Diagnosis and Management of Pituitary Disorders - part 7 docx

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As a consequence, aggressive use of medical and revascularization therapies are appropriate for patients with DM given this increased risk. Among patients with chronic stable CAD, patients with DM have been demonstrated to benefit from specific therapies, including antiplatelet, renin-angiotensin-aldosterone system (RAAS) antagonists, aggressive blood pressure control, and aggressive lipid management. In addition, attention to angina and evaluation of ischemic symptoms is important in the outpatient management of the diabetic patient with CAD. Presentation with Acute Coronary Syndromes (ACS) is currently characterized as ST Elevation Myocardial Infarction (STEMI), and Unstable Angina or Non-ST Elevation MI (UA/NSTEMI). Specific characteristics of diabetic patients have been identified among both ACS conditions, and particular benefits have been described from use of antiplatelet and anticoagulation therapies, reperfusion therapy, administration of beta adrenergic and RAAS antagonists, lipid lowering therapy, and revascularization techniques. In general, an aggressive approach to treatment of DM and CAD is recommended for both the stable and ACS populations. Key Words: Coronary artery disease (CAD), acute coronary syndrome (ACS), myocardial infarction (MI), coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI). INTRODUCTION Coronary artery disease (CAD) and its complications are the most common cause of death for patients with diabetes mellitus (DM). Compared to patients without DM, patients with DM and CAD have a higher mortality risk at presentation with acute MI and during long term follow-up (1–4). As a consequence, it is important for providers caring for patients with DM to understand the acute and chronic management of CAD in DM, which is based on the general principles of management of CAD. As most studies of CAD have included patients with DM, considerable knowledge has been gained regarding medical and revascularization treatment in patients with DM. This chapter will discuss the increased risk of DM and CAD, outline the general approach to management of CAD, and highlight specific key recommendations in patients with DM. From: Contemporary Endocrinology: Type 2 Diabetes Mellitus: An Evidence-Based Approach to Practical Management Edited by: M. N. Feinglos and M. A. Bethel © Humana Press, Totowa, NJ 289 290 Petersen and McGuire EPIDEMIOLOGY OF DIABETES MELLITUS AND CORONARY ARTERY DISEASE The increased cardiovascular disease (CVD) risk associated with DM is well documented in the setting of stable and unstable CAD (Table 1) (4–20). Although most studies of CVD have not distinguished Type 1 and Type 2 DM, most analyses include a large proportion of type 2 DM patients as the prevalence is considerably higher than Type 1 disease (6). In addition, some studies have demonstrated a high incidence of DM among patients presenting with sentinel CAD events, and the prevalence of DM in this setting likely well exceeds current estimates. DM is associated with increased short- and long-term CVD risk in the setting of unstable CAD. A potentially important interaction between DM and gender had been observed, with diabetic women having an especially poor prognosis. Based on these findings, it is clear that an aggressive approach to secondary prevention is appropriate for optimal management of patients with DM and CAD. Prevalence of Diabetes among Patients with Coronary Artery Disease The prevalence of DM ranges from 15–25% among patients presenting with unstable disease (5,6). In addition, a significant number of patients presenting with acute coronary syndromes (ACS) or chronic stable CAD have undiagnosed DM, and some studies have found the incidence of a new diagnosis to be up to 25% of patients at the time of presentation with CAD (21). Thus, given the high prevalence and incidence of DM in CAD populations, routine DM screening should be performed to identify and treat patients with DM when presenting with CAD. Risk of Cardiovascular Events among Patients with Diabetes and Coronary Artery Disease Diabetes and Cardiovascular Risk in Patients with Stable CAD Among patients with stable CAD, DM is associated with an increased risk of subsequent CVD events, even in the setting of optimal medical management (Table 1). For example, in both the Scandinavian Simvastatin Survival Study (4S) and the Heart Protection Study (HPS), DM was associated with a significantly increased risk of death and CVD events (5,6). Similarly, in studies of percutaneous coronary intervention (PCI), DM is associated with increased long-term CVD (7,8). In total, these findings demonstrate the increased risk of patients with DM in the outpatient setting and support an aggressive approach to chronic medical therapy. Diabetes and Cardiovascular Risk in Patients with Unstable CAD In the setting of unstable CAD, patients with DM are at increased risk of death, MI, and stroke immediately following MI and during long term follow up (Table 1). In the First Global Utilization of Streptokinase and Tissue Plasminogen Activator to Open Occluded Coronary Arteries (GUSTO I) trial, a study of 4 thrombolytic strategies for STEMI, 30-d mortality rates were significantly higher for patients with DM (4). Patients with DM in the Second Global Utilization of Strategies to Open Occluded Coronary Arteries (GUSTO IIb) study also had an increased risk of 30-d mortality (adjusted OR 1.75; 95% CI [1.5, 2.1]) and the combined endpoint of death or MI (13.1% versus 8.5%; adjusted OR 1.63; 95% CI [1.4, 1.9]) (9). In the 1st and 2nd Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events post Acute Coronary Syndromes (SYMPHONY) studies, the unadjusted risk of death, MI, or severe recurrent ischemia at 90 d was significantly higher for patients with DM (10). Likewise, in the Second Gruppo Italiano perlo Studio della Soprevvievenza nell’Infarcto Miocardico study (GISSI-2), increased risk of in hospital events was noted in patients with DM (11). Other data sources, such as the pooled analysis from the Fibrinolytic Therapy Trialists (FTT), the Thrombosis in Acute MI (TAMI) studies, and observational data from the Global Registry of Acute Coronary Events (GRACE) also corroborate these findings (12–17). Increased risk of long-term mortality and CVD events has been demonstrated for patients with DM and unstable CAD. Long-term follow up from the GUSTO I study demonstrated that the initial increase in short-term mortality following STEMI is sustained to at least 1 yr after presentation (4), with similar findings observed during 6 mo of follow-up in the GUSTO IIb study (9), and during 1-yr of follow-up in the SYMPHONY studies (10). Data from the Organization to Assess Strategies for Ischemic Syndromes (OASIS), a large international registry of patients presenting with ACS, has shown an increased risk of death over 2 yr and an increased long-term risk of cardiovascular complications was appreciated among women with DM (18). Analysis of long term events from Table 1 Risk of Death and Cardiovascular Events Among Diabetic Patients and CAD N Total Event Rates Trial Population Study Type N DM (%) Endpoint No DM DM Statistical Comparison 4S Post MI Post Hoc 4,444 5 Yr Mortality 9.4% 19.3% p < 0.01 RCT Analysis 202 (4.5) HPS* High Risk Prespecifed 1,1405 5 Yr CV Events 22.7% 35.6% p < 0.01 1° Prevention RCT Analysis 1,981 (17.4) TARGET PCI Post Hoc 4,809 1 Yr Mortality 1.6% 2.5% p = 0.056 RCT Analysis 1,117 (23.2) ESPRIT PCI Post Hoc 2,064 1 Yr CV Events 18.4% 24.5% p = 0.008 RCT Analysis 466 (22.6) GUSTO I STEMI Post Hoc 41,021 30 D Mortality 6.2% 10.5% OR 1.77, 95% CI [1.6, 1.9] RCT Analysis 5,944 (14.5) 1 Yr Mortality 8.9% 14.5% p = 0.0001 GUSTO IIb ACS Post Hoc 12,142 30 D Mortality 8.5% 13.1% OR 1.75, 95% CI [1.5, 2.1] RCT Analysis 2175 (17.9) 6 Mo Death/MI 11.4% 18.8% p = 0.0001 SYMPHONY/2 nd SYMPHONY UA/NSTEMI Post Hoc 90 D CV Events 9.0% 11.4% OR 1.3, 95% CI [1.2, 1.5] RCT Analysis 1 Yr CV Events 16.7% 23.8% OR 1.3, 95% CI [1.1, 1.5] GISSI 2 STEMI Post Hoc 11,667 In-Hospital Mortality 5.8%a 8.7%c OR 1.7, 95% CI [0.8, 3.3] RCT Analysis 1838 (15.7) 10.1%d OR 2.0, 95% CI [1.6, 2.6] 13.9%b 24.0%c OR 2.2, 95% CI [1.4, 3.5] FTT STEMI Metaanalysis 83,000 30 D Mortality 7.1% 11.6% OR 1.71, 95% CI [1.60, 1.83] NA TAMI STEMI Pooled RCT 1,071 In Hospital Mortality 6% 11% p <0.02 Analysis 148 (13.8) GRACE ACS Prospective 15,000 In Hospital Mortality 6.4%e 11.7%e RR 1.48, 95% CI [1.03, 2.13] Registry NA 5.1%f 6.3%f RR 1.14, 95% CI [0.85. 1.52] 2.9%g 3.9%g RR 1.41, 95% CI [1.02, 1.95] OASIS ACS Prospective 8,013 2 Yr Mortality 10% 18% RR 1.57, 95% CI [1.38, 1.81]j Registry 1,718 (21.4) RR 1.28, 95% CI [1.06, 1.56]a,j RR 1.98, 95% CI [1.60, 2.44]b,j (Continued) Table 1 (Continued) N Total Event Rates Trial Population Study Type N DM (%) Endpoint No DM DM Statistical Comparison VALIANT ACS / CHF Post Hoc 14,703 1 Yr Mortality 10.9% 16.2%h HR 1.50 [1.21, 1.85] RCT Analysis 3980 (27.1) 17.7%i HR 1.43 [1.29, 1.59] SAVE CHF Post Hoc 2231 3.5 Yr Mortality 20.1% 31.3% OR1.39 [1.14, 1.68] RCT Analysis 496 (22.2) *Among population with known CAD in study a Males b Females c Insulin Requiring d Noninsulin requiring e STEMI f NSTEMI g UA h New Diagnosis of DM i Previous Diagnosis of DM j adjusted analysis DM: Diabetes Mellitus STEMI: ST Elevation Myocardial Infarction ACS Acute Coronary Syndrome MI Myocardial Infarction CHF Congestive Heart Failure PCI Percutaneous Coronary Intervention CV Cardiovascular RCT Randomized Controlled Trial ACE Angiotensin Converting Enzyme Inhibitor ARB Angiotensin Receptor Blocker GUSTO Global Utilization of Streptokinase and Tissue Plasminogen Activator to Open Occluded Coronary Arteries GISSI Gruppo Italiano perlo Studio della Soprevvievenza nell’Infarcto Miocardico FTT Fibrinolytic Therapy Trialists TAMI Thrombolysis and Acute Myocardial Infarction GRACE Global Registry of Acute Coronary Events VALIANT Valsartan in Acute Myocardial Infarction Trial SAVE Survival and Ventricular Enlargement OASIS Organization to Assess Strategies for Ischemic Syndromes 4S Scandinavian Simvastatin Survival Study HPS Heart Protection Study TARGET Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial ESPRIT Enhanced Suppression of Platelet IIb/IIIa Receptor with Integrilin Therapy Chapter 18 / Management of Coronary Artery Disease in Type 2 Diabetes Mellitus 293 the Survival and Ventricular Enlargement (SAVE) and Valsartan in Acute MI Trial (VALIANT) studies, which evaluated captopril and valsartan in unstable CAD patients, demonstrated similarly increased CVD risk associated with DM (19,20). Interaction between Sex and DM among Patients with CAD Some analyses have suggested an interaction between sex and DM, with DM affecting prognosis in women more than men in the setting of ACS. In the Second Gruppo Italiano perlo Studio della Soprevvievenza nell’Infarcto Miocardico study (GISSI-2), in hospital mortality for women with insulin-requiring DM was nearly double that of non-DM patients, with similar observations from registry data including the Worcester Heart Attack Study and the Framingham study (11,22,23). A proposed cause for this interaction is that women with DM are at significantly higher risk of cardiogenic shock and tend to have more extensive CAD than non-diabetic women. Interestingly, analysis from the Second National Registry of MI found an increased prevalence of DM in younger women with MI but no interaction with outcome despite an increased risk of mortality for younger women (24). Epidemiology Conclusions In sum, most analyses of the DM subgroups from a variety of populations of patients with CAD have found an increased risk of death and cardiovascular events. Although the exact mechanisms remain to be elucidated, it is likely that multiple pathological processes associated with DM contribute to the increased risk of atherosclerosis. Increased platelet aggregation, worse endothelial dysfunction, higher levels of systemic markers of inflammation, and enhanced smooth muscle cell migration have all been demonstrated in patients with DM and likely accelerate the pathogenesis of atherosclerosis (25–28). Optimal management of these patients requires an aggressive and multi-pronged approach to treatment, including aggressive use of antiplatelet, antihypertensive and lipid lowering therapy, in conjunction with appropriate use of revascularization. CLINICAL DESCRIPTION AND GENERAL APPROACH TO MANAGEMENT OF STABLE CORONARY ARTERY DISEASE CAD is a dynamic disease process characterized by prolonged periods of quiescent development and progression of atherosclerotic plaque, with sporadic episodes of acute plaque rupture that can lead to unstable angina or MI. As a consequence, most cardiovascular studies now identify 2 distinct populations: 1) chronic stable CAD, characterized by atherosclerotic disease development and insidious progression that may or may not be associated with clinical symptoms caused by imbalance of myocardial blood supply and demand resulting from a fixed obstructive atherosclerotic lesion; and 2) acute coronary syndromes (ACS), including unstable angina and MI, characterized by an acute clinical presentation caused by the rupture of an unstable coronary artery atherosclerotic plaque with subsequent development of arterial thrombus and impairment of coronary blood flow. The focus of management of patients with stable CAD is risk stratification to guide therapeutic decision-making and the application of interventions to reduce the likelihood of future unstable CAD events. Risk Stratification of Patients with Stable Coronary Artery Disease Risk stratification is based on evaluation of clinical symptoms of angina and information derived from cardiac stress testing, and the American Heart Association (AHA) and American College of Cardiology (ACC) have established guidelines for appropriate use of these techniques to evaluate CAD (29). Exercise stress testing on a treadmill continues to be recognized as the best studied modality for evaluating ischemia and provides the most important prognostic information (30,31). The diagnostic accuracy of exercise stress testing can be improved with additional imaging modalities, such as Single Photon Emission Computerized Tomography (SPECT) and transthoracic echocardiography (29). Use of these imaging techniques is important in populations in which the diagnostic accuracy of stress testing is reduced, including female patients and patients with baseline electrocar- diographic abnormalities. Patients who are unable to exercise can be stressed pharmacologically with vasodilators such as adenosine or dipyridimole or with dobutamine. Recent advances in stress imaging also include cardiac MRI and CT angiography; however the relationship with prognosis for these tests is less well defined. 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