Acute coronary syndromes: introducing new therapies into established guidelines
Christopher Granger, M.D. Dr.

Granger is associate professor of medicine, and director, cardiac care unit, Duke University Medical Center.

Over the last 20 years, we have evolved from a period of ignorance to one of complexity and confusion in the management of acute coronary syndromes (ACSs). The challenge in the 1980s was to develop effective therapies, whereas in 2000 a new challenge is how to best integrate and customize therapy for the individual patient given a menu of proven effective therapies. For example, enoxaparin, intravenous IIb/IIIa inhibitors, and direct thrombin inhibitors have all been shown to reduce the incidence of myocardial (re)infarction, and yet there are inadequate data evaluating their combinations. The clinician is constantly faced with the question of which therapies to use for which patients.

August 2000 was a pivotal time for information on ACSs, and yet many new questions were raised. Three major events occurred regarding categorization and treatment of ACSs. Myocardial infarction (MI) was redefined in a European Society of Cardiology and American College of Cardiology consensus document incorporating troponin information,1 raising concern that we may have even more difficulty in categorizing patients who may not have true ACSs but have positive troponin. Updated practice guidelines were published for unstable angina and non–ST-elevation MI,2 which call for GP Ilb/IIIa inhibitors for high-risk ACS patients. And finally, the GUSTO IV ACS trial results3 raised new questions about both of these documents within days of their first dissemination. Specifically, the GUSTO IV ACS trial found no benefit to using abciximab for patients presenting with ACS who were not going to undergo early angioplasty. To what extent these results should temper enthusiasm for the widespread use of intravenous GP Ilb/IIIa inhibitors for patients presenting with ACS, and especially those not undergoing early angioplasty, is controversial. The trial also collected information on troponin and C-reactive protein, reaffirming the prognostic significance of these markers, but challenging their value as markers predicting treatment effect with GP IIb/IIIa inhibitors.

When should we use the more potent but also more expensive therapies? One important factor is patient risk. Four variables account for most of the predictive information of death or MI in patients with ACSs: whether there is ST segment shift, whether myocardial markers are positive (troponin or creatine kinase-MB [CPK-MB]), patient age, and hemodynamic status. A simplified model that can be used at the bedside to predict risk has recently been published by the TIMI group, although this model is far from ideal.4,5 The period of increased risk of death or (re)infarction lasts longer than the typical 3- to 5-day hospitalization, suggesting a need for extended therapy.

It is now well recognized that the pathophysiology of unstable angina involves rupture of an atherosclerotic plaque followed by coronary thrombosis, which, when transiently occlusive or subocclusive, results in MI or unstable angina. A central aspect of the management of these patients is to inhibit thrombosis by inhibiting platelet activity and the coagulation cascade.

Heparin

In addition to the benefit of aspirin, heparin is beneficial during the acute phase of unstable angina, although a sustained benefit is less clear. It is now commonly believed that lower-dose heparin, with a target aPTT in the 50- to 75-second range, is associated with best outcomes. The reason that higher doses of intravenous heparin do not translate into clinical benefit may in part be that although heparin is effective at inhibiting thrombin activity, new thrombin continues to be generated (as assessed by prothrombin F1.2 levels) in spite of heparin treatment. It is possible that the continued accumulation of thrombin may limit the long-term effectiveness of heparin, especially following its discontinuation.

Rebound reactivation of thrombosis after stopping heparin

It is now clear that there is a clustering of reinfarction following the discontinuation of intravenous heparin both when treating unstable angina and following thrombolysis. In GUSTO I, of patients who suffered reinfarction after stopping intravenous heparin, there was an excess risk within 10 hours of stopping intravenous heparin, with a peak incidence at 2 to 4 hours.6 This reactivation phenomenon has been confirmed in the GUSTO IIb and TRIM trials. One appealing possibility is that upstream inhibition of the coagulation cascade, for example with low molecular weight heparins (LMWHs), may mitigate this problem.

Low molecular weight heparins

Several trials have evaluated LMWHs for unstable angina. The FRISC investigators found that dalteparin was effective (compared with placebo) reducing death and (re)infarction at 7 days. The FRISC trial showed that dalteparin was similar to unfractionated heparin with regards to clinical outcomes. The ESSENCE trial showed that an average of 2.4 days of enoxaparin compared with intravenous unfractionated heparin reduced the endpoint of death, (re)infarction, and recurrent angina at 14 days (risk reduction 16.2%, P=0.019).7 The TIMI IIB trial found a similar 15% relative risk reduction of death, (re)MI, and urgent revascularization at 14 days (P=0.03). Highest-risk patients derived the greatest benefit.8,9 The FAXIS trial, on the other hand, found no benefit of nadroparin compared with unfractionated heparin.

Direct thrombin inhibitors

Direct thrombin inhibitors in the hirudin class appear to be effective at preventing myocardial (re)infarction, at the expense of a moderately higher bleeding rate, except for bivalirudin that appears to have a lower bleeding rate than heparin. No agent in this class has been approved for ACS treatment, although hirudin is approved for heparin-associated thrombocytopenia, and bivalirudin is approved for angioplasty.

Overall experience with glycoprotein IIb/IIIa inhibitors

The combined experience of this class of drugs for treatment of coronary artery disease includes over 43,000 randomized patients, with 16,000 in coronary intervention and 27,000 in ACS trials.10 Overall, there is a highly significant (P <0.001) 15% to 20% relative reduction, and 1.5% absolute reduction, in death or mi, which persists for at least 6 months.

glycoprotein iib/iiia inhibitors in ascs

In 1998, three large trials of glycoprotein (GP) Ilb/IIIa inhibitors in the treatment of non–ST-segment elevation ACSs led to approval of eptifibatide and tirofiban: the PRISM, PRISM-PLUS, and PURSUIT trials.11-13 The CAPTURE trial, although designed to address the issue of adjunctive treatment with angioplasty, provides further evidence of benefit from abciximab in treatment of ACSs as well.14

The PRISM, PRISM-PLUS, and PURSUIT trials randomized a total of over 16,000 patients with non–ST-elevation ACSs. In PRISM, patients were lower risk and angioplasty was not allowed during study drug administration, whereas in PRISM-PLUS and PURSUIT patients were higher risk and many underwent angioplasty during or soon after study drug administration. Treatment resulted in relative reductions in the 30-day composite of 18%, 30%, and 10%, which corresponded to absolute reductions of 1.3%, 3.2%, and 1.5%, respectively, in the three trials. Although the benefit was more evident among patients undergoing early intervention, much of the benefit for those undergoing intervention occurred prior to the intervention,15 and there was some benefit among patients not undergoing intervention.

GUSTO IV ACS enrolled 7,800 patients who were not to undergo early intervention except for severe refractory ischemia. They were randomized to placebo, abciximab for 24 hours, or abciximab for 48 hours. Only 1.6% of patients underwent early coronary intervention while on study drug. The primary endpoint of death and non-fatal MI occurred in 8.0%, 8.2%, and 9.1% of patients, respectively. The event rates were lower than expected, and many patients were enrolled in Poland and the Czech Republic. The lack of benefit observed in the GUSTO IV ACS trial raises questions as to which patients presenting with ACS should immediately be placed on GP IIb/IIIa inhibitors. The benefit for patients with ACS undergoing intervention is clear and compelling. There is likewise a strong rationale for use of IIb/IIIa inhibitors for high-risk patients and/or patients with refractory ischemia in an environment where coronary intervention is likely to be used, as is typically the case in the United States.

Coronary intervention in ACS

The TIMI IIIb, VANQWISH, and FRISC-II trials have evaluated the role of coronary intervention/revascularization in ACS. TIMI IIIb is largely of historical interest. VANQWISH effectively challenged routine intervention, but was limited by high operative mortality and its VA population that may differ from general populations in some important aspects. The FRISC-II trial provided the most pure experiment of the value of revascularization compared with medical therapy, and it showed that routine revascularization following a few days of LMWH in a high-risk population was associated with a survival advantage.16 Based on these findings, the American College of Cardiology/American Heart Association guidelines call for an early invasive strategy for high-risk patients, and allow for either an early invasive or early conservative strategy for patients with ACS and without high-risk features.

Summary

Quantitative (or semiquantitative) risk stratification is becoming a more accurate and feasible way to define both overall risk and likelihood of benefit from more potent and invasive therapies. LMWH appears to be at least as good, and likely modestly better than, unfractionated heparin, and when used for patients undergoing revascularization, it should be continued until revascularization. GP IIb/IIIa inhibitors are highly effective for coronary intervention, as well as for Òup-frontÓ use in high-risk ACS patients in an environment in which intervention is commonly used. In spite of the new guidelines, a clear delineation to the practitioner of which treatments are proven effective, in which patients, and in what combinations, remains challenging. Best estimates are that only 50% to 75% of ideal patients are currently receiving proven therapies. Better methods are needed to fully integrate proven effective treatments into practice.

References

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