October 2010 Vol. 16 No.

10
From the publishers of The New England Journal of Medicine

CA RDI OLOGY
CYP2C19 and Clopidogrel: Dont Order That Test Just Yet
New evidence casts doubt on the role of genetic variation in determining treatment effects.

Experts debate the usefulness of genetic testing to help determine the optimal antiplatelet regimen after an acute coronary syndrome or stent placement. Patients who carry a loss-of-function CYP2C19 allele have reduced conversion of clopidogrel to its active metabolite and decreased inhibition of platelet activation, which prompted the FDA to issue a black-box warning that clopidogrel can be less effective in carriers than in noncarriers. Another protein, encoded by the ABCB1 gene, is important in thienopyridine absorption and might also influence the effects of these drugs. Two key questions drive the debate: (1) Does an individuals genetic profile affect his or her relative responses to clopidogrel, placebo, or other agents? (2) Does an individuals genetic profile affect his or her risk for adverse events during treatment with specific medications? To address the first question, investigators examined genetic data from three trials of clopidogrel versus a comparator. Two

studies compared clopidogrel with placebo: the CURE trial involving patients with acute coronary syndromes (JW Cardiol Nov 2001, p. 85, and N Engl J Med 2001; 345:494), and ACTIVE A involving patients with atrial fibrillation (JW Cardiol Nov 2009, p. 44, and N Engl J Med 2009; 360:2066). These authors found that in both studies, clopidogrels superiority to placebo was similar, regardless of patients genotype. In the PLATO trial, investigators compared clopidogrel with ticagrelor in patients with acute coronary syndromes (JW Cardiol Nov 2009, p. 89, and N Engl J Med 2009; 361:1045). Ticagrelor reduced risk further than clopidogrel, but again, the effect difference did not vary significantly by CYP2C19 genotype. To address the second question, investigators assessed the prognostic importance of CYP2C19 and ABCB1 alleles in these studies and a fourth. They found that in CURE and ACTIVE A, loss-of-function CYP2C19 allele carrier status was not significantly associated with outcomes, and in PLATO, neither CYP2C19 nor ABCB1 carrier status significantly affected outcomes, although none of the studies could exclude a modest effect. In the TRITONTIMI 38

trial of clopidogrel versus prasugrel in patients with acute coronary syndromes who underwent percutaneous coronary intervention (JW Cardiol Dec 2007, p. 94, and N Engl J Med 2007; 357:2001), ABCB1 carrier status increased risk for adverse outcomes in the clopidogrel group but not in the prasugrel group. The TRITONTIMI 38 investigators did not assess the influence of genetic profile on the difference between the effects of clopidogrel and prasugrel.
COMMENT

CONTENTS
SUMMARY & COMMENT

These findings indicate that CYP2C19 genotype does not influence the effectiveness of clopidogrel in comparison to placebo or ticagrelor; whether genotype influences the effectiveness of clopidogrel compared with prasugrel remains unknown. These results may surprise experts who support recommendations for genetic testing to guide treatment strategies based on results of platelet activation studies, and they undermine arguments that patients with lossof-function alleles derive less benefit from clopidogrel than patients without loss-offunction alleles. The findings about the prognostic value of genetic profiles were inconsistent. For now, the role of genetic testing in risk stratification remains unclear. Harlan M. Krumholz, MD, SM
Pare G et al. Effects of CYP2C19 genotype on the efficacy and safety of clopidogrel treatment. N Engl J Med 2010 Aug 29; [e-pub ahead of print]. (http:// www.nejm.org/doi/full/10.1056/NEJMoa1008410) Wallentin L et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: A genetic substudy of the PLATO trial. Lancet 2010 Aug 29; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(10)61274-3) Mega JL et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON TIMI 38 trial: A pharmacogenetic analysis. Lancet 2010 Aug 29; [e-pub ahead of print]. (http://dx.doi .org/10.1016/S0140-6736(10)61273-1)

Prophylactic Use of an IABP..................................... 80 Start the Clock: Time to Treatment for MI......................................... 81 When Is D2B Time Most Important?........................ 82 More European Results on TAVI............................... 82 Is Better Risk Assessment Within REACH?............ 82 Shifting Attention to Heart Rate................................ 83 A Head-to-Head Comparison of Two Drugs for Atrial Fibrillation.................................................. 83 More Good News About Dabigatran ..................................................... 84
CASE DISCUSSION

CYP2C19 and Clopidogrel: Dont Order That Test Just Yet ............................... 77 Clopidogrel and Aspirin for ACS: Have We Found an OASIS? ......................... 78

Does Omega-3 Fatty Acid Supplementation Prevent Cardiovascular Events? ........................... 78 Sibutramine Raises Risk for Adverse Cardiovascular Events............................................. 79 Low-Fat or Low-Carb Diet: Does It Make a Difference? ................................... 79 Does Intensive BP Control Delay Progression of Kidney Disease? ........................... 80 Unfractionated Heparin in Fondaparinux-Treated Patients Undergoing PCI ......................................................... 80

The Tests Say Intervene, but the Patient Feels Fine........................................ 81

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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 Womens 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 OHalloran, Copy Editor; Misty Horten, Layout; Matthew ORourke, Director, Editorial and Product Development; Robert Dall, Editorial Director; Art Wilschek, Christine Miller, Lew Wetzel, Advertising Sales; William Paige, Publishing Services; Bette Clancy, Customer Service Published 12 times a year. Subscription rates per year: $119 (U.S.), C$166.67 (Canada), US$165 (Intl); Residents/Students/Nurses/PAs: $69 (U.S.), C$96.19 (Canada), US$80 (Intl); Institutions: $219 (U.S.), C$256.19 (Canada), US$230 (Intl); individual print only: $89 (U.S.). Prices do not include GST, HST, or VAT. In Canada remit to: Massachusetts Medical Society C/O #B9162, P.O. Box 9100, Postal Station F, Toronto, Ontario, M4Y 3A5. All others remit to: Journal Watch Cardiology, P.O. Box 9085, Waltham, MA 02454-9085 or call 1-800-843-6356. E-mail inquiries or comments via the Contact Us page at JWatch.org. Information on our conflict-of-interest policy can be found at JWatch.org/misc/conflict.dtl

CARDIOLOGY

Vol. 16

No. 10

Clopidogrel and Aspirin for ACS: Have We Found an OASIS?

Trial data provide scant sustenance on the quest for an optimal dosing strategy.

dose group (1.6% vs. 1.1%; HR, 1.41; 95% CI, 1.091.83).
COMMENT

Although the efficacy of clopidogrel plus aspirin for treating acute coronary syndromes (ACS) is well established, considerable uncertainty remains about dosing. Investigators for the manufacturer-sponsored CURRENTOASIS 7 trial employed a 22 factorial design to examine the effects of doubling the standard loading dose and first-week maintenance dose of clopidogrel (from 300 to 600 mg and from 75 to 150 mg, respectively), and to compare the effects of high-dose (300325 mg/day) versus low-dose (75100 mg/day) aspirin. All 25,086 patients (mean age, 61; 27% women) had ACS and were scheduled for coronary angiography with percutaneous coronary intervention (PCI) as indicated within 72 hours after randomization, and all received a loading aspirin dose of >300 mg. The primary 30-day outcome was a composite of cardiovascular death, myocardial infarction (MI), and stroke. The study had 80% power to detect a 16% reduction in risk. In the clopidogrel comparison, the rate of the primary outcome was similar in the double-dose and standard-dose groups (4.2% and 4.4%, respectively; hazard ratio, 0.94; 95% confidence interval, 0.831.06). Major bleeding, as determined by increased red-cell transfusion, was more common in the double-dose group (2.5% vs. 2.0%; HR, 1.24; 95% CI, 1.051.46; P=0.01). In the aspirin comparison, the rates of the primary outcome in both groups were the same as in the clopidogrel comparison, but the betweengroup bleeding rates were also similar. In a prespecified analysis involving the 17,263 participants who underwent PCI (95% received a stent), a primary endpoint occurred in 3.9% of the doubledose clopidogrel group compared with 4.5% of the standard-dose clopidogrel group (HR, 0.86; 95% CI, 0.740.99; P=0.04); the difference was mostly attributable to the difference in MI rate. The stent thrombosis rate was significantly lower in the double-dose group than in the standard-dose group (1.6% vs. 2.3%; HR, 0.68; 95% CI, 0.550.85). The rate of major bleeding was higher in the double-

This study failed to show a benefit of high-dose clopidogrel or high-dose aspirin in patients with ACS who were expected to undergo cardiac catheterization. However, benefits were found in those who did undergo PCI, albeit at the cost of an increase in major bleeding. These findings were significant, although they were not adjusted for multiple comparisons. The comparison in the PCI recipients, as an expanded subgroup analysis, cannot bear the same weight as the full trial in the body of evidence. Interpretation of the aspirin results is problematic because the effect of the loading dose lasts for a week or more, and many patients on the higher dose also received a proton-pump inhibitor. The best antiplatelet regimen for PCI, therefore, remains uncertain.
Harlan M. Krumholz, MD, SM
The CURRENTOASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010 Sep 2; 363:930. Fuster V. Fine-tuning therapy for acute coronary syndromes. N Engl J Med 2010 Sep 2; 363:976. Mehta SR et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): A randomized factorial trial. Lancet 2010 Sep 1; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(10)61088-4) Stone GW. Acute coronary syndromes: Finding meaning in OASIS 7. Lancet 2010 Sep 1; [e-pub ahead of print]. (http://dx.doi.org/10.1016/ S0140-6736(10)61262-7)

Does Omega-3 Fatty Acid Supplementation Prevent Cardiovascular Events?

In a new study, adding omega-3 fatty acids to patients diets conferred no benefit.

Findings from several studies have suggested that the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the plantderived omega-3 fatty acid alpha-linolenic acid (ALA) reduce the risk for cardiovascular events. To find out whether low doses of EPA/DHA (400 mg/day), ALA (2 g/day), or both, provided in margarine, would reduce rates of cardiovascular events, investigators for the multicenter, double-blind, placebo-controlled Alpha Omega trial

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a 22 factorial design with EPA/DHA and ALA recruited 4837 older patients (mean age, 69; 78% men) who had survived a myocardial infarction (MI) within the previous 10 years. Eighty-six percent of enrolled patients were receiving lipid-lowering agents, primarily statins. The primary composite endpoint included fatal or nonfatal cardiovascular disease and revascularization by percutaneous coronary intervention or coronary artery bypass grafting. During a median follow-up of 40.8 months, neither supplement was demonstrated to have a significant advantage over placebo: A primary endpoint occurred in 14.0% of the EPA/DHA group versus 13.8% of the ALA-only or placebo group (hazard ratio, 1.01; 95% confidence interval, 0.871.17) and in 13.2% of the ALA group versus 14.5% of the EPA/ DHA-only or placebo group (HR, 0.91; 95% CI, 0.781.05). Results were similar for secondary outcomes and in prespecified subgroup analyses.
COMMENT

everyone received the weight-loss drug sibutramine (Meridia), those who tolerated it were randomized to receive sibutramine or placebo. All patients received advice on diet and exercise. During mean follow-up of 3.4 years, average weight reduction was 2 kg more in the sibutramine group than in the placebo group. However, the incidence of the primary endpoint (mainly nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular death) was significantly higher in the sibutramine group (11.4% vs. 10.0%; P=0.02). A significant excess of adverse outcomes with sibutramine was noted for nonfatal MI and nonfatal stroke, but not for cardiovascular or all-cause mortality.
COMMENT

In this study, unlike in previous studies, adding EPA/DHA or ALA to the diet did not reduce cardiovascular risk. Perhaps a larger number of patients or a dietary substrate other than margarine might have yielded a different result, especially for ALA. Nonetheless, the questions raised about the value of omega-3 fatty acid supplements for secondary prevention in optimally treated patients make it difficult to recommend such supplements without reservation.
Harlan M. Krumholz, MD, SM
Kromhout D et al for the Alpha Omega Trial Group. n3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010 Aug 29; [e-pub ahead of print]. (http://www.nejm.org/doi/ full/10.1056/NEJMoa1003603)

In the U.S., the FDA recently ruled that sibutramine is contraindicated in patients with cardiovascular disease or uncontrolled hypertension; this study confirms the wisdom of that ruling. In fact, the drug should not be used at all, in my view: Compared with placebo, sibutramine resulted in average short-term weight loss of only about 10 pounds in clinical trials, and long-term safety is unclear even in presumably healthy people. A European drug regulation authority has already recommended that the drug be withdrawn.
Allan S. Brett, MD, Journal Watch General Medicine
James WPT et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010 Sep 2; 363:905. Curfman GD et al. Sibutramine Another flawed diet pill. N Engl J Med 2010 Sep 2; 363:972.

Participants in both groups lost approximately 11% of their baseline weight in 6 to 12 months; subsequent gains resulted in a total loss of 7% of baseline weight at 2 years. Systolic blood pressure fell with weight loss in both diet groups but did not differ significantly between the groups at any time point. The low-fat group had a significantly greater decrease in LDL cholesterol level than the low-carb group at 3 and 6 months, but the difference did not persist beyond 6 months. Early decreases in triglyceride level and increases in HDL cholesterol level were significantly greater in the low-carb group than in the low-fat group, but only the difference in HDL level remained significant at 2 years. The groups did not differ in bone-mineral density or body composition. Significantly more patients in the low-carb group than in the low-fat group reported adverse symptoms. The rate of attrition at 2 years, including participants who withdrew and those who missed appointments, was 32% in the low-fat group and 42% in the low-carb group.
COMMENT

These findings show that weight loss can successfully be achieved with either a low-fat or a low-carb diet when a comprehensive behavioral program is included in the treatment. Although the low-carb diet appears to have improved the cardiovascular risk profile to a somewhat greater extent than the low-fat diet, the most important factor is maintaining the diet. Ultimately, most patients need an ELF (eat less food) diet. Joel M. Gore, MD
Foster GD et al. Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: A randomized trial. Ann Intern Med 2010 Aug 3; 153:147.

Low-Fat or Low-Carb Diet: Does It Make a Difference?

If behavior-modification therapy is part of the weight-loss program, probably not.

Sibutramine Raises Risk for Adverse Cardiovascular Events

Should the drug be used at all?

One reason to encourage weight reduction is to favorably influence risk factors for cardiovascular disease. In this industrysponsored study, researchers enrolled more than 10,000 overweight or obese people with known cardiovascular disease or with type 2 diabetes plus another risk factor. After a 6-week run-in period during which

Multiple weight-loss strategies, including low-carbohydrate and low-fat diets, have been investigated; however, many study treatments have not included an extensive behavioral component. In this 2-year, randomized, parallel-group trial, researchers assigned 307 women and men (mean age, 45.5) to a low-carb or low-fat diet combined with a comprehensive lifestyle modification program.

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CARDIOLOGY

Vol. 16

No. 10

Does Intensive BP Control Delay Progression of Kidney Disease?

Maybe, in patients with proteinuria.

subgroup. According to the authors, the mechanism for the observed proteinuriarelated differential effect is unclear.
Allan S. Brett, MD, Journal Watch General Medicine
Appel LJ et al. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med 2010 Sep 2; 363:918. (http://dx.doi.org/10.1056/ NEJMoa0910975)

bus rates were very low in both groups (0.5% vs. 0.1%).
COMMENT

In the previously published AfricanAmerican Study of Kidney Disease and Hypertension (AASK), 1094 nondiabetic black patients with hypertension-related chronic kidney disease were randomized to intensive or standard blood pressure (BP) control. Despite significantly lower average BP with intensive treatment (130/78 mm Hg vs. 141/86 mm Hg), a composite outcome (50% reduction in glomerular filtration rate, end-stage renal disease, or death) was similar in the two groups at 4 years (JAMA 2002; 288:2421). In the AASK trial, researchers also compared ramipril, metoprolol, and amlodipine as initial therapies; outcomes were best with ramipril. After the randomized phase, patients were followed for about 6 more years in a cohort phase, during which the target BP was <130/80 mm Hg, and all patients received ramipril (plus other drugs if necessary). During this phase, BP remained slightly lower in the initial intensivetreatment group (by an average of 3 mm Hg systolic) than in the standard-control group. The researchers now report final 10-year outcomes. The rate of a composite endpoint (doubling of serum creatinine, end-stage renal disease, or death) remained similar in the two groups about 7 events per 100 person-years. However, in patients whose baseline protein-to-creatinine ratio exceeded 0.22 (roughly equivalent to 300 mg proteinuria daily), intensive BP control was associated with a significantly lower incidence of the endpoint, compared with standard control (hazard ratio, 0.73). In contrast, among patients with protein-tocreatinine ratios 0.22, intensive BP control was associated with a nonsignificantly higher incidence of the endpoint, compared with standard control (HR, 1.18).
COMMENT

Unfractionated Heparin in Fondaparinux-Treated Patients Undergoing PCI

In this trial, fondaparinux-treated patients had similar rates of adverse events with standard-dose versus low-dose heparin.

These findings suggest that neither standard-dose nor low-dose unfractionated heparin increases rates of major bleeding, and they support the addition of standard-dose heparin guided by ACT to fondaparinux in high-risk patients with nonST-segment-elevated ACS undergoing PCI. However, whether this regimen beats the favorable safety and efficacy profile of the specific thrombin inhibitor bivalirudin remains unknown.
Beat J. Meyer, MD
The FUTURA/OASIS-8 Trial Group. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: The FUTURA/ OASIS-8 randomized trial. JAMA 2010 Aug 31; [e-pub ahead of print]. (http://dx.doi.org/10.1001/ jama.2010.1320)

Fondaparinux, a synthetic factor Xa inhibitor, has recently emerged as an effective and safe alternative to low-molecularweight heparin in patients with acute coronary syndromes (ACS). However, fondaparinux does not offer adequate antithrombotic protection during percutaneous coronary intervention (PCI). Although both European and American guidelines recommend adjunctive unfractionated heparin in this setting, they differ on the dose. In the manufacturer-sponsored FUTURA/OASIS-8 trial, 3235 patients with nonST-segment elevation ACS were treated with subcutaneous fondaparinux (2.5 mg). The 2026 patients slated for PCI were then randomized to receive unfractionated heparin either at a fixed, low dose (50 U/kg) or at a standard dose (85 U/kg) adjusted in a blinded manner according to activated clotting time (ACT). Most patients (about 72%) received fondaparinux for about 2 days after PCI. Rates of the primary composite safety outcome major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI did not differ significantly between the low-dose and standard-dose groups (4.7% vs. 5.8%, respectively; P=0.27). A small difference was observed in rates of minor bleeding between the low-dose and standard-dose groups (0.7% vs. 1.7%; P=0.04). The difference in rates of the secondary composite safety outcome death, myocardial infarction, or target-vessel revascularization between the low-dose and standarddose groups was statistically nonsignificant (4.5% vs. 2.9%; P=0.06). Catheter throm-

Prophylactic Use of an IABP

Findings show no benefit in high-risk patients undergoing PCI.

Intra-aortic balloon pumps (IABPs) are commonly used to reduce the likelihood of complications in stable high-risk patients undergoing percutaneous coronary intervention (PCI). Investigators for the randomized controlled Balloon PumpAssisted Coronary Intervention Study evaluated this practice in 301 patients (mean age, 71; 80% men) with left ventricular (LV) ejection fractions of 30% and a large amount of myocardium at risk. The investigators excluded patients who fulfill American College of Cardiology/American Heart Association Class I and II recommendations for IABP use: cardiogenic shock, acute myocardial infarction (AMI) within 48 hours before scheduled PCI, or complications of AMI requiring circulatory support. The primary endpoint was the composite of death, AMI, stroke, or further revascularization before hospital discharge. Twelve percent of patients assigned to no planned IABP underwent rescue IABP insertion. A primary endpoint occurred in 15% of the IABP group and in 16% of the no-plannedIABP group. Three deaths occurred in the IABP group compared with one death in the no-plannedIABP group. MI occurred in about 13% of each group. Two strokes occurred in the IABP group

Overall, the AASK trial does not a support the idea that a target BP of 130/80 mm Hg prevents progression of hypertensive renal disease. However, the subgroup of patients with substantial proteinuria appeared to benefit from lowering BP to this target, and additional research should focus on that

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and none in the no-plannedIABP group. Predefined procedural complications (primarily hypotension) were less frequent in the IABP group than in the no-planned IABP group (1% vs. 11%). However, bleeding was more common in the IABP group (19% vs. 11%), as were access-site complications (3% vs. 0%).
COMMENT

CASE DISCUSSION The Tests Say Intervene, but the Patient Feels Fine
The following case, with a response by Dr. James Fang, was published in CardioExchange, an online forum for cardiology news and discussion. The case prompted a lively conversation, which you can access and join by registering for CardioExchange at www.cardioexchange.org.

This trial failed to demonstrate a benefit of elective IABP use in stable high-risk patients undergoing PCI. The results are not definitive; importantly, patients with a Class I or II indication for the device were excluded, and the guideline recommendation for hemodynamic support in these highest-risk patients remains unchallenged. Nonetheless, these findings not only call into question the merits of routine IABP placement in patients with severe LV dysfunction and extensive coronary disease, they also illustrate the importance of testing such common-sense strategies in clinical trials. Harlan M. Krumholz, MD, SM
Perera D et al. for the BCIS-1 Investigators. Elective intra-aortic balloon counterpulsation during highrisk percutaneous coronary intervention: A randomized controlled trial. JAMA 2010 Aug 25; 304:867.

A 58-year-old asymptomatic man with hypertension and hyperlipidemia had an abnormal electrocardiogram (ECG) during routine annual physical examination. His primary care physician ordered a treadmill stress test. The patient exercised for 6 minutes and 39 seconds of a standard Bruce protocol, achieving 8.1 metabolic equivalents. He stopped because of dyspnea. His heart rate increased from 63 beats per minute (bpm) at rest to 133 bpm at peak exercise, and his blood pressure changed from 176/86 mm Hg to 164/90 mm Hg. An ECG showed 3.5-mm horizontal ST-segment depressions in leads I, II, III, aVF, and V3 through V6 that began 5 minutes into the test and resolved 8 minutes into recovery. During exercise, the patient had isolated premature ventricular contractions but no other arrhythmias. A myocardial perfusion scan revealed a resting left ventricular ejection fraction (LVEF) of 65% that decreased to 55% during exercise. No regional perfusion defects consistent with scar or ischemia were found. Cardiac catheterization revealed three-vessel coronary artery disease (CAD) with 50% distal left-main disease, 60% ostial and 90% mid-left anterior descending (LAD) artery stenoses,

an occluded first obtuse marginal branch, 70% proximal right CAD, and an occluded posterior descending artery. Extensive left-to-left and left-to-right collaterals were identified. The patient was referred to a cardiologist, who recommended coronary artery bypass grafting (CABG). The patient refused surgery because he was asymptomatic during his routine daily activities. He was treated with aspirin, a beta-blocker, an angiotensin-converting enzyme inhibitor, and a statin. At reevaluation 1 year later, the patient reported excellent functional status and no new chest pain or dyspnea. Results of a repeat stress test and echocardiogram were essentially identical to the previous findings.
Questions

Start the Clock: Time to Treatment for MI

D2B time is only one of several systemperformance measures requiring improvement.

Are the results of the 1-year evaluation good news or bad news i.e., have the medications kept the disease stable (making surgery unnecessary), or is revascularization still advisable because theres been no improvement? If you recommend revascularization, would you advise surgery or high-risk angioplasty?

In our efforts to improve care of patients with ST-segment-elevation myocardial infarction (STEMI), we have made great strides in reducing door-to-balloon (D2B) times for primary percutaneous coronary intervention (PCI). However, delays in other segments of the time from symptom onset to treatment also deserve our attention. These investigators used registry data from three centers in western Denmark to evaluate the association between outcomes and the time from patients first contact with the healthcare system to the initiation of reperfusion therapy, considered as part of overall system performance. The study sample included 6209 STEMI patients admitted for primary PCI within 12 hours of symptom onset from January 2002 through December 2008. Overall, about half the patients had a system delay of more than 120 minutes. Of

Anju Nohria, MD
Dr. Nohria is Associate Physician and Instructor, Cardiovascular Division, Brigham and Womens Hospital, Boston.

patients field-triaged directly to a PCI hospital, 72% had a system delay of 120 minutes, compared with 35% of those transferred from a non-PCI hospital and 48% of the entire cohort. Longer system delays were independently associated with mortality at a median follow-up of 3.4 years (10% increase/1 hour delay; 95% confidence interval, 4%16%). Longer D2B times were also independently associated with mortality (14% increase/1 hour delay; 95% CI, 5%24%). D2B times of <90 minutes were achieved for 86% of those fieldtriaged directly to a PCI hospital, 80% of

transferred patients, and 82% of the entire cohort.

COMMENT

This study reinforces the importance of timely transportation of the STEMI patient to the PCI hospital from the field. In the U.S., national initiatives by the American Heart Association and American College of Cardiology are in place to assist healthcare professionals not only to maintain the improvements they have achieved in D2B times, but also to extend their focus to outof-hospital emergency response systems.

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CARDIOLOGY
Brodie BR et al. When is door-to-balloon time critical? Analysis from the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) and CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) Trials. J Am Coll Cardiol 2010 Jul 27; 56:407.

Vol. 16

No. 10

The causes of prehospital system delays remain unknown; however, the bottom line is that we can do better, and if we do, we are likely to save lives.
Harlan M. Krumholz, MD, SM
Terkelsen CJ et al. System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA 2010 Aug 18; 304:763.

Thomas M et al. Thirty-day results of the SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry: A European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve. Circulation 2010 Jul 6; 122:62. Tuzcu EM et al. SOURCE of enthusiasm for transcatheter aortic valve implantation. Circulation 2010 Jul 6; 122:8.

More European Results on TAVI

Encouraging findings from a study of short-term registry data

Is Better Risk Assessment Within REACH?

An analysis of registry data could be a first step toward an improved strategy.

When Is D2B Time Most Important?

Retrospective findings suggest that high-risk patients presenting early after symptom onset stand to lose the most from delays.

Subgroup analyses from studies of primary percutaneous coronary intervention for treatment of myocardial infarction (MI) have suggested that door-to-balloon time (DBT) matters more for some patients than for others. In a retrospective study of data from two trials including 4548 patients with ST-segment-elevation MI, investigators evaluated whether the effect of DBT on 1-year mortality depends on clinical risk, time to presentation, or both. They used a modified Thrombolysis in MI (TIMI) score to assess clinical risk. The median time from symptom onset to presentation was 112 minutes, and the median DBT was 107 minutes. Patients with DBTs of 90 minutes had lower 1-year mortality than patients with DBTs of >90 minutes (3.1% vs. 4.3%; P=0.045). In patients who presented 90 minutes after symptom onset, those with DBTs of 90 minutes had lower 1-year mortality than those with longer DBTs (1.9% vs. 3.8%; hazard ratio, 0.49; P=0.029). In patients with longer times to presentation, DBT did not affect mortality. Among high-risk patients, mortality trended lower in those with a short DBT than in those with a long DBT.
COMMENT

Treatment of aortic stenosis with transcatheter aortic valve implantation (TAVI) is becoming routine outside the U.S.; two devices are now available. These investigators report 30-day outcomes in 32 European centers participating in the manufacturersponsored SOURCE registry following commercial release of the SAPIEN device. The cohort included 1038 adults (mean age, 81), 463 of whom received the device transfemorally (TF) and 575 transapically (TA). All patients were at high risk (logistic EuroSCORE, 29% with TA; 26% with TF) for complications of surgical aortic valve replacement (AVR). The procedural success rate was >90%, but important complications included valve embolization (0.3%), coronary obstruction (0.6%), and conversion to surgical AVR (2.7%). Adverse events at 30 days included death (8.5%), new need for a pacemaker (7.0%), major vascular complications (7.0%), renal failure requiring dialysis (4.3%), and stroke (2.5%). Mortality was slightly higher and vascular complications lower in the TA group than in the TF group; the authors attributed the increased mortality in the TA group to their higher baseline risk profile.
COMMENT

Several algorithms for predicting an individuals risk for cardiovascular events are available, but none has proven to be accurate, easy to use, and applicable to a broad population. To evaluate the relative importance of various risk factors, investigators for the industry-supported REACH Registry in 29 countries enrolled outpatients aged 45 who had either stable coronary artery, peripheral arterial, or cerebrovascular disease or three or more risk factors for atherosclerosis. Risk factors included diabetes, diabetic nephropathy, ankle-brachial index <0.9, asymptomatic carotid stenosis 70%, carotid intimamedia thickness at least twice that of adjacent sites, systolic blood pressure 150 mm Hg despite treatment, hypercholesterolemia requiring treatment, current smoking, and age 65 for men or 70 for women. A total of 45,227 patients had baseline data, kept at least one follow-up appointment, and were enrolled at centers that participated for the entire study period. The cumulative 4-year incidence of cardiovascular death, myocardial infarction, or stroke was about 12%. The strongest predictor of events was the presence of polyvascular disease (atherothrombosis in two or three arterial beds), which nearly doubled the risk for a cardiovascular event compared with the presence of risk factors only (hazard ratio, 1.99; 95% confidence interval, 1.782.24). Other important event predictors were the presence of heart failure and an ischemic event within 1 year before enrollment. Patients in Eastern Europe and the Middle East were at higher risk than those in other regions.
COMMENT

These observational findings indicate that a short DBT is most beneficial early after symptom onset and in patients at high clinical risk. The results are consistent with those of most, but not all, prior studies. The authors propose that high-risk patients who present early but face a long anticipated DBT might benefit from alternative or facilitated reperfusion strategies; this hypothesis should be tested in future trials. Howard C. Herrmann, MD

This early real-world experience with a TAVI device in high-risk patients with aortic stenosis demonstrates a high short-term procedural success rate and low overall 30-day mortality and also reveals opportunities for improvement (e.g., avoidance of vascular complications, valve malposition). Data on long-term survival and comparison with surgically and medically managed patients are needed to further define the role of this new therapy.
Howard C. Herrmann, MD

This study provides risk estimates for outpatients with or at high risk for cardiovascular disease. The identified

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predictors are not surprising, but the findings show that event rates in patients with these factors are high and vary considerably by clinical characteristics and region. I would like to see these results translated into a score and compared with other scores that purportedly stratify patient risk. Harlan M. Krumholz, MD, SM
Bhatt DL et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010 Aug 30; 304:[e-pub ahead of print]. (http://dx .doi.org/10.1001/jama.2010.1322)

In a separate analysis, the risk for a primary endpoint increased by 3% for every beat increase in heart rate per minute at baseline. In the ivabradine group, heart rate at 28 days correlated directly with risk for a primary endpoint.
COMMENT

Shifting Attention to Heart Rate

Slowing heart rates with ivabradine improves outcomes in patients with heart failure.

A fast heart rate predicts adverse outcomes in patients with chronic heart failure, but is it a marker or a mediator? In SHIFT, a randomized, placebo-controlled, manufacturersponsored study, investigators evaluated the effects of ivabradine, a selective sinusnode inhibitor, in 6505 adults (mean age, 60; 76% men) with symptomatic heart failure, left ventricular ejection fractions 35%, and baseline heart rates 70 beats per minute (bpm). The primary endpoint was a composite of cardiovascular death and hospitalization for heart failure. Median follow-up was 22.9 months. At baseline, mean heart rate was 80 bpm, and average systolic blood pressure was 122 mm Hg. About 90% of the participants took beta-blockers, although only 56% received at least 50% of the guidelinerecommended doses. At 1 month, mean heart rate was 64 bpm in the ivabradine group and 75 bpm in the placebo group. A primary endpoint occurred in 24% of the ivabradine group and 29% of the placebo group (hazard ratio, 0.82; 95% confidence interval, 0.750.90). The most marked reductions with ivabradine were in death from heart failure (3% vs. 5% with placebo; HR, 0.74; 95% CI, 0.580.94) and hospital admission for heart failure (16% vs. 21%; HR, 0.74; 95% CI, 0.660.83). However, the between-group differences were nonsignificant in patients with baseline heart rates <77 bpm. Study withdrawal was slightly more common in the ivabradine group than in the placebo group (21% vs. 19%; HR, 1.14; 95% CI, 1.021.27), but serious adverse events were more common in the placebo group (45% vs. 48%; P=0.025).

The benefits of ivabradine apparent in this study are diminished by the fact that many patients were not receiving target doses of beta-blockers. The authors caution that the results should be interpreted as favoring ivabradine only in patients with heart rates 70 bpm who cannot tolerate optimal doses of beta-blockers. Importantly, these findings support a mediating role for heart rate in outcomes of heart failure and suggest (although the study neither tests nor proves it) a benefit from titrating betablockers to achieve a target heart rate.
Harlan M. Krumholz, MD, SM
Swedberg K et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebocontrolled study. Lancet 2010 Aug 29; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736 (10)61198-1) Bhm M et al. Heart rate as a risk factor in chronic heart failure (SHIFT): The association between heart rate and outcomes in a randomised placebocontrolled trial. Lancet 2010 Sep 11; 376:886.

During a median of 7 months of follow-up, the rate of AF recurrence was higher in the dronedarone group than in the amiodarone group (64% vs. 42%). The rate of drug discontinuation was higher in the amiodarone group than in the dronedarone group (13% vs. 10%), and drug discontinuation because of any adverse effects (e.g., thyroid, neurological, and skin) was significantly more common in the amiodarone group (11% vs. 5%).
COMMENT

The holy grail of an effective, well-tolerated medical treatment for AF remains elusive. Dronedarone, like other antiarrhythmic agents, appears to be safer than amiodarone but not as effective: For every 100 patients treated with amiodarone, 22 more than those treated with dronedarone avoided a recurrence of AF, but 6 more had a serious adverse event. Dronedarones precise place in the antiarrhythmic pantheon remains to be determined, but its safety profile is reassuring, and it is a welcome new drug. Mark S. Link, MD
Le Heuzey J-Y et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: The DIONYSOS Study. J Cardiovasc Electrophysiol 2010 Jun 1; 21:597.

A Head-to-Head Comparison of Two Drugs for Atrial Fibrillation

In a short-term randomized study, dronedarone was less toxic than amiodarone, but also less effective.

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Amiodarone is the most effective agent for treating persistent atrial fibrillation (AF). However, it is not FDA approved for this indication, and its adverse effects on thyroid, liver, and pulmonary function limit its use, especially in the long term. Dronedarone, which received FDA approval for AF treatment in 2009, is chemically similar to amiodarone but differs in iodine content and tissue absorption, putatively reducing its toxicity a hypothesis supported by the results of the placebocontrolled ATHENA trial (JW Cardiol Mar 2009, p. 23, and N Engl J Med 2009; 360:668). Now, investigators have compared the effectiveness and safety of dronedarone and amiodarone in an international, manufacturer-sponsored, randomized controlled trial involving 504 patients with AF requiring cardioversion.

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JOURNAL WATCH SUBSCRIBERS HAVE 10 FREE CREDITS! This is one of four questions in a recent Journal Watch Online CME exam. from Clopidogrel and Aspirin for ACS: Have We Found an OASIS? (p. 78) Which of the following statements best describes a finding from the CURRENTOASIS 7 trial of aspirin and clopidogrel dosing for acute coronary syndromes? A. In PCI recipients, double-dose clopidogrel reduced the risk for MI compared with standard-dose clopidogrel. B. In the cohort as a whole, double-dose clopidogrel did not increase the risk for major bleeding compared with standard-dose clopidogrel. C. In PCI recipients, high-dose aspirin increased the risk for major bleeding compared with low-dose aspirin. D. All of the above. Category: Cardiovascular Diseases Exam Title: Clopidogrel Therapy Posted Date: Sep 21 2010 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. 10

More Good News About Dabigatran

Dabigatrans advantages over warfarin are increased at centers with poor control of INR in warfarin therapy.

secondary endpoints in the warfarin and dabigatran groups in each quartile. Of 5791 participants assigned to warfarin, those treated at centers with higher rates of therapeutic INR time had lower risks for the composite endpoint of stroke and systemic embolism, major bleeding, and mortality than those treated at centers with lower rates of therapeutic INR time. At centers with lower rates of therapeutic INR time, dabigatran was associated with significant reductions in the composite endpoint of cardiovascular events and total mortality, as compared with warfarin.
COMMENT

Wallentin L et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: An analysis of the RE-LY trial. Lancet 2010 Sep 11; 376:875.

The race is on to find an alternative to warfarin, which is currently the most effective agent for preventing stroke in patients with atrial fibrillation (AF) but has a narrow therapeutic range that is difficult and inconvenient to sustain. A new agent, dabigatran, has recently demonstrated noninferiority to warfarin in >18,000 patients with documented AF and at least one other risk factor for stroke who participated in RE-LY, a manufacturer-funded international trial (JW Cardiol Oct 2009, p. 82, and N Engl J Med 2009; 361:1139). In a prespecified substudy, the RE-LY investigators divided the trial centers into quartiles by the average time participants on warfarin had international normalized ratios (INRs) within therapeutic range, and compared rates of the primary and

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In this study, poor control of INR in patients assigned to warfarin amplified the relative benefits of dabigatran. One would expect that patients who are enrolled in clinical trials would achieve better INR rates than patients who are not. Therefore, these findings suggest that in real-life clinical situations, the advantages of dabigatran over warfarin could be even greater than they were in the RE-LY trial. Mark S. Link, MD

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