Coronary Artery Disease: Cannon CP

Harrington RA, Becker RC, Cannon CP, Gutterman D, Lincoff AM, Popma JJ, Steg G, Guyatt GH, Goodman SG, Anonymous00138. · Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27705, USA. · Chest. · Pubmed #18574276 links to  free full text

Abstract: This chapter about antithrombotic therapy for coronary artery disease is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicans Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggestions are weaker as there is uncertainty regarding the benefits, risks and costs such that individual patients' values may lead to different choices (for a full understanding of the grading see the "Grades of Recommendation for Antithrombotic Agents" chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations are the following: for all patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS), without a clear allergy to aspirin, we recommend immediate aspirin (162 to 325 mg po) and then daily oral aspirin (75 to 100 mg) [Grade 1A]. For NSTE ACS patients who are at at least moderate risk for an ischemic event and who will undergo an early invasive management strategy, we recommend "upstream" treatment either with clopidogrel (300 mg po bolus, followed by 75 mg/d) or a small-molecule IV glycoprotein (GP) IIb/IIIa inhibitor (eptifibatide or tirofiban) [Grade 1A]. For NSTE ACS patients who are at least moderate risk for an ischemic event and for whom an early conservative or a delayed invasive strategy of management is to be used, we recommend "upstream" treatment with clopidogrel (300 mg oral bolus, followed by 75 mg/d) [Grade 1A]. For NSTE ACS patients who undergo PCI, we recommend treatment with both clopidogrel and an IV GP IIb/IIIa inhibitor (Grade 1A). We recommend a loading dose of 600 mg of clopidogrel given at least 2 h prior to planned PCI followed by 75 mg/d (Grade 1B). For all patients presenting with NSTE ACS, we recommend anticoagulation with UFH or LMWH or bivalirudin or fondaparinux over no anticoagulation (Grade 1A). For NSTE ACS patients who will undergo an early invasive strategy of management, we recommend UFH (with a GP IIb/IIIa inhibitor) over either LMWH or fondaparinux (Grade 1B). For NSTE ACS patients in whom an early conservative or a delayed invasive strategy of management is to be used, we recommend fondaparinux over enoxaparin (Grade 1A) and LMWH over UFH (Grade 1B). We recommend continuing LMWH during PCI treatment of patients with NSTE ACS when it has been started as the "upstream" anticoagulant (Grade 1B). In low- to moderate-risk patients with NSTE ACS undergoing PCI, we recommend either bivalirudin with provisional ("bail-out") GP IIb/IIIa inhibitors or UFH plus a GP IIb/IIIa inhibitor over alternative antithrombotic regimens (Grade 1B).

Ray KK, Cannon CP, Braunwald E. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Int J Clin Pract. · Pubmed #17577297 links to  free full text

Abstract: The global burden of coronary artery disease has pushed lipid-lowering therapy to the forefront of medical management of this condition. Recent clinical trials have compared the efficacy of more intensive lipid lowering with statins against the normal standard of care. Other agents such as fibrates, glitazones, which also favourably modify lipid levels have also been assessed recently. This narrative review summarises the key recent clinical trials of lipid lowering since 2004 and their implications for future patient care.

Wiviott SD, Cannon CP. · Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Curr Opin Lipidol. · Pubmed #17095906 No free full text.

Abstract: PURPOSE OF REVIEW: The benefits of lipid lowering with statins are established in patients with or at risk for coronary artery disease. Recent trials with high doses of potent statins have examined treating to very low levels of LDL-cholesterol. Concerns have been raised about the safety of this strategy. This review examines the safety and efficacy of treating to very low LDL-cholesterol. RECENT FINDINGS: Four clinical trials, Treating to New Targets (TNT) and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) in stable coronary artery disease and Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 following acute coronary syndromes, have examined intensive statin therapy compared to moderate statin therapy. These trials and a meta-analysis demonstrated that intensive statin therapy reduces cardiovascular events. Subsequent analyses from these trials suggest that very low levels of LDL-cholesterol can be achieved safely and may improve clinical outcomes. A note of caution regarding hemorrhagic events following stroke with intensive statin therapy was raised by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial despite impressive reductions in cardiovascular events. SUMMARY: A growing body of evidence suggests progressive benefit for lowering LDL-cholesterol aggressively with intensive statin therapy in coronary artery disease. Future trials will be needed to define whether there is a level of LDL-cholesterol beyond which further benefit is not seen or safety concerns emerge.

Wiviott SD, Cannon CP. · TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. · Nat Clin Pract Cardiovasc Med. · Pubmed #16874355 No free full text.

Abstract: Serum cholesterol has long been recognized as an important risk factor for the development and progression of atherosclerotic vascular disease. For more than 30 years, improved outcomes with lipid lowering have been demonstrated. As a result of these data, the National Heart, Lung, and Blood Institute (NHLBI) convened the National Cholesterol Education Program-Adult Treatment Panel I (NCEP ATP I). This panel and similar ones around the world have served to set the standards for lipid lowering in clinical practice. Subsequent revisions of these standards (NCEP ATP II and III) have led to greater focus being placed on LDL, and targets for lowering LDL levels being based on patients' risk of subsequent coronary disease events. Since the publication of the NCEP ATP III guidelines, several large-scale clinical trials of cholesterol lowering have been conducted, the findings of which have the potential to impact on clinical practice standards. In this article we focus on current guidelines for lipid-lowering therapy, review the results and implications of important completed clinical trials, and consider the utility of additional targets for preventive therapy, such as C-reactive protein and HDL. We also consider the prospects for treatments in development and future goals.

Cannon CP. · Harvard Medical School, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Clin Cornerstone. · Pubmed #16473257 No free full text.

Abstract: The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors--cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)--and their natural ligands. The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism. When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance. Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome. Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease. Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors.

Cannon CP. · Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. · Cardiol Clin. · Pubmed #16278114 No free full text.

Abstract: For patients who have acute coronary syndromes (ACS), risk stratification is key to initiating appropriate treatment. For ST-segment elevation MI, immediate reperfusion therapy is needed, and thus rapid identification of ST elevation on the ECG is critical. Then, having a standardized protocol for rapid treatment- with either primary percutaneous coronary intervention or thrombolysis - is critical. For unstable angina/non-ST elevation ACS, after first identifying the patients who have a higher likelihood of actually having an ACS (as opposed to noncardiac chest pain) stratification to high versus lower risk is needed to choose appropriate therapies. Thus, it is important for risk stratification to be a central part of all management of patients who have ACS.

Ray KK, Cannon CP. · Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA. · Curr Opin Cardiol. · Pubmed #16234625 No free full text.

Abstract: PURPOSE OF REVIEW: Coronary artery disease is the largest cause of premature death in the Western world. Lipid-lowering therapy with statins has revolutionized the management of this condition over the past decade. RECENT DEVELOPMENTS: Successive clinical trials have lowered the treatment bar for statin therapy in patients with coronary artery disease. In addition to traditional markers of efficacy such as low-density lipoprotein cholesterol, emerging targets such as C-reactive protein are becoming recognized as important therapeutic goals. SUMMARY: This review focuses on the important contributions to the literature during the past year and provides an expert opinion of the therapeutic goals for statin therapy.

Ray KK, Cannon CP. · Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. · J Am Coll Cardiol. · Pubmed #16226165 No free full text.

Abstract: Emerging data suggest that acute presentations of coronary artery disease may involve a complex interplay between the vessel wall, inflammatory cells, and the coagulation cascade. Although a culprit thrombotic lesion may be treated effectively by antithrombotic therapy and revascularization, this will have little effect on the global processes that determine recurrent events at non-culprit sites. Thus, additional systemic treatment is required to modulate the adverse biological features that are the hallmark of acute coronary syndromes (ACS). Statins possess multiple beneficial effects that are independent of low-density-lipoprotein cholesterol (LDL-C) lowering and that have favorable effects on inflammation, the endothelium, and the coagulation cascade. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, differences were seen based on achieved LDL-C that could be further discriminated by the achieved C-reactive protein level. Studies of non-vascular disease such as multiple sclerosis have shown that statins reduce inflammation, supporting the presence of lipid-independent effects of statins. This review focuses on the potential importance of these effects in the management of ACS.

Ray KK, Cannon CP. · Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. · J Thromb Thrombolysis. · Pubmed #15789175 No free full text.

Abstract: Considerable progress has been made in our understanding of the pathophysiology of coronary artery disease (CAD), their acute presentations as acute coronary syndromes (ACS) and the role of LDL cholesterol. In particular there is clear evidence that atherosclerosis is far from being a process that leads to an amorphous flow limiting lesion on an angiogram, but rather involves a complex interplay between the endothelium, inflammatory cells and the coagulation cascade occurring throughout the coronary vascular bed. While a culprit flow limiting lesion may be effectively treated by a drug eluting stent or coronary bypass surgery, this will have little impact on the global molecular processes that determine recurrent plaque instability at non-culprit sites. The search for systemic long term therapy, which is safe and effective and reduces the changes in inflammation, endothelial function and thrombosis that are the hallmark of ACS, has pushed statins to the forefront. A number of recent clinical trials have shown the benefits of early statin therapy in the treatment of ACS. In addition to their effects on LDL cholesterol, statins have a number of properties collectively referred to as pleiotropic effects, which enable them to modulate the adverse biological changes that are associated with ACS. The purpose of this review is to acquaint the reader with the biological changes that accompany ACS, highlight how these pathways may be modulated for clinical benefit by statins and identify potential novel targets for future therapy.

Ray KK, Cannon CP. · TIMI Study Group, Cardiovascular Division, Department of Medicine Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Curr Opin Lipidol. · Pubmed #15529022 No free full text.

Abstract: PURPOSE OF REVIEW: The results of a landmark clinical study comparing intensive statin therapy with conventional statin therapy, in patients with acute coronary syndromes (ACS), are reviewed. The mechanisms behind these results are analysed drawing data from vascular and cell biology. RECENT FINDINGS: The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) study showed that intensive statin therapy with 80 mg of atorvastatin to achieve a low-density lipoprotein cholesterol of 62 mg/dl resulted in a 3.9% absolute and a 16% relative risk reduction in death or major cardiovascular events up to 2 years, compared to 40 mg of pravastatin, in patients with ACS. The results were especially significant as intensive statin therapy resulted in a very early benefit (<30 days) and occurred against a background of percutaneous coronary intervention (69%) for the index admission and high use of medications for secondary prevention. The PROVE IT and the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) C-reactive protein sub-study also showed that atorvastatin (80 mg) resulted in a significant reduction in markers of inflammation, whilst the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study showed that intensive statin therapy was associated with reduced progression of atherosclerosis compared with conventional doses of statins. SUMMARY: Intensive statin therapy results in a significant early reduction in adverse cardiac events in ACS patients which are sustained over 2 years. The early benefits seen are likely to result from modulation of inflammation, endothelial function and coagulation, i.e. the pleiotropic effects, whereas the greater reduction in low-density lipoprotein cholesterol results in reduced long-term events.

Gelfand EV, Cannon CP. · Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass, USA. · Am Heart J. · Pubmed #14760314 No free full text.

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Cannon CP. · Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Clin Cardiol. · Pubmed #12918637 No free full text.

Abstract: With the central importance of antiplatelet therapy in patients with coronary artery disease and the numerous positive trials with glycoprotein (GP) IIb/IIa inhibitors given intravenously, it was hoped that one could extend the benefit of IIb/IIIa inhibition to long-term treatment. Although the hypothesis that prolonged oral IIb/IIIa inhibition was appealing, many issues have been identified in the initial Phase II trials that would limit the usefulness of these compounds. Variability of the level of platelet inhibition was one major culprit that distinguished the oral compounds from intravenous ones. The problems that arose were that increased bleeding has been seen when levels of platelet inhibition are high (e.g., > 90%) and that, conversely, efficacy would likely be limited when levels of platelet inhibition were low. If further development of this class of drugs is undertaken, formal dosing studies would have to establish an oral dosing strategy that achieves appropriately high (80-95% inhibition) and steady levels of inhibition.

O'Rourke RA, Hochman JS, Cohen MC, Lucore CL, Popma JJ, Cannon CP. · Division of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78284, USA. · Arch Intern Med. · Pubmed #11231699 links to  free full text

Abstract: Recently, it has been demonstrated in multiple clinical research studies that non-Q-wave myocardial infarction shares many of the features of unstable angina pectoris and that both diseases initially are managed similarly. Important new antiplatelet drugs (glycoprotein IIb-IIIa inhibitors) and antithrombin agents (low-molecular-weight heparin) are currently recommended for patients with unstable angina pectoris/non-ST-segment elevation MI who are at high or intermediate risk on the basis of symptoms, electrocardiographic findings, and the presence or absence of serum markers (eg, troponin I, troponin T, and creatine kinase-MB). This review provides important information concerning the results of clinical studies of glycoprotein IIb-IIIa inhibitors (tirofiban hydrochloride and eptifibatide) when used with unfractionated heparin in patients with this syndrome or with low-molecular weight heparin (enoxaparin sodium) in similar patients. The Thrombolysis in Myocardial Infarction IIIB, Veterans Affairs Non-Q-Wave Infarction Studies in Hospital, and Fast Revascularization During Instability in Coronary Artery Disease II studies evaluating a conservative, ischemia-guided approach vs an early aggressive approach to such patients are presented, with a practical algorithm for treating such patients.

Cannon CP. · Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. · Coron Artery Dis. · Pubmed #10599534 No free full text.

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Tanasijevic MJ, Cannon CP, Antman EM. · Clinical Laboratories, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Clin Cardiol. · Pubmed #9929748 No free full text.

Abstract: In patients with chest pain at rest but no ST-segment elevation on the electrocardiogram, the diagnoses of unstable angina and non-Q-wave myocardial infarction (MI) are usually considered together because they cannot be differentiated clinically or angiographically. Since the extent of myocardial necrosis is an important determinant of the risk of death, it is important to identify serum markers with which to predict prognosis, in order to initiate appropriate medical treatment and/or invasive procedures in these patients. Cardiac troponin-I (cTnI), one of the subunits of the troponin regulatory complex, binds to actin and inhibits interactions between actin and myosin. The presence of elevated cTnI in serum is a significant prognostic indicator in patients with unstable angina and non-Q wave MI. Its independent prognostic potential persists even after adjustment for independent baseline variables known to be significantly associated with an increased risk of cardiac events. The use of cTnI in the triage of patients with unstable coronary disease may identify those at greater risk for adverse cardiac events.

Smith CS, Cannon CP, McCabe CH, Murphy SA, Bentley J, Braunwald E. · TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass 02115, USA. · Am Heart J. · Pubmed #15864232 No free full text.

Abstract: BACKGROUND: Lipid-lowering is effective in the prevention of cardiovascular morbidity and mortality in patients with coronary artery disease, but effective strategies for improving the implementation of these therapies are needed. METHODS: In the 10,288 patients in the OPUS-TIMI 16 trial, patients were stratified by use of lipid-lowering therapy during index hospitalization and were compared for use of lipid-lowering therapy at follow-up as well as for clinical outcomes. RESULTS: Lipid-lowering therapy was used in 38% of patients during the index hospitalization, of which 94% were statins. At 10 months, 88% of patients who were discharged on lipid-lowering medications remained on these drugs. Conversely, only 34% of patients not discharged on lipid-lowering medications were receiving them at 10 months. Forty-one percent of patients with prior history of hyperlipidemia requiring treatment were not discharged on lipid-lowering therapy, and of these, only 51% were subsequently started on a lipid-lowering medication as an outpatient despite clear indications. Patients treated as inpatients with lipid-lowering therapy had a lower mortality rate at 10 months adjusted by propensity analysis (3.1% vs 5.1%, P < .0001) than patients not treated with lipid-lowering therapy. CONCLUSION: In patients with acute coronary syndromes, the initiation of lipid-lowering therapy in the inpatient setting increases the rate of its subsequent use at 10 months, making this an important method of ensuring appropriate secondary prevention.

Sadanandan S, Cannon CP, Gibson CM, Murphy SA, DiBattiste PM, Braunwald E, Anonymous00367. · Oklahoma University Health Sciences Center, Oklahoma City, USA. · J Am Coll Cardiol. · Pubmed #15312862 No free full text.

Abstract: OBJECTIVES: A simple risk score on admission to estimate the likelihood of in-hospital coronary artery bypass graft surgery (CABG) might be useful in selecting patients for early clopidogrel therapy. BACKGROUND: Routine early use of clopidogrel in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) is associated with increased risk of bleeding in patients who undergo early CABG. METHODS: The test cohort utilized to derive the score was the 2,220 patients with UA/NSTEMI enrolled in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction-18 (TACTICS-TIMI-18) trial. Patients who underwent CABG after randomization during index hospitalization were identified and were compared with patients who did not undergo in-hospital CABG. RESULTS: Overall, 362 patients (16.3%) underwent CABG during the index hospitalization. Patients with a history of prior CABG (n = 484) were significantly less likely to undergo in-hospital CABG (odds ratio [OR], 0.34). Five additional variables independently associated with CABG were identified: elevated troponin (OR, 3.9), prior stable angina (OR, 1.8), ST-segment deviation >or=0.5 mm (OR, 1.7), male gender (OR, 1.6), and history of peripheral arterial disease (OR, 1.6). A CABG risk score was generated by assigning numerical values to each of the variables based upon these odds ratios. Coronary artery bypass surgery rates increased significantly with increasing risk scores (6.2% for a risk score <3.0, 21.9% for 3 to 5, and 54.6% for >5.0). The association of the risk score with CABG was highly significant (p < 0.0001, c-statistic 0.72). The association remained significant in the validation cohorts from TIMI-11B trial and TIMI-III registry. CONCLUSIONS: Among patients with UA/NSTEMI, a novel risk score based on admission clinical variables can be used to estimate the likelihood of CABG. These data may assist in the identification of patients who might derive optimal benefit from early initiation of clopidogrel therapy.

Wylie JV, Murphy SA, Morrow DA, de Lemos JA, Antman EM, Cannon CP. · Division of Cardiology, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Mass 02215, USA. · Am Heart J. · Pubmed #15215808 No free full text.

Abstract: BACKGROUND: Few data are available about development of congestive heart failure (CHF) in patients with unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI). We developed and validated a risk score to predict which patients will develop CHF. METHODS: A subset of 4681 patients from the Orbofiban in Patients With Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction (OPUS-TIMI 16) trial with UA/NSTEMI and without a history of CHF were included in this analysis and stratified according to the development of CHF at 10 months. A risk score was created from significant variables and validated in the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI 18) trial. B-type natriuretic peptide (BNP) was then added to the initial multivariate analysis and validated in the TACTICS-TIMI 18 trial. RESULTS: The incidence of CHF at 30 days was 4.9%, and at 10 months it was 5.6%. Significant variables on multivariate analysis included age >65 years, heart rate >100 beats/min, history of diabetes mellitus, lateral electrocardiographic changes, and history of angiographically confirmed coronary artery disease. The risk of CHF increased 10-fold across the number of risk factors (P <.001). When validated in the TACTICS-TIMI 18 trial, the risk score was significantly associated with CHF at 6 months (P =.01). The median BNP value doubled across the number of risk factors (P <.001 for trend). The addition of BNP to the risk score improved its discriminatory capacity. CONCLUSIONS: In patients with UA/NSTEMI, a simple clinical risk score can aid in assessing the risk of developing CHF. BNP adds to the predictive capacity of this risk score. This score may assist in identifying patients who warrant more careful monitoring and therapy for CHF prevention inhospital and during follow-up.

Wiviott SD, Cannon CP, Morrow DA, Murphy SA, Gibson CM, McCabe CH, Sabatine MS, Rifai N, Giugliano RP, DiBattiste PM, Demopoulos LA, Antman EM, Braunwald E. · Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, Mass 02115, USA. · Circulation. · Pubmed #14769678 links to  free full text

Abstract: BACKGROUND: Diagnosis of coronary artery disease in women is more difficult because of lower specificity of symptoms and diagnostic accuracy of noninvasive testing. We sought to examine the relationship between gender and cardiac biomarkers in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: In the TACTICS-TIMI 18, OPUS-TIMI 16, and TIMI 11 studies, baseline samples were analyzed in the Thrombolysis In Myocardial Infarction (TIMI) biomarker core laboratory. We examined the relationship between gender and elevated biomarkers. Of 1865 patients from TACTICS-TIMI 18, 34% were women. Fewer women had elevated creatine kinase-MB or troponins, whereas more had elevated high-sensitivity C-reactive protein or brain natriuretic peptide. Presence of ST-segment deviation and TIMI risk scores were not significantly different. This pattern was confirmed in TIMI 11 and OPUS-TIMI 16. The prognostic value of the markers in TACTICS-TIMI 18 was similar in women and men. When a multimarker approach was examined, a greater proportion of high-risk women were identified. Marker-positive patients of both genders had improved outcome with an invasive strategy; however, marker-negative women appeared to have improved outcomes with a conservative strategy. CONCLUSIONS: In patients with UA/NSTEMI, there was a different pattern of presenting biomarkers. Men were more likely to have elevated creatine kinase-MB and troponins, whereas women were more likely to have elevated C-reactive protein and brain natriuretic peptide. This suggests that a multimarker approach may aid the initial risk assessment of UA/NSTEMI, especially in women. Further research is necessary to elucidate whether gender-related pathophysiological differences exist in presentation with acute coronary syndromes.

Cotter G, Cannon CP, McCabe CH, Michowitz Y, Kaluski E, Charlesworth A, Milo O, Bentley J, Blatt A, Krakover R, Zimlichman R, Reisin L, Marmor A, Lewis B, Vered Z, Caspi A, Braunwald E, Anonymous00253. · Cardiology Institutes of Assaf-Harofeh Medical Center, Zerifin, Israel. · Am Heart J. · Pubmed #12679757 No free full text.

Abstract: BACKGROUND: Cerebrovascular accidents (CVAs), transient ischemic attacks (TIAs), and peripheral arterial disease (PAD) frequently coexist with coronary artery disease (CAD) and were previously reported to adversely affect the prognosis of patients with chronic CAD. METHODS: We examined the effect of prior CVA/TIA or PAD (extra-cardiac vascular disease [EVD]) on the outcome of 10,281 patients with acute coronary syndromes enrolled in the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction (OPUS-TIMI) 16 trial of the oral glycoprotein IIb/IIIa antagonist orbofiban plus aspirin versus aspirin alone. We evaluated mortality, recurrent cardiac events, and stroke and used multivariate analysis to control for differences in baseline characteristics. RESULTS: Patients with EVD were older, had more coronary risk factors, had a history of CAD, and received more intensive medical treatment at baseline. The acute event in these patients was more often unstable angina pectoris and less commonly Q-wave myocardial infarction. With coronary angiography, patients with prior EVD more often had multivessel disease. During the 10 months of follow-up, the presence of EVD was predictive of an increased hazard of death, reinfarction, recurrent ischemia, stroke, and a composite of these events. Despite the increased severity of the CAD and increased risk of events, patients with EVD were treated less frequently with beta-blockers and more frequently with calcium blockers. Despite patients with EVD having a 45% higher incidence of hypercholesterolemia, lipid-lowering agents were prescribed in a similar percentage of patients as patients without EVD. CONCLUSION: In patients with acute coronary syndromes, the presence of prior CVA, TIA, or PAD is associated with more extensive CAD and worse outcome. These patients appear to receive less aggressive treatment, which may explain, at least in part, their worse outcome.

Glaser R, Herrmann HC, Murphy SA, Demopoulos LA, DiBattiste PM, Cannon CP, Braunwald E. · Department of Medicine, University of Pennsylvania, Philadelphia, USA. · JAMA. · Pubmed #12495392 links to  free full text

Abstract: CONTEXT: Women who present with acute coronary syndromes (ACSs) have different characteristics than men. Reports have conflicted about whether different outcomes exist for women with use of a routine invasive management strategy. However, these studies were performed prior to the widespread use of platelet glycoprotein IIb/IIIa inhibitors and intracoronary stents. OBJECTIVE: To determine sex differences in baseline characteristics and outcomes in ACS and whether women benefit from a contemporary early invasive management strategy. DESIGN AND SETTING: Prospective analysis of women and men enrolled in the TACTICS-TIMI 18 randomized trial, conducted December 1997 to December 1999 in 169 centers in 9 countries in North America and Europe, with follow-up at 1 and 6 months. PARTICIPANTS: A total of 2220 patients (757 women and 1463 men) with ACS. INTERVENTIONS: All patients received aspirin, 325 mg/d; intravenous unfractionated heparin; and tirofiban for 48 hours or until revascularization, with tirofiban administered for at least 12 hours after percutaneous coronary revascularization. Patients assigned to the early invasive strategy (n = 1114) underwent coronary angiography 4 to 48 hours after randomization and revascularization when appropriate. Patients assigned to the early conservative strategy (n = 1106) were treated medically and underwent coronary angiography and appropriate revascularization only if they met specified criteria. MAIN OUTCOME MEASURES: Baseline characteristics and the primary composite end point of death, myocardial infarction, or rehospitalization for ACS at 6 months in women and men assigned to early invasive vs conservative management. RESULTS: Women were older and more frequently had hypertension (P<.001 for both). Women less frequently had previous myocardial infarction, coronary artery bypass grafting, and elevations in cardiac markers (P<.001 for all), but there was no difference in distribution of TIMI risk scores (P =.76). Angiography and intervention rates were similar, but women had less severe coronary artery disease, including no critical lesions in 17% of women vs 9% of men (P<.001). Women had a 28% odds reduction in the primary end point with an early invasive strategy (adjusted odds ratio [OR], 0.72; 95% confidence interval [CI], 0.47-1.11), similar to the benefit in men (adjusted OR, 0.64; 95% CI, 0.47-0.88; P =.60 for sex interaction). When adjusted for baseline characteristics, the benefit of invasive therapy in women with elevated troponin T levels was further enhanced (adjusted OR, 0.47; 95% CI, 0.26-0.83). CONCLUSIONS: Despite differences between women and men in baseline characteristics, the benefit of an early invasive strategy incorporating tirofiban and intracoronary stents was similar in women and men and was enhanced in women presenting with markers of increased risk.

Sabatine MS, Morrow DA, Cannon CP, Murphy SA, Demopoulos LA, DiBattiste PM, McCabe CH, Braunwald E, Gibson CM. · TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. · J Am Coll Cardiol. · Pubmed #12446059 No free full text.

Abstract: OBJECTIVES: This study was designed to determine the relationship between baseline white blood cell (WBC) count and angiographic and clinical outcomes in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) and to see if WBC count was a significant predictor of outcomes independent of other biomarkers. BACKGROUND: Inflammation has been shown to play a role in atherosclerosis and acute coronary syndromes. METHODS: We evaluated the relationship between baseline WBC count, other baseline variables and biomarkers, angiographic findings, and clinical outcomes in 2,208 patients in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) trial. RESULTS: Higher baseline WBC counts were associated with lower Thrombolysis In Myocardial Infarction (TIMI) flow grades (p = 0.0045) and TIMI myocardial perfusion grades (p = 0.03) as well as a greater extent of coronary artery disease (CAD) (p < 0.0001). A higher baseline WBC count was predictive of higher six-month mortality, ranging from 1.5% to 3.6% to 5.1% for patients with low, intermediate, and high WBC counts, respectively (p = 0.0017). In a multivariable proportional hazards model, patients with a low C-reactive protein (CRP) but an elevated WBC remained at significantly higher risk of death at six months (hazard ratio [HR] 4.3, p = 0.049), and patients with a high CRP were at even higher risk (HR 8.6, p = 0.004). conclusions: In patients with UA/NSTEMI, elevations in a simple, widely available blood test, the WBC count, were associated with impaired epicardial and myocardial perfusion, more extensive CAD, and higher six-month mortality. After adjustment for traditional risk factors and other biomarkers, assessment of two inflammatory markers, WBC count and CRP, can be used to stratify patients across an eightfold gradation of six-month mortality risk.

Angeja BG, Kermgard S, Chen MS, McKay M, Murphy SA, Antman EM, Cannon CP, Braunwald E, Gibson CM. · Cardiovascular Division, Department of Medicine, University of California, San Francisco, USA. · J Thromb Thrombolysis. · Pubmed #12355029 No free full text.

Abstract: BACKGROUND: Despite increased risk for coronary artery disease and acute myocardial infarction (AMI), smokers have a paradoxically lower mortality after thrombolysis for AMI than non-smokers. We determined the clinical risk profiles and coronary flow characteristics of patients in the TIMI trials according to smoking status, focusing on microvascular flow. METHODS: Among 2,573 patients in the TIMI 4, 10A, 10B and TIMI 14 trials, epicardial flow post-thrombolysis was measured using angiographic TIMI flow grades and the corrected TIMI frame count (CTFC). Microvascular flow was measured by TIMI Myocardial Perfusion Grade (TMPG) and, in TIMI 14, the percentage of ST segment resolution. RESULTS: Clinically, the mean age (54 vs. 62 years), the prevalence of diabetes mellitus (11% vs. 16%) and hypertension (26% vs. 40%), and the 30-day mortality (2.6% vs. 6.2%) were lower among smokers than non-smokers (all p < or = 0.001). Angiographically, single-vessel disease (48% vs. 40%) and non-left anterior descending infarct arteries (65.4% vs. 60.8%) were more common among smokers (both p < or = 0.01). Epicardial TIMI grade 3 flow was achieved more often in smokers than non-smokers (61% vs. 56%) and the CTFC was faster (34 vs. 37 frames/sec, both p < or = 0.01), especially in LAD lesions. However, the frequency of normal microvascular flow (TMPG 3) was similar among smokers and non-smokers (24% vs. 29%, p = 0.16), as was the frequency of complete ST segment resolution (50% vs. 46%, p = 0.29). CONCLUSIONS: Smokers have lower mortality after AMI than non-smokers, due in large part to lower clinical risk profiles and faster epicardial flow. Differences in tissue-level perfusion do not appear to contribute to lower mortality in smokers.

Wong GC, Morrow DA, Murphy S, Kraimer N, Pai R, James D, Robertson DH, Demopoulos LA, DiBattiste P, Cannon CP, Gibson CM. · Department of Medicine, Brigham and Women's Hospital, Boston, Mass, USA. · Circulation. · Pubmed #12105159 links to  free full text

Abstract: BACKGROUND: Cardiac troponin T (cTnT) and I elevations are associated with a higher risk of adverse events, a higher incidence of multivessel disease, complex lesions, and visible thrombus in the setting of non-ST elevation (NSTE) acute coronary syndromes (ACS). Other pathophysiological mechanisms underlying troponin elevation remain unclear. METHODS AND RESULTS: We evaluated the relationship between troponin elevation and tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) in 310 patients with NSTE-ACS in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial. TMPG 0/1 ("closed" microvasculature) was observed more frequently in cTnT-positive patients both before (58.1% versus 42.1%; P=0.007) and after percutaneous coronary intervention (55.4% versus 35.6%; P=0.004). cTnT levels were higher among patients with TMPG 0/1 versus patients with TMPG 2/3 (0.50 versus 0.31 ng/mL; P=0.006). cTnT-positive patients were more likely to have thrombus (42.5% versus 29.3%), tighter stenoses (72.0% versus 64.8%), and higher rates of TIMI flow grade 0/1 (15.6% versus 7.0%; all P<0.05). TMPG 0/1 remained independently associated with cTnT elevation (odds ratio, 1.81; P=0.02), even after adjusting for epicardial TIMI flow grade, presence of thrombus, and prior myocardial infarction. TMPG 0/1 flow both before and after intervention was associated with increased risk of death or myocardial infarction at 6 months. CONCLUSIONS: Similar to what has been observed in the setting of ST-elevation myocardial infarction, abnormal tissue level perfusion is also associated with adverse outcomes in the NSTE-ACS setting. Independent of the presence of thrombus and abnormal flow in the epicardial artery, impaired tissue level perfusion is associated with a 1.8-fold increased risk of cTnT elevation.

Bray PF, Cannon CP, Goldschmidt-Clermont P, Moyé LA, Pfeffer MA, Sacks FM, Braunwald E. · Department of Medicine, Thrombosis Research Section, Baylor College of Medicine, Houston, Texas 77030, USA. · Am J Cardiol. · Pubmed #11545752 No free full text.

Abstract: Chromosome 17q21-23 harbors genes for platelet glycoprotein IIIa and angiotensin-converting enzyme (ACE), which are polymorphic for alleles Pl(A2) and ACE "D." These alleles have been independently and often associated with ischemic coronary artery disease (CAD). We sought to determine if the Pl(A2) and ACE D polymorphisms were risk factors for recurrent coronary events. In the Cholesterol And Recurrent Events (CARE) trial, 4,159 men and women with documented myocardial infarction (MI) were randomized to receive either placebo or pravastatin, and were followed prospectively for 5 years. Pl(A) and ACE genotypes were determined in 767 patients: 385 cases who had experienced a recurrent primary event (death due to coronary disease or nonfatal MI), and 382 age- and gender-matched controls. In patients receiving placebo, the Pl(A1,A2) genotype conferred a relative risk (RR) of 1.38 (confidence intervals [CI] 1.04 to 1.83; p = 0.028; adjusted RR = 1.32, CI = 0.99 to 1.76; p = 0.058]) for the primary end point. Compared with the placebo group, pravastatin reduced the excess RR of coronary disease death and recurrent MI in the Pl(A1,A2) patient population by 31% (p = 0.06). The ACE D allele appeared to have modestly additive effects on the Pl(A1,A2) risk. Among the Pl(A1,A2) patients, pravastatin had little effect on the risk of recurrent events with the ACE II genotype, but reduced the adjusted RR from 1.42 (placebo) to 0.58 for ACE ID patients, and from 1.56 (placebo) to 0.83 for ACE DD. The Pl(A1,A2) genotype was associated with an excess of recurrent coronary events in patients after MI who did not receive pravastatin, and the ACE D allele added to this risk. These data suggest that it would be important to perform a larger study to address the potential role of these genotypes in therapeutic decision making.