By: Addolorata Ciccone, Co-Copy Editor

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Acute Coronary Syndromes

Acute coronary syndrome (ACS) is a myocardial ischemia caused by obstruction of coronary arteries.  ACS is stratified into three types, based on electrocardiogram (EKG) changes and the presence of cardiac biomarkers (e.g. troponin, creatinine phosphokinase, and myoglobin).  To guide treatment plans, it is important to identify the exact type of ACS the patient is experiencing.  An EKG with ST-segment elevation and positive cardiac biomarkers characterizes ST-segment elevation myocardial infarction (STEMI), the most severe type of ACS.  Non−ST-segment elevation myocardial infarction (NSTEMI) has no EKG changes but positive cardiac biomarkers.  Unstable angina (UA) has neither EKG changes nor cardiac biomarkers present.  Principles in therapy for all types of ACS include maximizing oxygen saturation; managing pain; decreasing workload of the heart; increasing coronary blood flow; decreasing further clot formation; and, decreasing cardiac remodeling.  In the management of STEMI, early (<24 hours) invasive catheterization and revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) is recommended.¹  Pharmacological agents utilized in the treatment of ACS include fibrinolytics, anti-ischemic agents (e.g. nitroglycerin, morphine, beta-blockers, and angiotensin-converting enzyme inhibitors), lipid-lowering agents (e.g. statins), antiplatelets (e.g. aspirin, P2Y12 inhibitors, and GP IIb/IIIa inhibitors), and anticoagulants (e.g. unfractionated heparin, low-molecular-weight heparins, direct thrombin inhibitors, and factor Xa inhibitors).^1—2

Thienopyridines

Ticlopidine (Ticlid®), clopidogrel (Plavix®), prasugrel (Effient®), and ticagrelor (Brilinta®) are the four thienopyridines providing cardiologists with treatment options for stroke prevention in ACS patients after PCI.^2—6  The thienopyridines, better known as P2Y12 inhibitors, inhibit P2Y12 receptors on the surface of platelets, decreasing platelet activation and aggregation, increasing bleeding time, and reducing blood viscosity.²

Ticlopidine

The pilot drug ticlopidine carries labeled ACS indications for UA or NSTEMI undergoing PCI.  It is a prodrug requiring activation via the hepatic CYP 3A4 enzyme.  A loading dose of 500mg should be administered once six hours prior to PCI; maintenance doses are 250mg twice daily.  The drug has a black box warning (BBW) against life-threatening hematologic disorders (e.g. neutropenia, agranulocytosis, thrombotic thrombocytopenic purpura [TTP], aplastic anemia).  Potential adverse effects include diarrhea, nausea, and dyspepsia.  It is recommended that white blood cells (WBC), neutrophils, and platelets be monitored in patients on ticlopidine.^{2, 3}  Use of this thienopyridine is unfavorable due to its life-threatening side effects, gastrointestinal (GI) upset, and twice daily dosing; these characteristics spurred the development of newer P2Y12 inhibitors.

Clopidogrel

Clopidogrel was the next thienopyridine discovered.  This agent is indicated for all three types of ACS with or without PCI.  As a prodrug, clopidogrel requires activation via CYP 2C19 (rather than 3A4), which prompts us to screen for further potential drug-drug interactions (DDI).  The administered loading dose is 300—600mg once, with a maintenance dose of 75mg once daily.  There is a BBW stating that heterogeneity of CYP 2C19 genes may reduce conversion of clopidogrel into its active metabolite, which may result in reduced platelet inhibition and a higher rate of cardiovascular events following myocardial infarction (MI) or stent thrombosis following PCI.  Adverse effects seen include bleeding, bruising, and rash, thus signs of bleeding should be closely monitored for in patients on clopidogrel.^{2, 4}

A landmark prospective, multicenter, international, double-blinded, parallel group, placebo-controlled, randomized clinical trial compared combination aspirin and clopidogrel versus aspirin alone in 12,562 UA/NSTEMI patients.⁷  The primary endpoint of cardiovascular death, MI, or stroke was lower in the combination group than in the group taking aspirin alone (9.3% vs. 11.4%; P<0.001).  A secondary safety endpoint looking at fatal bleeding revealed that rates were significantly higher in the combination group (P<0.001).  This increase in bleeding particularly occurred in CABG patients within five days of initiating clopidogrel. Discontinuing clopidogrel à increased bleeding?  This CURE trial thus concluded that the addition of clopidogrel to aspirin was beneficial in UA/NSTEMI in reducing mortality, MI, and stroke; however, there was an increase in major and minor bleeding rates with the combination.⁷

Another landmark trial comparing the use of clopidogrel with and without aspirin was the CLARITY TIMI-28 trial.⁸  This prospective, multicenter, international, double-blinded, parallel group, placebo-controlled, randomized clinical trial was conducted with 3,491 STEMI patients, providing data on the same clinical endpoints in an ACS patient population excluded in the CURE trial.^7,8  Cardiovascular death, MI, or stroke was lower in the combination group than in the group taking aspirin alone (15% vs. 21.7%; P<0.001).  Major and minor bleeding rates were similar in both groups through PCI (1.3% vs. 1.1%) and at 30 days (1.9% vs. 1.7%).  It was concluded from this study that the addition of clopidogrel to aspirin is beneficial in patients with ACS, PCI, and acute MI; yet, for primary prevention of cardiovascular disease, there is no evidence that the combination offers an advantage over aspirin alone, and for secondary prevention, while substitution of clopidogrel for aspirin may provide a marginal benefit at a higher cost; the benefit of adding clopidogrel to aspirin is undetermined.⁸

Drawbacks to using clopidogrel include genetic polymorphism, a DDI with proton-pump inhibitors (PPIs), its slow onset and long duration, increased bleeding risk, and low degree of platelet inhibition (<50%).^{2, 4}  Also, a high rate of recurrent atherothrombotic events post-ACS was seen despite the administration of dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel.⁹  These reasons sparked a great interest in finding newer, more potent inhibitors of the P2Y12 ADP receptor.

Prasugrel

Prasugrel is a newer thienopyridine indicated for use in UA/NSTEMI, or in STEMI with PCI.  This prodrug requires activation via the CYP 3A4 and CYP 2B6 enzymes.  The loading dose is 60mg once; subsequently, 5—10mg daily is the maintenance dose.  Interestingly, although the 5mg daily dose is for patients at high risk for bleeding, there is currently no real data to support this.  A BBW warns against significant, sometimes fatal, bleeding; fatal intracranial bleeding and uncertain benefit in patients aged ≥ 75 years old; and increased risk of bleeding with surgery.  Adverse effects to watch out for are unique in comparison to the other thienopyridines and include bleeding, hypertension, hyperlipidemia, headache, back pain, and epistaxis (nosebleeds).  As with the previous thienopyridines, patients need monitoring for signs of bleeding.^{2, 5}

The TRITON TIMI-38 trial compared prasugrel head-to-head with clopidogrel.  It was the phase 3 prospective, multicenter, international, double-blinded, parallel group, randomized clinical trial performed for prasugrel to enter the market.  Among 13,608 ACS patients scheduled for PCI, endpoints looked at were cardiovascular death, MI, or stroke; incidence of stent thrombosis; and fatal bleeding.  Cardiovascular death, MI, or stroke was lower with prasugrel than clopidogrel (9.9% vs. 12.1%; P<0.001).¹⁰  Incidence of stent thrombosis was also lower with prasugrel (1.1% vs. 2.4%; P<0.001), which was a clinically important finding as high incidence of stent thrombosis is a concern with clopidogrel.^9—10  Incidence of fatal bleeding, however, was higher with prasugrel than with clopidogrel (2.4% vs. 1.8%; P=0.03).  In regards to differences in type of ACS, there were no statistically significant differences in bleeding.  In conclusion, from this study, prasugrel is associated with significantly reduced rates of ischemic events and stent thrombosis, but an increased risk of fatal bleeding.  Subgroup analyses show decreased clinical benefit and increased bleeding risk in patients <60 kg; ≥75 years old; and with a past medical history of stroke or transient ischemic attack (TIA).  Mortality did not differ significantly between clopidogrel and prasugrel.¹⁰

Ticagrelor

The newest thienopyridine on the market is ticagrelor.  It is the first reversible P2Y12 inhibitor.  Like clopidogrel, it is for all three types of ACS with or without PCI.  This prodrug, like prasugrel, is not affected by CYP 2C19; it is rather activated by the CYP 3A4 enzyme like ticlopidine.  The loading dose for this agent is 180mg once; the maintenance dose is 90mg twice daily.  The BBWs for ticagrelor are its significant (sometimes fatal) bleeding and concomitant use with maintenance doses of aspirin >100mg daily reducing its effectiveness (and should be avoided).  Unique adverse effects include dyspnea, headache, cough, dizziness, nausea, atrial fibrillation, bradycardia, gynecomastia, and ventricular pauses.  Besides signs of bleeding, difficulty breathing should also be monitored for.^{2, 6}

The PLATO trial was a prospective, multicenter, international, double-blinded, parallel group, randomized clinical trial performed on 18,624 ACS patients comparing ticagrelor head-to-head with clopidogrel.  The primary endpoint of cardiovascular death, MI, or stroke resulted lower with ticagrelor than clopidogrel (9.8% vs. 11.7%; P<0.001).  As far as the safety endpoint of fatal bleeding, no statistically significant difference was seen between the two groups (11.6% vs. 11.2%; P=0.43); except for non-CABG-related bleeding, which was greater in the ticagrelor group (4.5% vs. 3.8%; P = 0.03).  In conclusion, in patients with ACS (regardless of ST-segment elevation, PCI status, or clopidogrel loading beforehand) ticagrelor is associated with significantly reduced rates of ischemic events and a significant decrease in mortality; there is also no significant difference in overall risk of fatal bleeding, but increased risk of non-procedure-related fatal bleeding.¹¹

Based partly on the methods used in the PLATO trial, ticagrelor and clopidogrel were further compared in the ONSET/OFFSET study.^{11, 12}  As can be seen in the data provided, ticagrelor has a faster, greater onset; a greater degree of platelet inhibition maintained throughout therapy; and a faster offset as compared to clopidogrel.¹²  Perhaps clopidogrel has a slower offset than ticagrelor due to its irreversible P2Y12 binding as compared to the reversible nature of ticagrelor’s P2Y12 binding.  In view of the results from this study, ticagrelor is therefore preferable in ACS patients for immediate platelet inhibition or if patients require a CABG or another unanticipated surgical procedure.¹²

     The newer P2Y12 inhibitors prasugrel and ticagrelor produce stronger platelet inhibition than clopidogrel.^{2, 5, 6, 12}  Previous studies compared these new agents head-to-head with clopidogrel, the standing agent of choice in comparison to ticlopidine, but never to one another.  In July 2012, the first direct pharmacodynamic comparison between prasugrel and ticagrelor was published in the Journal of the American College of Cardiology.¹³  This prospective, single-center, single-blind crossover study was performed on 44/139 screened ACS patients who did not respond to clopidogrel treatment 24 hours post-PCI.  Patients with high platelet reactivity on clopidogrel received either ticagrelor 90mg twice daily or prasugrel 10mg once daily for 15 days and then directly crossed over to the alternate treatment for another 15 days.  Platelet reactivity was lower for ticagrelor (32.9 vs. 101.3, P<0.001).  High on-treatment platelet reactivity was seen in 0% of patients taking ticagrelor in comparison to 2.4% of patients taking prasugrel (P=0.5).  Furthermore, no patients in either treatment group experienced a major bleeding event, but ticagrelor had more mild side effects (e.g. dyspepsia, dyspnea).  In conclusion, in patients with persistently high platelet reactivity after initiating clopidogrel, ticagrelor produces a statistically significant higher degree of platelet inhibition in comparison to prasugrel.¹³  It would be interesting to see the results of a well-designed, large, randomized, prospective, placebo-controlled clinical trial comparing prasugrel and ticagrelor to compare them to the results of this smaller study and observe if these pharmacodynamic differences translate into significant differences in efficacy or safety .

Summary 

Antiplatelet agents improve clinical outcomes for patients with ACS.^{1, 7, 8}  Evidence supports early initiation of DAPT with a thienopyridine and aspirin.^{1, 7—9, 14}  The thienopyridines decrease morbidity and mortality, with some increased bleeding.^{1, 7, 8, 10—13}  Overall mortality is not statistically different between the agents.^10—12  ACS guidelines do not specifically endorse any one thienopyridine over the others.¹  The comparison of these four agents is only based upon a handful of trials; and more are needed to make a definitive guideline stating that one is best.  While the evidence on these medications continues expand, we must utilize clinical guidelines and evidence-based medicine to formulate individual patients’ antiplatelet regimens.  A thienopyridine should be chosen depending on the given patient’s risks, concomitant disease states, and current drug regimens.  The information in the comparative chart compiled above may be of assistance.

In choosing among these agents, benefits of antiplatelet therapy must be weighed against risks of bleeding and stent thrombosis.  Although it does appear that newer thienopyridines overcome several issues associated with earlier ticlopidine and clopidogrel, further trials would be useful in generalizing evidence for broad clinical use.^10—13

SOURCES:

1. Kumar A, Cannnon CP. Acute coronary syndromes: diagnosis and management, part 1.  Mayo Clin Proc. 2009;84(11):1021—36.
2. Lexi-Comp Online.  Available at http://www.crlonline.com/crlsql/servlet/crlonline.  Accessed July 10, 2012.
3. Ticlid [package insert].  Nutley, NJ: Roche Pharmaceuticals; 2001.
4. Plavix [package insert].  Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals, 2011.
5. Effient [package insert].  Indianapolis, IN: Eli Lilly and Company, 2011.
6. Brilinta [package insert].  Wilmington, DE: AstraZeneca, 2011.
7. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med. 2001;345:494—507.
8. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.  N Engl J Med. 2005;352:1179—89.
9. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment.  Circulation.  2007;116:745—54.
10. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes.  N Engl J Med. 2007;357:2001—15.
11. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.  N Engl J Med. 2009;361:1—13.
12. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.  Circulation.  2009;120:2577—85.
13. Alexopoulos D, Galati A, Xanthopoulou I, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study.  J Am Coll Cardiol.  2012;60:193—9.
14. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the efficacy of Xience/Promus versus Cypher to reduce late loss after stenting (EXCELLENT) randomized, multicenter study.  Circulation.  2012;125:505—13.

Published by Rho Chi Post