Emerging Treatment Strategies for ACS Management: Improving Patient Outcomes

In the presentation “Emerging Treatment Strategies for Acute Coronary Syndrome (ACS) Management: Improving Patient Outcomes,” Frederick Korley, MD, an emergency medicine practitioner from John Hopkins, reviewed the role of available antiplatelet and anticoagulant agents for the treatment of ACS.

Dr Korely began his presentation by reviewing some relevant statistics including that ACS in the United States was associated with 1.1 million hospitalizations in 2010; of that number 322,000 had unstable angina, and 813,000 had a myocardial infarction (MI).

For patients with an MI, about 29% to 38% have a diagnosis of an ST-segment elevation MI (STEMI) occurring when a coronary artery is totally occluded by a blood clot. The diagnosis of STEMI is typically confirmed by blood testing or cardiac imaging, and Dr Korely noted that this number has decreased over the last decade due to the increasing sensitivity of troponin-measuring diagnostics to differentiate unstable angina versus MI.

From there, Dr Korely described the relevant mechanisms of action for a number of antiplatelet agents including aspirin (a COX-1 inhibitor), P2Y₁₂ inhibitors (ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor), and lastly the glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, and tirofiban). He noted the benefits of aspirin use as an adjunctive treatment and the fact that ticlopidine was the first P2Y₁₂ inhibitor, but is no longer available.

Clinical benefits of clopidogrel were described in results from the CURE trial. Dr Korely reviewed the increased mortality at 12 months with clopidogrel plus aspirin compared to placebo. He did note that this trial used a loading dose of clopidogrel 300 mg (then 75 mg QD), however the current standard of care is now a loading dose of 600 mg, still followed by 75 mg QD.

Of note, a number of factors play a role into non-response to clopidogrel. These “non-responders” included patients that were obese, older, or had a polymorphism in cytochrome P-450 system (specifically the CYP2C19 substrate). When making a choice about use of clopidogrel, these points were important to consider.

Moving to prasugrel, Dr Korely cited the Triton-TIMI 38 study, comparing prasugrel to clopidogrel. In this trial prasugrel was associated with increased efficacy (in terms of death, non-fatal MI, and non-fatal stroke) and reduced incidence of major bleeding. However, subgroups not demonstrating clinical benefit included patients over 75 years of age, those under 60 kg, and those with a history of transient ischemic attacks (TIA) or stroke.

In his review of ticagrelor, Dr Korely mentioned the PLATO trial where ticagrelor was compared to clopidogrel. In that trial Dr Korely focused his discussion around safety issues (adverse event and bleeding risks), which were significantly lower in the ticagrelor group.

When choosing a P2Y₁₂ inhibitor of those discussed thus far, Dr Korely stated that it really should be focused on patient status, risk factors for poor response and for bleeding, as well as product availability (including what is on formulary and what is covered by the patient’s insurance).

Switching focus to cangrelor, which is administered IV because of its short half-life, Dr Korely mentioned that it went through 3 major clinical trials (the CHAMPION trials) before its benefits were identified. In the 3rd trial (CHAMPION Phoenix), efficacy was seen to be significantly higher than clopidogrel over 48 hours. He noted that because of the short half-life, cangrelor was a good option if practitioners were still deciding if surgical intervention would be appropriate, the short half-life allows the clinical effects to stop after a few hours.

After the discussion of the P2Y₁₂ inhibitors, Dr Korely provided a broad overview of the evidence for use of glycoprotein (GP) IIb/IIIa inhibitors, where efficacy was demonstrated in a number of patient groups undergoing PCI or CABG.

Dr Korely then brought up a diagram of the coagulation cascade, mentioning direct and indirect factor Xa inhibitors, and direct thrombin inhibitors. His specific focus here was on unfractionated heparin (UFH) and low molecular weight heparin (LMWH).

The use of UFH and LMWH in ACS, as he described, was focused on a few key points, primarily that the use of UFH should be focused in cases where its short half-life would of greatest benefit. In addition, the increased incidence of heparin-induced thrombocytopenia (HIT) with UFH makes LMWH a more attractive option.

In closing, Dr Korely reiterated that treatment strategies should be guided by risk profile, patient characteristics, and the ability for patients to adhere to their treatment. In addition, treatment should be started as early as possible and practitioners need to be vigilant for opportunities to prevent (or reverse, if necessary) life-threatening bleeding.