November 2010 Vol. 16 No.

From the publishers of The New England Journal of Medicine

TAVI: A Promising Development for Patients with Few Options
In the PARTNER trial, TAVI significantly improved 12-month outcomes.

Validation of transcatheter aortic valve implantation (TAVI), an emerging therapeutic option for patients with severe aortic stenosis who cannot undergo valve replacement surgery (JW Cardiol Oct 2010, p. 82, and Circulation 2010; 122:62), hinges on forthcoming results of clinical trials. In this first report of the industry-sponsored PARTNER trial, investigators randomized 358 patients with severe aortic stenosis (mean age, 83; 46% men) to undergo TAVI or receive standard treatment. All participants were determined (by agreement of two surgeons) not to be candidates for surgery because of high surgical risk or a coexisting condition. Mean baseline aortic valve area was 0.6 cm2, and >90% of patients had New York Heart Association (NYHA) class III or IV heart failure symptoms. The primary endpoint was mortality during follow-up (median, 1.6 years). Of 179 patients in the TAVI group, 173 underwent the procedure. Of 179 in the

standard-care group, 84% underwent balloon valvuloplasty, 10% eventually underwent aortic valve replacement, and 2% underwent TAVI at a nonparticipating institution. Major vascular complications occurred in 17% of the TAVI group and 2% of the standard-care group (P<0.001), and major bleeding occurred in 22% of the TAVI group and 11% of the standardcare group (P=0.007). At 30 days, mortality was nonsignificantly higher in the TAVI group than in the standard-care group (5.0% vs. 2.8%); however, at 1 year, mortality was significantly lower in the TAVI group (30.7% vs. 50.7%; P<0.001). At 1 year, the stroke rate was nonsignificantly higher in the TAVI group than in the standard-care group (7.8% vs. 3.9%; P=0.18), but 75% of patients in the TAVI group had improved heart failure symptoms (NYHA class I or II), compared with 42% of the standardcare group (P<0.001).

and medical care, TAVI conferred substantial mortality and symptom-relief benefits — at a modest cost of increased vascular complications and bleeding — in elderly patients with aortic stenosis who were not operative candidates. TAVI is established in Europe, and these findings support its use in the U.S. as an option for these patients. We will need to monitor the results of less-experienced centers as the procedure catches on.
— Harlan M. Krumholz, MD, SM
Leon MB et al. for the PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010 Oct 21; 363:1597.

New Perioperative Risk Index for Vascular Surgery Patients
Four procedure-specific calculators predict cardiovascular risk.

Compared with standard treatment that included a mix of valvuloplasty, surgery,

TAVI: A Promising Development for Patients with Few Options ...................................................... 85 New Perioperative Risk Index for Vascular Surgery Patients ................................ 85 Radiation Exposure from Cardiac Imaging Procedures ................................. 86 Are Patients and Cardiologists Speaking the Same Language? ............................................... 86 How Do Rates of Cardiac Interventions Compare in New York and Ontario?...................... 87 Treating Depression in Patients with Heart Failure .................... 87 Abacavir and Cardiovascular Disease — Pieces of the Puzzle? ............................................... 89 Stability of High Cholesterol Levels in Children..... 89 I’ll Have a Statin with My Burger ............................. 89 Supervised Exercise Therapy for Intermittent Claudication .................................. 90 Vascular Risk Reduction in Patients with Ehlers-Danlos Syndrome ............................... 90 Cooling Cardiac-Arrest Patients: The Sooner, the Better? .......................................... 90 Predictors of Antiplatelet Therapy Discontinuation in Patients with DES ................... 91 PPIs and Cardiovascular Risk ................................... 91 PPIs and Clopidogrel: COGENT Findings ................ 92

The Revised Cardiac Risk Index (RCRI) — widely used to determine cardiac risk in patients undergoing noncardiac surgery — was derived from analysis of 4300 patients at one Boston teaching hospital; vascular surgical procedures comprised only 900 of those surgeries (Circulation 1999; 100:1043). Now, researchers from a consortium of 20 New England hospitals have derived a new risk index from a database of 10,000 patients who underwent carotid endarterectomy (53%), lower-extremity bypass (27%), or open (11%) or endovascular (10%) repair of abdominal aortic aneurysms (AAAs). Six percent of patients suffered perioperative cardiac complications (myocardial infarction, clinically significant arrhythmia, or congestive heart failure). Using multivariate analysis, the researchers identified eight positive predictors of complications (older age, coronary disease, congestive heart failure, chronic obstructive

Rolofylline for Acute Heart Failure? Maybe Not...... 88 Outcomes of Drug Trials and Association with Funding Source ................................................ 88 Hypoglycemia and Adverse Cardiovascular Outcomes: Are They Related? ............................... 88


EDITOR-IN-CHIEF Harlan M. Krumholz, MD, SM, Harold H. Hines, Jr., Professor of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven EXECUTIVE EDITOR Kristin L. Odmark Massachusetts Medical Society DEPUTY EDITOR Howard C. Herrmann, MD, Professor of Medicine, Director, Interventional Cardiology and Cardiac Catheterization Laboratories, University of Pennsylvania Medical Center, Philadelphia ASSOCIATE EDITORS JoAnne M. Foody, MD, Director, Cardiovascular Wellness Center, Brigham and Women’s Hospital, Boston Joel M. Gore, MD, Edward Budnitz Professor of Cardiovascular Medicine, University of Massachusetts, Worcester Mark S. Link, MD, Associate Professor of Medicine, New England Medical Center and Tufts University School of Medicine, Boston Frederick A. Masoudi, MD, MSPH, Division of Cardiology, Denver Health Medical Center and Associate Professor of Medicine, University of Colorado at Denver Beat J. Meyer, MD, Associate Professor of Cardiology, University of Bern; Chief, Division of Cardiology, Lindenhofspital, Bern, Switzerland CONTRIBUTING EDITORS William T. Abraham, MD, Professor of Medicine, Chief, Division of Cardiovascular Medicine, The Ohio State University Heart Center, Columbus Hugh Calkins, MD, Professor of Medicine and Director of Electrophysiology, The Johns Hopkins Hospital, Baltimore FOUNDING EDITOR Kim A. Eagle, MD, Albion Walter Hewlett Professor of Internal Medicine and Chief of Clinical Cardiology, Division of Cardiology, University of Michigan Medical Center, Ann Arbor MASSACHUSETTS MEDICAL SOCIETY Christopher R. Lynch, Vice President for Publishing; Alberta L. Fitzpatrick, Publisher Betty Barrer, Christine Sadlowski, Sharon S. Salinger, Staff Editors; Kara O’Halloran, Copy Editor; Misty Horten, Layout; Matthew O’Rourke, Director, Editorial and Product Development; Robert Dall, Editorial Director; Art Wilschek, Christine Miller, Lew Wetzel, Advertising Sales; William Paige, Publishing Services; Bette Clancy, Customer Service Published 12 times a year. Subscription rates per year: $119 (U.S.), C$166.67 (Canada), US$165 (Intl); Residents/Students/Nurses/PAs: $69 (U.S.), C$96.19 (Canada), US$80 (Intl); Institutions: $219 (U.S.), C$256.19 (Canada), US$230 (Intl); individual print only: $89 (U.S.). Prices do not include GST, HST, or VAT. In Canada remit to: Massachusetts Medical Society C/O #B9162, P.O. Box 9100, Postal Station F, Toronto, Ontario, M4Y 3A5. All others remit to: Journal Watch Cardiology, P.O. Box 9085, Waltham, MA 02454-9085 or call 1-800-843-6356. E-mail inquiries or comments via the Contact Us page at Information on our conflict-of-interest policy can be found at


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pulmonary disease, creatinine level ≥1.8 mg/dL, smoking, insulin-dependent diabetes, and long-term β -blockade) and one negative predictor (history of coronary revascularization); each predictor is weighted according to a point scale, and the sum of points (maximum, 15) determines risk for cardiac complications. Risks — ranging from 2.6% (for patients with ≤3 points) to 14.3% (for those with ≥8 points) — are displayed in a table in the article.

imaging (MPI). About half of all cardiac imaging procedures — and three quarters of MPIs and cardiac computed tomography scans — were performed in physicians’ offices. Effective radiation doses that exceeded the background level from natural sources by >3 mSv annually occurred in 92.3 per 1000 enrollees, and doses exceeding annual limits for occupational exposure (>20 mSv) occurred in 3.3 per 1000.

This study gives clinicians a tool (called the “VSG-CRI”) for predicting perioperative risk in vascular surgery patients. The researchers applied the RCRI to their cohort and found that it generally underestimated risk, but that’s not surprising, given the quite different populations from which the two models were derived. In addition, the VSG-CRI might be more generalizable than the RCRI because it was derived from data from a larger number of hospitals than was the RCRI. Four VSG-CRI risk calculators ( — specific for carotid endarterectomy, lower-extremity bypass, and open or endovascular AAA repair — are available online.
— Allan S. Brett, MD, Journal Watch General Medicine
Bertges DJ et al. The Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) predicts cardiac complications more accurately than the Revised Cardiac Risk Index in vascular surgery patients. J Vasc Surg 2010 Sep; 52:674.

The questions, of course, are whether these imaging procedures were appropriate and whether risks from radiation exposure were offset by sufficient benefit. Editorialists point to ongoing efforts to minimize radiation exposure and contend that the estimates used here are too high. They also remind us that the morbidity and mortality associated with coronary heart disease can be mitigated by accurate diagnostic testing. However, as cumulative radiation doses become a bigger issue, alternative forms of testing that do not employ ionizing radiation will be needed and preferable.
— Kirsten E. Fleischmann, MD, MPH, Journal Watch General Medicine
Chen J et al. Cumulative exposure to ionizing radiation from diagnostic and therapeutic cardiac imaging procedures: A population-based analysis. J Am Coll Cardiol 2010 Jul 7; Aug 24; 56:702. Budoff MJ and Gupta M. Radiation exposure from cardiac imaging procedures: Do the risks outweigh the benefits? J Am Coll Cardiol 2010 Jul 7; Aug 24; 56:712.

Radiation Exposure from Cardiac Imaging Procedures
Annual exposure that exceeded background levels by >3 millisieverts was not uncommon among insured adults.

Are Patients and Cardiologists Speaking the Same Language?
Even after informed consent, patients’ understanding of the benefits of PCI differed from that of their cardiologists.

How does radiation exposure from typical use of medical imaging compare with background radiation or accepted occupational exposures? In this analysis, authors used administrative data from a large insurer to evaluate cardiac imaging use in almost one million adults (age, <65) and estimated the effective dose of radiation from such procedures. From 2005 to 2007, 90,121 patients (9.5%) underwent at least one cardiac imaging procedure, with a mean cumulative effective dose of 16.4 millisieverts (range, 1.5–189.5 mSv). Most of the effective dose (74%) came from myocardial perfusion

In patients with chronic stable angina, percutaneous coronary intervention (PCI) reduces symptoms but does not affect mortality or risk for acute myocardial infarction (MI). Do patients understand this? Investigators at a single center surveyed 153 patients scheduled to undergo elective coronary catheterization and possible PCI to assess the patients’ knowledge and expectations of PCI. Ten of 11 cardiologists who performed the procedures completed an abbreviated form of this survey, and 27 of 32 interventionalists and referring cardiologists completed a general survey assessing their beliefs about PCI for stable angina.

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Forty-two percent of the patients had angina that limited their activities, 77% had positive stress test results, and 29% had previous MI. Most patients reported that physicians spent at least 5 minutes explaining the procedure, and 96% reported that they understood why they might undergo PCI. However, 88% believed that PCI would reduce their risk for MI, and 82% believed that it would reduce their risk for death. In contrast, the cardiologists believed that PCI would reduce the risk for MI in only 17% — and the risk for death in only 15% — of the case patients. The responses of the 53 patients who underwent PCI were similar to those of the 100 who did not, and their beliefs differed not only from those of physicians in general but also from those of their individual cardiologists. Cardiologists were also more likely than patients to believe that the patients participated in decision making. Patients with lower incomes and those with greater chest discomfort were more likely than those without these characteristics to believe that PCI would reduce their risk for death or MI.

has about twice as many interventional cardiologists, cardiac surgeons, and hospitals with cardiac invasive facilities as Ontario. During 2004–2006, the age- and sexadjusted rate of coronary revascularization was 1.7 times higher in NY than in Ontario, a difference due almost entirely to a higher rate of percutaneous coronary intervention (PCI). The difference was greater in patients without myocardial infarction (MI) than in those with MI. In patients with acute MI, the PCI rate in Ontario increased from 24 per 100,000 residents in 1997–2000 to 65 per 100,000 in 2004–2006; however, even in the latter time period, it remained about 30% lower than in NY (86 per 100,000).

this study, 469 adults aged ≥45 (mean age, 62) with symptomatic systolic heart failure (mean left ventricular ejection fraction, 30%) and major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition criteria) depressive symptoms were randomized to receive placebo or sertraline (50 mg initially, titrated toward a maximum dose of 200 mg) for 12 weeks. All patients received nursefacilitated support. Only 138 of 234 patients in the sertraline group and 152 of 235 in the placebo group completed therapy. More sertraline patients than placebo patients discontinued treatment because of adverse effects (11.5% vs. 6.0%). Depression scores improved significantly in both groups, but the improvements did not differ significantly between the groups. The proportions of patients whose cardiovascular clinical status improved, was unchanged, or worsened also did not differ between the sertraline group (40.6%, 29.5%, and 29.9%, respectively) and the placebo group (43.8%, 25.1%, and 31.1%, respectively). The rates of serious adverse events at 12 weeks and adverse cardiovascular events during a mean of 2.2 years of follow-up were similar in the two groups.

These results confirm that patients’ expectations of the benefits of PCI differ considerably from those of their physicians. I agree with the editorialist: True informed consent requires that we not only tell our patients about the risks, but also make sure they fully understand what they can — and cannot — gain from the treatments we offer them. — Joel M. Gore, MD
Rothberg MB et al. Patients’ and cardiologists’ perceptions of the benefits of percutaneous coronary intervention for stable coronary disease. Ann Intern Med 2010 Sep 7; 153:307. Fernandez A. Improving the quality of informed consent: It is not all about the risks. Ann Intern Med 2010 Sep 7; 153:342.

Assuming that the underlying prevalence of coronary disease is similar in these two geographic areas, these findings suggest that the U.S. healthcare reimbursement system leads to a much greater use of PCI for patients without acute MI, compared with a government-regulated single-payer system. However, the same findings suggest that the U.S. model enables better access to emergency interventions. This study highlights the challenges of weighing potential policy options that limit rising healthcare costs against the need to optimize patient outcomes.
— Howard C. Herrmann, MD
Ko DT et al. Temporal trends in the use of percutaneous coronary intervention and coronary artery bypass surgery in New York State and Ontario. Circulation 2010 Jun 22; 121:2635. Ryan TJ. Large cardiac registries: The path to higher quality and lower cost in our healthcare system. Circulation 2010 Jun 22; 121:2612.

Surprisingly, sertraline did not affect depressive symptoms, let alone cardiovascular outcomes, in these patients with HF. Whether competing beneficial effects of nurse support or the remarkably high dropout rates in this study influenced these findings is a matter for speculation. Although I still believe that screening for and treating depression in patients with cardiovascular disease are worthwhile, these results oblige circumspection in discussions of benefits

Treating Depression in Patients with Heart Failure
Disappointing findings from a trial of a selective serotonin reuptake inhibitor

• Become a fan of Journal Watch on Facebook and follow us on Twitter! • Listen to the lead investigator of a sham-controlled vertebroplasty trial discuss whether this procedure is still acceptable for fracture.

How Do Rates of Cardiac Interventions Compare in New York and Ontario?
A tale of two databases

In this retrospective study, researchers used registry data to compare rates of invasive cardiac procedures in two similarly populated areas with different healthcare reimbursement systems: New York State (NY) and Ontario, Canada. Per capita, NY

Depression is common and independently associated with increased morbidity and mortality in patients with heart failure (HF), but no studies have demonstrated that treating depression improves outcomes in this high-risk population. Selective serotonin reuptake inhibitors used to treat depression have ancillary (e.g., antiinflammatory) effects that might be of particular benefit to patients with HF. In



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with HF patients. A larger, forthcoming study of escitalopram in HF patients (MOOD-HF) should provide further insights into this challenging clinical problem.
— Frederick A. Masoudi, MD, MSPH
O’Connor CM et al. Safety and efficacy of sertraline for depression in patients with heart failure: Results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol 2010 Aug 24; 56:692.

tations of success can wither under the scrutiny of researchers in a well-constructed trial. — Harlan M. Krumholz, MD, SM
Massie BM et al. for the PROTECT Investigators and Committees. Rolofylline, an adenosine A1– receptor antagonist, in acute heart failure. N Engl J Med 2010 Oct 7; 363:1419.

Bourgeois FT et al. Outcome reporting among drug trials registered in Ann Intern Med 2010 Aug 3; 153:158.

Hypoglycemia and Adverse Cardiovascular Outcomes: Are They Related?
A large trial demonstrated an association, but not necessarily a causal one.

Rolofylline for Acute Heart Failure? Maybe Not
A phase III trial dashes hopes.

Outcomes of Drug Trials and Association with Funding Source
Industry-funded trials were more likely to report positive outcomes.

Declining renal function is common and a harbinger of poor outcome in patients with heart failure (HF). Research has suggested that compensatory responses mediated by adenosine contribute to this complication. Rolofylline is an adenosine A1–receptor antagonist that relieved dyspnea and reduced renal dysfunction in previous studies. In an industry-sponsored, phase III trial, investigators compared rolofylline with placebo in patients hospitalized with acute HF. All patients had impaired renal function (creatinine clearance, 20–80 mL/ minute). The primary endpoint was patient-reported treatment success, defined as moderate or marked improvement in dyspnea; or treatment failure, defined as any of the following through day 7: death or HF readmission, worsening HF symptoms or signs, or persistently worsening renal function. A total of 2033 patients were randomized in a 2:1 ratio to intravenous rolofylline or placebo within 24 hours after presenting to the hospital, and treatment lasted 3 days. Rolofylline treatment did not improve outcomes. Moreover, treatment failure was more common in the rolofylline group than in the placebo group, although the difference was statistically nonsignificant (21.8% and 19.8%; P=0.30). The rate of persistent renal dysfunction did not differ significantly between the rolofylline and placebo groups (15.0% and 13.7%; P=0.44).

Web-based clinical trial registries such as ( have been developed to increase transparency and reduce publication bias. In this study, U.S. and Canadian researchers examined more than 500 drug trials listed in that registry to investigate whether funding sources affected outcomes. The assessed clinical trials began after 1999 and were completed by 2006 and involved lipidlowering agents, antidepressants, antipsychotics, proton-pump inhibitors, or vasodilators. The trials were funded by industry (63%), nonprofit organizations (23%; half also received industry funding), and government (14%). Industry-funded trials, which were more likely to be later-phase trials, were also most likely to report positive outcomes even after adjustments for trial phase (industry-funded, 85%; nonprofit with industry support, 85%; nonprofit without industry support, 61%; and government-funded, 50%). Rates of trial publication within 24 months of study completion were lowest for industry-funded trials (industry-funded, 32%; nonprofit with industry support, 39%; nonprofit without industry support, 56%; and government-funded, 54%).

In the ADVANCE trial, intensive glycemic control was compared with standard control in 11,000 adults with long-standing type 2 diabetes. As the investigators reported previously (JW Cardiol Jul 2008, p. 53, and N Engl J Med 2008; 358:2560), intensive control did not lower rates of cardiovascular events or death, and the proportion of patients with hypoglycemia was greater in the intensive-treatment group than in the standard-treatment group (2.7% vs. 1.5% for severe hypoglycemia; 52% vs. 37% for minor hypoglycemia). One question is whether hypoglycemia was related to adverse vascular outcomes or excess mortality in ADVANCE; to address this question, the researchers conducted this additional analysis. Severe hypoglycemia indeed was associated with significantly elevated risk for macrovascular events, microvascular events, cardiovascular death, and all-cause mortality. However, several observations call into question whether this association was causal: An average delay of 1 year occurred between onset of severe hypoglycemia and adverse vascular events or death, no dose– response relation existed between numbers of hypoglycemic episodes and adverse vascular events or death, and severe hypoglycemia also was associated with noncardiovascular adverse outcomes (e.g., respiratory, digestive).

Despite the mechanistic appeal of targeting the adenosine pathway and the promising preliminary study results, rolofylline failed to improve outcomes of acute HF in this study. These findings illustrate how expec-

This study documents substantial differences in the conduct and results of clinical trials, based on funding source. Although use of trial registries such as ClinicalTrials. gov should improve transparency, clinicians still face difficulty when trying to discern when the conduct of a clinical trial and its published outcomes are influenced substantially by commercial concerns.
— Jamaluddin Moloo, MD, MPH, Journal Watch General Medicine

These findings, along with results from the analogous ACCORD trial (BMJ 2010; 340:b4909), confirm an association — but not necessarily a causal one — between severe hypoglycemia and adverse vascular events or deaths reported in these studies of intensive glycemic control. More likely, susceptibility to severe hypoglycemia was a marker for poorer health generally. Of course, this interpretation does not negate the fact that, in individual cases, severe hypoglycemia can have serious consequences.
— Allan S. Brett, MD, Journal Watch General Medicine

November 2010
Zoungas S et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010 Oct 7; 363:1410.


lesterol, may be relevant, but the suggested role of increased inflammation and coagulation was not demonstrated in these studies. — Charles B. Hicks, MD,
Journal Watch AIDS Clinical Care
Sinn K et al. Lower arterial stiffness and Framingham score after switching abacavir to tenofovir in men at high cardiovascular risk. AIDS 2010 Sep 24; 24:2403. Martin A et al. Abacavir does not affect circulating levels of inflammatory or coagulopathic biomarkers in suppressed HIV: A randomized clinical trial. AIDS 2010 Sep 7; [e-pub ahead of print]. (http://

These results further dampen my enthusiasm for the AAP recommendation which — in my view — should be reconsidered and rewritten. — Howard Bauchner, MD,
Journal Watch Pediatrics and Adolescent Medicine
Freedman DS et al. Changes and variability in high levels of low-density lipoprotein cholesterol among children. Pediatrics 2010 Aug; 126:266.

Abacavir and Cardiovascular Disease — Pieces of the Puzzle?
The underlying reasons for this potential association remain unknown.

Data from the DAD study indicate that current or recent use of abacavir is associated with increased risk for symptomatic coronary artery disease (CAD), but the mechanism behind any such association has not been established (JW Cardiol Jun 2008, p. 51, and Lancet 2008; 26:371). Two new studies explore whether increased inflammation and coagulation play a role. Sinn and colleagues recruited 20 HIV-infected men at relatively high risk for CAD to switch the abacavir in their regimens to tenofovir. Four weeks later, both arterial stiffness (as measured by the augmentation index from the radial artery waveform) and total cholesterol levels had declined significantly, with the latter resulting in lower Framingham risk scores. No significant changes were seen in markers of increased risk for thrombosis and inflammation (C-reactive protein, d -dimer, and interleukin [IL]-6). In the STEAL trial, Martin and colleagues randomized patients to switch the nucleoside component of their regimens to either tenofovir/FTC or abacavir/3TC. During 96 weeks of follow-up, the abacavir/3TC group had a significantly higher rate of cardiovascular events than the tenofovir/FTC group (Clin Infect Dis 2009; 49:1591). However, an in-depth analysis of biomarkers during the first 12 weeks showed no significant differences between the groups with respect to changes in markers of endothelial activation (vascular and intracellular adhesion molecules), systemic inflammation (high-sensitivity C-reactive protein, IL-6, IL-10, macrophage migration inhibitory factor 1, amyloid A, and amyloid P), or the platelet and coagulation cascade (d-dimer, soluble P-selectin, and fibrinogen).

I’ll Have a Statin with My Burger
Can a single statin dose counteract the cardiovascular risk conferred by an unhealthy meal?

Stability of High Cholesterol Levels in Children
Most children with high LDL cholesterol levels had substantially lower levels at the next examination.

The American Academy of Pediatrics (AAP) 2008 guideline for cholesterol management in children (JW Cardiol Dec 2008, p. 96, and Pediatrics 2008; 122:198) suggests that pharmacologic treatment be considered for children with low-density lipoprotein (LDL) cholesterol levels ≥190 mg/dL or ≥160 mg/dL if other risk factors are present. Investigators examined the stability of LDL cholesterol levels in 6827 children (37% black) who participated in the Bogalusa (Louisiana) Heart Study (1973– 2002). The children were retested an average of five times (median interval, 3 years) from age 5 years to 44 years. Overall, correlations between initial and subsequent LDL cholesterol levels were moderate to high. Most children with initial LDL cholesterol levels between 160 and 189 mg/dL (201 children) or ≥190 mg/dL (44 children) had substantially lower levels at the next examination; only 34% and 39%, respectively, had levels as high or higher on the subsequent test.

Daily doses of statins reduce the relative risk for myocardial infarction by 20% to 70%. In contrast, reductions in cardiovascular risk associated with decreasing dietary fat intake have not always been statistically significant. Interventional studies to examine whether taking statins can mitigate the harmful effects of an unhealthy diet are unlikely to take place. Therefore, investigators used a meta-analysis of seven randomized controlled trials (42,848 patients) of statins for primary prevention of coronary artery disease and data from a cohort study of the effects of dietary fat on cardiovascular risk (43,757 men) to calculate a “neutralization tariff” with the following assumptions: • Each unhealthy meal consumed contributes to an increase in cardiovascular risk. Each statin tablet taken contributes to a decrease in risk. No high-risk patient group has been identified in whom statins appear to be ineffective. If the beneficial effects of one statin dose and the harmful effects of one unhealthy meal are approximately equal, the mechanisms or timing of the two effects need not correlate directly.

• •

The mechanism by which abacavir may be associated with increased risk for CAD remains uncertain. Changes in arterial stiffness, perhaps mediated by increases in cho-

Data collection for the Bogalusa Heart Study ended in 2002, before the obesity epidemic began; only 21% of the children in this study were overweight or obese. Family history of cardiovascular disease was recently reported to be a poor predictor of elevated cholesterol in children (Pediatrics 2010; 126:260), and now it seems that only a minority of children whose initial cholesterol screen would qualify them for pharmacologic therapy would still qualify based on a subsequent measure.

By plotting the logarithm of the reduction in relative cardiovascular risk associated with statins in different trials against the logarithm of the increase in relative risk associated with the consumption of fast foods high in total fat and trans-fat, the investigators found that most daily statin regimens can offset the increased relative risk of eating a Quarter Pounder with cheese and a small milkshake.



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According to this provocative analysis, most statin doses could neutralize the ill effects of an unhealthy meal. The adoption of a healthy diet is a cornerstone of any strategy for primary prevention of heart disease. However, many patients at high cardiovascular risk fail to achieve the necessary lifestyle modifications. Would providing statins with fast foods decrease the overall burden of heart disease in the world? — Joel M. Gore, MD
Ferenczi EA et al. Can a statin neutralize the cardiovascular risk of unhealthy dietary choices? Am J Cardiol 2010 Aug 15; 106:587.

At 1 year, median walking distance was significantly longer in supervised patients than in advice-only patients (600 vs. 400 m). Use of the accelerometer did not improve walking beyond that achieved with supervised training alone. Several quality-of-life scores were higher in the supervised groups than in the advice-only group.

at baseline. All but two celiprolol recipients achieved the maximum dosage. After a mean follow-up of 47 months, the trial was stopped early because the rate of the primary endpoint, arterial rupture or dissection, was significantly lower in celiprolol recipients than in controls (20% vs. 50%; hazard ratio, 0.36; 95% confidence interval, 0.15–0.88). Blood pressure levels and heart rates did not differ significantly between the two groups. Only one patient discontinued celiprolol because of fatigue.

Supervised Exercise Therapy for Intermittent Claudication
Median walking distance was longer in supervised patients than in advice-only patients.

In clinical trials, supervised exercise training consistently has outperformed “go home and walk” advice to patients with intermittent claudication. Whether specific elements of training sessions — or simply encouragement by therapists, with better adherence to home exercising — account for these findings is unclear. One caveat: Some U.S. insurers might not pay for this intervention. — Allan S. Brett, MD,
Journal Watch General Medicine
Nicolaï SPA et al. Multicenter randomized clinical trial of supervised exercise therapy with or without feedback versus walking advice for intermittent claudication. J Vasc Surg 2010 Aug; 52:348.

In a 2006 systematic review of eight small studies, supervised exercise programs were superior to unsupervised exercise for lengthening walking distance in patients with intermittent vascular claudication. Now, Dutch researchers have conducted a trial with 304 patients — a cohort nearly equal to that of the previous trials combined. All patients had ankle-brachial indexes <0.90 (mean, 0.66) and could walk no farther than 500 m (median, 250 m). Patients were randomized to three treatments: (1) verbal advice and written instructions to walk at home until maximum pain nine times daily; (2) supervised exercise sessions with a physical therapist, initially two or three times weekly, then less often; or (3) the same supervised exercise intervention, plus home use of an accelerometer — a device that measures physical activity — to provide daily feedback on progress. Supervised patients received the same home walking instructions as did advice-only patients.
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Vascular Risk Reduction in Patients with Ehlers-Danlos Syndrome
In a randomized trial, celiprolol, an inexpensive, well-tolerated drug, decreased incidence of arterial rupture or dissection.

These findings suggest that celiprolol can prevent life-threatening complications of vascular Ehlers-Danlos syndrome. Although more data are needed to elucidate how celiprolol exerts its therapeutic effect independently of a hemodynamic effect, an editorialist notes that beta-blockers seem to suppress transforming growth factor β (TGFβ ) expression, which might decrease matrix turnover and stabilize aneurysms in these patients. The possible role of other drugs that block TGFβ (e.g., angiotensinreceptor blockers) in vascular EhlersDanlos syndrome remains to be determined.
— Beat J. Meyer, MD
Ong K-T et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: A prospective randomised, open, blindedendpoints trial. Lancet 2010 Sep 7; [e-pub ahead of print]. ( Brooke BS. Celiprolol therapy for vascular EhlersDanlos syndrome. Lancet 2010 Sep 7; [e-pub ahead of print]. ( S0140-6736(10)61155-5)

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Ehlers-Danlos syndrome arises from defects in type III collagen, causing skin hyperelasticity and fragility and joint hypermobility. Fatal complications, which occur at a median age of 40–50, can include mitral valve prolapse and spontaneous rupture of large- and medium-sized arteries. Although propranolol is known to lower rates of aortic dilatation and death in Marfan syndrome, the preventive role of beta-blockers in Ehlers-Danlos syndrome is unknown. Celiprolol, a β1-adrenoceptor antagonist with partial β2-adrenoceptor agonist action, has been used for hypertension in various countries since 1989 but is currently unavailable in the U.S. In an open-label trial with blinded assessment of clinical events, investigators in France and Belgium randomized 53 patients with clinical vascular Ehlers-Danlos syndrome (33 of whom had mutations of COL3A1) to celiprolol (uptitrated by 100 mg every 6 months to a maximum of 400 mg twice daily) or no beta-blocker treatment for 5 years. Most patients were normotensive

Cooling Cardiac-Arrest Patients: The Sooner, the Better?
Prehospital and intra-arrest cooling are safe and could improve outcomes.

Cooling patients resuscitated from cardiac arrest (therapeutic hypothermia) saves lives and is now routine in many hospitals. Two new studies explore the potential benefits of initiating cooling before the return of spontaneous circulation (intra-arrest) and in the field by paramedics. In a manufacturer-sponsored feasibility trial, investigators in five European countries randomized 194 patients with witnessed cardiac arrest to systemic cooling after hospital arrival with or without intraarrest cooling in the field via a portable

November 2010


transnasal cooling device. Transnasal cooling was initiated a median of 23 minutes after collapse and about 100 minutes before systemic cooling. Although the overall rate of survival to hospital discharge was higher in patients who received transnasal cooling than in those who did not (44% and 31%, respectively), the difference was not statistically significant. However, among patients in whom cardiopulmonary resuscitation (CPR) was initiated within 10 minutes after collapse, transnasal cooling was associated with improved survival (56% vs. 29%; P=0.04). In an Australian randomized study, ice-cold lactated Ringer’s solution was infused to induce hypothermia either by paramedics in the field (118 patients) or upon hospital arrival (116 patients). At hospital arrival, body temperatures were significantly lower in field-cooled patients than in patients who did not receive prehospital cooling, although the two groups achieved similar temperatures by 30 minutes after arrival. The rate of unfavorable outcome (death or discharge to a long-term nursing facility) did not differ significantly between field-cooled and hospital-cooled patients (52% and 47%, respectively). Adverse effects of prehospital cooling were minimal in both studies.

Predictors of Antiplatelet Therapy Discontinuation in Patients with DES
Only a quarter of discontinuations in this study were for severe bleeding or major medical procedures.

occasionally by the patient. Better communication with patients is needed on the importance of maintaining dual antiplatelet therapy after DES placement.
— Joel M. Gore, MD
Ferreira-González I et al. Background, incidence, and predictors of antiplatelet therapy discontinuation during the first year after drug-eluting stent implantation. Circulation 2010 Sep 7; 122:1017. Jarvie JL and Foody JM. Predictors of early discontinuation of dual-antiplatelet therapy: Room for improvement. Circulation 2010 Sep 7; 122:946.

Current guidelines recommend that patients receiving a drug-eluting stent (DES) remain on dual antiplatelet therapy for at least 1 year. To determine how often such therapy is discontinued early and why, researchers prospectively followed patients who received at least one DES at one of 29 participating hospitals in Spain between January and April 2008. Patients were contacted by phone at 3, 6, 9, and 12 months to determine whether any antiplatelet drugs had been discontinued. Reasons for discontinuation were determined during these interviews and through clinical record review. Of 1622 participants, 234 (14.4%) interrupted at least one antiplatelet drug. Fifty patients did so within the first 3 months, and these individuals were significantly more likely than all others to either die or be hospitalized for acute coronary syndrome within the first year of follow-up (12.0% vs. 4.9%). The circumstances surrounding discontinuation were determined for 218 patients: • 109 had bleeding or invasive procedures, although only 56 of these events were serious enough to require hospitalization. 70 discontinued the drug for medical reasons unrelated to a bleeding event. Independent predictors of these discontinuations were concomitant anticoagulation therapy and lack of written patient instructions. 39 initiated the drug discontinuation themselves. Independent predictors of these discontinuations were immigrant status and the use of psychotropic drugs.

PPIs and Cardiovascular Risk
In a population-wide cohort study, use of a PPI was an independent predictor of poor outcome after MI, regardless of clopidogrel use.

Clopidogrel is standard therapy in coronary stent recipients. Many stent recipients take proton-pump inhibitors (PPIs) as well; therefore, evidence that PPIs reduce the antiplatelet effects of clopidogrel has aroused great concern. These investigators examined registry data on 56,406 patients hospitalized with myocardial infarction (MI) in Denmark to assess the risks for adverse cardiovascular events associated with clopidogrel and PPIs used alone and concomitantly. The primary outcome was a composite of MI, stroke, and cardiovascular death. Of 24,704 patients who claimed a prescription for clopidogrel within 30 days of discharge, 6753 received PPIs during 1-year follow-up. The use of PPIs was similar in clopidogrel recipients and nonrecipients (who were older, more often female, and received more concomitant medical treatment than clopidogrel recipients). At 1 year, a primary endpoint had occurred in 9137 patients (16%). Event rates were lower in clopidogrel recipients than in nonrecipients and higher in PPI recipients than in nonrecipients; the event rates were highest in patients who received PPIs without clopidogrel. PPI therapy was associated with a significantly higher risk for a primary endpoint in both clopidogrel recipients and nonrecipients (hazard ratio, 1.29 in both groups). The risk estimates did not differ according to the type of PPI, independent of clopidogrel use.

Both of these small trials demonstrate the safety and feasibility of initiating therapeutic hypothermia after cardiac arrest by paramedics before hospital arrival. Although prehospital cooling did not clearly improve clinical outcomes in either study, both were underpowered and limited by the type and extent of cooling achieved. The magnitude of this problem and the suggestion of benefit in patients receiving cooling early after cardiac arrest or during CPR should drive further study of intra-arrest and prehospital cooling.
— Howard C. Herrmann, MD
Castrén M et al. Intra-arrest transnasal evaporative cooling: A randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness). Circulation 2010 Aug 17; 122:729. Bernard SA et al. for the Rapid Infusion of Cold Hartmanns (RICH) Investigators. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: A randomized controlled trial. Circulation 2010 Aug 17; 122:737. Becker LB. Cooling heads and hearts versus cooling our heels. Circulation 2010 Aug 17; 122:679.


The proportion of patients who discontinued antiplatelet therapy earlier than recommended was lower in this study (14%) than in many others. Notably, only a quarter of the discontinuations were for severe bleeding or major medical procedures. In the other instances, discontinuation was typically initiated by the provider but also

In this study, the use of PPIs was associated with an increased risk for adverse cardiovascular outcomes after hospitalization for MI, regardless of clopidogrel use. These

JOURNAL WATCH SUBSCRIBERS HAVE 10 FREE CREDITS! This is one of four questions in a recent Journal Watch Online CME exam. from “Treating Depression in Patients with Heart Failure” (p. 87) Which of the following statements accurately describes a finding from a trial of sertraline for treatment of depression in patients with heart failure? A. Depression scores improved significantly more in the sertraline group than in the placebo group. B. Significantly more patients in the sertraline group than in the placebo group had improved cardiovascular clinical status. C. More patients in the sertraline group than in the placebo group discontinued treatment because of adverse effects. D. At 2 years, the cardiovascular event rate was lower in the sertraline group than in the placebo group. Category: Cardiovascular Diseases Exam Title: Depression and Cardiovascular Disease Posted Date: Oct 19 2010 View this exam and others at User name and password are required. CME FACULTY Kelly Anne Spratt, DO, FACC, Section Editor, Cardiology

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findings, along with those of the COGENT study (see following summary), suggest that PPIs are associated with cardiovascular risk, but not through their interaction with clopidogrel. — Joel M. Gore, MD
Charlot M et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: A nationwide cohort study. Ann Intern Med 2010 Sep 21; 153:378.

trial evidence, the COGENT investigators randomized 3873 patients (mean age, 68; 68% men) requiring dual antiplatelet therapy to receive clopidogrel plus either omeprazole or placebo (both groups received aspirin). The primary cardiovascular endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, coronary revascularization, and stroke. The rate of gastrointestinal (GI) events at 180 days was lower in the omeprazole group than in the placebo group (1.1% vs. 2.9%; hazard ratio, 0.34; 95% confidence interval, 0.18–0.63; P<0.001). The rate of the primary cardiovascular endpoint was similar in the two groups (4.9% and 5.7%; HR, 0.99; 95% CI, 0.68–1.44; P=0.96). Adverse event rates were also similar between the two groups.

PPIs and Clopidogrel: COGENT Findings
In a randomized trial, concomitant omeprazole and dual antiplatelet therapy did not affect cardiovascular outcomes.

aspirin alone. Opinions about the use of PPIs and clopidogrel are likely to continue to diverge: Some readers will conclude that the previous platelet reactivity findings do not translate into variances in clinical outcomes; others will discount the current study as lacking power to detect clinically meaningful differences. With regard to reducing GI bleeding rates, these results support a small absolute benefit for PPI use in patients on dual antiplatelet therapy.
— Harlan M. Krumholz, MD, SM
Bhatt DL et al. for the COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010 Oct 6; [e-pub ahead of print]. ( full/10.1056/NEJMoa1007964)

Observational and platelet reactivity studies suggest that proton-pump inhibitors (PPIs) inhibit clopidogrel’s antiplatelet effects (JW Cardiol Oct 2009, p. 79, and Lancet 2009; 374:989). Should patients taking clopidogrel avoid PPIs; switch to another antiplatelet agent; or, in the absence of definitive trial findings, continue using the drugs together despite warnings from many directions? To address the lack of

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