Managing acute coronary syndromes: Decades of progress
ABSTRACTIn managing acute coronary syndromes, physicians can draw on a large body of evidence from clinical trials. This article reviews clinical trials that inform current standards of practice regarding reperfusion, aggressive vs conservative initial approaches, and the appropriate use of aspirin, dual antiplatelet therapy, glycoprotein IIb/IIIa antagonists, anticoagulants, and statins.
KEY POINTS
- For acute ST-elevation myocardial infarction, primary percutaneous coronary intervention is preferred over fibrinolytic therapy if it is available within 90 minutes of first medical contact.
- For non-ST-elevation acute coronary syndromes, either an early invasive or conservative strategy is recommended depending on patient risk and whether intensive medical therapy is available and appropriate.
- Daily aspirin therapy is indicated for all patients with acute coronary syndromes unless they have a true aspirin allergy.
- Adenosine diphosphate receptor inhibitors—clopidogrel, prasugrel, and ticagrelor—reduce ischemic events but increase bleeding risk and should be used only for patients with no history of stroke or transient ischemic attack.
MANAGING NSTEMI AND UNSTABLE ANGINA
For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.
The TACTICS trial,13 the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.
The ICTUS trial.14 Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.15
The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,16 in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.
When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.
The TIMACS trial,17 with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.
Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.18
ANTITHROMBOTIC THERAPIES
Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.
Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.19
Aspirin for secondary prevention
Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.
The ISIS-2 trial20 compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.
Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.
For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.
The CURRENT-OASIS 7 trial21 showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.
DUAL ANTIPLATELET THERAPY IS STANDARD
Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.
Clopidogrel: Well studied with aspirin
The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.
The CURE trial22 randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.
COMMIT23 found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.
The CURRENT-OASIS 7 trial21 randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.
Ticagrelor and prasugrel: New alternatives to clopidogrel
The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.
Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.24 Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.25 Ticagrelor is active as absorbed.26
Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.
Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.
