainly some interest and long term we will have to see if the results are favorable. I think it could be.

Dr. DeMaria: Not having heard those trials presented, one of the questions I have relates to the length of antiplatelet therapy in them. What were they doing?

Dr. Knopf: I can’t answer that question about the specific trials, but the recommendation now is to give aspirin and clopidogrel for 12 months. There was one trial that was very interesting; it was small and called the Low Responsiveness to Clopidogrel and Sirolimus- or Paclitaxel-Eluting Stent Thrombosis, or RE-CLOSE trial (40). The investigators demonstrated that people who were nonresponders to clopidogrel seemed to have a greater incidence of late stent thrombosis.

This raises the question: Are we giving the right antiplatelet strategy? And, if we are, how are we monitoring those patients? Should we be monitoring them more than we are? Obviously we’re not really monitoring patients at all for this; we’re empirically giving these drugs. Would monitoring for antiplatelet effectiveness impact things? However, from the western Denmark trial anyway, the incidence of late stent thrombosis at 12 months was no different whether patients were on or off clopidogrel (37).

Dr. Tuzcu: Before you finish, can I ask you a question: when you are back to your practice in Atlanta after this meeting, what are you going to change as far as your use of DES?

Dr. Knopf: Right now there is a trend to be more judicious about using DES. We learned that in patients with acute MI, perhaps BMS are better for the long term, although you do sacrifice the restenosis benefit of DES. Also, for patients with large vessels or short lesions where the restenosis rate is low, those patients definitely can benefit from a BMS and not a DES. Therefore, we’re beginning to categorize patients who might not necessarily need a DES and that’s important. At this moment, the overall market penetration is back up to about 30% for BMS versus 70% for DES in the U.S.

	Valvular Heart Disease

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
There were 67 presentations related to valvular heart disease at the ACC.07 Scientific Session, including insights into the mechanisms and treatment of aortic stenosis (AS) and the results of studies evaluating percutaneous approaches to valvular repair or replacement. These presentations were selected from a total of 175 abstracts submitted to the Program Committee. Importantly, a number of presentations at the i2 Summit related to valvular heart disease.

Dr. Kapadia is an interventional cardiologist at the Cleveland Clinic and the presenter of valvular heart disease highlights from ACC.07 and the i2 Summit. He noted that some of the most important information was related to the progression of AS with multiple laboratories reporting different mechanisms of AS progression, including LDL-related mechanisms and cytokine-, adipokine-, and even parathormone-related mechanisms (41–43). (Parathormone is a hormone made by the parathyroid gland.)

Other unique mechanisms for AS involve matrix-Gla proteins in bone that increase mineralization (44) and alpha2-HS glycoprotein, also known as fetuin-A, which is a plasma protein displaying high-affinity interaction with calcium phosphate, by which ectopic vascular calcification is prevented (45). All of these studies suggest that different mechanisms affect different populations, such that an elderly population may have different mechanisms for AS than a younger population. Plus, there may be differences in the way patients with atherosclerosis respond to different kinds of progression of calcification in AS.

One trial, highlighted by Dr. Kapadia, evaluated the role of oxidized low-density lipoprotein (ox-LDL) in AS. Considering that ox-LDL is a powerful inflammatory factor in atherosclerotic plaques, several studies have suggested that calcified AS is related to an atherosclerotic-like process. The objective of the study presented at ACC.07 by a team of Canadian investigators in Quebec was to examine the association between: 1) the plasma metabolic profile and the presence of ox-LDL within the aortic valve; and 2) the ox-LDL accumulation and the degree of valvular inflammation (41). There was a significant association between the percentage of small-size LDL particles in the plasma and ox-LDL score within the valve (p = 0.03), whereas total cholesterol and LDL levels were not associated with ox-LDL. Patients with the highest ox-LDL scores (on a scale of 0 to 3) had a greater percentage of small-size LDL particles compared with those with a score of 0. In turn, valves with higher ox-LDL content were associated with increased numbers of leucocytes (p = 0.03), macrophages (p = 0.008), and T cells (p = 0.03) as well as with increased expression of tumor necrosis factor-alpha (p = 0.002). Finally, patients with an ox-LDL score of 3 also had a much more rapid preoperative hemodynamic progression of their stenosis as measured by the annualized progression rate of peak transvalvular pressure gradient (p = 0.04).

Another important topic highlighted during this meeting was patient prosthesis mismatch (PPM) with mitral valve replacement (MVR). There are several studies in which researchers have examined PPM in patients after aortic valve replacement, but little retrospective data exist in patients who have undergone MVR. Two studies presented as posters at ACC.07 evaluated patients with moderate (1.2 cm²/m²) or severe (0.9 cm²/m²) PPM and outcomes for these patients compared with those with no or lesser degrees of PPM (clinically insignificant PPM: >1.2 cm²/m²) after MVR (46,47). Both had the same message: PPM is associated with greater mortality and a greater risk of pulmonary hypertension or heart failure after MVR. In one study of 929 consecutive patients, for example, multivariate analysis indicated that severe PPM was associated with a hazard ratio for mortality of 3.2 (95% confidence interval [CI] 1.5 to 6.8; p = 0.003). The results highlight the importance of implanting a sufficiently large prosthesis in adult patients to optimize clinical results.

Patients who undergo ring annuloplasty for ischemic mitral regurgitation (MR) often have recurrent MR, although the factors that cause recurrence are unclear. It has been suggested that late recurrent MR is caused by leaflet tethering and remodeling of the left ventricle, which increases sphericity of the left ventricle over time. Therefore, a group of Cleveland Clinic investigators examined LV sphericity and its relation to late recurrent MR after annuloplasty in 106 patients (48). In this echocardiographic study, recurrent ischemic MR late after annuloplasty was associated with decreasing left ventricular ejection fraction (LVEF) and increasing width and thus sphericity of the left ventricle during follow-up, emphasizing the ventricular mechanism of this lesion. According to Dr. Kapadia, the LV actually dilates, and the change in sphericity of the left ventricle appeared largely responsible for MR recurrence, perhaps suggesting different ways to treat MR in this specific situation.

Recently in JACC, the RAAVE (Rosuvastatin Affecting Aortic Valve Endothelium) investigators reported the effects of rosuvastatin in patients with elevated LDL and moderate-to-severe AS (49). They evaluated the progression of AS in 121 consecutive patients with asymptomatic moderate-to-severe AS (aortic valve area 1.0 cm²) and normal cholesterol levels. Patients with elevated LDL >130 mg/dl received rosuvastatin and those with LDL <130 mg/dl did not receive the therapy. After 1.5 years of follow-up, treated patients demonstrated a slowing of echocardiographic parameters including peak aortic valve jet velocity, mean gradient, and aortic valve area. There was also a weak correlation between successful treatment of LDL and improvement of these echocardiographic parameters. Although this trial was not a randomized one, Dr. Kapadia noted that controlling lipids in patients with elevated cholesterol levels and moderate AS appears to decrease disease progression.

Percutaneous Interventional Options.   The use of aortic valve replacement in symptomatic patients with AS results in excellent symptom relief and long-term survival in most. However, a growing number of patients are poor surgical candidates as the result of advanced age, comorbidities, or previous cardiac surgery. During the past 2 decades, major advances have occurred in the development of catheter-based interventions that may permit more of these high-risk patients to benefit from aortic valve replacement, including recently published results from small trials (Table 8).

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 6 Heart Valve Function Over Time in Patients Undergoing Percutaneous Aortic Valve Implantation AVA = final valve area; PHV = percutaneous heart valve.

Other studies are exploring the effectiveness of catheter-based approaches in repairing the mitral valve (MV). Karl Heinz Kuck, MD, St. George’s Hospital, Hamburg, Germany, reported the interim results of EVOLUTION (Clinical EValuation Of the Edwards Lifesciences PercUTaneous MItral AnnulOplasty System for the Treatment of Mitral RegurgitatioN), which is evaluating the MONARC system (Edwards Life Sciences) (52). The MONARC system uses a 12-F guiding catheter and 9-F delivery system to introduce the 2 stent-like anchors and spring-bridge connecting the proximal and distal anchors (Fig. 7). The bridge contains a biodegradable element and, during the course of approximately 4 to 6 weeks, the biodegradable substance disappears and the spring bridge shortens, creating tension around the MV, gradually reshaping the leaflets and surrounding structures (Fig 8). The result is improved leaflet function and a reduction in MR.

View larger version (58K): [in this window] [in a new window] [Download PPT slide]   Figure 7 Edwards MONARC System for Percutaneous Mitral Valve Repair

View larger version (73K): [in this window] [in a new window] [Download PPT slide]   Figure 8 Percutaneous System Applies Sustained Tension to MV, Gradually Reshapes the Geometry of the Heart MV = mitral valve.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 9 Mean MR Reduction Over Time From EVOLUTION Study Interim Performance Data MR = mitral regurgitation.

Although all patients had moderate (3+) to severe (4+) MR at baseline, acute procedural success was 85% (79 of 93 implanted clips), defined as MR 2+, of which nearly two-thirds had MR 1+. Importantly, when the clip procedure cannot be successfully completed or it is performed but fails to sufficiently reduce MR or the MR returns, surgery remains an option. Twenty-eight patients underwent successful MV surgical repair up to 18 months after the clip procedure, and 20 (71%) were successful. There is a procedural learning curve and, as a surgeon gains experience, the median time in the catheterization lab for device implantation decreases from 3 h or more to approximately 1.5 h (Fig. 10). With up to 3-year follow-up available for the 79 patients with acute procedural success, the Kaplan-Meier curves show 97% freedom from death, 80% freedom from surgery, and 67% freedom from death, surgery, or an MR >2+. Thus, durable success is evident for up to 36 months.

View larger version (9K): [in this window] [in a new window] [Download PPT slide]   Figure 10 EVEREST Trial: Procedural Learning Curve, Single-Center Experience With MitraClip Device Yellow bars = 1-clip case; blue bars = 2-clip cases.

Dr. Kapadia: I’m sure in the future percutaneous valve procedures indeed will take a significant number of surgical patients, but it will take some time until we get to that stage. Currently, it looks very promising.

Dr. Tuzcu: Mitral valve intervention, particularly with the Evalve clip, has Kaplan-Meier curves extending out to 3 years?

Dr. Kapadia: Yes, but at this time, 3-year data are available for only about half of the patients receiving the clips. But, 36-month data are available and there remain stable rates of MR in patients who had good reduction in MR with the procedure.

Dr. Tuzcu: This is encouraging because, as you know, the surgical literature had suggested that the so-called Alfieri stitch without an annuloplasty was thought to be only applicable for a very small minority of patients. Maybe that’s not the case.

Dr. Kapadia: Yet, even in the surgical literature, the initial separation of the Kaplan-Meier curves was very early on. Only when they didn’t get a good result to start with did they seem to have problems later. And in surgical literature, 75% of people did well after 4 years, so this is very comparable and very promising data.

Dr. Starling: These percutaneous valve techniques are developing, but it was noted in another session, Controversies in Valvular Heart Disease, that mortality rates for valvular surgery are becoming extremely low, even in low ejection fraction patients. At the same time, these new techniques offer the advantage obviously of shorter hospital stays and not requiring mediastinotomy.

	Cardiac Function and Heart Failure

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
Heart failure is the fastest growing cardiovascular diagnosis in the U.S., with direct and indirect costs exceeding $33 billion per year (55). There were 228 presentations related to cardiac function and heart failure at ACC.07/i2 Summit, including several important clinical trials with negative results. The highlights discussion, led by Lynne E. Wagoner, MD, FACC, includes data from SPICE (Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in CHF) (an herbal extract), FUSION II (Follow-up Serial Infusions of Nesiritide for the Management of Patients with Heart Failure), EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival), and EVEREST (tolvaptan). Also, data are summarized from HeartMate II, which is evaluating a new left ventricular assist device (LVAD). The cardiac function and heart failure presentations were selected from a total of 650 abstracts submitted to the Program Committee.

Despite the fact that a number of large clinical trials presented at ACC.07 had largely negative results, Dr. Wagoner noted that there are still important lessons from these trials evaluating newer and even some older agents. One of the most exciting presentations, she said, included the results of a trial investigating an herbal agent suggesting a benefit in class II and class III heart failure (56). The SPICE study was the first mortality/morbidity trial with an herbal medicinal product for treating heart failure. The agent is an extract of the hawthorn plant that has been used for centuries in traditional European medicines to treat heart failure. Suggested mechanisms of action include a positive inotrope effect, vasodilating properties, anti-ischemic effects, antiarrhythmic effects, and antioxidative properties As add-on treatment, WS 1442 was safe and, with 24 months of treatment and follow-up, the agent was associated with no significant improvement in the primary composite end point (cardiac mortality, nonfatal MI, hospitalization due to progressive heart failure), but with a significant improvement in cardiac mortality after 6 and 18 months as well as a significant reduction in the subgroup of patients with an LVEF 25%, which reached significance at 12 months; this benefit was sustained at 24 months (p = 0.025).

The FUSION II trial was a 12-week study of intermittent nesiritide in patients with congestive heart failure (57). Patients were randomized to nesiritide twice or once a week or placebo (nesiritide dosing = 2 µg/kg bolus, then 0.01 µg/kg/min infusion for 4 to 6 h). Compared with phase I (FUSION I) (58), the FUSION II trial patients were more than 6 times more likely to receive carvedilol and much more likely to receive evidence-based device therapy than the FUSION I trial. The primary efficacy end point was time to all-cause death or first cardiovascular and/or renal hospitalization through week 12.

There was no significant difference in the primary composite end point, in its individual components (Table 9), or in secondary end points, such as the number of cardiovascular/renal hospitalizations, days alive out of hospital, and cardiovascular mortality. Although nesiritide has been the subject of some controversy regarding its safety profile in the setting of acute decompensated heart failure (ADHF), Dr. Wagoner said, "It did demonstrate that it is a safe compound. In this particular trial, there was no increased mortality with the patients treated with nesiritide and there was no signal of increased incidence of renal insufficiency." So, although the intermittent use of this agent may not be a feasible way to proceed, the encouraging safety data may "relieve some of our angst" regarding the use of nesiritide. More data are needed, which may come soon from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial.

During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (p = 0.68) (61). There was no significant difference in the composite of cardiovascular death or hospitalization for heart failure, which occurred in 871 patients receiving tolvaptan (42.0%) and 829 patients receiving placebo (40.2%; p = 0.55), nor was there any difference in the individual outcomes of the composite end point (Fig. 11). Thus, despite short-term benefits, tolvaptan initiated for acute treatment of patients hospitalized with ADHF had no effect on long-term mortality or heart failure-related morbidity.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 11 Kaplan-Meier Analyses of All-Cause Mortality and Cardiovascular Mortality or Hospitalization for Heart Failure in the EVEREST Trial Reprinted with permission from Konstam et al. (61).

New data for an older drug were presented in the EPHESUS study, originally published by Pitt et al. in 2003 (62). This subanalysis of the original trial data compared early (3 to 7 days) versus late (8 to 14 days) administration of eplerenone versus placebo (63). The hypothesis was that early administration of an aldosterone blocker would improve outcomes, based at least in part on 2006 data demonstrating the pivotal role of aldosterone levels on survival after STEMI (64). Aldosterone, the final mediator of the renin-angiotensin-aldosterone pathway, is at its highest plasma levels at presentation after STEMI. The study by Beygui et al. (64) showed that, among patients referred for primary PCI for STEMI, plasma aldosterone levels on admission were associated with early and late adverse clinical outcomes, including mortality, and the increased risk was independent of age, heart failure, and reperfusion status.

The new EPHESUS subanalysis used the original cohort of post-acute myocardial infarction (AMI) patients with clinical heart failure and LVEF 40%. Randomization was to eplerenone (25 mg titrated to 50 mg/day; n = 3,313) or placebo (n = 3,319) in addition to standard heart failure therapy 3 to 14 days after AMI. Within each group, one-half of the patients had early initiation of drug therapy and one-half had late initiation. Among the primary end points (Table 10) at 16 months, there was a 23% decrease in all-cause mortality in favor of early eplerenone administration (p = 0.003 vs. placebo). The coprimary end point of cardiovascular death or hospitalization for cardiovascular causes also showed greater benefit associated with early administration of eplerenone (p = 0.01 vs. placebo). The most striking difference was the 37% decreased risk of sudden death associated with early initiation of eplerenone (95% CI 0.48 to 0.84; p = 0.002). Conversely, patients who started taking eplerenone after the first week enjoyed none of these benefits. Said Dr. Wagoner, "Going forward, this is information we need to carry back to our practice and it will potentially impact our guidelines for the initiation of aldosterone blockade post-MI."

Mechanical circulatory support with an LVAD has become a standard therapy for patients with refractory heart failure as a bridge to heart transplantation. New devices are being examined for their safety and efficacy in the growing population of patients awaiting transplantation as well as in patients deemed ineligible for heart transplantation. One novel LVAD called HeartMate II (Thoratec Corp., Pleasanton, California) uses miniature continuous flow technology designed to provide mechanical circulatory support for 5 to 10 years. The implantable LV assist system, powered by a rotary pumping mechanism, is significantly smaller than currently approved devices, enabling easier implantation in a broader population of patients, and it is much quieter than currently available units because it has only a single moving part. In a prospective, multicenter trial, 133 patients were enrolled at 26 centers from March 2005 through May 2006, and the data reported reflect patient follow-up through December 2006 (66). In this trial, the device was being evaluated as a bridge to transplantation; a separate ongoing clinical trial is evaluating the HeartMate II as destination therapy.

In this nonrandomized, phase II, prospective study, device placement led to rapid improvements in both cardiac index and pulmonary capillary wedge pressure (p < 0.001 for both vs. baseline) within 24 h of implantation. One hundred patients (75%) met the trial’s primary end point, which was cardiac transplantation or survival at 180 days while remaining eligible for transplantation. There were 68 patients (51%) who underwent transplantation with 29 (21.8%) continuing on LVAD support for longer than 180 days (average duration of support: 168 ± 148 days). Three patients showed unexpected cardiac recovery permitting device explantation. A total of 33 patients (24.8%) did not meet the primary end point, mostly as the result of death on the device within 180 days. The data also showed that the trial met or exceeded the objectives for the secondary end points, including frequency of adverse events, improved functional status, and enhanced quality of life.

According to Dr. Wagoner, "It was a very positive trial and the key point here to take home was the fact that this HeartMate II continuous flow device was associated with less bleeding, fewer infections, less stroke, and less need for a right ventricular assist device after implantation compared with [the pulsatile flow HeartMate VE]" (Table 11). "The message here is we’re getting better with our left ventricular assist device therapy and the HeartMate II device is likely to go forward and replace our current HeartMate VE," she added.

Dr. DeMaria: If you were to project in the future 5 to 10 years, given smaller more effective devices, what role do you see for transplantation? Do you see it diminishing dramatically as these small devices come on line?

Dr. Wagoner: Obviously there is a huge cohort of patients who will never have the benefit of cardiac transplantation. Eventually, we will have a large cohort of patients going on device therapy. There is still a ways to go in terms of showing long-term benefit with these devices, but certainly the profile of these looks much more promising than the current systems we have, which tend to have a life expectancy of only about a year to a year and a half.

Dr. Starling: Tony, just to give you quickly my editorial comments on that question. Transplantation survival is 85% to 95% at 1 year, but that’s at the cost of long-term immunosuppression, which isn’t pretty, and perhaps 10% of patients having end-stage renal disease by 5 years. Given these results, we’re going to see devices like (HeartMate II) move from class IV patients to appropriate therapy for kind of a refractory class III patient population. This is clearly going to be the wave of the future.

Dr. Conti: Lynne, let’s go back to another study for a moment. FUSION II enrolled sick heart failure patients who had 2 prior hospitalizations. When we look at the days alive and out of the hospital and the number of hospitalizations, we don’t see any differences. One of the messages, as I see it, is that for patients who come into the clinic once or twice a week—and in some cases receive intravenous diuretics—we can really have an impact.

Dr. Wagoner: Absolutely. Patients in both arms of FUSION II received good careful attention from a multidisciplinary heart failure team. Perhaps that’s the most important lesson from this particular trial.

Going forward, it appears that the intermittent use of an agent, either nesiritide or inotrope, is probably not a reasonable way to go. For those patients in the community having trouble with repeat hospitalizations, perhaps the way to go is to consider referral of these patients to a multidisciplinary heart failure program.

Dr. Starling: It’s also important to point out that the use of inotropes was really not allowed in this trial, which perhaps contributed to the greater event rate in the study than FUSION I. And as we heard in the preliminary results of COURAGE (67), evidence-based medicine is very important and all of these patients in FUSION II had their angiotensin-converting enzyme inhibitors and beta-blockers optimized.

Dr. Wagoner: And these trials are being conducted in the era of increased ICD use. That will likely have an effect on mortality outcome with a lot of these trials.

Dr. Conti: Lynne, tell me again the timing of the use of the aldosterone blocker in EPHESUS.

Dr. Wagoner: This substudy of the original EPHESUS trial used 7 days as the cutoff for early versus late initiation. Early initiation was a mean of 5.5 days.

Dr. Conti: That message needs to be explained carefully because you don’t want to be giving this drug to unstable patients with AMI and heart failure because of the complexities of giving all the other drugs they require, including some that raise potassium.

Dr. Wagoner: The message is to try to get eplerenone onboard before 7 days; it definitely is not a drug you’re going to be giving in the emergency department as they come in the door.

Dr. Tuzcu: Is this going to be a medication that we are going to be score-carded on? We now are measured by how many patients we have on angiotensin-converting enzyme inhibitors, statins, aspirin, and so forth. Is this going to be a drug for all myocardial infarction patients or....

Dr. Conti: If ejection fraction is <40%, it’s a class I indication now. Isn’t that right, Lynne?

Dr. Wagoner: That is right. Yes, it potentially could be one of the drugs used for quality assessment in that population.

	Cardiac Arrhythmias

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
At the 2007 ACC Scientific Session and i2 Summit, there were 153 accepted abstracts in the topic area of cardiac arrhythmias, including a comprehensive meta-analysis of outcomes and safety data for ICDs and cardiac resynchronization therapy (CRT). The highlights discussion, led by Dr. Markowitz, also included results from the ALPHA (T-Wave Alternans in Patients With Heart Failure) trial and a summary of new technologies and techniques for ablation of atrial fibrillation. The cardiac arrhythmia presentations were selected from a total of 424 abstracts submitted to the Program Committee.

According to Dr. Markowitz, the most exciting sessions were the live and recorded cases from various centers around the world, including a live case using ablation therapy to treat ventricular arrhythmia and a live lead extraction done by Charles L. Byrd, MD, FACC, during the session entitled Challenges in Device Implantation and Extraction (68). "In fact," said Dr. Markowitz, "after that extraction, Dr. Byrd extracted a vegetation from the heart that was adherent to the wall that was next to the leads. It was a very exciting case and the first time any of us had seen this, including all the experienced panelists."

With regard to data presented at ACC.07/i2 Summit, he said there were important studies on risk stratification for sudden death, which is common in patients with heart failure despite the use of optimal therapy. Ezekowitz et al. (69) conducted a systematic review to determine the comparative efficacy, effectiveness, and safety of CRT and ICDs in patients with heart failure. (The CRT analysis was subsequently published in June 2007) [70]. Dr. Markowitz noted that the comprehensive meta-analysis was sponsored by the ACC, American Heart Association, and Heart Rhythm Society, and it included all known ICD trials to date, published and unpublished, including randomized and observational trials. The studies included primary and secondary indications for ICD or CRT in the management of ventricular arrhythmias in nonischemic cardiomyopathy patients, ischemic populations, as well as early post-MI and late post-MI patients. "A very heterogeneous group of studies and very comprehensive," said Dr. Markowitz.

The analysis suggests that ICDs indeed reduce the risk of death, with a relative risk of death of 0.80. Importantly, the number needed to treat to save 1 life after 35 months was 20 patients. "That number is somewhat larger than some of the landmark trials," said Dr. Markowitz, "because it included trials with less of an impact, less of a treatment effect." As for CRT, the systematic review suggests a relative risk of death of 0.78 and number needed to treat of 13 patients to save 1 life after 2 years. He said the data underscore the strong need to identify reliable risk stratifiers among heart failure patients who are candidates for ICD prophylaxis. Also, he added, "We need to be cognizant in the cardiology community of not only the economic impact but the medical risk of implanting these devices and the psychological burden."

T-Wave Alternans (TWA).   The need to better stratify patients for sudden death risk is particularly true for patients with heart failure of nonischemic origin. In general, there are several significant predictors of arrhythmic events that can be assessed noninvasively, such as impaired heart rate variability <20 ms, late potentials, ventricular ectopic beat frequency, repetitive ventricular forms, LVEF <40%, and Killip class. However, specificity is low as is the positive predictive value of each of these markers. Moreover, there are limited data on the value of these markers in patients with nonischemic cardiomyopathy.

T-wave alternans have a greaer specificity in predicting arrhythmic events and may identify low-risk subjects among a post-MI population with depressed LV function, but their predictive role in nonischemic heart failure also is unclear. The ALPHA study enrolled 446 stage II and III heart failure patients with nonischemic cardiomyopathy, LVEF 40%, and no history of malignant arrhythmias (71). In this primary prevention study, patients were given a TWA test at 9 hospitals in Italy and followed for 18 to 24 months to assess combined rates of cardiac death plus life-threatening ventricular arrhythmias (the primary end point), all-cause mortality rates, the combination of arrhythmic death plus life-threatening arrhythmias, and hospitalization rates. In the patients studied, there were 154 negative TWA tests, 200 positive tests, and 92 indeterminate tests; the latter 2 groups were combined for a total of 292 patients with abnormal TWA tests.

Salerno-Uriarte et al. (71) reported that an abnormal TWA test was associated with a much greater risk of cardiac death and arrhythmic death compared with patients with a normal TWA (Table 12). Also, during follow-up, there was a much greater incidence of arrhythmias and hospitalizations in the abnormal TWA group. The Kaplan-Meier curves for the primary end point separated early on, and the difference at 21 months was significant (p = 0.002) (Fig. 12). The unadjusted hazard ratio for an abnormal TWA test was 4.01; after adjusting for age, gender, New York Heart Association (NYHA) functional class, and LVEF, the hazard ratio was 3.21 (hazard ratio 1.12 to 9.22; p = 0.013). The authors concluded that among patients with NYHA functional class II or III nonischemic cardiomyopathy, an abnormal TWA is associated with a 4-fold greater risk of cardiac death and life-threatening arrhythmias. Conversely, patients with a normal TWA test have a very good prognosis and are unlikely to benefit from ICD therapy. Dr. Markowitz said the ALPHA trial results are "pointing the way to the future," although other trials are expected to more fully explore the use of TWA testing.

View larger version (51K): [in this window] [in a new window] [Download PPT slide]   Figure 12 Event-Free Survival in the ALPHA Study Based on the Primary End Point Primary end point is cardiac death and life-threatening arrhythmias. TWA = T-wave alternans.

View larger version (33K): [in this window] [in a new window] [Download PPT slide]   Figure 13 Predictive Value of Dyssynchrony Patterns Dyssynchrony was assessed in 2 planes: longitudinal (tissue Doppler imaging) and radial (speckle tracking radial strain). Response was defined as end-systolic volume (ESV) decrease 10% or ejection fraction (EF) increase 15%. Of 173 patients, 119 (69%) were EF responders. Light blue bars = ESV responders; dark blue bars = EF responders. *p < 0.05 versus both; #p < 0.05 versus either.

Atrial Fibrillation (AF).   Rate control is a reasonable management strategy for many patients with AF. However, the majority of patients enrolled in the clinical trials evaluating rate control still had persistent AF.

Two epidemiologic studies presented at ACC.07 addressed the question of rate versus rhythm control. One study analyzed data from a retrospective cohort of a large health benefits company (74). Individuals with new-onset AF were stratified into 2 categories using pharmacy utilization codes: rate control only and rhythm (antiarrhytmics) control. Of a total 19,341 patients, 14,093 subjects (72.9%) were in the rate-control group and 5,248 subjects (27.1%) were in the rhythm-control group. During 12-month follow-up, 7,160 patients were hospitalized and 2,347 had a stroke. Cox proportional hazard models were used to estimate the relative hazard of stroke and hospitalization. The relative hazard of hospitalization for individuals in the rhythm-control group was 1.12 (95% CI 1.07 to 1.18) compared with those in the rate-control group after adjusting for demographics, congestive heart failure, MI, hypertension, diabetes, abnormal lipids, and peripheral vascular disease. The relative hazard of stroke for patients in the rhythm-control group was 1.16 (95% CI 1.05 to 1.29) versus those in the rate-control group adjusted for the same covariates plus the use of warfarin. Also, adjusted 1-year total health care costs were greater for the rhythm-control group ($37,828; 95% CI $36,575 to $39,080) when compared with the rate-control group ($31,902; 95% CI $31,141 to $32,664). Said Dr. Markowitz, "Marginally higher health care utilization costs and stroke incidence, so no benefit to rhythm control in this population."

Similar results were evident in a different analysis of AF and diastolic heart failure (75). Although no clinical trial evidence exists on the optimal management of AF in patients with isolated diastolic heart failure, it has been hypothesized that rhythm control is more advantageous due to the dependence of these patients’ LV filling on atrial contraction. Investigators used the Duke Cardiovascular Database (1995 to 2005) to identify patients with diastolic heart failure and then sought to determine whether such patients survive longer with rhythm versus rate control.

A total of 471 patients met inclusion criteria; 338 (71.8%) were treated with rate control and 133 (28.2%) treated with rhythm control. There was little difference in 1-, 3- and 5-year survival rates between the 2 groups (p > 0.1). After baseline adjustments, no difference in mortality was evident (Fig. 14). "The implications here are that in patients who are minimally symptomatic, whose rate can be adequately controlled—especially in the older segment of the population—rate control is a perfectly acceptable strategy if not preferable and that physicians can feel comfortable and not compelled to restore sinus rhythm in that majority of patients experiencing atrial fibrillation," said Dr. Markowitz.

View larger version (9K): [in this window] [in a new window] [Download PPT slide]   Figure 14 Survival Curves for Rate Versus Rhythm Control in Patients With AF and Diastolic Heart Failure Using a 60-day landmark view to assess medication usage, Kaplan-Meier curves for rate versus rhythm control were adjusted for baseline patient differences using Cox proportional hazards modeling. AF = atrial fibrillation.

Dr. DeMaria: It still doesn’t account for quality of life, does it? And my recollection of the data is that quality of life still seems to be a little bit higher if you’re in normal sinus rhythm.

Dr. Markowitz: If you can maintain sinus rhythm. That’s why I qualified my comments and slipped in that patients have to be minimally symptomatic with adequate rate control. I would also caution that most of these studies, such as the randomized AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study (76), involved older patients and this does not necessarily apply to the 40-year-old patient with paroxysmal AF. They are often very symptomatic and in those patients rhythm control is much more important. Also, rhythm control may be much more important in patients with heart failure exacerbations.

Dr. Starling: Any cool new technology that you can use when you actually need to do these techniques?

Dr. Markowitz: Funny you mention that because, yes, we did hear about some novel technology. There are instances where we have to maintain sinus rhythm, and antiarrhythmic drugs have been disappointing and associated with substantial toxicities. Atrial fibrillation ablation has been moving more and more into the mainstream over the years, and there has been an effort to develop new technologies to improve the efficacy of AF ablation. One such technology presented at the meeting, a catheter that is a combined ultrasound mapping catheter, is in preclinical studies. It’s a National Institutes of Health-sponsored bioengineering research project. And the other topics discussed with regard to AF ablation were differential approaches to treating persistent versus paroxysmal AF in the laboratory. New types of energy delivery may hold promise for the future. Also, studies are underway on how to integrate imaging into the lab whether it’s CT, magnetic resonance, or echocardiography, as well as the emerging role of robotic technology.

Dr. Tuzcu: I want to go back to this idea of stratifying patients for risk of sudden death; it is interesting as we try to get some control over costs. If we really go ahead and put defibrillators and CRT devices in all these patients based on LV function criteria, it is going to be very difficult to afford all these devices, not only in the U.S. but everywhere else. You’re suggesting that in the near future we will probably have some predictive models that will help us to select the best patients for these techniques?

Dr. Markowitz: In terms of CRT, yes, I believe we will. The challenges are 2-fold in terms of assessing dyssynchrony as a guide for CRT implantation. First, we have to be able to make this efficient and practical in clinical practice. Right now in the setting of an academic institution or as part of a research study, we can assess dyssynchrony offline with complex programs. It may indeed hold prognostic significance, but how are we going to translate that into the clinical arena so a physician can do it in his office and select the patient for CRT? The second challenge is to show these measures can predict not only remodeling—most of the end points have been anatomical remodeling—but we want to show that we can use these selection criteria to choose patients and then achieve hard outcomes that reduce heart failure, hospitalizations, and improve mortality.

Dr. Thomas: There are very important data on speckle tracking because it’s emerging as a very robust way of looking at cardiac mechanics. Although still largely confined to academic laboratories, it actually is pretty easy to do. It’s easier probably than tissue Doppler-based indices and as packages get migrated from offline analysis onto the machine, you’ll see sort of some push-button approaches to this that should be much more convenient and applicable in the general population.

Dr. DeMaria: I’ll throw some controversy in here. This is yet another criterion of unproven value in determining whether or not somebody should get biventricular pacing. It’s maybe the fifth or sixth such criteria, but none of them are really perfect and to deny a patient in heart failure the benefit of CRT and risk missing some of the 24% who might respond is intellectually attractive but functionally not too helpful.

Dr. Markowitz: That’s a good point. Right now we’re left with making decisions based on depressed LV function, increased LV dimensions, and a wide QRS.

Dr. Thomas: But this could be applicable to patients who otherwise wouldn’t fit the criteria but have evidence of dyssynchrony or a narrow QRS complex. Those studies are ones we’re still waiting to hear from.

Dr. Markowitz: Also, we want to do no harm as well. Of course, we don’t want to miss responders, but if someone doesn’t have dyssynchrony, especially if we’re talking about the populations you were referring to in the future, potentially one can worsen LV performance by pacing, even pacing both ventricles. It’s not clear that pacing both ventricles is better than normal native conduction. Probably it is not.

Dr. Starling: Steve, at this point in time the guidelines tell us to select patients with nonischemic cardiomyopathy, EF 30% or less, NYHA functional class II and III, and if they meet the criteria, consider an ICD. What do we do with this T-wave alternans information?

Dr. Markowitz: I would advocate that everyone practice according to those guidelines, but it’s possible that the guidelines will be modified in the future in light of further data.

Several more TWA studies are expected in the future. We have one multicenter study presented last year, called the ABCD (Alternans Before Cardioverter Defibrillator) Study (77), which did suggest that TWA had good negative prognostic value. In that population, combined with invasive electrophysiology studies, those patients have the lowest event rate. But we’re expecting further studies in the ischemic population and the nonischemic population. If those bear out the predictive value of TWA, it’s very possible that we could modify the recommendations.

Dr. Conti: One comment I have regarding any laboratory test is that they all look good in populations, but you still have the problem: What do you do with the individual where you’re not quite sure it’s positive or negative? You still have to use the compilation of all the things that we look at rather than focusing on one thing. I like TWA and it’s got potential, but you still have to look at the big picture.

I don’t know how many in the audience know about speckle tracking. The only thing I know about it is what Jim Thomas taught me about it 4 or 5 years ago and I’m not sure everybody knows what it is or, if they do, they have it on their machines.

Dr. Thomas: It’s not on all machines, but it’s spreading pretty rapidly. All manufacturers are working on it. It’s basically looking at deformation of the ventricle using the actual little speckles that you see. We used to call that "noise" and try to ignore; now we’re trying to analyze them.

	Imaging and Diagnostic Testing

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
A total of 329 abstracts related to imaging and diagnostic testing were accepted for presentation at the ACC.07 Scientific Session, selected from a total of 904 abstracts in this category submitted to the Program Committee. Dr. Villanueva offered a number of general impressions and themes from the annual meeting and i2 Summit.

She picked up on a theme Dr. DeMaria raised during the highlights discussion on cardiac arrhythmias: the proliferation of yet more new criteria based on advances in technology and imaging. Reviewing all of the abstracts in imaging, Dr. Villanueva agreed that diagnostic imaging technology keeps advancing, "arguably at a faster rate than we can digest them," with imaging options that are increasingly diverse and complex. There are ongoing debates, too, further complicating matters: the benefits of better visualizing anatomy (computed tomography angiography [CTA]) versus physiology (myocardial perfusion imaging [MPI]); the question of when a deeper level of visualization is necessary to study endocardial necrosis (cardiac magnetic resonance [CMR]), plaque components (CMR, positron emission tomography [PET]/CT), or do molecular imaging (CMR, PET, echocardiography); and there is ongoing concern regarding the incremental value of any given imaging strategy versus convenience versus safety versus costs. Consequently, Dr. Villanueva said, "The challenge for the clinician is how to balance the appeal of pretty pictures, of which we’ve seen so many at this conference, with the rational use of technology on behalf of the patient."

In a session on Integrated Imaging in Diagnosis and Management of Coronary Artery Disease, Robert M. Califf, MD, MACC, asked: what is the evidence base in imaging? (78) On the basis of ACC/American Heart Association guidelines relating to imaging, there are 745 recommendations, half of which are class I; however, in terms of "strength of evidence," only 1% of those class I recommendations are level A (Fig. 15). (Level A evidence is based on data derived from multiple randomized clinical trials or meta-analyses.) "This is a problem we have to fix," said Dr. Califf in his presentation. "I am pleased to say that Michael Wolk, Steve Nissen, and the other leaders of the ACC have been taking this very seriously and continue developing appropriateness criteria for cardiovascular imaging." In that spirit, Dr. Villanueva used her highlights summary to cite a few studies where imaging made—or may make—a difference, i.e., where evidence-based imaging can be used to enhance patient care.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 15 Evidence Base in Imaging: Guidelines Recommendations Versus "Strength" of Evidence

The PARR-2 study is the largest randomized study to evaluate whether fluorodeoxyglucose (FDG)-PET-directed therapy has a beneficial effect on clinical outcomes (79). Investigators enrolled 430 patients with poor LV function (LVEF <35%) and used PET imaging to guide therapy choices in an effort to improve clinical outcome compared with standard therapy. The investigators noted that it is the first randomized trial to evaluate viability imaging with a focus on patients with severe LV dysfunction.

Study patients were being considered (but not accepted) for revascularization, cardiac transplantation, heart failure workup, or were—in the opinion of the attending physician or surgeon—likely to benefit from FDG-PET-guided therapy. A total of 218 patients received PET-guided therapy and 212 patients received standard therapy. Researchers tracked the composite rates of cardiac death, heart attack, transplantation, or rehospitalization for cardiac reasons. The study found that patients with poor LV function who received FDG-PET-guided therapy had fewer cardiac events over the course of 1 year compared with patients who received standard care (hazard ratio = 0.81), but this rate did not reach statistical significance. However, among those patients who had not recently undergone angiography, PET-guided therapy significantly reduced cardiac death rates compared with those receiving standard care (hazard ratio = 0.4; p = 0.035) (Fig. 16). Overall, the study was too small to detect a significant benefit with PET imaging. However, compared with standard care, the FDG-PET arm did have more patients directed to revascularization and tended to reduce cardiovascular events within 1 year, although this did not reach statistical significance. The investigators then took a closer look and found that patients without recent angiography tended to be an older and sicker group and there was a significant decrease in cardiac death if they received PET-guided therapy. While acknowledging the study was inconclusive with respect to the primary outcome measurements, the authors concluded, "The results appear promising in supporting the use of FDG-PET viability imaging in this patient population."

View larger version (8K): [in this window] [in a new window] [Download PPT slide]   Figure 16 Survival Free of Cardiac Death in Patients Without Recent Angiography Chi-square = 4.5; hazard ratio = 0.4; 95% confidence interval = 0.17 to 0.96; p = 0.035. PET = positron emission tomography.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 17 Increases in PET SSS Translates Into Proportional Increases in Predicted Mortality p = 0.0003. PET = positron emission tomography; SSS = summed stress score.

Cardiac CTA, with its excellent negative predictive value, is a good tool for evaluating symptomatic patients with an intermediate likelihood of CAD. Investigators sought to evaluate the prevalence of normal and nonobstructive CAD (<50% stenosis) in an outpatient setting using CTA and then analyze the clinical outcomes in those patients over a period of 30 months (82). The investigators reported an excellent 30-month prognosis in this population of symptomatic patients with suspected CAD, thereby confirming the strong negative predictive value of this technology.

Dr. Villanueva finished up with 3 studies that used imaging that might guide clinical decisions in therapy. One used 64-slice multidetector CT as a first diagnostic approach in patients presenting to the emergency department with acute chest pain (83). Randomization was to a conventional diagnostic strategy versus CTA to make a decision about admission. In a high-risk group (definite angina but uncertainty regarding myocardial infarction), there was no difference between multidetector CT versus a conventional strategy. However, in intermediate- and low-risk groups (probable angina and probable not angina), unnecessary admission was significantly reduced with multidetector CT (p = 0.037).

Improvements in LV function and reverse remodeling after CRT are larger in patients with nonischemic dilated cardiomyopathy than in patients with ischemic dilated cardiomyopathy. In the second study cited, investigators used CMR imaging to evaluate the influence of scar burden on response to CRT (84). Dr. Villanueva said, "[CMR] predicted response to CRT with a threshold of scar burden predicting no response at all to CRT."

Finally, transplantation of circulating progenitor cells has been shown to improve LV function after successful recanalization of a chronic total occlusion at short-term follow-up. Thiele et al. (85) used CMR imaging to serially assess changes in LV function in an effort to uncover underlying mechanisms by measuring myocardial perfusion and infarct size at mid-term (3 months) and long-term (15 months) follow-up. In analyzing total scar burden, they found that CMR predicted response to intracoronary circulating progenitor cells in terms of improved myocardial perfusion, reduction in infarct size, and subsequent improved recovery of LV function as compared with controls (inactive serum) at mid-term and long-term follow-up. "These 3 studies were good examples of how imaging can be used to track new therapies," said Dr. Villanueva.

Question and Answer
Dr. Thomas: It’s an interesting concept to study those "false-positive" patients. We feel like we’ve done a bad thing if we send a patient to the cath lab and it’s negative. We say it’s a false-positive test, but the data suggest it may really mean something in terms of prognosis.

Dr. Villanueva: Exactly.

Dr. Harrington: I don’t think there is anything wrong with sending them to the cath lab when there is a level of uncertainty. In fact, that’s a reasonable recommendation to send people for angiography.

Dr. Thomas: Also, if it’s a real hard read on the ischemia there, it probably means you need to look carefully for what’s causing that ischemia even if it isn’t epicardial coronary disease.

Dr. Harrington: And the other information you get in the cath lab, Jim, as you know, is a measure of end-diastolic pressure. We can do a right-heart cath. We can provide additional diagnostic information that may be helpful in that particular group of patients.

Dr. Villanueva: The study really highlights how perfusion imaging gives you different information than catheterization. It weighs in on the strength of physiologic imaging and functional imaging for assessing patients above and beyond just anatomic imaging.

Dr. Tuzcu: Liza, if we have to go back to our offices and tell colleagues 2 or 3 things that probably will change practice, even to a small degree, do you think that PET is one of them? Or will it be more utilization of CT in the emergency room?

Dr. Villanueva: I think the jury is still out on a lot these imaging studies because the numbers have been small and we don’t have long-term follow-up on some these trials. There is strong promise and confirmation that some sort of viability assessment will help to risk stratify patients who would benefit from revascularization. We are starting to sort through all of the data with CT and it does have very strong negative predictive value, because it’s such a sensitive test, but it still suffers from positive predictive value issues.

Dr. Thomas: I was glad to see those data from Matt Budoff because I think there has been a lot of long-term data on calcification because the technology goes back 10 years. Now, for the first time, we are seeing some long-term data on prognosis from CTA. The jury is out in terms of exactly how we integrate this into our practice, especially considering radiation risks and things like that. But it’s data like Dr. Budoff’s that will define the utility of CTA.

Dr. DeMaria: If you ask me for my take-home message on imaging, it’s just what Liza said: we didn’t get a take-home message. We got small studies that were nondefinitive and we still don’t understand the role of all these studies. Even the PARR-2 trial—35% of the people recommended to have revascularization never received it. So, there is not a lot I’m going to do differently tomorrow based on what was presented here.

Dr. Conti: Just one quick comment. We have laid aside coronary angiography and ventriculography and never really looked at it as carefully as we like. In these days when every 1 of these patients has had coronary angiography and ventriculography, every 1 of them has proximal stenoses and good distal vessels, otherwise we wouldn’t be bothering looking for viability. We need to look at myocardial perfusion at the microvascular level. We need to look at collaterals. All of those things define viability pretty darn well. So, we’re pretty sloppy in the cath lab in terms of angiography. I think we need to take a step back and look harder at that.

Dr. Tuzcu: You really hit something very dear to my heart. You are absolutely right. We probably use only 10% of the information we get from a good left-heart catheterization. I will add to that some hemodynamic data that we can gather with careful assessment. If you look at those ventriculographies and coronary angiographies outside the coronary arteries, you will find a lot of things.

Dr. Starling: And there will be hopefully a large body of information that comes from the STICH (Surgical Treatments for Ischemic Heart Failure) trial that won’t randomize patients based on viability studies, but it will be collected in a very prospective manner. So, a lot more yet to learn in that area.

	Pediatric Cardiology and Adult Congenital Heart Disease

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
On the basis of abstract submissions by topic, a total of 191 abstracts relating to pediatric cardiology and adult congenital heart disease were submitted to the ACC.07 Scientific Session Program Committee. Of these submissions, 76 were selected for presentation. Dr. Rhodes summarized key sessions and noted at the beginning, "Pediatric cardiology is sort of a different world than everyone else on this panel lives in. We don’t have as many resources to develop registries and do clinical trials and we don’t have the patient volumes to answer things as accurately as other specialties." That being said, he added, pediatric cardiology is growing quickly—even if patient volume is not—because the survival of patients is improving, "so much so that the adult congenital population is growing tremendously. Everyone in this audience needs to start thinking about learning a little about congenital heart disease," said Dr. Rhodes.

The first paper he discussed evaluated a prenatal cardiac intervention presented by Doff B. McElhinney, MD, of Children’s Hospital, Boston (86). Hypoplastic left heart syndrome frequently is diagnosed prenatally and, during a 6-year period, 80 fetuses have undergone a prenatal cardiac intervention via percutaneous entry through the chest wall of the mother, through the uterus, and through the free wall of the left ventricle. Once the needle is in position, a guidewire is placed followed by "a coronary balloon, believe it or not," to open the aortic valve and improve flow to the left ventricle. Of the percutaneous in utero cardiac interventions, 63 (79%) were successful. All fetuses regained normal heart rate and ventricular function after 1 to 32 min.

The hypothesis was that fetal aortic valvuloplasty may prevent progression of AS to hypoplastic left heart syndrome. In reviewing fetal echocardiograms before intervention and then 2 years later, endocardial fibroelastosis and the small, thickened chamber showed significant improvement. "This technology is going to continue to develop, mainly in large medical centers," said Dr. Rhodes, "We don’t know exactly which direction it’s going to go, but it has a lot of application."

Peak oxygen consumption, VE/VCO ₂ slope, and parameters of heart rate response were recently identified as strong predictors of mortality in adult congenital heart disease (ACHD) patients. Diller et al. (87) compared the prognostic power of exercise parameters in a large population of patients with ACHD. Ventilatory efficiency and heart rate reserve were the strongest exercise predictors of survival in adults with noncyanotic ACHD and, in combination, provided an invaluable clinical tool for risk stratification.

According to a population-based study, a large percentage of children and adults with congenital heart disease are lost to follow-up (88). The study population consisted of individuals born in 1983 and alive at age 22 who were diagnosed with congenital heart disease by a cardiologist in Quebec, Canada, before 6 years of age (n = 563). Patients were typically without cardiology follow-up through childhood and adolescence; so much so that only 39% were still seeing a cardiologist as young adults (Fig. 18). Even among patients with lesions that generally warrant lifelong follow-up, a substantial proportion of patients were no longer being seen within the pediatric age range.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 18 Proportion of Children and Young Adults With CHD Receiving Outpatient Care Declines With Age CHD = congenital heart disease.

View larger version (32K): [in this window] [in a new window] [Download PPT slide]   Figure 19 Changing Age Distribution of Death in CHD From 1988 to 2005 From a Population-Based Study CHD = congenital heart disease.

Challenges of Contraception.   One ACC.07 symposium focused on Family Planning for Adult Congenital Heart Disease Patients. This can be a challenge given that women with congenital heart disease are often told they are at too high a risk for pregnancy, but also too high a risk for many of the available contraceptives, including those that are estrogen-based. There are several options (91). Progestin-only birth control methods are associated with little or no increased risk of cerebrovascular accident or AMI; there is a small, nonsignificant increase in the odds ratio for venous thromboembolism; and the evidence is encouraging regarding safe use in women with hypertension, although more studies are needed. Effectiveness of a progestin-only pill is the same as the combined estrogen/progestin pill (92% for both), but oral progestin-only contraception is highly time sensitive, requiring daily use and use at about the same time every day. Also, a progestin-only pill may affect international normalized ratio, especially when initiating therapy.

Longer-lasting options are available. IMPLANON is a small, thin, implantable hormonal contraceptive that is effective for up to 3 years. Also, progestin-only injectables are available: Depo-Provera, which is administered by a health care professional, and Depo-SubQ Provera, which can be self-administered monthly. Although fraught with controversy for many years, an intrauterine device has a low incidence of pelvic inflammatory disease and contraceptive efficacy equivalent to that of combined oral contraceptives. It has been approved for women at risk of endocarditis. "Progesterone-only methods and intrauterine devices could be even more effective in preventing unwanted pregnancy in congenital heart patients," said Dr. Rhodes, adding that prevention of teenage pregnancy is "also very critical" and requires a sexual history and a frank discussion to try to prevent pregnancy in teenage girls with congenital heart disease.

Finally, as interventional cardiologists consider the potential of a bioabsorbable stent, new bioabsorbable closure technology is being evaluated for advanced septal repair of ACHD. Said Dr. Rhodes, "This is going to have a lot of applications for patients with congenital heart disease."

Question and Answer
Dr. Thomas: Let’s see you do one of those percutaneous fetal interventions live at i2 next year, Bill.

Dr. Knopf: We may be doing one of those live next year.

Dr. Thomas: You have got to come to Chicago, folks.

Dr. Tuzcu: Thank you, John; a wonderful overview and very exciting. We are delighted to have Pediatric Cardiology and Pediatric Cardiac Surgery in our program, and Bill will attest to that. We are moving forward to form more bridges with pediatric cardiology interventions, which really form the basis of many of our structural heart disease interventions. I very much welcome your contribution to that.

	Special Topics

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
At ACC.07, 239 abstracts were submitted in the Special Topics category, 92 of which were accepted for presentation. Dr. Foody was given the opportunity to present highlights from these papers. Overall, she said, the scientific sessions "speak to the diversity, the innovation of the cardiovascular community." Giving what she said is the "30,000-foot view," it’s clear that among the ACC.07/i2 Summit sessions "tremendous technological advances" were highlighted; yet she harkened back to a quote from Marc A. Pfeffer, MD, PhD, FACC, who at the Opening Session delivered the year’s Simon Dack Lecture, "Seeking Balance: Research and Education." Said Dr. Pfeffer: "Trials in isolation are a hollow victory."

"But the real message from this meeting is that we are making significant strides," said Dr. Foody, although there is still some distance to go given that a review of 439 indications of quality of care found that patients receive only 55% of recommended care and all demographic groups are at risk of poor quality of care. "But we have the ACC’s effort to develop a comprehensive national cardiovascular registry, the ACTION Registry, to address this," she added.

Among the exciting issues from ACC.07, she said, were the CRUSADE Initiative data. "We’ve seen dramatic increases over the last several years with respect to overall adherence trends in cardiovascular care," she said (Fig. 20), and the data are echoed in multiple registries with respect to care. "However, as much as this care is significantly improved, significant gaps remain and hopefully lessons learned here from Special Topics will help develop interventions that continue to advance the application of evidence-based care to our patients," she said.

View larger version (53K): [in this window] [in a new window] [Download PPT slide]   Figure 20 Overall Adherence Trends Over Time, CRUSADE Quarter 1, 2002 to Quarter 4, 2006 Available at: http://www.crusadeqi.com/Main/Ecab/Slides/CRUSADEResults2006Q4.ppt.

"It is certainly apropos that we sit here in New Orleans," said Dr. Foody. "We’ve all been struck by the effect of [Hurricane] Katrina," which she said amplified deficiencies, vulnerabilities, and disparities in heath care. "We have a tremendous opportunity and Special Topics has really led the way in research looking at innovations and improving care for those patients who are most vulnerable."

Dr. Tuzcu: Thank you, JoAnne. Dr. Conti, Dr. DeMaria, thank you very much for being with us; you have been very, very helpful. To the topic coordinators, we thank you; as the co-chairs, we deeply appreciate your input.

And we conclude the 56th Scientific Session of the American College of Cardiology.

	References

Top Introduction Vascular Disease, Hypertension,... Myocardial Ischemia and... Innovation in Intervention: i2... Valvular Heart Disease Cardiac Function and Heart... Cardiac Arrhythmias Imaging and Diagnostic Testing Pediatric Cardiology and Adult... Special Topics References

 
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