January 2010 Vol. 16 No.

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From the publishers of The New England Journal of Medicine

CA RDI OLOGY
ARBITER 6-HALTS: A Surprise Knockout
Niacin’s clear win over ezetimibe as an adjunct to statin therapy challenges assumptions about lipid management.

ezetimibe group and by 10 mg/dL in the niacin group. The mean HDL level decreased by 3 mg/dL in the ezetimibe group and increased by 8 mg/dL in the niacin group. Niacin, but not ezetimibe, was associated with a significant reduction in CIMT. In the ezetimibe group, paradoxically, greater decreases in LDL levels were associated with greater increases in CIMT. The rate of major cardiovascular events was higher in the ezetimibe group than in the niacin group (5% vs. 1%; P=0.04).
COMMENT

important outcomes of large trials of ezetimibe will not be available for many years. In the meantime, ezetimibe should be a drug of last resort, if it is used at all.
— Harlan M. Krumholz, MD, SM
Taylor AJ et al. Extended-release niacin or ezetimibe and carotid intima–media thickness. N Engl J Med 2009 Nov 26; 361:2113.

To compare the effects of niacin versus ezetimibe when added to statin treatment, investigators conducted a randomized, open-label trial with blinded adjudication of endpoints. All patients were already taking a statin and had LDL levels <100 mg/dL, HDL levels <55 mg/dL, and coronary heart disease or a risk equivalent (e.g., diabetes or a 10-year Framingham risk score of ≥20%). The primary endpoint was change in carotid intima–media thickness (CIMT) after 14 months. The industry-funded, investigatorinitiated trial was terminated early on the basis of results of prespecified interim analysis. A total of 208 participants (mean age, 65; 80% men) had 14-month endpoint data. At baseline, mean levels of LDL and HDL were 82 mg/dL and 42 mg/dL, respectively. At 14 months, the mean LDL level had decreased by 18 mg/dL in the

ARBs in Heart Failure: What Difference Does a Dose Make?
High-dose losartan yielded small but significant improvements in clinical outcomes, compared with a lower dose.

In this small trial, niacin was superior to ezetimibe in high-risk patients on statin monotherapy. These findings do not deliver a final verdict on ezetimibe. (Nor do they prove that the niacin-statin combination confers clinical benefit beyond statin monotherapy in this patient population.) However, they add to concerns about a medication that continues to be quite popular, despite a lack of evidence that its ability to reduce LDL levels translates into patient benefits. Unfortunately, patient-

CONTENTS
SUMMARY & COMMENT

ARBITER 6-HALTS: A Surprise Knockout

In-Hospital Mortality After MI: Vive la Différence? ..................................................... 4 Self-Management for Hypertension ......................... 5 Lipids, Apolipoproteins, and Vascular Disease: What to Measure? ..................................................... 5 Folic Acid and Cancer................................................... 6 Revascularization Is Ineffective for Atherosclerotic Renal Artery Stenosis ............ 6 Two Clopidogrel Loading Doses Compared in Patients with STEMI .............................................. 6 Cangrelor Is Not the New Champion......................... 7
CLINICAL PRACTICE GUIDELINE WATCH

A growing body of data suggests that angiotensin-receptor blocker doses higher than those currently given could achieve clinical benefits in patients with heart failure. In the international, double-blind, manufacturer-sponsored and manufacturer-administered HEAAL study, 3846 patients with NYHA class II–IV heart failure symptoms, LV ejection fractions ≤40%, and intolerance to ACE inhibitors were randomly assigned to receive either 150 mg or 50 mg of losartan daily. Most patients were taking standard therapies for heart failure at enrollment, including diuretics (76%), beta-blockers (72%), and aldosterone blockers (38%). During a median follow-up of 4.7 years, high-dose losartan significantly reduced the rate of the primary composite outcome of death or hospital admission for heart failure, compared with low-dose losartan (43% vs. 46%; P=0.027); both components of the composite endpoint contributed to the overall result. The composite outcome of death or cardiovascular admission occurred in 54% of patients in the high-dose group and in 57% in the low-dose group. The rate of studydrug discontinuation during follow-up

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ARBs in Heart Failure: What Difference Does a Dose Make? .................... 1 Should Patients with Heart Failure “Pump” Iron?............................................................... 2 LV Assistance for End-Stage Heart Failure: Have We Reached Our Destination? ...................... 2 Again I Say, Again: Avoid Pacing the Right Ventricle! ........................................................... 3 Primary PCI for STEMI: How Important Are Hospitals’ Procedure Volumes?....................... 3 Reducing Door-to-ECG Time Without Increasing ED Staffing............................................... 4 Investigation of Incidental Findings on Cardiac CT .............................................................. 4

USPSTF Doesn’t Recommend Using Nontraditional Risk Factors for CHD Risk .............. 7

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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 Operations and Development; 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 JWatch.org. Information on our conflict-of-interest policy can be found at JWatch.org/misc/conflict.dtl

CARDIOLOGY

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was substantial (28% and 27% in the high- and low-dose groups, respectively). Adverse events, including hyperkalemia, hypotension, and renal impairment, were significantly more common in the high-dose group than in the low-dose group.
COMMENT

These findings suggest a favorable effect of 150 mg of losartan, compared with 50 mg, in patients with systolic heart failure, although the benefit came at a cost of adverse events. As an editorialist points out, we cannot assume similar results in patients who can tolerate ACE inhibitors, and this trial does not compare a highdose ARB with a high-dose ACE inhibitor. We are well reminded, however, to uptitrate all medications to the highest efficacious dose (according to the best available trial evidence), as tolerated by the patient. — Joel M. Gore, MD
Konstam MA et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): A randomised, double-blind trial. Lancet 2009 Nov 28; 374:1840. Krum H. Optimising management of chronic heart failure. Lancet 2009 Nov 28; 374:1808.

Iron recipients were significantly more likely than placebo recipients to improve clinically, as measured by the primary endpoints — Patient Global Assessment (odds ratio, 2.51) and NHYA classification (OR, 2.40) — as well as by health-related quality of life and 6-minute walk distance. The benefits were apparent by 4 weeks and were similar in patients with and without anemia. Aside from a higher rate of injection-site discomfort or discoloration (6 iron recipients vs. zero placebo recipients), adverse events did not differ significantly between the two groups.
COMMENT

Should Patients with Heart Failure “Pump” Iron?
In a randomized trial, intravenous iron improved symptoms, even in patients without anemia.

Anemia is common and associated with adverse outcomes in patients with heart failure. Iron deficiency is also common in heart failure, sometimes in the absence of frank anemia. Although results of small trials suggest benefits of iron supplementation for iron deficiency in heart failure patients, definitive evidence has been lacking. In the manufacturer-sponsored FAIR-HF trial, 459 patients with systolic heart failure, iron deficiency, and NYHA class II–III symptoms were randomized in a 2:1 ratio to receive intravenous ferric carboxymaltose or placebo. Notably, half of the patients had normal baseline hemoglobin levels, and patients with clinically significant renal dysfunction were excluded. Participants were treated for 24 weeks: weekly until estimated iron repletion was achieved and monthly thereafter.

In this trial, intravenous ferric carboxymaltose significantly improved symptoms and sense of well-being in patients with systolic heart failure, suggesting that iron has benefits beyond anemia treatment per se (e.g., improved muscle energetics). We don’t know if (1) oral iron — considerably less expensive and more convenient than intravenous iron — confers the same benefits, (2) all intravenous iron preparations are equivalent in this context (ferric carboxymaltose is currently unavailable in the U.S.), or (3) this therapy benefits patients with clinically important renal dysfunction, which also commonly causes anemia. Nonetheless, these provocative findings suggest possible benefits of screening for and treating iron deficiency in patients with heart failure — even those without anemia.
— Frederick A. Masoudi, MD, MSPH
Anker SD et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009 Nov 17; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0908355) Dec GW. Anemia and iron deficiency — New therapeutic targets in heart failure? N Engl J Med 2009 Nov 17; [e-pub ahead of print]. (http://dx.doi .org/10.1056/NEJMe0910313)

LV Assistance for End-Stage Heart Failure: Have We Reached Our Destination?
A continuous-flow device achieves impressive results in a randomized trial.

LV assistance has been proposed as permanent, or destination, therapy for patients with advanced heart failure who are not candidates for cardiac transplantation. Findings from the REMATCH trial

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Yu C-M et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med 2009 Nov 26; 361:2123.

(JW Cardiol Feb 2002, p. 20, and N Engl J Med 2001; 345:1435) provided proof of concept for this approach, demonstrating improved survival in end-stage heart failure patients randomized to receive a pulsatile-flow LV assist device (LVAD) versus ongoing medical treatment. However, survival in the LVAD group was limited by device complications, including stroke, infection, and the need for reoperation. In a manufacturer-sponsored, randomized controlled trial, investigators compared an FDA-approved pulsatile-flow LVAD with a second-generation, investigational continuous-flow LVAD. Two hundred patients with advanced heart failure who were not considered candidates for cardiac transplantation were randomized in a 2:1 ratio to receive the continuous-flow or the pulsatile-flow LVAD. The primary composite endpoint was survival free from disabling stroke and device repair or replacement at 2 years. Secondary endpoints included survival, frequency of adverse events, quality-of-life changes, and functional capacity. Sixtytwo patients (46%) in the continuous-flow group achieved the primary endpoint compared with 7 patients (11%) in the pulsatile-flow group (hazard ratio, 0.38; 95% confidence interval, 0.27–0.54; P<0.001). Continuous-flow device recipients had a better actuarial survival rate at 2 years than pulsatile-flow device recipients (58% vs. 24%; P=0.008), as well as fewer adverse events and device replacements.
COMMENT

Again I Say, Again: Avoid Pacing the Right Ventricle!
Findings from yet another study show the detriment of RV pacing.

Biventricular pacing, or cardiac resynchronization therapy (CRT), has been shown to benefit patients with reduced LV ejection fractions and NYHA class III heart failure symptoms and, more recently, those with NYHA class I or II symptoms (JW Cardiol Oct 2009, p. 77, and N Engl J Med 2009; 361:1329). By contrast, although RV-only pacing has long been suspected of causing LV dysfunction and is thought to have resulted in worsened heart failure in the DAVID trial (JW Cardiol Apr 2003, p. 31, and JAMA 2002; 288:3115), evidence of its detrimental effects is relatively scarce. In a multicenter, manufacturersponsored trial of RV pacing versus CRT in patients with preserved LV function, 177 patients received a CRT device and were randomized to programmed RV-only or biventricular pacing. The indication for pacing was advanced atrioventricular block in 104 participants (59%) and sinus node dysfunction in 73 (41%). The study protocol called for obligatory RV pacing in all patients assigned to it, even those with intact AV conduction systems. At 12 months of follow-up, the average percentage of patients with ventricular pacing was 98% in the CRT group and 97% in the RV-pacing group (P=0.95). Mean LVEF was significantly lower in the RV-pacing group than in the CRT group (54.8% vs. 62.2%), although no betweengroup differences were seen in 6-minute walk distance, hospitalization for heart failure, or quality-of-life measures.
COMMENT

Primary PCI for STEMI: How Important Are Hospitals’ Procedure Volumes?
Lower-than-recommended procedure volume was common but not associated with elevated mortality.

Guidelines recommend that at hospitals offering primary percutaneous coronary intervention for patients with ST-segmentelevation MI, at least 36 such procedures — and at least 200 angioplasties — should be performed per year. To assess the association between volume of primary PCI and patient outcomes, investigators identified 29,513 patients hospitalized for STEMI who underwent primary PCI at 166 hospitals participating in the American Heart Association’s Get With The Guidelines quality-improvement registry from 2001 through 2007. The participating hospitals’ annual primary PCI volumes ranged from 9 to 224 and were characterized as high (>70), medium (36–70), or low (<36). Sixty-five percent of hospitals met the guideline recommendation of 36 procedures per year. High-volume hospitals had shorter doorto-balloon times than medium- or lowvolume hospitals (median times, 88, 90, and 98 minutes, respectively). Patients at low-volume hospitals were less likely than those at high-volume hospitals to receive smoking-cessation counseling or prescriptions for aspirin, beta-blockers, and ACE inhibitors or angiotensin-receptor blockers at discharge.

A new, continuous-flow LVAD is superior to the currently available pulsatile-flow device at improving morbidity and mortality in end-stage heart failure patients who are not candidates for cardiac transplantation. Good candidates for such destination therapy are patients with very low LV ejection fractions, advanced heart failure symptoms, and recurrent hospitalization or inotropic support. — William T. Abraham, MD
Slaughter MS et al. for the HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009 Dec 3; 361:2241. Fang JC. Rise of the machines — Left ventricular assist devices as permanent therapy for advanced heart failure. N Engl J Med 2009 Dec 3; 361:2282.

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These results add to those of a series of studies demonstrating the potential detriment of RV pacing. However, this study’s findings are weakened by the protocolmandated RV pacing, which is not the standard of care for patients with intact AV conduction systems, and by the lack of between-group differences in clinical outcomes. These results should not change current recommendations, in which pacing the right ventricle is avoided if possible, but CRT is not indicated in patients with preserved LV function. — Mark S. Link, MD

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CARDIOLOGY

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In-hospital mortality was 3.2% overall, with the lowest rate at the high-volume hospitals (3.0%, vs. 3.2% and 3.9% in medium- and low-volume hospitals, respectively). In an adjusted analysis, mortality did not differ significantly among the three groups. Duration of stay was also similar in all groups.
COMMENT

These findings indicate that many hospitals do not meet the guideline recommendations for primary PCI volume. However, the researchers failed to detect an association between volume and patient outcomes in this sample of hospitals, which participate in a national quality-improvement initiative and comprise about 10% of U.S. hospitals that offer PCI. We do not know whether these results can be generalized to other hospitals.
— Harlan M. Krumholz, MD, SM
Kumbhani DJ et al. for the Get With the Guidelines Steering Committee and Investigators. Association of hospital primary angioplasty volume in ST-segment elevation myocardial infarction with quality and outcomes. JAMA 2009 Nov 25; 302:2207.

increased significantly from 16% before the intervention to 64% after. Median time to ECG decreased from 16 to 9 minutes. An ECG was obtained within 10 minutes in none of four patients with ST-segmentelevation myocardial infarction before the intervention and in all seven patients with STEMI after the intervention. (Two STEMI patients before the intervention had dehydration or shortness of breath as the chief complaint, whereas all seven STEMI patients after the intervention had chest pain as the chief complaint.)
COMMENT

As ED volume increases, adhering to the 10-minute presentation-to-ECG guideline for patients with chest pain becomes more challenging. This simple intervention offers a starting point, but the goal must be ECGs within the 10-minute window for 100% of patients. Meeting that goal requires constant measurement and adjustment, willingness to deploy or dedicate additional staff, and detailed review of every significant failure.
— Diane M. Birnbaumer, MD, FACEP, Journal Watch Emergency Medicine
Takakuwa KM et al. A method for improving arrivalto-electrocardiogram time in emergency department chest pain patients and the effect on door-to-balloon time for ST-segment elevation myocardial infarction. Acad Emerg Med 2009 Oct; 16:921.

ules/cysts). After a mean 18-month follow-up, no indeterminate finding became clinically significant, although three malignancies were diagnosed after subsequent diagnostic tests. Noncardiac and cancer death rates were not significantly different between patients with and without incidental findings. In all, 164 additional diagnostic tests and procedures were performed in the 80 patients with indeterminate or clinically significant incidental findings, including 1 patient who suffered empyema and abdominal abscesses as a complication of transthoracic biopsy.
COMMENT

Reducing Door-to-ECG Time Without Increasing ED Staffing
Training registration clerks to page dedicated ECG technicians when patients present with chest pain significantly reduced time to ECG.

This study highlights the dilemma posed by incidental findings that are a common byproduct of cardiac CT. These findings are clinically relevant in only a few cases but are associated with real risks and costs as well as benefits. Editorialists suggest one way of dealing with the issue: Ask patients about their concerns and preferences and then reconstruct images of and evaluate noncardiac structures only if patients provide informed consent. In the meantime, as CCT becomes more widespread, individual clinicians will continue to struggle with the best way to address “incidentalomas.”
— Kirsten E. Fleischmann, MD, MPH, Journal Watch General Medicine
MacHaalany J et al. Potential clinical and economic consequences of noncardiac incidental findings on cardiac computed tomography. J Am Coll Cardiol 2009 Oct 13; 54:1533. Hlatky MA and Iribarren C. The dilemma of incidental findings on cardiac computed tomography. J Am Coll Cardiol 2009 Oct 13; 54:1542.

Guidelines from the American College of Cardiology and the American Heart Association state that an electrocardiogram should be obtained within 10 minutes after patients present with chest pain. These authors evaluated the effect on time to ECG of an intervention that involved training registration clerks to page dedicated emergency department ECG technicians when patients present with chest pain or other complaints associated with acute coronary syndromes. The technician immediately delivered the ECG to an emergency physician for interpretation. Before the intervention, patients were registered by clerks and triaged by nurses before an ECG was ordered. The authors compared data for 313 consecutive adult patients who presented with chest pain during the month before the intervention and 405 such patients who presented during the month after at a single urban academic emergency department (ED). The proportion of patients for whom an ECG was obtained within 10 minutes

Investigation of Incidental Findings on Cardiac CT
These findings are clinically relevant in only a minority of cases and are associated with risks and costs.

Cardiac computed tomography (CCT), which is increasingly popular for evaluating patients with coronary calcification and arterial disease, often produces noncardiac incidental findings. To evaluate the incidence, clinical importance, and costs of these incidental findings, researchers studied 966 consecutive patients who underwent CCT during 12 months at a single Canadian institution. Incidental findings were noted in 401 patients (41.5%); of these, 12 were deemed to be clinically significant (e.g., 5 thrombi, 1 aortic dissection that was not clinically suspected, 1 ruptured breast implant), and 68 were deemed to be indeterminate (e.g., 34 noncalcified pulmonary nodules <1 cm, 11 larger lung nodules, 9 liver nod-

In-Hospital Mortality After MI: Vive la Différence?
Sex differences in survival to discharge are getting smaller.

Previous prospective, observational data from the National Registry of Myocardial Infarction (NRMI) have shown that the risk for death after MI is higher in women than in men, particularly in younger patients (N Engl J Med 1999; 341:217). In a new NRMI study, researchers examined whether that sex difference persists. The analysis included 916,380 patients hospitalized with confirmed acute coronary ischemia from 1994 through 2006.

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During this period, the prevalence of many coexisting conditions increased across age and sex subgroups, and the proportion of patients with ST-segment-elevation MI decreased. Diabetes, heart failure, and stroke were more prevalent among younger women than among younger men. Over time, in-hospital mortality rates declined across the age spectrum, generally more in women than in men. The decline in mortality was most pronounced in women younger than 55 (from 5.1% in 1994–1995 to 2.4% in 2004–2006). Within the <55 age group, the unadjusted female-to-male odds ratio for death declined from 1.93 in 1994– 1995 to 1.34 in 2004–2006, although it remained statistically significant. Notably, multivariable analyses showed that the narrowing of the risk between young women and young men resulted from changes in coexisting illnesses and clinical features at admission rather than in processes of care.
COMMENT

telephone calls, with tailored behavioral counseling focused on medication adherence; thrice-weekly home blood pressure measurement, with values recorded in logs (logs were mailed to primary care providers every 2 months); both interventions; or usual care. Blood pressure control was defined as systolic blood pressure (SBP) <140 mm Hg and diastolic blood pressure (DBP) <90 mm Hg for patients without diabetes, and SBP <130 mm Hg and DBP <80 mm Hg for patients with diabetes. At 24 months, blood pressure control was achieved by 11% more patients in the combined-intervention group than in the usual-care group. The drop in SBP from baseline was also significant only for the combined-intervention group (3.9 mm Hg lower than usual care alone).
COMMENT

and North America, with a total population of 300,000 patients and mean followup of about 6 years. Risk for coronary disease, adjusted for several demographic and clinical risk factors, was associated with higher values of non-HDL and LDL, higher ratios of non-HDL/HDL and apo B/A1, and lower values of HDL. Risks for coronary disease and ischemic stroke were not associated with triglyceride levels, and risk for ischemic stroke was only weakly associated with HDL or non-HDL levels. No difference in risk prediction was observed between fasting and nonfasting measurements.
COMMENT

Sex differences in in-hospital mortality after MI have narrowed over time, particularly among younger people. However, the analysis suggests that this temporal trend stems from concomitant changes in clinical profiles rather than from improvements in care. Furthermore, changes in practice patterns (e.g., shorter hospital stays and more frequent use of skilled nursing facilities) might result in lower in-hospital mortality rates that do not reflect improved longer-term outcomes. Gratifying as these data are, there is still ample room for the medical community to do better.
— Frederick A. Masoudi, MD, MSPH
Vaccarino V et al. Sex differences in mortality after acute myocardial infarction: Changes from 1994 to 2006. Arch Intern Med 2009 Oct 26; 169:1767.

To achieve better outcomes for patients with chronic conditions, we need to go beyond what we can do in the confines of office visits. Implementation of these two strategies for management of hypertension seems feasible, as long as resources are available. Similar strategies likely would work for other chronic conditions.
— Richard Saitz, MD, MPH, FACP, FASAM, Journal Watch General Medicine
Bosworth HB et al. Two self-management interventions to improve hypertension control: A randomized trial. Ann Intern Med 2009 Nov 17; 151:687.

Because many physicians have relatively easier access to standard cholesterol profiles than to apolipoprotein measurements, because patients appreciate the convenience of nonfasting tests, and because risk was similar for all lipid parameters including non-HDL or directly measured LDL, one efficient approach supported by this study is to use nonfasting cholesterol profiles (without triglyceride or LDL levels) for assessing risk for vascular disease. Although some clinicians already use this approach, considerable effort will be required to change the current culture of lipid management, with its heavy emphasis on LDL.
— Thomas L. Schwenk, MD, Journal Watch General Medicine
Di Angelantonio E et al. for the Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009 Nov 11; 302:1993.

Lipids, Apolipoproteins, and Vascular Disease: What to Measure?
Total and HDL cholesterol and apolipoproteins, fasting or not, are equally accurate.

Self-Management for Hypertension
Two interventions helped patients reach blood pressure goals.

Because many hypertensive patients do not achieve good control of blood pressure, strategies are needed beyond physician adjustment of medication based on office-visit blood pressure measurements. In a study of two self-management strategies, North Carolina investigators randomized 636 patients with hypertension to receive bimonthly nurse-delivered

To assess vascular disease risk conferred by serum lipids, we typically measure fasting levels of total cholesterol, HDL, and triglycerides, and the laboratory calculates LDL from the other results. However, an alternative is to measure only total cholesterol and HDL (neither measurement requires fasting); subtracting HDL from total cholesterol yields the so-called non-HDL cholesterol, which roughly parallels LDL. Less commonly measured predictors are apolipoproteins (apo) A1 and B. To investigate the capacity of these markers to predict vascular risk, researchers collapsed 68 long-term studies of lipids and vascular disease, mostly from Europe

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CARDIOLOGY
Ebbing M et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009 Nov 18; 302:2119. Drake BF and Colditz GA. Assessing cancer prevention studies — A matter of time. JAMA 2009 Nov 18; 302:2152.

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Folic Acid and Cancer
Cancer incidence and mortality rose with vitamin use.

Since 1998, when the U.S. mandated folic acid (FA) fortification of flour and other grain foods to lower risk for neural tube defects, FA intake has risen dramatically. Supplementation with FA and other B vitamins also has been proposed to prevent cardiovascular disease (by lowering homocysteine levels), although no studies yet have shown such benefit. To examine a possible association between FA treatment and cancer risk, researchers combined the results of two Norwegian trials of vitamin B supplementation in nearly 7000 patients with ischemic heart disease. More than 70% of patients were current or former smokers. Norway does not mandate FA fortification of foods. Patients were randomized to one of four daily regimens: FA (0.8 mg) plus vitamin B12 (0.4 mg) plus vitamin B6 (40 mg); FA plus vitamin B12; vitamin B6 alone; or placebo. After a median of 78 months of treatment and follow-up, risk for developing cancer in groups that were taking FA compared with those that were not taking FA was 21% higher (number needed to harm [NNH], about 63). Risk for dying from cancer was 38% higher in the FA groups (NNH, 91), and, for all-cause mortality, risk was 18% higher (NNH, 43). Lung cancer incidence accounted for much of the risk for developing or dying from cancer.
COMMENT

Revascularization Is Ineffective for Atherosclerotic Renal Artery Stenosis
This procedure conferred substantial risk without clinical benefit.

people who required revascularization, in their doctors’ opinions: Examples are patients with flash pulmonary edema or acute renal injury (or rapidly progressing disease) that was thought to be caused by renal artery stenosis. Whether such patients benefit from revascularization is unknown. But, for most people, revascularization for renal artery stenosis does not appear to be associated with clinical benefit.
— Richard Saitz, MD, MPH, FACP, FASAM, Journal Watch General Medicine
The ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med 2009 Nov 12; 361:1953.

Revascularization for atherosclerotic renal artery stenosis can improve artery patency, but is it associated with clinical benefit? In a 5-year U.K. study, investigators randomized 806 patients with renal artery stenosis and related clinical findings (such as difficult-to-control hypertension or unexplained renal dysfunction) to medical management alone or to medical management plus angioplasty (with stenting at the discretion of treating physicians). In all cases, treating physicians were uncertain whether revascularization would confer benefit. Median follow-up was 34 months. Among participants who were assigned to revascularization, 17% did not undergo the procedure, mainly because angiography revealed that their stenoses were less severe than expected. Compared with medical management–only patients, those assigned to revascularization had a borderline significant mean lower rate of disease progression (as measured by the reciprocal of the mean serum creatinine level; P=0.06). However, no significant differences were noted between groups in serum creatinine level, systolic blood pressure, adverse renal events, adverse cardiovascular events, or death. Mean diastolic blood pressure was significantly lower in the medical management–only group. Researchers found no effects of revascularization in subgroups as defined by stenosis or renal dysfunction severity. Twenty-three patients suffered serious complications related to revascularization.
COMMENT

Two Clopidogrel Loading Doses Compared in Patients with STEMI
STEMI patients who underwent primary PCI had better clinical outcomes with a 600-mg loading dose than with 300 mg.

Because folic acid impairs immune surveillance of cancer cells and might stimulate the growth of established cancers, these findings have a biological basis; indeed, in another 2009 trial, folic acid supplementation was associated with excess risk for prostate cancer (J Natl Cancer Inst 2009; 101:432). Differences in baseline FA intake and smoking history might account for the results of earlier studies that did not show elevated risk for cancer. In any case, these results provide further reason not to recommend FA supplements for most middle-aged or older adults. The issue of what to do about FA fortification of foods is much more complicated, but editorialists believe that U.S. fortification places the population well within safe limits.
— Thomas L. Schwenk, MD, Journal Watch General Medicine

Given that platelet inhibition during percutaneous coronary intervention is more rapid and complete when a 600-mg loading dose of clopidogrel is used, it is often preferred over a 300-mg dose, both for PCI with stenting and in acute coronary syndrome patients who undergo PCI. Now, using data from the HORIZONSAMI trial (JW Cardiol Aug 2008, p. 67, and N Engl J Med 2008; 358:2218), investigators have compared outcomes in patients with ST-segment-elevation MI who received a 300-mg (1153 patients) or a 600-mg (2158 patients) loading dose of clopidogrel before being randomized either to bivalirudin alone or to unfractionated heparin plus a glycoprotein (GP) IIb/IIIa inhibitor. For each of the 30-day endpoints — death, reinfarction, major adverse cardiovascular events, and major bleeding unrelated to bypass surgery — recipients of the 600-mg clopidogrel loading dose fared significantly better than recipients of the 300-mg dose, without any greater risk for stroke or thrombocytopenia and regardless of antithrombotic-therapy assignment. Among stent recipients, the incidence of definite or probable stent thrombosis was significantly lower with 600-mg than with 300-mg of clopidogrel (1.7% vs. 2.8%).

A small recently published study suggested that revascularization produced no benefit (Ann Intern Med 2009; 150:840); now, a much larger study yielded similar findings. The authors note that the main limitation of their study is that they excluded

January 2010
COMMENT

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STEMI patients who underwent PCI had significantly better ischemic outcomes with a 600-mg loading dose of clopidogrel compared with 300 mg without any greater risk for bleeding, regardless of which antithrombotic therapy was used and whether a GP IIb/IIIa inhibitor was included. The findings are consistent with data from the TRITON-TIMI 38 trial, in which prasugrel (which achieves greater platelet inhibition than clopidogrel) outperformed clopidogrel in terms of patient outcomes (J Am Coll Cardiol 2009; 54:678). Based in part on these results, the newly revised American College of Cardiology/American Heart Association STEMI guidelines support the use of 300–600 mg of clopidogrel before primary PCI.
— Howard C. Herrmann, MD
Dangas G et al. for the HORIZONS-AMI Trial Investigators. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: Results from the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial. J Am Coll Cardiol 2009 Oct 6; 54:1438. Simon DI and Parikh SA. Hunting for the “sweet spot” in P2Y12 receptor blockade. J Am Coll Cardiol 2009 Oct 6; 54:1447.

CLINICAL PRACTICE GUIDELINE WATCH USPSTF Doesn’t Recommend Using Nontraditional Risk Factors for CHD Risk
The task force finds the evidence to be insufficient to make a recommendation.

The U.S. Preventive Services Task Force (USPSTF) has issued a new guideline about the use of nontraditional markers for coronary heart disease risk to screen patients, particularly those at intermediate risk according to traditional risk factors (Framingham score). The task force evaluated nine nontraditional markers: high-sensitivity C-reactive protein (hs-CRP), ankle-brachial index (ABI), leukocyte count, fasting blood glucose level, periodontal disease, carotid intima–media thickness, coronary artery calcification score as determined by electron-beam computed tomography, homocysteine level, and lipoprotein(a) level. The USPSTF concluded that evidence is insufficient to assess the balance of benefits and harms of using nontraditional risk factors to screen asymptomatic men and women with no histories of CHD to prevent subsequent CHD events. I statement (insufficient evidence; the grading system can be accessed on the USPSTF website.) In the evidence review, researchers found that 11% of men with intermediate CHD risk would be reclassified as having high risk and 12% would have low risk by hs-CRP; 10% of women would be reclassified as having high risk by ABI. Data are insufficient for all other tests. The evidence is also insufficient to determine whether CHD events (and deaths) would be lessened following nontraditional risk factor screening. The USPSTF also cites possible harms of screening, such as adverse psychological consequences of

overestimating CHD risk, expense of testing, and side effects of any preventive interventions (such as statins) that generally are safe but have known side effects that would be acceptable only if the interventions provide benefits.
COMMENT

The temptation exists to collect as much information as possible to prevent a common cause of death. However, based on current data, the best outcome of screening with nontraditional risk factors would be to reclassify a small proportion of patients; such screening would not necessarily be associated with preventing CHD. Some experts still might advocate testing because they hope that the evidence will catch up to clinical practice. Although this approach perhaps is not entirely unreasonable, it is problematic, because it could distract us from focusing on preventive health interventions of proven benefit.
— Richard Saitz, MD, MPH, FACP, FASAM, Journal Watch General Medicine
U.S. Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009 Oct 6; 151:474. Buckley DI et al. C-reactive protein as a risk factor for coronary heart disease: A systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med 2009 Oct 6; 151:483. Helfand M et al. Emerging risk factors for coronary heart disease: A summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Ann Intern Med 2009 Oct 6; 151:496.

Cangrelor Is Not the New Champion
Unexpected setbacks for a promising new antiplatelet agent illustrate the gap between laboratory results and clinical efficacy.

Cangrelor, an investigational intravenous agent that reversibly inhibits the platelet P2Y12 adenosine diphosphate receptor, has two potential advantages over clopidogrel: a rapid onset of action and a short half-life that allows normalization of platelet function within 60 minutes of discontinuation. In two manufacturer-sponsored studies, investigators assessed cangrelor’s efficacy in patients undergoing percutaneous coronary intervention. Both trials were terminated early based on findings from interim analyses. In the CHAMPION PLATFORM trial, 5301 patients undergoing PCI for acute coronary syndromes were randomized to receive cangrelor or placebo for 2 to 4 hours during the procedure and clopidogrel (600 mg) at the end of the procedure. Glycoprotein (GP) IIb/IIIa

inhibitors were used in 9.2% of patients. The primary composite endpoint of death, MI, or ischemia-driven revascularization within 48 hours occurred in 7% of cangrelor recipients and in 8% of placebo recipients, a nonsignificant difference. However, cangrelor was associated with significant reductions in the stent throm-

bosis rate (0.2%, vs. 0.6% with placebo) and mortality (0.2% vs. 0.7%). Major and minor bleeding rates were similar in the two groups, although groin hematomas occurred more frequently in cangrelor recipients. Dyspnea was more common in cangrelor recipients (1.4%) than in placebo recipients (0.5%).

JW ONLINE CME
JOURNAL WATCH SUBSCRIBERS HAVE 10 FREE CREDITS! This is one of four questions in a recent Journal Watch Online CME exam. from “ARBITER 6-HALTS: A Surprise Knockout” (p. 1) Which of the following statements describes a finding from a randomized trial of statin therapy plus ezetimibe or extended-release niacin in patients at high risk for cardiovascular events? A. The mean low-density lipoprotein (LDL) level increased significantly in the ezetimibe group. B. The mean high-density lipoprotein (HDL) level decreased significantly in the niacin group. C. Carotid intima–media thickness decreased significantly in the niacin group. D. The major cardiovascular event rate was significantly lower in the ezetimibe group than in the niacin group. Category: Cardiovascular Diseases Exam Title: HDL Cholesterol Posted Date: Dec 15 2009 View this exam and others at http://cme.jwatch.org User name and password are required. CME FACULTY Kelly Anne Spratt, DO, FACC, Section Editor, Cardiology

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CARDIOLOGY

Vol. 16

No. 1

In the CHAMPION PCI trial, 8877 patients undergoing PCI were randomized to receive either 600 mg of clopidogrel or cangrelor at the beginning of the procedure. GPIIb/IIIa inhibitors were used in 26.5% of patients. Cangrelor recipients received clopidogrel at the end of the infusion. The rate of the composite endpoint of death, MI, or ischemia-driven revascularization did not differ significantly between the two groups at either 48 hours or 30 days or among subgroups with stable angina, unstable angina, and STsegment-elevation MI. Bleeding rates were similar in the two treatment groups, but dyspnea occurred in slightly more cangrelor recipients (1.0%) than clopidogrel recipients (0.4%).
COMMENT

greater platelet inhibition than clopidogrel alone — is surprising. Study design issues, including the definition of periprocedural MI and the abrupt transition to an oral antiplatelet after cangrelor infusion, could have contributed to these negative results. However, newer oral agents with a faster onset of action and more-consistent platelet inhibition than clopidogrel are now available and will pose a further challenge to cangrelor’s development.
— Howard C. Herrmann, MD
Dr. Herrmann was a site investigator for the CHAMPION PCI study but was not involved in data analysis or manuscript preparation.

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Bhatt DL et al for the CHAMPION PLATFORM Investigators. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009 Dec 10; 361:2330. Harrington RA et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009 Dec 10; 361:2318. Kastrati A and Ndrepepa G. Cangrelor — A champion lost in translation? N Engl J Med 2009 Dec 10; 361:2382.

Given the importance of platelet inhibition in ACS treatment and PCI, the fact that cangrelor did not improve outcomes — despite presumably achieving earlier and