Secondary Prevention in Patients With Unstable Angina and Non-ST-Segment Elevation MI:

July 1, 2004

ABSTRACT: Guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction have been updated following results from pivotal controlled trials. The new American College of Cardiology/American Heart Association guidelines stress risk factor modification and long-term management. Medications that have been shown to reduce the incidence of future cardiovascular events in patients with acute coronary syndromes include antiplatelet agents, statins, ß-blockers, and angiotensin-converting enzyme inhibitors. Other long-term management strategies include smoking cessation, achievement and maintenance of optimal weight, daily exercise, appropriate diet, and control of hypertension and diabetes.

Coronary artery disease (CAD) remains the leading cause of mortality and morbidity in the United States.1 Chest pain and related symptoms account for 5.3 million visits to US emergency departments2 and 1.4 million hospitalizations annually.1

CAD manifests in many ways, including acute coronary syndromes. These syndromes can be further differentiated electrocardiographically according to the presence or absence of ST-segment elevation:

CAD with ST-segment elevation evolves, in most cases, into Q-wave myocardial infarction (MI).

CAD with no ST-segment eleva- tion presents as unstable angina and non-ST-segment elevation MI (formerly referred to as non-Q-wave MI) (UA/NSTEMI). Approximately 10% to 15% of persons who present with UA/NSTEMI will suffer infarction or reinfarction or die within 30 days.3

To develop a standard of care for the treatment of UA/NSTEMI, the American College of Cardiology and the American Heart Association (ACC/AHA) assembled a group of experts; both private practice and academic medicine were represented. The ACC/AHA Task Force on Practice Guidelines published its initial evidence-based recommendations for treatment of UA/NSTEMI in September 2000.1

Results from pivotal large, randomized, controlled studies of patients with acute coronary syndromes (Table 1) necessitated significant updates in the ACC/AHA guidelines, especially in the areas of long-term medical management and risk factor reduction.2 Those studies assessed the use of multiple therapies in the reduction of recurrent MI, stroke, and other cardiovascular events in patients who presented initially with UA/NSTEMI. The studies also evaluated traditional therapies for acute coronary syndromes, such as unfractionated heparin and aspirin, and more recent treatments, including low molecular weight heparin, antiplatelet therapy (intravenous glycoprotein IIb/IIIa antagonists and clopidogrel), lipid-lowering therapy, and antihypertensive agents.2

For the primary care physician, the key components of the updated guidelines are the changes in recommendations for long-term management to reduce the risk of subsequent cardiovascular events (death, recurrent MI, stroke) in patients with UA/NSTEMI. Here we provide an overview of these changes.

ANTIPLATELET THERAPY

The new guidelines recommend long-term dual-antiplatelet therapy with aspirin and clopidogrel as the standard of care in the treatment of patients with UA/NSTEMI.2 Aspirin, 162 or 325 mg/d, is initiated as quickly as possible after presentation and continued indefinitely unless contraindicated because of hypersensitivity or intolerance. Emerging long-term data from the CURE trial show that a dose of 81 mg/d may be optimal because of the lower risk of bleeding.4,5 Clopidogrel is recommended for patients who cannot tolerate aspirin.

Clopidogrel (300-mg loading dose, 75 mg/d) is added to aspirin therapy and continued for up to 9 months in patients who are being treated medically and for those not at high risk for bleeding in whom percutaneous coronary intervention (PCI), such as stenting, is undertaken.2

Evidence in the new guidelines, based on the CURE4 and PCI-CURE6studies, is further supported by the recent CREDO study, which demonstrated a 27% relative reduction in the combined risk of death, MI, or stroke (P = .02) with long-term (12-month) aspirin-plus-clopidogrel therapy compared with aspirin alone in patients undergoing PCI.7

In the acute setting, unfractionated or low molecular weight heparin is used in all patients, and glycoprotein IIb/IIIa inhibitors are used in those who are being treated invasively.

LONG-TERM MEDICAL THERAPY AND RISK FACTOR MODIFICATION

The most recent guidelines put greater emphasis than the previous recommendations on the importance of multifaceted risk factor modification. The primary care clinician can play a central role in this domain for patients recently discharged following an acute coronary syndrome. The principal recommendations for long-term medical therapy and risk factor modification are summarized in Table 2.

In addition to aspirin and clopidogrel, there are 3 key long-term medications that significantly reduce the incidence of cardiovascular events in patients with recent UA/NSTEMI: statins, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors. These are included in the Class I recommendations of the guidelines.

The guidelines recommend that statin and dietary therapybe started 24 to 96 hours after admission and continued indefinitelyafter discharge for patients with low-density lipoprotein (LDL) cholesterol levels greater than 100 mg/dL.2 The guidelines note that in-hospital initiation of statins is help- ful in ensuring long-term compliance. These recommendations are supported by the MIRACL8 and recent PROVE IT-TIMI 229 trials, which found greater benefit with intensive lipid-lowering therapy.The latter study showed that high-dose statin therapy provided greater benefit than standard-dose therapy. The average LDL cholesterol level achieved in the high-dose group was 62 mg/dL. Thus, the "target" LDL cholesterol level for patients following acute coronary syndrome should be substantially below 100 mg/dL.

The guidelines also suggest that a fibrate or niacin be added if high-density lipoprotein (HDL) cholesterol levels are below 40 mg/dL.2 A β-blocker and an ACE inhibitor are recommended for patients following acute coronary syndromes. An ACE inhibitor is recommended for patients with congestive heart failure, left ventricular dysfunction (ejection fraction less than 40%), hypertension, or diabetes. The most recent trial shows benefit in all patients who have coronary artery disease.10

Primary care physicians have a crucial role in helping prevent recurrent cardiovascular morbidity and mortality by ensuring that patients who have had an acute coronary syndrome are receiving all of the 4 recommended agents for long-term management and are following all recommended strategies for cardiovascular risk reduction. Although these agents should be initiated in the hospital, often they are not-either through oversight or because blood pressure levels did not permit. It is thus critical to make sure that patients are taking these agents and, if they are not, to initiate them at the post-acute coronary syndrome follow-up visit. n

References:

REFERENCES:

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3. The PURSUIT Trial Investigators. Inhibition of

platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med. 1998;339:436-443.

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7. Steinhubl SR, Berger PB, Mann JT, for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA. 2002;288:2411-2420.

8. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285: 1711-1718.

9. Cannon CP, Braunwald E, McCabe CH, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

10. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.