Further information: Treatment of Acute ST-Elevation Myocardial Infarction (see p963) and Percutaneous Coronary Intervention for Acute Myocardial Infarction (see p1021) from Cardiovascular Medicine, 3rd Edn*

The wisdom of discouraging the performance of percutaneous coronary intervention (PCI) in non-infarct related arteries (non-IRA) concurrently with primary PCI was evaluated by investigators in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial [1]. Guidelines from the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) discourage the practice of performing PCI in non-IRAs concurrently with primary PCI in stable ST-elevation myocardial infarction (STEMI) patients. However, additional examination of the issue was needed because the guideline recommendations were based on observational studies from an earlier era. Therefore, the investigators used the data from the APEX-AMI trial, the largest report of its kind to date, to reach a more timely recommendation by examining 90 day outcomes following non-IRA interventions performed at the time of primary PCI. After comparing the current data with the data obtained from the earlier studies, the investigators found the interventions were associated with increased mortality and adverse outcomes, and they continue to strongly support the ESC and ACC/AHA guideline recommendations.

[1] Toma M, Buller CE, Westerhout CM, et al. Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial. European Heart Journal 2010;31:1701-7

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Further information: Coronary Artery Bypass Surgery and Percutaneous Coronary Revascularization: Impact on Morbidity and Mortality in Patients with Coronary Artery Disease (see p1073) from Cardiovascular Medicine, 3rd Edn*

Results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial were published in 2006 in The New England Journal of Medicine [1] and the trial was the longest and largest study ever conducted to evaluate the risks of dual antiplatelet therapy (DAPT) in patients who had undergone percutaneous coronary intervention with either bare metal or drug-eluting stents. The study determined that dual antiplatelet therapy (DAPT), aspirin and clopidogrel, reduced thrombotic events in patients with ST-segment elevation acute coronary syndromes and with non-ST-segment elevation acute coronary syndromes.

Two areas of uncertainly addressed by the current analysis [2] of the CHARISMA data were the amount of time DAPT should be continued in patients with known risk factors, as well as in stable patients with known vascular disease, by studying the frequency and time course of bleeding and whether bleeding is associated with mortality. Data from 15,603 patients were analyzed. Bleeding risk was found to be greatest in the first year: with clopidogrel, severe bleeding occurred in 1.7% vs. 1.3% on placebo (P=0.087), moderate bleeding occurred in 2.1% vs. 1.3%, respectively (P=0.001). Investigators found that when a patient did not have either severe or moderate bleeding the first year, bleeding thereafter was no more likely than for placebo patients. Multivariable analysis showed a strong relationship between moderate bleeding and all-cause mortality (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.71–3.80; P<0.0001), as well as with myocardial infarction (HR, 2.92; 95% CI, 2.04–4.18; P<0.0001), and stroke (HR, 4.20; 95% CI, 3.05–5.77; P<0.0001). This analysis of the CHARISMA data provides important data for the clinician as to the risks and benefits of DAPT in the treatment of stable patients or patients with vascular disease or known risk factors for vascular disease.

[1] Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17

[2] Berger PB, Bhatt DL, Fuster V, et al. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease (CHARISMA). Circulation 2010;121:2575-83

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Further information: Coronary Artery Disease: Pathologic Anatomy and Pathogenesis (see p593), Arterial Compliance (see p1811), Atrial Fibrillation and Flutter (see p1955), and Sudden Cardiac Death (see p2039) from Cardiovascular Medicine, 3rd Edn*

In 1985 and 1986 respectively, two articles were published in Circulation [1,2] that reported that myocardial platelet thrombi were embolic and that the emboli were a cause of acute coronary syndromes (ACS). Although prior histopathological studies had shown intramyocardial microemboli and microvascular obstruction (MVO) were present in patients with ischemic cardiac death, the association between culprit coronary morphology and intramyocardial emboli had not been reported. Therefore, the investigators in this study [3] determined to evaluate the frequency of intramyocardial microemboli and MVO in sudden cardiac death from acute coronary thrombosis. Differentiating between plaque rupture and plaque erosion were important elements of the study. Plaque rupture was defined as “disruption of a fibrocellular cap overlying a pool of lipid with pultaceous debris,” and plaque erosion was defined as “surface ulceration of the upper plaque layers without rupture into a lipid core.”

Through analysis at autopsy of coronary arteries of 44 hearts, 26 plaque ruptures and 21 erosions were found, and there was a mean of 4.5 microemboli per heart. Microemboli and MVO occurred in eroded plaques more often, and although all vessels contained fibrin and platelets, microemboli and occluded intramyocardial vessels were more common in the LAD of the coronary artery. The mean stenosis of the culprit lesion was 74% in the arteries with microemboli and 75% in those without (P=NS). Intramyocardial microemboli were more common in plaque erosion than in plaque rupture.

The investigators concluded that plaque erosion was dominant in the histopathology of clot embolization causing sudden cardiac death, was more likely to occur in vessels of less than 120 µm, and was associated with focal necrosis.

[1] Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985;71:699-708

[2] Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986;73:418-27

[3] Schwartz RS, Burke A, Farb A, et al. Microemboli and microvascular obstruction in acute coronary thrombosis and sudden coronary death. J Am Coll Cardiol 2009;54:2167-73

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Further information: Medical Treatment of Unstable Angina, Acute Non–ST-Elevation Myocardial Infarction, and Coronary Artery Spasm (see p937), Pathophysiology and Clinical Impact of Diastolic Heart Failure (see p1201) and Dilated Cardiomyopathy (see p1233) from Cardiovascular Medicine, 3rd Edn*

This article [1] contains observations from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis in Myocardial Infarction 36) Trial (MERLIN-TIMI 36), a trial conducted at 440 sites between 2004 and 2007 to determine the efficacy and safety of ranolazine in long-term treatment of 6500 patients with non-ST segment elevation acute coronary syndromes (ACS). As part of the MERLIN-TIMI 36 trial, investigators designed a prospective evaluation of the interaction between B-type natriuretic peptide (BNP) and the effect of ranolazine in patients with ACS. Because elevated BNP and the N-terminal portion of BNP prohormone identify patients at high risk of death and heart failure (HF), intense effort is being made to find treatments that would mitigate the risk of elevated BNP. There were 4543 baseline samples in which BNP had been measured from patients who had been randomized to ranolazine or placebo, and the patients were followed for 343 days. BNP elevation was defined as >80 pg/ml. The primary end point was a composite of cardiovascular (CV) death, myocardial infarction (MI), and recurrent ischemia.

Results showed that in 1935 patients with elevated BNP (>80 pg/ml), the risk of the primary end-point was higher (26.4% vs. 20.4%, P=0.0001), higher for CV death (8.0% vs. 2.1%, P<0.001, and higher for MI (10.6% vs. 5.8%, P<0.001) at 1 year. The primary end-point was reduced by ranolazine (hazard ratio [HR]; 0.79; 95% confidence internal [CI]: 0.66–0.94, P=0.009). For recurrent ischemia in patients with elevated BNP, the effect of ranolazine was directionally similar (HR: 0.78; 95% CI: 0.62–0.98; P=0.04) and CV death or MI (HR: 0.83; 95% CI: 0.66–1.05, P=0.12). Ranolazine had no effect on patients without elevated BNP, did not reduce BNP concentration over time, and did not reduce the clinical end-point for patients with new or worsening HF. Nevertheless, it did identify patients at high risk of recurrent myocardial ischemia ameliorated by ranolazine. Therefore, the investigators concluded that the effects of ranolazine warrant additional study.

In an editorial [2] in this same issue of JACC, the authors stated that while this carefully done study does not provide conclusive evidence that ranolazine should be used in patients with ACS and elevated BNP levels, it does lay the groundwork for a prospective clinical trial.

[1] Morrow DA, Scirica BM, Sabatine MS, et al. B-Type Natriuretic Peptide and the Effect of Ranolazine in Patients with Non-ST Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol 2009;55:1189-96

[2] Califf RM, Shah SH, Newby LK. Biomarker Bonanza? J Am Coll Cardiol 2009;55:1197-99
 
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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Exercise Testing (see p729),
Coronary Angiography (see p745),
Echocardiographic Evaluation of Coronary Artery Disease (see p811)
and Myocardial Perfusion Imaging Utilizing Single Photon Emission Computed Tomography Techniques (see p841) from Cardiovascular Medicine, 3rd Edn*

At University Medical Center in Rotterdam, The Netherlands, investigators conducted an observational study [1] to compare the accuracy of noninvasive diagnostic testing in the diagnosis of coronary artery disease (CAD) in patients with chest symptoms. The reference standard for diagnosing CAD is invasive coronary angiography (ICA), an expensive test when compared to noninvasive diagnostic testing. Noninvasive diagnostic stress tests include exercise electrocardiography (ECG), single-photon emission computed tomography (SPECT), or stress echocardiography, and while these tests are less expensive, they are also less accurate. A newer noninvasive diagnostic test is computed tomography coronary angiography (CTCA).

The purpose of the study was to compare the accuracy and clinical utility of CTCA with stress testing when determining which patients required invasive testing. In two enrollment periods, investigators enrolled 517 patients who had been referred to the medical center by their physicians. The first group of 297 patients underwent stress testing, CTCA, and ICA. The second group of 220 patients underwent stress testing and CTCA.

Investigators concluded that in patients with low pretest probability of CAD, stress testing was adequate as a first diagnostic test. They determined that CTCA was more accurate when used in patients with a pretest intermediate probability because it was better able to determine which patients required invasive testing. In patients with a high pretest probability, neither stress testing nor CTCA served as an additional diagnostic tool, and physicians should prescribe ICA immediately.

[1] Weustink AC, Mollet NR, Neefjes LA, et al. Diagnostic accuracy and clinical utility of noninvasive testing for coronary artery disease. Ann Intern Med 2010;152:630-39

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Further information: Percutaneous Coronary Intervention for Acute Myocardial Infarction (see p1021) and  Drug-Eluting Coronary Stents (see p1031) from Cardiovascular Medicine, 3rd Edn*

Current guidelines for patients who have undergone percutaneous coronary intervention (PCI) recommend that patients who are not at risk of bleeding should be given clopidogrel (anti-platelet therapy), 75 mg daily, for 12 months following their procedure. However, the length of time that anti-platelet therapy should be further extended beyond 12 months has not been determined. The current study [1] evaluated data from two concurrent, randomized, clinical trials that compared continuation and discontinuation of clopidogrel: Correlation of Clopidogrel Therapy Discontinuation in Real-world Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events (REAL-LATE) and Evaluation of the Long-Term Safety after Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesion-Late Coronary Arterial Thrombotic Events (ZEST-LATE). Enrollment occurred from July 2007 through September 2008 in 22 cardiac centers in South Korea, and the two trials enrolled a total of 2701 patients who were free of major adverse cardiac or cerebrovascular events and major bleeding for at least 12 months after PCI. The group who had aspirin only and for whom clopidogrel was discontinued was assigned 1344 patients, and in the group for whom clopidogrel plus aspirin were continued, there were 1357 patients. The primary end point was the first occurrence of myocardial infarction (MI) or death from cardiac causes after group assignment. Secondary end points were death from any cause, MI, stroke, stent thrombosis, repeat revascularization, composite of MI or death from any cause, and major bleeding.

Cumulatively, the risk of primary outcome at 2 years was 1.8% with clopidogrel plus aspirin, as compared with 1.2% with aspirin alone (hazard ratio [HR], 1.65; 95% confidence interval [CI], 0.80–3.36; P=0.17). There was a non-significant difference in primary individual risks between the two groups, and there was a nonsignificant increase in composite risks in the group having both clopidogrel and aspirin.

The investigators concluded that the extended use of dual antiplatelet therapy (clopidogrel and aspirin) for more than 12 months after PCI was not significantly more effective than the use of aspirin alone to reduce risk of MI or death from cardiac causes.

[1] Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;362:1374-82

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Further information: Intervention for Unstable Coronary Artery Disease (see p1005) from Cardiovascular Medicine, 3rd Edn* Percutaneous Coronary

Although atorvastatin is currently administered 3–7 days prior to percutaneous coronary intervention (PCI), the Naples II study [1] was conducted to determine if a single, high-loading 80 mg dose of atorvastatin administered within 24 hr prior to a procedure for PCI could reduce the incidence of periprocedural elevation of the cardiac enzyme creatine kinase-myocardial isoenzyme (CK-MB), an indicator of myocardial infarction (MI). The Naples II trial was a two-center, prospective, randomized study that enrolled 668 statin-naïve patients. Of that total, 338 were assigned to receive 80 mg atorvastatin and 330 were in the no-statin control group. The primary end point of this study was CK-MB elevation more than three times upper-known limit (UKL) alone or associated with chest pain or ST-segment or T-wave abnormalities, while the secondary end-points included the rate of cTnl elevation more than three times ULN and the composite of all in-hospital events, i.e. death, MI, and repeated revascularization.

In the atorvastatin group, periprocedural MI was 9.5%, and it was 15.8% in the control group (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35–0.89; P=0.014). Median CK-MB peak after PCI was 2.10 ng/ml (interquartile range [IR] 1.00–12.50 ng/ml) in the atorvastatin group and 3.20 ng/ml (IR 1.37–16.07 ng/ml) in the control group (P=0.014). Cardiac troponin I elevation >3X ULN was 26.6 % in the atorvastatin group and 39.1 % in the control group (OR, 0.56; 95% CI, 0.40–0.78; P<0.001). The results of the study confirmed the effectiveness of the single high-loading 80 mg dose of atorvastatin when administered 24 hr before PCI, showing the cardioprotective effect of a statin independent from cholesterol reduction. Thus, for the statin-naive patient, the need to postpone PCI is unnecessary when atorvastatin is administered.

In an accompanying editorial [2], the author expressed his opinion that although the Naples II study confirmed the major benefit of a 24-hr pre-procedural administration of 80 mg atorvastatin, one drawback to the study was that it was not powered to assess long-term, hard end-points. For the clinician’s use of the Naples II trial data, he opined that the overall result showed that all patients should be treated with a high dose of a potent statin. For patients who were not statin-naive, the clinician should consider a high-dose reloading of a potent statin at least 12 hr prior to PCI.

[1] Briguori C, Visconti G, Focaccio A, et al. Novel approaches for preventing or limiting events (Naples) II Trial. JACC 2009;54:2157-63

[2] Tsimikas S. High-dose statins prior to percutaneous coronary intervention. JACC 2009;54:2164-6

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Further information: Medical Treatment of Unstable Angina, Acute Non–ST-Elevation Myocardial Infarction, and Coronary Artery Spasm (see p937) and Percutaneous Coronary Intervention for Unstable Coronary Artery Disease (see p1005) from Cardiovascular Medicine, 3rd Edn*

In August of 2009, a summary of an article published in JAMA [1] was posted on this website [2].  The article addressed the possibility of adverse effects occurring in patients who used clopidogrel and proton pump inhibitors (PPIs) together, with the primary concern being that the effectiveness of clopidogrel could be reduced, leaving patients at risk of thrombotic events.  During the American Heart Association 2009 Scientific Sessions in Orlando, FL, November 14–18, 2009, the Food and Drug Administration (FDA) issued a new public-health warning [3] that reinforced the concern regarding adverse reactions.  Several clinical investigators who were interviewed in Orlando expressed surprise over the FDA’s newly issued warning, citing several randomized trials whose results had not shown an indication of adversity.  The statement by the FDA recommended that patients taking clopidogrel should consult their healthcare provider before also taking a PPI, such as omeprazole.  An article [4] and editorial [5] recently published in Circulation are abstracted and cited here and add additional information to the controversy.

In view of the controversy surrounding the safety issues for patients using clopidogrel and a PPI together, investigators conducted a retrospective study [4] conducted from three large databases in order to address study design issues in an effort to determine whether a higher rate of adverse outcomes occurred in patients taking clopidogrel and PPIs versus patients taking clopidogrel alone.  Included in the current study were patients enrolled in the following programs: the Provincial Healthcare System funded by the British Columbia government; the Pharmaceutical Assistance Contract for the Elderly in Pennsylvania; and the Pharmaceutical Assistance to the Aged and Disabled in New Jersey.  In all, there were 64,561 patients of 65 years of age and over in the  cohort who underwent percutaneous coronary intervention or hospitalization for acute coronary syndrome between 2001 and 2005, and the results of the study showed a modest increase in risk of hospitalization or death from myocardial infarction (MI), but with wide confidence intervals and no substantial or statistically significant clopidogrel-PPI interaction, leading the authors to believe that the studies using conventional adjustment may not have adequately accounted for confounding in this treatment group.  In this study, the investigators employed a more extensive confounding adjustment and verified that after adjustment, the PPI users were not significantly more likely to be at increased risk for MI or death, and not likely to exceed a 20% risk increase.

In an editorial [5] that accompanied this article, the author studied the entire body of evidence and concluded that while he believed there was no doubt that a pharmacological interaction existed, the issue was not one of clinical relevance.  The majority of patients are not threatened by the interaction.  However, there are unidentifiable patients who would be adversely affected by the combined use of clopidogrel and a PPI because of their genetic profiles, other currently taken drugs, or with other comorbidities, and therefore, until further information can be obtained, caution in prescribing the use of the two drugs together should be exercised.

[1] Ho M, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary symptoms. JAMA 2009;301:937-44

[2] Risk of Adverse Outcomes Associated with Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following ACS. http://cardiovascular-medicine.com/?p=178

[3] Food and Drug Administration. Public-health advisory: Updated safety information about a drug interaction between clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed at Prilosec and Prilosec OTC). http://www.fda.gov/Drugs/drugsafety/publichealthadvisories/ucm190825.htm November 17, 2009

[4] Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009;120:2322-29

[5] Juurlink DN. Proton pump inhibitors and clopidogrel: putting the interaction in perspective. Circulation 2009;120:2310-12

Further information: Percutaneous Coronary Intervention for Acute Myocardial Infarction (see p1021) from Cardiovascular Medicine, 3rd Edn*

The same group of investigators conducted two large, phase 3, randomized clinical trials that compared cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist with clopidogrel, both P2Y12 antagonists. In one trial, “Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PCI),” [1] the drugs were administered to patients before percutaneous coronary intervention (PCI), and in a second trial, CHAMPION PLATFORM [2], the drugs were administered at the beginning and before the end of the procedure.

Trials conducted to find the most efficacious P2Y12 antagonist are important to patients with acute coronary syndromes (ACS) who need PCI. Current guidelines recommend an oral loading dose of 300–600 mg clopidogrel, preferably administered prior to PCI, and followed by 75 mg daily. Clopidogrel requires approximately an hour to achieve platelet inhibition, is irreversible, and platelets are slow to normalize after cessation of the drug, creating difficulty for patients who must undergo CABG instead of PCI. In addition, the effect of clopidogrel may be adversely influenced by genetic polymorphisms that create clopidogrel nonresponders. Conversely, cangrelor is administered intravenously, is rapid, predictable, and reversible.

CHAMPION PCI was a randomized, double-blind, double-dummy, active-control trial that enrolled 8877 patients and compared cangrelor with 600 mg clopidogrel in patients undergoing PCI. The drugs were administered at least 30 min before PCI and continued for at least 2 h or until the conclusion of the procedure. Patients were randomly assigned to either cangrelor or clopidogrel in a 1:1 double-blind, double-dummy design. The primary efficacy end-point of the study was composite of death from any cause, myocardial infarction (MI), or ischemia-driven revascularization at 48 h. The secondary end-points included death or MI at 48 h and at 30 days, or ischemia-driven revascularization.

Results showed that at 48 h, the primary end-point occurred in 7.5% of the cangrelor patients and 7.1% of patients in the clopidogrel group, and thus, cangrelor was not superior to clopidogrel. Results also showed that cangrelor was not significant at 30 days. Assessment of bleeding was based on three criteria: GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), TIMI (Thrombolysis in Myocardial Infarction) and ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy). Statistics for the rate of major bleeding differed with each tests, and results are reported in the article. For secondary end points, a trend toward cangrelor was shown, but it was not statistically significant (0.6% vs. 0.9%; odds ratio [OR], 0.67; 95% confidence interval [CI], 0.39–1.14; P=0.14). Investigators concluded that cangrelor, administered 30 min before PCI and continued for 2 h, was not superior to an oral loading dose of 600 mg clopidogrel that was administered 30 min before PCI in reducing the composite end-points of death, MI, or ischemia-driven revascularization in 48 h.

The major difference between the two trials was the timing of the administration of the study drugs, cangrelor vs. clopidogrel. In the first trial, both drugs were administered within 30 min prior to the start of PCI. In the second trial, cangrelor was administered at the beginning of PCI, and clopidogrel was administered at the end of the procedure. CHAMPION PLATFORM was a double-blind, placebo-controlled study in which a total of 5362 patients from 18 countries were enrolled from October 2006 to May 2009. Patients were assigned to receive either cangrelor (2654 patients) or placebo (2641 patients) at the time of PCI, followed later by 600 mg clopidogrel. The primary end-point was a composite of death, MI, or ischemia-driven revascularization 48 h post PCI, while the secondary end-points included individual rates of death, MI, new Q-wave MI, ischemia-driven revascularization, abrupt vessel closure, or stroke at 48 h.

Of the 2654 patients who received cangrelor, the primary end point occurred in 185 (7.0%) and of the 2641 patients who received placebo, it occurred in 210 (8.0%). An interim analysis was conducted that concluded the trial would be unlikely to show significant superiority for the primary end point. However, in the cangrelor group, two secondary end points were significantly reduced at 48 h. The rate of stent thrombosis was reduced from 0.6% to 0.2% (OR, 0.31; 95% CI, 0.11–0.85; P=0.02). The rate of death from any cause was reduced from 0.7% to 0.2% (OR 0.33; 95% CI, 0.13–0.83; P=0.02). There was no significant difference in the rate of blood transfusion. The rates of major bleeding did not differ significantly between the two groups according to the TIMI or GUSTO criteria, but according to the criteria for minor bleeding, ACUITY and GUSTO, the rates of minor bleeding were significantly higher in the cangrelor group because of the number of groin hematomas. The investigators concluded that additional study of cangrelor should be considered.

The writers of an accompanying editorial [3] recognized that cangrelor had negative results on the basis of the findings in both CHAMPION PCI and CHAMPION PLATFORM. The question raised in the editorial is whether or not the study design of the CHAMPION trials gave the drug an optimal chance to show better results that might be possible with cangrelor considering its advantages of intravenous administration and rapid onset and offset of action. The authors of the editorial believe that a drug with such assets warrants further study.

[1] Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI (CHAMPION PCI). N Engl J Med 2009;361:2318-2329

[2] Bhatt DL, Lincoff MA, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI (CHAMPION PLATFORM ). N Engl J Med 2009;361:2330-2341

[3] Kastrati AK, Ndrepepa G. Cangrelor—a champion lost in translation? N Engl J Med 2009;361:2382-2384

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Treatment of Acute ST-Elevation Myocardial Infarction (see p963) and Sudden Cardiac Death (see p2039) from Cardiovascular Medicine, 3rd Edn*

Investigators for the Immediate Risk Stratification Improves Survival (IRIS) trial sought to prove that when compared to optimal medical therapy after myocardial infarction (MI), early implantation of an implantable cardioverter-defibrillator (ICD) would improve survival of patients at risk of sudden death [1]. The trial was a multicenter, randomized, prospective trial that was investigator-initiated and open-label. From a total of 62,944 patients registered with MI between June 1999 and October 2007, 898 patients met the criteria for enrollment 5–31 days after the event. Of those, 453 were randomized to medical therapy alone and 445 to treatment with an ICD. Overall mortality was not reduced in the ICD group, although there were fewer sudden cardiac deaths ( 27 vs. 60; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.31–1.00; P=0.049). The number of cardiac deaths that were not sudden death was higher (68 vs. 39; HR, 1.92; 95% CI, 1.29–2.84; P=0.001). Investigators concluded that no evidence was found to substantiate that early implantation of an ICD improved survival in patients with acute MI who had clinical features that put them at increased risk of sudden death.

[1] Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantation early after myocardial infarction. N Engl J Med 2009;361:1427-1436

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