Use of Pharmacotherapy for CAD and MI in Diabetics

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1. Fibrinolytic Agents

Numerous studies have demonstrated that DM is a major independent predictor of acute and long-term post-MI morbidity and mortality. This is particularly true in women and in non-insulin-requiring diabetics. Many factors, including a greater extent and magnitude of angiographically severe CAD, associated comor-

bidity, metabolic disturbances, silent myocardial ischemia, and late or atypical clinical presentation (often without chest discomfort) may contribute to a lower utilization of fibrinolytic agents and may be causally implicated in a worse post- -g

MI prognosis among diabetic patients.

An overview by the Fibrinolytic Therapy Trialists' Collaborative Group Ja evaluated results from 4529 diabetic patients from a total sample of 43,073 pa- J

tients who presented with acute ST-segment-elevation MI. These results con-

& u firmed the important benefit of thrombolysis in diabetic patients. The absolute reduction in mortality was greater in diabetic patients than in nondiabetics (3.7% vs. 2.1%), despite a greater 35-day mortality rate in diabetics (13.6% vs. 8.7%). Diabetics also had a modestly higher absolute risk of developing hemorrhagic stroke than nondiabetics (0.6% vs. 0.4%). This difference was not statistically significant.

2. Insulin-Glucose Infusion

Long-term mortality in diabetic patients who are hospitalized for acute MI may be reduced by an insulin-glucose infusion followed by multidose insulin treatment. In the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study, an infusion of insulin and glucose followed by daily subcutaneous injections of insulin resulted in a 52% reduction in mortality within 1 year after myocardial infarction among patients with DM. This beneficial effect was attributed to improved metabolic control in the presence of an extreme increase in the level of catecholamines in blood and ischemic myocardium that is associated with sudden ischemic episodes. Insulin therapy appeared to beneficially influence acute cardiovascular mortality. A striking reduction in the incidence of fatal reinfarction and left ventricular failure was seen. These results are consistent with favorable effects in reducing mortality among diverse groups of patients treated with a glucose-insulin-potassium infusion in the setting of acute MI.

3. Antiplatelet Agents (Aspirin, Thienopyridines, Platelet Glycoprotein llb/llla Agents) and Antithrombin Agents

Platelet and coagulation abnormalities contribute to the development of CAD in diabetic patients. Results from diverse randomized clinical trials support the use of antiplatelet therapy in all diabetic patients. A meta-analysis of the Antiplatelet Trialists' Collaborative Group included over 47,000 patients (of whom approximately 10% were diabetics) and demonstrated an important benefit of aspirin therapy in diabetics with, or at increased risk for, vascular disease. The combined endpoint of vascular death, MI, or stroke was 22.3% in the control group and 18.5% in the aspirin group. The magnitude of benefit was similar in both diabetic -o and nondiabetic patients, and there was no evidence of excess bleeding in the former group. A preliminary report from the CURE trial investigators showed a S

significant 25% relative risk reduction in the composite endpoint of death and MI in 12,562 patients with acute coronary syndromes who were randomized to <j aspirin plus clopidogrel and compared with aspirin alone for up to 9 months of Ji blinded therapy. The favorable treatment effects were seen across all subgroups of patients studied, including patients with diabetes.

Clinical trials with low-molecular-weight heparins (LMWH) indicate that these agents are more effective than placebo and as beneficial as, if not superior to, standard unfractionated heparin (UFH) in the management of patients with non-ST-segment elevation acute coronary syndromes (unstable angina or non-Q-wave MI). For the most part, these studies demonstrate a consistent treatment benefit among patient subgroups. The ESSENCE trial demonstrated comparable benefits among diabetics and nondiabetics. In the TIMI-11B trial, enoxaparin was found to be superior to UFH in preventing cardiac death and nonfatal cardiac events (MI and unstable angina). Beneficial effects of enoxaparin were greatest in high-risk patients. In the GUSTO IIB trial, hirudin, a direct thrombin inhibitor, was more effective than UFH in the treatment of diabetic patients who presented with an acute coronary syndrome (ACS) and was not associated with increased risk of bleeding.

Results from randomized trials provide strong evidence that platelet glycoprotein (GP) IIb/IIIa inhibitors reduce the early and short-term incidence of death, MI, and recurrent angina in patients who present with non-ST-segment elevation acute coronary syndromes. In the PRISM-PLUS study, the benefit associated with tirofiban plus heparin in reducing cardiac events compared to heparin alone was comparable for both diabetic and nondiabetic subjects. Importantly, combination therapy of tirofiban plus heparin compared with heparin alone reduced significantly the secondary endpoint of death and MI much more profoundly in the diabetic subjects compared with that in the overall study population (88% vs. 43%; p = 0.005). In the PURSUIT trial, death and nonfatal MI were also significantly reduced by eptifibatide compared to placebo in both diabetic and non-diabetic subgroups of non-ST-segment elevation ACS. However, compared to nondiabetic patients, 30-day mortality was reduced to a greater extent in insulin-requiring diabetic patients. A meta-analysis that pooled diabetic patients from 10 recent trials of GP IIb/IIIa inhibitors revealed that diabetics had twice the absolute reduction in cardiac event rates compared to nondiabetics. There was a strong trend favoring an interaction between DM and the use of GP IIb/IIIa agents, but this did not reach statistical significance. The role of this class of agents when used adjunctively during PCI will be discussed in the section that details outcomes among diabetics who undergo myocardial revascularization.

4. Beta-Blockers g s

Pooled data from several trials of beta-blockers administered as secondary pre- S

vention post-MI demonstrate an overall 25% mortality reduction and a 29% g reduction in reinfarction. Diabetic subjects exhibit an almost threefold greater <j reduction in mortality compared to nondiabetics (37% vs. 13%). A similar M reduction in the incidence of reinfarction was apparent in those with and without diabetes. The results unquestionably underscore the important role of beta-

& u blocker therapy after MI in diabetic patients. Unless there is an overt contraindication, all diabetic patients with prior MI or established CAD should receive a beta-blocker as part of a standard secondary prevention regimen.

5. Angiotensin-Converting-Enzyme (ACE) Inhibitors

Post hoc analyses of many prospective, randomized studies indicate that the use of ACE inhibitors in diabetics with acute MI is associated with significant reductions in short-term mortality and occurrence rates of congestive heart failure. In addition, similar data support an important long-term benefit of these drugs in diabetic patients who have had an MI complicated by systolic left ventricular dysfunction. Recent results of the Danish TRACE trial revealed that the ACE inhibitor trandolapril after MI in diabetic patients with left ventricular dysfunction decreased mortality and reduced the risk of progression to severe heart failure. In addition, in studies of high-risk diabetic patients with CAD but no prior MI, ACE inhibitors have been shown to decrease cardiac events in those subjects with congestive heart failure. ACE inhibitors reduce morbidity and mortality to a greater extent in diabetic patients.

The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated the beneficial role of ACE inhibitors in high-risk diabetics with CAD. In this trial, a predefined group of 3651 middle-aged diabetic patients at risk for cardiovascular and renal disease were randomized to receive the ACE inhibitor ramipril or placebo for 4 years. The primary endpoint of cardiovascular death, MI, and stroke was reduced by 24% and mortality alone was reduced by 38% in the ramipril-treated patients. Moreover, diabetic complications and microvascular disease were reduced by 17%. An additional important finding of the HOPE trial was that the decrease in composite clinical events was similar among diabetic patients with or without systolic left ventricular dysfunction.

In summary, the data from numerous randomized, clinical trials assessing the impact of various pharmacotherapies on outcomes in diabetic patients provide abundant scientific evidence in support of a multifaceted, aggressive approach to medical treatment. All diabetic patients should receive intensive glycemic control. All diabetic patients should take 325 mg aspirin daily. Further analysis of the results of the CURE trial may lead to an additional recommendation for treatment with 75 mg clopidogrel daily. Hypertension should be managed aggressively with (preferably) an ACE inhibitor such as ramipril and, for diabetic patients who have sustained an MI, ACE inhibitor therapy should be administered as secondary prevention, along with a beta-blocker—ideally a cardioselective g1

beta-blocker such as atenolol or metoprolol. These cardioselective beta-blockers should limit the masking of promonitory symptoms of hypoglycemia. Additionally, if diabetic patients with CAD or MI exhibit evidence of systolic left ventricu- J lar dysfunction, an ACE inhibitor will have important salutary effects on ventricu- a

& u lar remodeling and decreased progression to advanced heart failure. In addition, several evidence-based pharmacological treatment strategies have shown convincing benefits in diabetic patients with CAD. Specifically, diabetic patients who present with non-ST-segment-elevation ACS should be treated with GP Ilb/IIIa inhibitors such as tirofiban in combination with UFH or LMWH to decrease thrombotic complications and reduce clinical events. Additional randomized studies should evaluate the role of tight glycemic control on the reduction of major cardiovascular events with or without coronary revascularization. The Bypass Angioplasty Revascularization Investigation (BARI) 2D trial has been initiated recently, and will be discussed in greater detail in the section on myocardial revascularization of the diabetic patient.

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