Antiplatelet Therapy for Coronary Stents

Introduction

The use of coronary stents has become routine in patients undergoing percutaneous coronary intervention (PCI). While these stents provide life-saving benefits, the issue of stent thrombosis remains problematic. Antiplatelet therapy, usually with two antiplatelet medications, is recommended in all patients who receive a coronary stent. This document reviews the recommendations for antiplatelet therapy in patients with coronary stents.

Bare-Metal Stents versus Drug-Eluting Stents

Using cardiac stents is a relatively new medical technique. In the 1970s and 1980s, issues with coronary artery collapse immediately following balloon angioplasty, or restenosis or reblockage of the artery in the months after the procedure, led to the development of cardiac stents. Stents are small, lattice-shaped metal tubes permanently inserted into the coronary arteries. The first stent was implanted into a human in 1986, and the first stent was approved by the Food and Drug Administration (FDA) in 1994. These stents were "bare-metal" stents or stents made of metal only.

However, while bare-metal stents solved the problem of artery collapse immediately after angioplasty, restenosis still occurred, usually approximately six months after the procedure in about 25% of the patients. Restenosis is typically not due to reaccumulation of plaque, but rather due to the body's response to angioplasty and resulting overgrowth of smooth muscle cells which can block the stent.¹

Problems with restenosis led to the development of drug-eluting stents which are coated with a medication such as sirolimus (Cypher stent, Johnson and Johnson/Cordis), paclitaxel (Taxus stent, Boston Scientific), or everolimus (Xience V stent, Abbott). The medication interferes with the restenosis process. These drug-eluting stents have been successful at reducing the rate of restenosis from approximately 25% to less than 4%.^1,2 However, thrombosis occurs more commonly with drug-eluting stents, likely due to delayed epithelialization. Consequently, despite the reduction in restenosis seen with drug-eluting stents, the long-term overall incidence of myocardial infarction and cardiac mortality continues to be similar with bare-metal stents and drug-eluting stents.³

Antiplatelet Medications

Following stent placement, patients must take aspirin plus clopidogrel (Plavix) or prasugrel (Effient) to prevent blood from clotting or thrombosing on the artery. Stent thrombosis can lead to devastating events such as myocardial infarction and death. Once a thin layer of endothelial cells grows over the stent and the stent becomes incorporated into the artery, the chance of clotting is reduced.¹ However, this process is disrupted with drug-eluting stents. This is because drug-eluting stents inhibit the growth of "scar tissue" within the stent, thereby reducing the rate of restenosis. But, if normal cell growth is inhibited too much, the stent does not become incorporated into the artery or epithelialized. This "foreign" surface attracts platelets leading to a clot or thrombus.⁴ In addition to the risk of thrombosis during the first year, observational studies have shown that the absolute rate of very late stent thrombosis (or thrombosis after one year) with drug-eluting stents is 0.5% per year or higher and that this can persist for many years.^5-7

With antiplatelet medications, thrombosis during the first month after placement of a drug- eluting stent is approximately 1%.⁸ A number of patient and angiographic characteristics have been identified as predictors of later drug-eluting stent thrombosis and therefore may necessitate a prolonged duration of antiplatelet therapy. Patient characteristics include older age, diabetes mellitus, a low cardiac ejection fraction, renal failure, and acute coronary syndrome. In addition, early discontinuation of antiplatelet medications has been identified as a risk for stent thrombosis. Angiographic characteristics such as long or overlapping stents, placement of stents in small vessels, bifurcation lesions, or suboptimal stent results also increase the risk of drug-eluting stent thrombosis.⁸

Proton pump inhibitors such as omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), and others are often prescribed prophylactically when clopidogrel is started, to prevent gastrointestinal complications such as ulceration and related bleeding due to dual-antiplatelet therapy. However, proton pump medications may reduce the efficacy of clopidogrel, but the clinical significance is not known.⁹

American College of Cardiology Foundation/American Heart Association Recommendations

The American College of Clinical Cardiology/American Heart Association/Society for Cardiovascular Angiography and Intervention guidelines for percutaneous coronary intervention were updated in 2007 and the guidelines for management of patients with ST-elevation myocardial infarction were updated in 2009.^9,10 Both of these guidelines contain recommendations for the prevention of stent thrombosis.

Aspirin therapy is recommended for all patients with coronary stents. For bare-metal stents, aspirin 162 mg to 325 mg daily should be given for at least one month after implantation of a bare-metal stent. Aspirin therapy, 162 mg to 325 mg daily should be continued for three months for patients with sirolimus-eluting stents and six months for those with a paclitaxel-eluting stent. Following the initial period of aspirin therapy, long-term use of aspirin should be continued indefinitely at a dose of 75 mg to 162 mg daily. In patients for whom there is concern about bleeding, lower doses of aspirin, 75 mg to 162 mg, can be considered.¹⁰

In addition to aspirin therapy, a second antiplatelet agent or dual antiplatelet therapy is warranted.⁹ For stable patients who receive a bare-metal stent during a percutaneous coronary intervention (PCI), clopidogrel 75 mg daily should be given for a minimum of one month and ideally up to 12 months. If the patient is at increased risk of bleeding, the duration of clopidogrel can be reduced to a minimum of two weeks.⁹ For patients receiving a bare-metal stent during PCI for acute coronary syndrome, dual antiplatelet therapy should be continued for at least 12 and up to 15 months.⁹

For all patients who have received a drug-eluting stent, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. If the risk of morbidity because of bleeding outweighs the anticipated benefit of clopidogrel therapy, earlier discontinuation can be considered. If the decision is made to use prasugrel, a dose of 10 mg daily should be given for at least 12 months. Patients weighing less than 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once-daily maintenance dose. Consideration should be given to lowering the maintenance dose to 5 mg in patients who weigh less than 60 kg. However, the effectiveness and safety of the 5 mg dose have not been prospectively studied. In patients older than 75 years of age, prasugrel is generally not recommended because of the increased risk of fatal and intracranial bleeding and uncertain benefit. The exception is in high-risk situations (e.g., patients with diabetes or a history of prior MI) in which prasugrel's effect appears to be greater and its use may be considered.⁹

Recent Information: Length of Dual Antiplatelet Therapy with Drug-Eluting Stents

In general, review of the literature demonstrates that drug-eluting stents increase the risk of stent thrombosis, especially after one year.^3,11-13 However, the morbidity and mortality associated with drug-eluting stents, when used for the labeled indications (e.g., 2.5 to 3.75 mm diameter vessels up to 28 to 30 mm in length), is similar to that of bare-metal stents. This similarity is likely due to the increased incidence of restenosis associated with bare-metal stents. When drug-eluting stents are used for "off-label indications" (e.g., chronic total occlusion of the vessel, cardiac ejection fraction less than 30%, following an acute myocardial infarction), the rate of stent thrombosis is significantly higher. But again, the morbidity and mortality associated with drug-eluting stents in these clinical situations is similar to that of bare-metal stents. This is also likely due to the increased incidence of restenosis associated with bare-metal stents.^3,11-13

Most recently, Park and colleagues conducted two trials involving more than 2,700 patients who had received a drug-eluting stent at least 12 months prior and randomized these patients to either aspirin alone or aspirin plus clopidogrel. These patients had not experienced any major adverse cardiac or cerebrovascular events or major bleeding since implantation of the stent.^14-16

After an average follow-up of 19.2 months, the investigators found the risk of primary outcome (a composite of myocardial infarction or death from a cardiac cause) was similar in both treatment groups (1.8% in patients who received aspirin plus clopidogrel versus 1.2% with aspirin alone, hazard ration 1.65, 95% CI 0.8 to 3.36, p=0.17). The investigators concluded that dual antiplatelet therapy for more than 12 months in patients who had received drug-eluting stents did not appear to reduce the rate of myocardial infarction or death from a cardiac cause, compared with aspirin alone. However, they caution that these finding should be confirmed with larger trials and longer follow-up periods.^14-16

Prevention of Premature Discontinuation of Dual Antiplatelet Therapy

Given the importance of adherence with dual antiplatelet therapy in patients with drug-eluting stents, the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association released a Scientific Advisory in early 2007. They note that there are a number of factors associated with premature cessation of thienopyridine therapy [such as clopidogrel or less commonly, ticlopidine (Ticlid); prasugrel was unavailable at the time of guideline release]. These include:⁸

• older age
• lower educational level
• unmarried
• lack of discharge instruction for medication use
• lack of referral to cardiac rehabilitation
• preexisting cardiovascular disease
• anemia
• lack of healthcare due to cost

In addition, the high cost of clopidogrel (approximately $4 per day) is prohibitive to adherence in some patients.⁸

The Scientific Advisory recommends the following to minimize premature discontinuation of antiplatelet medication:⁸

• Before insertion of a stent, patients should understand the need for a full, twelve-month course of dual antiplatelet therapy. If the patient is unlikely to complete the twelve-month treatment, then a drug-eluting stent may not be ideal for that patient.
• In patients who require an invasive or surgical procedure within twelve months following percutaneous coronary intervention, a bare-metal stent or provisional (temporary) stent should be considered.
• Prior to patient discharge from the hospital, the patient should be educated regarding the indication and risks associated with premature discontinuation of dual antiplatelet therapy.
• Patients should be instructed to contact their cardiologist prior to discontinuing antiplatelet therapy, even if instructed to do so by another healthcare professional.
• Healthcare providers who perform invasive or surgical procedures should understand the consequences of premature discontinuation of dual antiplatelet treatment and defer elective procedures until patients have completed the appropriate course of treatment.
• If premature discontinuation of antiplatelet therapy is necessary, patients should continue aspirin, if possible, and Plavix should be restarted as soon as possible after the procedure.

In addition to premature discontinuation, failure to fill the initial prescription is a major problem. In a study conducted by Ho and colleagues, of the 7,402 patients discharged from the hospital after drug-eluting stent implantation, 16% did not fill the prescription on the day of discharge and the median time delay was three days. Alarmingly, compared with patients who filled the prescription on the first day, those who did not fill the prescription on the day of discharge had an increased risk of death or myocardial infarction (14.2% versus 7.9%, p<0.001). Patients must be educated regarding the importance of filling and taking antiplatelet therapy correctly.¹⁷

Conclusion

Until more information is known, all patients with drug-eluting cardiac stents should take dual antiplatelet therapy for at least one year [Evidence level B; Lower quality RCT].^4,6,14 Patients with bare-metal stents following PCI should take dual antiplatelet therapy for at least one month and ideally up to 12 months. For patients receiving a bare-metal stent during PCI for acute coronary syndrome, dual antiplatelet therapy should be continued for 12 to 15 months. However, patients should understand that the treatment length can be variable and will depend on the risk of bleeding versus a clot. All patients should receive aspirin indefinitely after clopidogrel or prasugrel is discontinued, regardless of stent type.

 

Project Leader in preparation of this Detail-Document: Neeta Bahal O'Mara, Pharm.D., BCPS

References

1. Anon. Drug-eluting stent overview (revised September 2008). Angioplasty.org. http://www.ptca.org/stent.html. (Accessed May 10, 2010).
2. Popma JJ, Berger P, Ohman EM, et al. Antithrombotic therapy during percutaneous coronary intervention: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126(Suppl 3):5765-995.
3. Naidu SS. Three years since the FDA advisory panel on drug-eluting stents: what have we learned about off-label use and stent thrombosis? J Invasive Cardiol 2010;22:20-1.
4. Anon. Use of drug-eluting stents declines at some hospitals (June 22, 2006). Angioplasty.org. http://www.ptca.org/news/2006/0622.html. (Accessed May 10, 2010).
5. Pfisterer M, Brunner-La Rocca HP, Rickenbacher P, et al. Long-term benefit-risk balance of drug-eluting vs. bare-metal stents in daily practice: does stent diameter matter? Three-year follow-up of BASKET. Eur Heart J 2009;30:16-24.
6. Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stents in routine clinical practice: 4-year results form a large 2-institutional cohort study. J Am Coll Cardiol 2008;52:1134-40.
7. Butler MJ, Eccleston D, Clark DJ, et al. The effect of intended duration of clopidogrel use on early and late mortality and major adverse cardiac events in patients with drug-eluting stents. Am Heart J 2009;157:899-907.
8. Grines CL, Bonow RO, Casey DE, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents. A Science Advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115:813-8.
9. King SB III, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2008;117;261-95.
10. Kushner FG, Hand M, Smith SC Jr. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (Updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (Updating the 2005 guideline and 2007 focused update: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 2009;120:2271-306.
11. Smith SC Jr., Feldman TE, Hirchfield JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association task force of practice guidelines. (ACC/AHA/SCAI writing committee to update the 2001 guidelines for percutaneous coronary intervention). 2005. http://www.americanheart.org/downloadable/heart/1131740149971PCI_Final
    %20Final%20Clean%20Revision_AHA.pdf. (Accessed May 10, 2010).
12. Bavry AA, Kumbhani DJ, Helton TJ, et al. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006;119:1056-61.
13. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020-9.
14. Kirtane AJ, Gupta A, Iyengar S, et al. Safety and efficacy of drug-eluting and bare-metal stents: comprehensive meta-analysis of randomized trials and observational studies. Circulation 2009;119:3198-206.
15. Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;362:1374-82.
16. Berger PB. Optimal duration of clopidogrel use after implantation of drug-eluting stents-still in doubt. N Engl J Med 2010;362:1441-3.
17. Ho PM, Tsai TT, Maddox TM, et al. Delays in filling clopidogrel prescription after hospital discharge and adverse outcomes after drug-eluting stent implantation. Circ Cardiovasc Qual Outcomes 2010;3:261-266.

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.

Cite this Detail-Document as follows: Antiplatelet therapy for coronary stents. Pharmacist's Letter/Prescriber's Letter 2010;26(6):260604.

June 2010

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