From the publishers of

The New England Journal of Medicine

(66% vs. 58%) and 3 years (72% vs. 67%) but not at 5 years (74% vs. 72%).

May 2007

Vol. 13 No. 5

Does PCI Improve Survival and Prevent MI in Stable CAD?

Hochman JS and Steg PG. Does preventive PCI work? N Engl J Med 2007 Apr 12; 356:1572-4.

Comment:
In patients with stable CAD, the roughly 5-year incidence of death or MI was similar with a PCI strategy and one of optimal medical therapy alone, although PCI showed some advantage in relieving angina. As the editorialist notes, fewer than 10% of screened patients were eligible for this trial, and fewer than 75% of eligible patients were enrolled, raising questions about the generalizability of the results. On balance, the data highlight the benefits of optimal medical therapy in patients with stable CAD who do not have stress-test results that suggest high risk for events. The findings confirm the current guideline recommendation that PCI can be safely deferred in these patients. Howard C. Herrmann, MD
Boden WE et al. for the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007 Apr 12;356:1503-16.

ercutaneous coronary intervention (PCI) has survival and MI-prevention benefits in patients with acute coronary syndromes (ACS), and it reduces angina frequency and improves exercise tolerance in patients with stable coronary artery disease (CAD). Do the survival and MI-prevention benefits extend to stable CAD patients? In the COURAGE trial, 2287 patients (mean age, 62; 85% men; 33.5% with diabetes) were randomized to PCI plus optimal medical therapy or to optimal medical therapy alone. All patients had either 70% stenosis with objective evidence of ischemia or 80% stenosis with classic angina. Patients with a markedly positive stress test or a left ventricular ejection fraction (LVEF) <30% were excluded. Enrolled subjects had a mean LVEF of 61%. Of the PCI group, 94% received stents (97% were bare-metal), and 41% received more than one stent. Both groups had high rates of receiving optimal medical therapy and of adhering to healthful dietary regimens, regular exercise, and smoking cessation; they each achieved mean LDL-cholesterol levels of just above 70 mg/dL within 5 years. Median follow-up was 4.6 years (maximum, 7 years); about 9% of patients were lost to follow-up. The incidence of death or MI (the primary outcome) was similar in the two groups (PCI, 19.0%; medical therapy alone, 18.5%), as were the incidences of hospitalization for ACS (12.4% and 11.8%, respectively) and stroke (2.1% and 1.8%). The PCI group had a significantly lower revascularization rate during follow-up (21% vs. 33% with medical therapy alone), and they had a significant advantage in freedom from angina at 1 year

Torcetrapib Does Not Limit Atherosclerosis Progression

n December 2006, the manufacturer of torcetrapib, a cholesterol ester transfer protein (CETP) inhibitor aimed at raising HDL levels, halted the entire development program for this drug. The decision was made on the basis of data from ILLUMINATE, a randomized trial comparing torcetrapib/atorvastatin combination therapy with atorvastatin monotherapy. The data showed increased rates of cardiovascular events and mortality in the combinationtherapy group. We now have data from a separate, previously completed, manufacturerfunded trial of torcetrapib known as ILLUSTRATE, which focused on endpoints measured by intravascular ultrasound (IVUS). The trial, conducted in patients with coronary disease, started with a 4- to 10-week run-in phase of

TA B L E O F C O N T E N T S
CME: Does PCI Improve Survival and Prevent MI in Stable CAD? ........... 37 Torcetrapib Does Not Limit Atherosclerosis Progression................ 37 Torcetrapib Lacks Luster in RADIANCE ...................................... 38 Another Novel HDL-Raising Therapy, Another Negative Trial ........................ 39 METEOR: Does Rosuvastatin Benefit Low-Risk Patients?............................... 39 Fish Oil Supplement plus a Statin? .......... 39 Deaths from Heart Disease Among On-Duty Firefighters ........................... 40 Financial Barriers to Recovery 1 Year After MI .................................... 40 Sunshine Laws Shed Little Light.............. 40 Is Coronary Calcium Scanning Helpful in Patients Without Inducible Ischemia? ............................ 41 A Stepwise Approach to NSAID Use ....................................... 41 Large Trials of Tolvaptan in Acute Heart Failure ......................... 42 Elevated Glucose Levels and Risk for Incident Heart Failure ........................................ 42 Biphasic Defibrillation for Resistant VF: Dose Escalation Has an Edge ......................................... 42 Abnormal ECGs Predict CVD in Asymptomatic, Postmenopausal Women ................................................. 43 Mortality Benefit of GPIIb/IIIa Inhibitors During Primary PCI ........... 43 FDA Warns on Erythropoietin, Changes Dosing ................................... 43 Compression-Only CPR for Out-of-Hospital Cardiac Arrest...... 44

Journal Watch (and its design) is a registered trademark of the Massachusetts Medical Society.
An editorially independent literature-surveillance newsletter summarizing articles from major medical journals 2007 Massachusetts Medical Society. All rights reserved.

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JOURNAL WATCH CARDIOLOGY atorvastatin monotherapy. The 1188 subjects who came within 15 mg/dL of reaching the LDL target of 100 mg/dL were then randomized to receive daily atorvastatin monotherapy or atorvastatin plus 60-mg torcetrapib. After 2 years of treatment, there remained 910 patients (77%) who had both baseline and 2-year IVUS data. By 2 years, the combination-therapy group had experienced a significant increase in mean HDL (from 46 to 72 mg/dL) and a decrease in mean LDL (from 83 to 70 mg/dL); the monotherapy group had experienced a slight HDL decrease and a slight LDL increase. However, mean blood pressure rose significantly more with torcetrapib/ atorvastatin than with atorvastatin alone (by 6.5/2.8 vs. 2.0/0.8 mm Hg). The primary endpoint mean change in percent atheroma volume, an IVUS-measured surrogate marker of disease progression was similar in the two groups (+0.12% with combination therapy, +0.19% with monotherapy). One secondary IVUS measure significantly favored combination therapy (reduction in normalized atheroma volume, 9.5 mm3 vs. 6.3 mm3); however, the atheroma-volume change in the most diseased 10-mm subsegment was similar in the two groups.

Volume 13

Number 5

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
DEPUT Y EDITOR

Tall AR. CETP inhibitors to increase HDL cholesterol levels. N Engl J Med 2007 Mar 29; 356:1364-6.

Howard C. Herrmann, MD
Professor of Medicine, Director, Interventional Cardiology and Cardiac Catheterization Laboratories, University of Pennsylvania Medical Center, Philadelphia
EXECUTIVE EDITOR

Torcetrapib Lacks Luster in RADIANCE

orcetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has helped to raise HDL-cholesterol levels in clinical trials. However, it has raised blood pressure and has also failed on more important trial endpoints: Torcetrapib/ atorvastatin combination therapy was associated with worse cardiovascular and mortality outcomes than was atorvastatin monotherapy in the now-halted ILLUMINATE trial, and combination therapy showed no advantage in limiting coronary disease progression (assessed by intravascular ultrasound) in the ILLUSTRATE trial (see previous article, and New Engl J Med 2007; 356:1304). Now, we have results from the manufacturer-funded RADIANCE 1 trial of torcetrapib in patients with heterozygous familial hypercholesterolemia. It started with a run-in phase of atorvastatin monotherapy to achieve guideline-recommended LDL-cholesterol levels. Then, patients were randomized to receive, daily for 2 years, atorvastatin alone or atorvastatin plus 60-mg torcetrapib. Of 904 patients randomized, 850 had baseline and 2-year ultrasound data, used to assess carotid intimamedia thickness (CIMT) in 12 predefined segments. Combination therapy had significant advantages over monotherapy in lowering LDL levels and, especially, in raising HDL levels but a significant disadvantage in raising BP. Most important, CIMT in the 12 predefined segments worsened, although slightly, at an annual rate that was similar in the two groups.

Steven C. DeMaio
Massachusetts Medical Society
A S S O C I AT E E D I T O R S

JoAnne M. Foody, MD
Assistant Professor of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven

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

Associate Professor of Medicine, Division of Cardiology, Denver Health Medical Center and University of Colorado at Denver and Health Sciences Center

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

Comment:
Despite significantly raising HDL levels in patients with coronary disease, torcetrapib/atorvastatin combination therapy failed to limit IVUS-assessed disease progression and, consistent with previous data, raised blood pressure substantially. Given these negative findings and those from ILLUMINATE, the value of adding torcetrapib to aggressive LDL-lowering therapy clearly has not been demonstrated. We dont yet know whether the negative findings are due to BP effects, direct vascular effects, or effects on the functionality of HDL. Further studies will be required to truly illuminate these matters and, more broadly, the issue of whether raising HDL levels via CETP inhibition has an appropriate role in atherosclerosis treatment. JoAnne M. Foody, MD
Nissen SE et al. for the ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007 Mar 29; 356:1304-16.

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
M A S S AC H U S E T T S M E D I C A L S O C I E T Y

Christine Sadlowski, Elizabeth B. Schmidt, Kristin L. Odmark Staff Editors Ethel B. Garvin, Copy Editor Lisa Salvo, Sioux Waks, Layout

Comment:
Recent trials of torcetrapib collectively show that the drugs ability to raise HDL is outweighed by its raising of BP; its outcome disadvantages; and its failure to limit disease progression, whether represented by atheroma volume or CIMT. Unfortunately, we still understand little about the drugs mechanism of potential vascular toxicity. For now, torcetrapib will not see the clinical light of day. JoAnne M. Foody, MD
Kastelein JJP et al. for the RADIANCE 1 Investigators. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007 Apr 19; 356:1620-30.

Christopher R. Lynch,
Vice President for Publishing Alberta L. Fitzpatrick, Publisher Art Wilschek, Christine Miller, Lew Wetzel, Wayne Wickman, Advertising Sales William Paige, Robin Buttner, Publishing Services Bette Clancy, Customer Service
Published 12 times a year. Subscription rates U.S.: $109 per year; Residents/Students/ Nurses/PAs: $65; Institutions: $179; individual print only: $89. Canada: C$162.26 per year; Residents/ Students/Nurses/PAs: C$95.28; Institutions: C$250. Intl: US$139 per year; Physicians in Training/Nurses/PAs: US$75; Institutions: US$216. Prices do not include GST, HST, or VAT. Remittance 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 www.jwatch.org. Information on our conflict-of-interest policy can be found at www.jwatch.org/ misc/conflict.dtl.

May 2007

JOURNAL WATCH CARDIOLOGY

Nissen SE et al. Effects of a potent and selective PPAR- agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: Two randomized controlled trials. JAMA 2007 Mar 28; 297:1362-73.

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Another Novel HDL-Raising Therapy, Another Negative Trial

novel, potent, selective peroxisome proliferator-activated receptor- (PPAR- ) agonist, LY518674, has been touted for its potential to improve lipid profiles. To study its safety and efficacy, researchers conducted two manufacturerfunded, multicenter, randomized, controlled trials. One trial focused on raising HDL-cholesterol levels. A total of 309 patients with atherogenic dyslipidemia followed guideline-recommended lifestyle changes for a 4-week placebo run-in period. Then they were randomized to receive daily LY518674 (10, 25, 50, or 100 g), the weaker PPAR- agonist fenofibrate (200 mg), or placebo for 12 weeks. Clinically indicated statin use was permitted, but statin dose adjustments were not. For both raising HDL levels and lowering triglyceride levels, LY518674 and fenofibrate each outperformed placebo, with no significant differences between the two PPAR- agonists. LY518674 also raised LDL levels in a dose-dependent fashion and much more than fenofibrate did. The other trial focused on lowering LDL-cholesterol levels. A total of 304 statin-naive patients (baseline LDL levels, 100160 mg/dL) had a 4- to 6-week washout and then were randomized to receive daily atorvastatin (10 or 40 mg) or placebo for 4 weeks. Patients in both groups were then randomized to receive adjunctive daily LY518674 (10 or 50 g) or placebo for 12 weeks. LY518674 and atorvastatin each significantly reduced triglyceride and LDL levels, and increased HDL levels. In atorvastatin recipients, the addition of LY518674 further increased HDL levels (by 1% to 12%) and further reduced triglyceride levels, but it changed LDL levels little. In both trials, LY518674 showed evidence of increasing serum creatinine levels, sometimes substantially. Fenofibrate also increased creatinine levels in the first trial.

METEOR: Does Rosuvastatin Benefit Low-Risk Patients?

o patients at low risk for cardiovascular disease (CVD) benefit from LDL lowering with rosuvastatin? To find out, researchers conducted a manufacturer-sponsored, double-blind trial, known as METEOR, in which low-risk patients (mean age, 57) were randomized to receive rosuvastatin (40 mg/day; 702 patients) or placebo (282 patients) for 2 years. Carotid intimamedia thickness (CIMT) was assessed, using ultrasound, before randomization and every 6 months for 2 years. At baseline, all participants had 10-year Framingham risk scores <10% and mild to moderate CIMT (1.2 mm to <3.5 mm). LDL levels were <190 mg/dL in participants whose only CVD risk factor was older age and <160 mg/dL in those with multiple risk factors. The cohorts overall mean LDL level was about 155 mg/dL. During the 2-year study, LDL levels declined significantly more in the rosuvastatin group than in the placebo group (by 49% vs. 0.3%). The rate of change in maximum CIMT for 12 carotid sites (the primary endpoint) was significantly slower with rosuvastatin than with placebo (0.0014 mm/year [regression] vs. +0.0131 mm/year [progression]). Treatment produced no significant regression of atherosclerosis burden. The frequency of side effects was similar between groups.

now, physicians should continue to consult current lipid-lowering guidelines (NIH publication No. 01-3670; May 2001) for lower-risk patients, recalling that the AFCAPS/TexCAPS Study (which involved a similar group of patients) documented improved CVD outcomes with lovastatin ( JWC Aug 1998, p. 72, and JAMA 1998; 279; 1615). JoAnne M. Foody, MD
Crouse JR III et al. for the METEOR Study Group. Effect of rosuvastatin on progression of carotid intimamedia thickness in low-risk individuals with subclinical atherosclerosis: The METEOR trial. JAMA 2007 Mar 28; 297:1344-53. Lauer MS. Primary prevention of atherosclerotic cardiovascular disease: The high public burden of low individual risk. JAMA 2007 Mar 28; 297:1376-8.

Fish Oil Supplement plus a Statin?

Comment:
In this study, rosuvastatin treatment slowed progression of carotid intimamedia thickness but did not induce significant regression. Although these findings are of interest, larger, longer-term trials are needed to determine whether rosuvastatin reduces the risk for actual cardiovascular events. For

pidemiologic studies and clinical trials have demonstrated that intake of long-chain omega-3 polyunsaturated fatty acids (PUFAs) is inversely associated with coronary heart disease. Now, researchers in Japan have conducted a prospective, open-label trial, involving 18,645 hypercholesterolemic patients, to examine the incremental effectiveness of adding a supplement containing eicosapentaenoic acid (EPA) a PUFA found in fatty fish to statin therapy. The supplement manufacturer funded the study. Mean followup was 4.6 years. Patients, stratified by need for primary or secondary prevention, were randomized to receive either 1800 mg/day of EPA plus a statin (pravastatin 10 mg/day or simvastatin 5 mg/day) or the statin alone. Mean baseline levels of total cholesterol (275 mg/dL [7.1 mmol/L] and LDL cholesterol (180 mg/dL [4.7 mmol/L]) decreased by about 19% and 25%, respectively, in both the EPA/statin and statin-alone groups by studys end. Mean triglyceride levels decreased by 10% with combined therapy and 5% with a statin alone.

Comment:
This novel PPAR- agonist was no better than fenofibrate and statin monotherapy in achieving intended lipid improvements, and it appeared to worsen renal function. Specifically with regard to raising HDL levels, niacin remains our only effective evidence-based therapy. JoAnne M. Foody, MD

w w w.jwat ch .or g

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JOURNAL WATCH CARDIOLOGY portionately large percentage of on-duty CHD deaths relative to the time spent performing those duties.

Volume 13

Number 5

Incidence of the blindly adjudicated primary endpoint of major adverse coronary events (MACE) was significantly lower with combination therapy than with a statin alone (2.8% vs. 3.5%), an effect largely driven by a reduction in unstable angina (1.6% vs. 2.1%). EPA showed no incremental advantage in preventing either sudden death or coronary death. Combination therapys advantage over statin-only therapy was significant for secondary prevention of MACE (8.7% vs. 10.7%; P =0.048) but not for primary prevention (1.4% vs. 1.7%; P =0.13).

Comment:
These data show that firefighters risk for death from CHD is markedly elevated during emergency duties. The editorialists emphasize the importance of risk-factor modification and fitness programs for firefighters, as prevention of underlying CHD is the best way to prevent sudden cardiac death. Harlan M. Krumholz, MD, SM
Kales SN et al. Emergency duties and deaths from heart disease among firefighters in the United States. N Engl J Med 2007 Mar 22; 356:1207-15. Rosenstock L and Olsen J. Firefighting and death from cardiovascular causes. N Engl J Med 2007 Mar 22; 356:1261-3.

scores, and had significantly higher rehospitalization rates (57% vs. 38%) than their counterparts without such barriers. All differences held after adjustment for potential confounders.

Comment:
In this prospective, longitudinal study, financial barriers to use of healthcare services and especially to medication use were associated with disadvantages in angina, health status, quality of life, and rehospitalization 1 year after hospitalization for acute MI. Mortality numbers were too small to permit meaningful assessment. More than two thirds of the patients who reported financial barriers had health insurance, suggesting that under insurance likely plays a role. We need more studies in larger populations, both to document the problems magnitude and to identify potential solutions. The present study is an important step toward those goals. JoAnne M. Foody, MD
Rahimi AR et al. Financial barriers to health care and outcomes after acute myocardial infarction. JAMA 2007 Mar 14; 297:1063-72. Fontanarosa PB et al. Access to care as a component of health system reform. JAMA 2007 Mar 14; 297:1128-30.

Comment:
Its unclear whether these results of high-dose EPA supplementation in a population with extremely high fish consumption are applicable to populations with lower fish consumption or to people with lower LDL levels. The population characteristics might account for the lack of reduction in cardiac-mortality endpoints in this large, long-term trial. For now, clinicians should be guided by the AHA statement about fish consumption and fish oil (Circulation 2004; 110:637). It supports initially increasing dietary intake of omega-3 fatty acids and then, if required, using a highquality, contaminant-free supplement. JoAnne M. Foody, MD
Yokoyama M et al. for the JELIS Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients ( JELIS): A randomised open-label, blinded endpoint analysis. Lancet 2007 Mar 31; 369:1090-8. Mozaffarian D. JELIS, fish oil, and cardiac events. Lancet 2007 Mar 31; 369:1062-3.

Financial Barriers to Recovery 1 Year After MI

e have few prospective, longitudinal studies on how financial obstacles to healthcare relate to clinical outcomes. To enhance the evidence base, researchers prospectively studied 2498 adults hospitalized with acute MI from January 2003 through June 2004. All were enrolled in PREMIER, a 19-center U.S. MI registry. During their hospital stays, patients were asked whether, in the past year, they had avoided obtaining healthcare services because of cost and how often during that period they had not taken prescribed medications because of cost. Of the cohort, 18% reported financial barriers to use of healthcare services, and 13% reported financial barriers to medication use. Patients with financial barriers to use of healthcare services were, at 1-year follow-up, significantly more likely to report angina (30% vs. 18%), had significantly lower health-status and quality-of-life scores, and had significantly higher rehospitalization rates (49% vs. 38%) than their counterparts without such barriers. All but the angina difference held after adjustment for potentially confounding demographic, clinical, and inpatient care (e.g., coronary angiography and revascularization) variables. Patients with financial barriers to medication use were significantly more likely to report angina at 1-year followup (35% vs. 18%), had significantly lower health-status and quality-of-life

Sunshine Laws Shed Little Light

everal U.S. states and the District of Columbia have mandated disclosure of payments to physicians by pharmaceutical companies. This studys investigators performed a cross-sectional analysis of publicly available disclosure data in Vermont and Minnesota. They assessed not only the number, dollar value, and types of payments to healthcare providers (including physicians, organizations, and nonphysicians), but also the accessibility and quality of the data collected. Obtaining access to data was very difficult in both states. In Vermont, records for 61% of payments made from mid-2002 to mid-2004 were not publicly available because they were designated as trade secrets, and 75% of publicly disclosed payment records lacked information necessary to identify recipients. In Minnesota, only 25% of companies disclosed payments during 2002, 2003, and 2004. In Vermont, publicly disclosed payments of $100 or more totaled $1.76 million over 2 years, with a median physician payment of $177 (range, $100 $20,000). In Minnesota, publicly dis-

Deaths from Heart Disease Among On-Duty Firefighters

bout 45% of deaths among on-duty firefighters are caused by heart disease. To explore why heart disease is the leading cause of death in this context, researchers analyzed narrative summaries, collected by the U.S. Fire Administration, of deaths associated with firefighting from 1994 through 2004. Deaths associated with the terrorist attacks of September 11, 2001, were excluded. Of 1144 firefighter deaths, 449 (39%) were attributed to coronary heart disease; 144 of the 449 (32%) occurred during fire suppression even though that activity accounted for only an estimated 1% to 5% of firefighters on-duty time. Other emergency duties (e.g., alarm response and return) also accounted for a dispro-

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JOURNAL WATCH CARDIOLOGY

Page 41

closed payments of $100 or more totaled $30.96 million over 3 years, with a median physician payment of $1000 (range, $100$922,239).

SCI E NTI FI C S TATE M E NT

A Stepwise Approach to NSAID Use

Sponsoring Organization: American Heart Association Background: Evidence that selective COX-2 inhibitors, a type of nonsteroidal anti-inflammatory drug (NSAID), increase the risk for serious cardiovascular events has led to a cascade of drug warnings, safety advisories, and even withdrawals from the market. The lingering issue for practitioners has been to pinpoint the appropriate clinical roles for specific NSAIDs and other pain relievers. Now, the AHA has issued a scientific statement on NSAID use for patients with, or at high risk for, heart disease. The statement places management of musculoskeletal pain in a broader context, synthesizes recent evidence on pharmacologic treatment options, and proposes a stepwise approach to treatment. Key Contextual Points 1. The risks and benefits of any pain-management approach must be understood in light of current evidence, applied appropriately to the individual patient with musculoskeletal pain. 2. Musculoskeletal symptoms should be considered those from tendonitis/ bursitis, degenerative joint problems (e.g., osteoarthritis), or inflammatory joint problems (e.g., rheumatoid arthritis). 3. Initial treatment should focus on nonpharmacologic approaches such as physical therapy, heat or cold therapy, and orthotics. Stepwise Approach to Drug Therapy, If Needed Pre-NSAID Step 1 (short-term use): Use acetaminophen, aspirin, tramadol, or a narcotic analgesic at the lowest safe and efficacious dose. Bear in mind the potential for abuse of narcotics by some patients. Also, for low-dose aspirin users with histories of or risk for gastrointestinal bleeding, a concomitant proton-pump inhibitor may reduce that risk. Step 2: Use a nonacetylated salicylate such as salsalate, sodium salicylate, or choline magnesium trisalicylate. NSAID Step 3: Use a nonCOX-2 selective NSAID such as naproxen, ibuprofen, or indomethacin. Naproxen is the widely preferred choice from a cardiovascular standpoint. Step 4: Use an NSAID with some COX-2 activity such as diclofenac. (Diclofenac, along with other NSAIDs, carries a black box warning against use for perioperative pain in coronary artery bypass graft [CABG] surgery.) Step 5 (the last resort): Use a COX-2selective NSAID. The only one currently on the market is celecoxib (Celebrex), which carries a broad black box warning about risks for very serious cardiovascular events.

Comment:
The authors conclude that a large number of physicians accept payments of more than $100 from pharmaceutical companies. Unfortunately, current mandates for disclosure fail to ensure sufficient access to, or quality of, information about such payments. These failures compromise the goal of achieving transparency in the relationship between physicians and the pharmaceutical industry. JoAnne M. Foody, MD
Ross JS et al. Pharmaceutical company payments to physicians: Early experiences with disclosure laws in Vermont and Minnesota. JAMA 2007 Mar 21; 297:1216-23. Brennan TA and Mello MM. Sunshine laws and the pharmaceutical industry. JAMA 2007 Mar 21; 297:1255-7.

Is Coronary Calcium Scanning Helpful in Patients Without Inducible Ischemia?

se of coronary artery calcium (CAC) scanning is increasing. Does this risk-stratification tool actually add prognostic value to exercise myocardial perfusion scintigraphy (MPS) in identifying patients at risk for new, angiographically significant coronary artery disease? To find out, researchers compared 1153 patients who underwent CAC scanning (either electron-beam or multislice CT) plus MPS testing with a referent cohort of 9308 patients who had undergone only MPS testing. Mean follow-up was slightly less than 3 years. In the CAC+MPS group, the higher the baseline CAC score, the more likely a patient was to have inducible ischemia on MPS testing. However, only 64 patients in this group (5.6%) had inducible ischemia too few to enable adequate assessment of CAC scannings prognostic value in patients with inducible ischemia. Compared to patients with inducible ischemia in the CAC+MPS group, those without inducible ischemia (i.e., with nonischemic results) in that group had a significantly higher rate of survival free of cardiac events. When patients with nonischemic results in the CAC+MPS group were matched, by demographic and clinical variables, to patients with nonischemic results in the MPS-alone

Comment:
The authors are clear in saying that COX-2 inhibitor use has been associated with increased risks for MI, stroke, hypertension, and heart failure. They warn that even a relative lack of COX-2 selectivity does not completely eliminate the risk of cardiovascular events ... all drugs in the NSAID spectrum should only be prescribed after thorough consideration of the risk/benefit balance. Patients with recent CABG, unstable angina, MI, or ischemic stroke need to be especially cautious. COX-inhibitor use can lead to impaired renal perfusion, sodium retention, and increased blood pressure, thereby increasing the risk for adverse cardiovascular events. New evidence on the cardiovascular effects of drug therapy for musculoskeletal pain will continue to emerge (e.g., from the forthcoming PRECISION trial comparing celecoxib, ibuprofen, and naproxen; available at www.clinicaltrials.gov). Clinicians should stay abreast of these developments. For now, the AHAs stepwise approach is a practical one to follow. Joel M. Gore, MD
Antman EM et al. Use of nonsteroidal antiinflammatory drugs: An update for clinicians. A scientific statement from the American Heart Association. Circulation 2007 Mar 27; 115:1634-42.

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JOURNAL WATCH CARDIOLOGY placebo in decreasing total mortality. No significant difference between the groups was found, either in the composite of cardiovascular mortality or HF hospitalization, or in overall health status. Thirst and dry mouth were significantly more common with tolvaptan than with placebo.

Volume 13

Number 5

group, a high CAC score (even a score >1000) did not significantly enhance the prediction of cardiac events.

Comment:
Among patients with nonischemic results on exercise myocardial perfusion scintigraphy, coronary artery calcium scanning did not add significant prognostic value to the stress-test results themselves. CAC scanning results did correlate with MPS results, but the CAC testing essentially proved to be redundant. Harlan M. Krumholz, MD, SM
Rozanski A et al. Clinical outcomes after both coronary calcium scanning and exercise myocardial perfusion scintigraphy. J Am Coll Cardiol 2007 Mar 27; 49:1352-61.

Comment:
Building upon findings from the ACTIV in CHF trial ( JWC Jul 2004, p. 53, and JAMA 2004; 291:1963), the much larger EVEREST trials show that tolvaptan is safe in hospitalized ADHF patients who have reduced LVEFs. In these patients, treatment lowered body weight and corrected hyponatremia better than placebo, but it did not improve survival or overall patient well-being. As the editorialist notes, additional research, including studies in other populations, is needed to clarify the role of arginine vasopressin antagonists in HF. In the present trials, the long-term benefits were confined to surrogate outcomes, and the short-term symptom improvements were modest; therefore, the clinical value of tolvaptan, even in patients similar to those enrolled in EVEREST, remains unclear. Frederick A. Masoudi, MD, MSPH
Gheorghiade M et al. for the EVEREST Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials. JAMA 2007 Mar 28; 297:1332-43. Konstam MA et al. for the EVEREST Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA 2007 Mar 28; 297:1319-31. Yancy CW. Climbing the mountain of acute decompensated heart failure: The EVEREST trials. JAMA 2007 Mar 28; 297:1374-6.

Large Trials of Tolvaptan in Acute Heart Failure

he evidence base is much smaller for treatment of acute decompensated heart failure (ADHF) than for treatment of chronic heart failure. Now, researchers have conducted three randomized, controlled, manufacturersponsored studies of tolvaptan, a selective vasopressin V2-receptor antagonist: two identical trials of its efficacy and safety in short-term management of ADHF, and a larger combined trial of its long-term effects on clinical outcomes. Collectively, the trials involved 4133 adults (LV ejection fractions 40%) who were hospitalized for worsening congestive heart failure. Participants were randomized to receive tolvaptan (30 mg daily) or placebo for at least 60 days. Both groups also received standard HF therapy. In the short term (by hospital discharge or by day 7, if earlier), improvement in an endpoint comprising global clinical status and body weight was significantly greater with tolvaptan than with placebo. The difference was driven entirely by greater mean weight loss with tolvaptan (a <1-kg difference with placebo in both trials). However, patientreported dyspnea and physician-assessed dyspnea, fatigue, rales, and edema also improved significantly, although modestly. Serum sodium levels increased by a mean 2.01 mEq/L with tolvaptan and decreased by a mean 1.06 mEq/L with placebo a significant difference. Mean serum creatinine increased modestly more with tolvaptan (by 0.08 mg/dL vs. 0.02 mg/dL with placebo). In the long term, tolvaptan was found to be neither superior nor inferior to

(ONTARGET and TRANSCEND). All subjects had histories of symptomatic CVD or of diabetes with end-organ damage. Patients were placed in five categories: low-normal fasting plasma glucose (FPG) level (<5.0 mmol/L); high-normal FPG (5.0 mmol/L to <5.6 mmol/L); impaired FPG (5.6 mmol/L to <7.0 mmol/L); new diabetes (FPG 7.0 mmol/L); or previously diagnosed diabetes. Compared with the low-normal FPG group, the two groups of diabetes patients had significantly increased risks for HF hospitalization (hazard ratios: new diabetes group, 1.74; previously diagnosed diabetes group, 2.59). In addition, each 1-mmol increment in FPG was associated, in the cohort as a whole, with significantly higher risks for HF hospitalization (HR, 1.05; 95% CI, 1.021.08) and the composite of HF hospitalization or CVD-related death (HR, 1.09; 95% CI, 1.071.10). This incremental risk was consistent between patients with and without diabetes.

Comment:
This study of high-risk patients (both diabetics and nondiabetics) documents an important association between plasma glucose elevation and the development of clinical HF. The mechanisms underlying this association, however, remain elusive: Hyperglycemia could plausibly have caused HF or have resulted from subclinical HF. As the editorialists point out, until better mechanistic data are available, it would be premature to conduct a trial testing whether lowering blood glucose levels reduces the risk for new HF. Frederick A. Masoudi, MD, MSPH
Held C et al. for the ONTARGET/TRANSCEND Investigators. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation 2007 Mar 20; 115:1371-5. Petrie MC and McMurray JJV. Dysglycemia and heart failure hospitalization: What is the link? Circulation 2007 Mar 20; 115:1334-5.

Elevated Glucose Levels and Risk for Incident Heart Failure

eople with diabetes are at increased risk for new heart failure (HF), especially when glucose levels are poorly controlled. Are elevated glucose levels associated with incident HF in a broader group of patients at high risk for cardiovascular disease (CVD)? To find out, researchers analyzed data from more than 30,000 patients (age 55) without known HF who were enrolled in two manufacturer-funded, randomized, controlled trials of the angiotensin-receptor blocker telmisartan

Biphasic Defibrillation for Resistant VF: Dose Escalation Has an Edge

ost commercially available biphasic automated external defibrillators (AEDs) have initial shock energies of 150 to 200 J. However, it is unclear whether escalation of energy levels confers any additional benefit in cases of resistant ventricular fibrillation (VF). In a Canadi-

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an prospective treatment trial funded by an AED manufacturer, individuals who had out-of-hospital cardiac arrest were randomized to receive fixed-energy (150150150 J) or escalating-energy (200300360 J) biphasic defibrillation. The researchers analyzed data from 221 patients (114 in the fixed-energy group and 107 in the escalating-energy group). In about half of both groups, VF was terminated or successfully converted on the first shock. Among the 106 patients who required subsequent shocks, successful conversion to organized rhythm was achieved with 36.6% of escalating-energy shocks and 24.7% of fixed-energy shocks (P =0.035). There were no differences in clinical or adverse outcomes between the groups.

FDA Warns on Erythropoietin, Changes Dosing

E rythropoiesis-stimulating agents (ESAs) should be given in the lowest possible dose required to gradually increase hemoglobin to the lowest level sufficient to avoid the need for blood transfusions, according to an FDA alert (available at www.fda.gov/cder). The FDA said the ESAs darbepoetin (Aranesp) and epoetin (Epogen and Procrit) will carry updated warnings and new dosing instructions. Several recent studies suggest the agents can increase the risk for cardiovascular and thromboembolic events, as well as shorten the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy accordiing to an FDA alert (available at www.fda.gov/cder). The FDA recommends measuring hemoglobin twice a week for 2 to 6 weeks after any dosage adjustment and withholding the dose if hemoglobin levels exceed 12 g/dL or rise by 1 g/dL in any 2-week period. The agency said it believes these new concerns apply to all ESAs and is reevaluating how to safely use this product class.
Originally published in Physician's First Watch

Comment:
In this randomized trial comparing fixed- with escalating-shock energies (one of the few of these trials to date), escalating energies had a higher percentage of conversion than fixed energies in patients requiring multiple shocks. However, first-shock success was similar in the two groups, and their clinical outcomes did not differ (although the study was underpowered for such an analysis). The study is also limited by comparing different dose strategies for only one biphasic waveform, rather than different biphasic waveforms used by manufacturers of other AEDs. On the basis of current efficacy data, no commercially available AED appears to be better than another. Mark S. Link, MD
Stiell IG et al. BIPHASIC Trial: A randomized comparison of fixed lower versus escalating higher energy levels for defibrillation in out-of-hospital cardiac arrest. Circulation 2007 Mar 27; 115:1511-7.

abnormalities (e.g., atrial fibrillation, bundle-branch block). During a mean follow-up of 5.6 years, annual CHD event rates per 10,000 women were 21 among those with normal baseline ECGs, 40 among those with minor ECG abnormalities, and 75 among those with major ECG abnormalities. Corresponding figures for incident CVD events were 55, 91, and 168, respectively. In analyses adjusted for traditional risk factors in which women with normal baseline ECGs were the reference group, women with minor ECG abnormalities had significantly increased risks for CHD events (hazard ratio, 1.55) and CVD events (HR, 1.39), as did women with major ECG abnormalities (HRs, 3.01 and 2.34, respectively). Hormone therapy assignment (for the WHI study) did not affect the findings. Adding baseline ECG abnormality status to traditional risk-prediction models significantly improved their predictive value.

Mortality Benefit of GPIIb/IIIa Inhibitors During Primary PCI

Abnormal ECGs Predict CVD in Asymptomatic, Postmenopausal Women

Comment:
Independent of traditional risk factors, baseline ECG abnormalities (both minor and major) predicted incident CHD and CVD events in asymptomatic, postmenopausal participants in the WHI primary-prevention trial of hormone therapy. The data do not clarify whether ECG abnormalities reflected subclinical disease or were associated with traditional risk markers such as high cholesterol and hypertension. Mark S. Link, MD
Denes P et al. Major and minor ECG abnormalities in asymptomatic women and risk of cardiovascular events and mortality. JAMA 2007 Mar 7; 297:978-85.

en who present with electrocardiographic abnormalities are at increased risk for incident coronary heart disease (CHD) and cardiovascular disease (CVD) events. To find out whether this association applies to women, researchers analyzed data from 14,749 asymptomatic, postmenopausal Womens Health Initiative (WHI) participants (age 5079): 66% had normal baseline ECGs, 28% had minor ECG abnormalities (e.g., nonspecific ST-segment changes), and 6% had major ECG

andomized trials have shown that acute-MI patients benefit from use of a glycoprotein IIb/IIIa inhibitor during primary percutaneous coronary intervention (PCI). However, these trials have been small and underpowered to prove a survival benefit, and most have excluded high-risk patients. Now, researchers have analyzed data from all 7321 patients who underwent primary PCI within 12 hours of MI symptom onset in New York State from 2000 through 2002; 78.5% received GPIIb/IIIa inhibitors. GPIIb/IIIa-inhibitor use was associated with younger age, male sex, greater body-mass index, earlier presentation, and less comorbidity. Recipients of GPIIb/IIIa inhibitors had a significantly lower in-hospital mortality rate than nonrecipients (3.0% vs. 6.2%), without a significant disadvantage in stroke or vascular damage. The significant mortality advantage of GPIIb/IIIa inhibition persisted after adjustment for patients characteristics and their likelihood, according to a propensity analysis, of receiving a GPIIb/IIIa inhibitor (adjusted odds ratio for mortality, 0.63). It also persisted in both low-risk patients (1.4% vs. 3.2%) and high-risk patients (16.2% vs. 22.4%), according to Mayo Clinic Risk Score stratification. The overall mortality advantage was similar for abciximab and small-molecule GPIIb/IIIa inhibitors, according to data from 2002.

Journal Watch Online CME Program Subscribers have 10 FREE exam credits
Can you answer the following question about the summary Does PCI Improve Survival and Prevent MI in Stable CAD? (on page 37)?

No part of this newsletter may be reproduced or otherwise incorporated into any information retrieval system without the written permission of the Massachusetts Medical Society. Printed in the USA. ISSN 1521-5822.

In the COURAGE randomized trial, 2287 patients with stable coronary artery disease (CAD) received percutaneous coronary intervention (PCI) plus optimal medical therapy or optimal medical therapy alone. Which of the following was true? A. Most patients in the PCI group received drugeluting stents. B. Both groups achieved mean LDL-cholesterol levels of just above 70 mg/dL. C. The PCI group had a significant advantage in myocardial infarction (MI)-free survival over the group randomized to medical therapy alone. D. At 1 year, the two groups had a similar rate of freedom from angina. * Category: Cardiovascular Diseases Exam Title: Treatment of Stable Coronary Artery Disease Posted Date: April 10, 2007
CME Faculty: Kelly Anne Spratt, DO This is one of four questions in a recent Journal Watch Online CME exam.* Click on the CME link from the Journal Watch summary online at http://www.jwatch.org or go to http://cme.jwatch.org and view the exam listings. User name and password are required.

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JOURNAL WATCH CARDIOLOGY ventilation. In a prospective, multicenter, nonrandomized study from Japan, researchers examined 30-day neurologic outcomes among 4068 adults who experienced out-of-hospital cardiac arrests witnessed by bystanders: 71.7% received no bystander CPR, 17.5% received conventional CPR, and 10.8% received only chest compressions. A favorable neurologic outcome at 30 days was significantly more common among patients who received any CPR than among those who received none (5% vs. 2%), with no difference by CPR type in the overall cohort. However, compression-only CPR outperformed conventional CPR in patients with apnea (6% vs. 3%), those with shockable rhythm (19% vs. 11%), and those for whom CPR was attempted within 4 minutes of the arrest (10% vs. 5%). The addition of mouth-to-mouth ventilation did not benefit any subgroup significantly.

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Number 5

Comment:
In this large, observational analysis of primary PCI patients, GPIIb/IIIainhibitor use was associated with about a 50% overall reduction in in-hospital mortality, without increases in stroke or vascular injury. Though not randomized, this study is the largest to date to document a benefit of GPIIb/IIIa inhibition in both low- and high-risk patients and with both abciximab and small-molecule inhibitors. Howard C. Herrmann, MD
Srinivas VS et al. Effectiveness of glycoprotein IIb/IIIa inhibitor use during primary coronary angioplasty: Results of propensity analysis using the New York State Percutaneous Coronary Intervention Reporting System. Am J Cardiol 2007 Feb 15; 99:482-5.

study is also limited by its observational design. Nevertheless, the data bolster the case for compression-only CPR for witnessed, out-of-hospital cardiac arrest in adults. An editorialist argues that these and previous findings should convince CPR guideline authors to recommend compression alone for nonrespiratory arrests. For now, the guidelines emphasize that the most important aspect of CPR is delivering long series of uninterrupted chest compressions to produce blood flow, and these data certainly reinforce that point. Mark S. Link, MD
SOS-KANTO study group. Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): An observational study. Lancet 2007 Mar 17; 369:920-6. Ewy GA. Cardiac arrest Guideline changes urgently needed. Lancet 2007 Mar 17; 369: 882-4.

Compression-Only CPR for Out-of-Hospital Cardiac Arrest

Comment:
This study was conducted when a compression:ventilation ratio of 15:2 was standard; guidelines now recommend a 30:2 ratio ( JWC Mar 2006, p. 25, and Circulation 2005; 112:Suppl:IV). The

or bystander-witnessed cardiac arrests, some experts debate the value of the mouth-to-mouth ventilation component of conventional CPR, and many witnesses are reluctant to perform the

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