Management of Coronary Artery Disease in Patients with Diabetes ...

Editorial

Indian Heart J 2001; 53: 147–154

Management of Coronary Artery Disease in Patients with Diabetes Mellitus VK Bahl, Sandeep Seth Department of Cardiology, All India Institute of Medical Sciences, New Delhi

D

iabetes mellitus (DM) is a common medical problem and a major risk factor for the development of atherosclerotic coronary artery disease (CAD). Worldwide, more than 100 million people have DM and this figure is projected to double in the next 20 years. In India alone, it is estimated that there are more than 20 million diabetics.1 There is no doubt that DM is going to be a major burden on the health care system in the twenty-first century. DM is not only associated with increased incidence and prevalence of CAD, but diabetic patients also have a 2-fold increase in mortality after acute myocardial infarction (AMI). The outcome following coronary angioplasty (PTCA) and coronary bypass grafting (CABG) is also poor. The Framingham Heart Study data showed that patients with DM, particularly women, exhibited an increased risk of cardiovascular events including angina, stroke, claudication, heart failure, myocardial infarction and sudden death. 2 Diabetics have the same degree of cardiovascular risk as non-diabetics who have had a myocardial infarction (MI). A number of pathophysiological mechanisms contribute to the development of both macrovascular and microvascular complications in patients with DM. The presence of associated risk factors for atherosclerosis like obesity, advanced age, dyslipidemia and hypertension, as well as multiple metabolic abnormalities like hyperglycemia, hyperinsulinemia and abnormalities of platelet function and coagulation contribute to the cardiovascular complications. Control of Risk Factors In diabetics, coronary risk factors are magnified several times, and these need to be strictly controlled. Smoking is an independent predictor of mortality in diabetics and cessation of smoking should be recommended for all patients. Weight loss and increased physical activity have been shown to improve glycemic control, lipid profile and insulin resistance. Intense glycemic control is highly effective in preventing and retarding microvascular and, to some extent, Correspondence: Dr VK Bahl, Professor of Cardiology, All India Institute of Medical Sciences, New Delhi, e-mail: [email protected]

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macrovascular complications in both insulin-requiring DM (IRDM) and non-insulin requiring DM (NIRDM). There is no specific trial addressing the effect of lipid lowering in diabetic patients; however, subgroup analyses from a number of trials with statins have shown the efficacy of this therapy. The Scandinavian Simvastatin Survival Study (4S) trial, which enrolled 202 diabetic patients, indicated that simvastatin reduced five-year mortality by 43% in diabetic patients with hypercholesterolemia and CAD, as compared to 29% reduction in non-diabetic patients.3 The Cholesterol and Recurrent Events Trial (CARE) enrolled post-MI patients with average cholesterol levels. Treatment with pravastatin showed a greater reduction in major coronary event rate during a five-year follow-up in patients with DM compared to non-diabetics (37% v. 29%). 4 In the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study (which enrolled 811 diabetics), pravastatin therapy showed a 19% reduction in the composite end-point of CAD-related death and MI during 6 years of follow-up in the subgroup of diabetics with past history of MI or unstable angina.5 The data available from studies on the use of fibrate therapy is limited. The Helsinki Heart Study had suggested a trend towards decreased coronary events in diabetic patients treated with gemfibrozil compared to non-diabetics.6 There are a number of studies which have shown that adequate control of blood pressure markedly reduces major cardiovascular events. Most of the available data are from studies using beta-blockers and diuretics and they continue to be recommended as first-line therapy. There are sufficient data to show that they reduce mortality and morbidity in patients with diabetic nephropathy and in NIRDM patients. Strict control of blood pressure to a mean of 144/82 mmHg has been shown to significantly reduce strokes, diabetesrelated deaths, heart failure, microvascular complications and visual loss in UKPDS trial.7 There is a growing amount of data coming up in support of angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. The revised guidelines of the Joint National Committee (JNC) on Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommended a level of 130/85 mmHg for diabetic patients.

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Issues in Management Managing CAD patients with DM requires special attention. The majority of data on the management of CAD in DM are based on retrospective subgroup analysis of major clinical trials, which on an average included 20%–30% diabetic patients. Patients with DM have a number of adverse clinical, angiographic and metabolic features contributing to poor prognosis. Diabetic patients with CAD are more often female, obese and hypertensive. They usually have severe angina, history of previous MI or CABG and marked left ventricular failure. They have abnormal endothelial function with reduced coronary flow reserve. There is platelet activation with increased thromboxane A2 secretion. The levels of fibrinogen and Factor VII are higher than normal, while antithrombin III and plasma fibrinolytic activity are lower. Angiographically, they have diffuse, extensive involvement of smaller reference vessels, multivessel involvement, higher incidence of left main coronary artery disease, poorer collaterals, lower ejection fraction and more thrombus formation. Two important issues need to be considered in the management of CAD in patients with DM—management of acute myocardial infarction and coronary revascularization (both surgical and catheter-based). Management of Acute Myocardial Infarction Management strategies include the use of thrombolytics, beta-blockers, ACE inhibitors, nitrates and antiplatelet agents. Thrombolytic therapy: Diabetic patients are less likely to receive thrombolytic therapy as they present late and/or with atypical symptoms, perhaps due to impaired sensation of pain. There is also undue concern regarding the adverse effects of thrombolytic agents, especially ocular complications. The efficacy of thrombolysis may also be reduced in DM due to enhanced platelet activity, elevated procoagulant activity and imparied intrinsic fibrinolysis. Despite achieving similar patency rates (70%) as nondiabetics, the mortality is higher in diabetics (17.3% v. 10.2%), probably because of impaired endothelial function and diminished myocardial flow reserve.8 Reocclusion with recurrent ischemia was also higher in diabetics (9.2% v. 5.3%) in the Global Use of Strategies To Open Occluded Arteries (GUSTO) study.9 However, in spite of several factors unfavorable for thrombolysis, they still derive substantial benefit from it. The Fibrinolytic Therapy Trialists (FTT) Collaborative Group in an overview of 58 600 patients including 4529 diabetics, showed that the absolute reduction

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in the 35-day mortality after thrombolysis in patients with DM was 3.7% compared with 1.5% in non-diabetics. In diabetic patients it fell to 13.6% following thrombolysis as compared to 17.3% in the control group, while in the nondiabetic group, the mortality was reduced to 8.7% versus 10.2% in the control group.8 The fear of increased adverse effects of thrombolytic therapy in diabetics is not borne out by the available data. The data from the FTT Collaborative Group showed no statistically significant increase in hemorrhagic stroke in patients with DM receiving thrombolytic therapy (0.6% v. 0.4%). In the GUSTO study, the incidence of clinically evident ocular complications was only 0.02% and there was no case of intraocular hemorrhage. Stroke rates were comparable in diabetics and non-diabetics (1.9% v. 1.4%). Vitreous hemorrhage in diabetic patients was rare.8 There are some data to show the superiority of an accelerated tissue plasminogen activator (tpa) regimen in patients with DM. In the GUSTO-1 study, diabetics given tpa had a 30-day mortality of 8% compared to 10.2% in the group given streptokinase (STK). The stroke rate was not significantly different in two groups (1.7% in the tpa group and 1.4% in the STK group). Thus, the accelerated tpa regimen appears to be better than STK. However, the cost-effectiveness of this regimen in our country remains questionable. Post-thrombolysis strategies: Whether to follow a conservative or an invasive approach following thrombolysis in AMI, is a matter of debate. Clinical variables collected for the 3339 patients of the Thrombolysis In Myocardial Infarction (TIMI)-II study were analyzed retrospectively to identify predictors of clinical events at 42 days, so as to identify the subgroups in which an invasive or conservative strategy might be superior. Patients with DM had a higher mortality in the invasive compared to the conservative strategy group (14.8% v. 4.2%, p2 anginal symptoms in past 24 hours), aspirin use within the past 7 days, and increased values for serum cardiac markers (CK-MB fraction or cardiac-specific troponin level). In contrast, similar scores can predict insignificant coronary artery disease by simple nomograms. These are important because patients with minimal disease at coronary angiography do not seem to benefit from glycoprotein (Gp) IIb/IIIa receptor inhibitors.11 The risk stratification and prognostication with the available scores would help identify patients at higher risk for adverse

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cardiac events and would allow cardiologists to stratify these patients into different plans of management. Medical Treatment The medical management of all patients admitted with a diagnosis of UA/NSTEMI includes bed rest, aspirin, intravenously administered heparin, nitrates, and βadrenergic blockers. Angiotensin-converting enzyme inhibitors are added in patients with depressed left ventricular systolic function and diabetes mellitus. Glycoprotein IIb/IIIa receptor inhibitors have significantly improved the outcome of patients presenting with UA/NSTEMI. The 3 agents approved for clinical use are: (1) the monoclonal antibody abciximab; (2) the peptide receptor antagonist eptifibatide; and (3) the nonpeptide receptor antagonist tirofiban. In the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) study,12 the 2099 patients who had balloon angioplasty or directional atherectomy had a 35% reduction in the composite end-points of death, nonfatal myocardial infarction, refractory ischemia, or urgent revascularization within 30 days. The benefit of abciximab persisted for up to 3 years after the procedure.13 The Evaluation in PTCA to Improve Long-term Outcome with Abciximab Gp IIb/IIIa blockade (EPILOG) trial14 tested the benefits of abciximab in patients at lesser risk who were given lower doses of weight-adjusted heparin. In 2972 enrolled patients, those who received abciximab and low-dose heparin had a 57% reduction in the composite end-points of death, myocardial infarction, or urgent revascularization (5.2%), compared with patients receiving standard heparin therapy (11.7%). In the Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment (CAPTURE) trial, 15 patients were randomized after coronary angiography to either placebo or abciximab. Abciximab therapy was given for 18 to 24 hours before coronary intervention and was continued for 1 hour after the intervention. The CAPTURE trial was prematurely terminated because the abciximab-treated patients had a significant reduction in the composite end-points at 30 days. Also, the progression of myocardial infarction before coronary intervention was significantly reduced (0.6% v. 2.1%; p=0.03). The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS),16 and the Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trials17 evaluated tirofiban. Among 1570 patients who had percutaneous coronary intervention (PCI) in PRISM-PLUS, there was a 42%

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Singh et al.

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Table 2. Short-term risk of death or nonfatal myocardial infarction in patients with unstable angina* Feature

High risk (at least 1 of the following features must be present)

Intermediate risk (no high-risk feature but must have 1 of the following features)

History

Accelerating tempo of ischemic symptoms in preceding 48 h

Prior MI, peripheral or cerebrovascular disease, or CABG; prior aspirin use

Character of pain

Prolonged ongoing (>20 min) rest pain

Prolonged (>20 min) rest angina, now resolved, with moderate or high likelihood of CAD Rest angina (70 years related to ischemia New or worsening MR murmur S3 or new or worsening rales Hypotension, bradycardia, tachycardia Age >75 year

ECG findings

Angina at rest with transient ST segment changes >0.05 mV Bundle branch block, new or presumed new Sustained ventricular tachycardia

T wave inversions >0.2 mV

Markedly elevated (e.g, TnT or TnI >0.1 ng/mL)

Slightly elevated (e.g. TnT >0.01 but