US Pharm. 2016;41(2):HS2-HS5.
ABSTRACT: Complications seen with percutaneous coronary intervention led to the development of bare metal stents and, later, drug-eluting stents. To prevent progressive atherosclerosis in the case of drug-eluting stents, current guidelines suggest a course of dual antiplatelet therapy for 12 months. Results from recent trials that analyzed outcomes of altering this duration of therapy suggest that, in comparison with second-generation drug-eluting stents, the extension of dual antiplatelet therapy in patients with first-generation drug-eluting stents shows benefits. Clinical decision making should also take into account the similarity in mortality rates between both types of drug-eluting stents and the increased risk of bleeding associated with extension of therapy.
Acute coronary syndrome (ACS) poses a great clinical and economic burden on U.S. healthcare and on patients. In 2010, 1.1 million patients were diagnosed with ACS in the U.S., and in 2011, one of every seven deaths was caused by coronary artery disease.1 The American Heart Association (AHA) has calculated that every 34 seconds one patient will have a coronary event and that every 1 minute and 24 seconds one patient will die from a coronary event.1
In order to appropriately diagnose, manage, treat, and prevent this condition, the AHA Task Force collaborated with the American College of Cardiology Foundation (ACCF) in 2013 to create evidence-based guidelines for the different forms of ACS. According to these guidelines, in addition to medication management, patients with ACS should be treated with either percutaneous coronary intervention (PCI) or coronary artery bypass graft, depending on the indication. There are two types of PCI: nonstent procedures (such as balloon angioplasty and atherectomy) and stent procedures using drug-eluting stents (DES) or bare metal stents (BMS). This article will focus on background information and the duration of dual antiplatelet therapy (DAPT) with regard to PCI using DES.2
DES and Thrombosis
With DES, the risk of thrombosis is related in part to their structure: a metallic backbone, an antiproliferative drug, and a polymer.3 During stent placement, arterial tissue becomes exposed to the intravascular system, which launches an inflammatory response.4 Effects of the antiproliferative drug result in slower healing of this area, thereby increasing the period of time that platelets can adhere to it and form a thrombus.2
DES are preferred when patients are able to tolerate 12 months of dual antiplatelet therapy and have a low bleeding risk.5 First-generation DES elute sirolimus and paclitaxel. Owing to concerns about thrombosis, second-generation DES were developed, including those eluting everolimus and zotarolimus. The benefit of second-generation DES was demonstrated in several studies comparing everolimus with sirolimus. Compared with sirolimus-eluting stents, everolimus-eluting stents resulted in longer-term reduction of the risk of stent thrombosis.6
According to the ACCF/AHA guidelines, after PCI is performed, aspirin 81 to 325 mg should be continued indefinitely. In most cases, DAPT with a P2Y12 inhibitor should be continued for at least 1 year.2,7 This recommendation was based on studies that compared DAPT administered for a shorter period of time (1-6 months) versus a longer time (8-12 months). Most studies concluded that patients who underwent DAPT for a longer period of time had a reduced risk of thrombotic events, but an increased risk of bleeds. Bleeding was defined according to Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) criteria.2,8 See TABLE 1.2,9-17
Studies Supporting Extended-Duration DAPT: Several trials support the increase of DAPT to more than 12 months.18-20 A recent randomized study compared outcomes of patients with DES who received DAPT for 12 months or 30 months.19 The 30-month DAPT group had reduced thrombosis rates (0.4% vs. 1.4%, P <.001), fewer major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%, P <.001), and a lower cumulative incidence of myocardial infarction (MI) compared with the 12-month DAPT group (2.1% vs. 4.1%, hazard ratio[HR] 0.47, P <.001). Both groups had similar death rates (2% for 30-month anticoagulation vs. 1.5% for 12-month anticoagulation, P = .05). Patients receiving DAPT for 30 months, however, had more bleeding complications than those receiving it for 12 months (2.5% vs. 1.6%, P = .001).20 Bleeding was defined according to GUSTO and Bleeding Academic Research Consortium (BARC) criteria.8
A 2015 meta-analysis compared various trials of DAPT ranging from shorter durations (3-6 months) to longer durations (12-36 months).20 This meta-analysis, which had an increased statistical power because the number of patients examined was larger than in other meta-analyses, highlighted that the key to determining the benefits of long-duration DAPT (L-DAPT) or short-duration DAPT (S-DAPT) is to differentiate between the types of DES (TABLE 2).20 Patients with second-generation DES had thrombosis rates of 0.6% for S-DAPT versus 0.4% for L-DAPT, with an odds ratio (OR) of 1.54 (95% CI, 0.96-2.47). In patients with first-generation DES, thrombosis rates were 2.4% versus 0.6% for S-DAPT and L-DAPT, respectively, with an OR of 3.94 (95% CI, 2.2-7.05). The relationship between DES generation and DAPT duration was significant (P = .008).20
The meta-analysis also found a statistically significant increase in risk of bleeding for L-DAPT patients defined according to TIMI and GUSTO criteria (1.2% vs. 1.9%, combined OR 0.63, 95% CI 0.52-0.75, P <.001).8 Based on calculations of incidence risk difference of stent thrombosis and bleeding, for every stent thrombosis event averted with L-DAPT, approximately 2.1 clinically significant bleeding events were estimated to occur.20 Both groups had similar stroke and mortality rates that were acceptable for this patient population.21 Based on these findings, patients with second-generation DES can safely undergo DAPT for 3 to 6 months, since thrombosis rates were similar in both groups and bleeding rates were lower with S-DAPT. In determining the duration of DAPT with first-generation DES, the lower thrombosis rates with L-DAPT must be weighed against the increased risk of bleeding.
Studies Supporting Shorter-Duration DAPT: Whereas the treatment durations discussed above are accepted by some physicians, opposing views from other trials should be kept in mind.22-26 In a randomized, multicenter, open-label trial analyzing DAPT duration, 1,970 patients with BMS and DES were randomized to receive either S-DAPT (6 months) or L-DAPT (24 months).24 The composite of death rate at 2 years was similar in both groups (10.1% vs. 10.0%, HR 0.98, 95% CI, 0.74-1.29, P = 0.91). The treatment groups were also similar in secondary outcomes (mortality, MI, stroke, stent thrombosis rate). A significant increase in bleeding risk according to BARC and TIMI criteria was noted in the L-DAPT group.8 In a subgroup analysis of patients who had only DES in place, death from any cause was similar between L-DAPT and S-DAPT patients (6.8% vs. 6%, P = .51). It was concluded that L-DAPT was not significantly more effective than S-DAPT. However, the study had some limitations—e.g., open-label design and inclusion of patients with BMS—that might skew the benefit of 24-month DAPT (L-DAPT).24
A 2014 article reviewed several major clinical trials pertaining to DAPT duration after DES implantation.25 The first trial assessed the continuation of clopidogrel beyond 12 months.11 MI or death from cardiac causes was similar between 12-month DAPT and 24-month DAPT (0.7% vs 1.8%, P = .17). Stent thrombosis was also similar: 0.2% at 12 months and 0.4% at 24 months (P = .76). Both groups had similar rates of major bleeding. In the second trial, which compared 6-month DAPT and 12-month DAPT in patients with DES, DAPT did not show any clinical benefit beyond 6 months.18 It was deduced that these results cannot be extrapolated to the general population.25 However, physicians may use these outcomes as a guide, depending on the case.
More support for S-DAPT was found in a 2015 meta-analysis of four studies.26 DAPT duration ranged from 3 to 24 months. A longer duration of DAPT did not reduce the risk of all-cause mortality (pooled OR 0.89, 95% CI, 0.67-1.17, P = .4), myocardial infarction (pooled OR 1.16, 95% CI, 0.85-1.57, P = .35), cardiac death (pooled OR 0.88, 95% CI, 0.61-1.25, P = .47), stent thrombosis (pooled OR 1.29, 95% CI, 0.76-2.21, P = .35), or cerebrovascular accidents (pooled OR 0.73, 95% CI, 0.41-1.27, P = .26) (TABLE 3).26 Extending DAPT past 6 months did not yield any clinical benefits and conferred an increased risk of bleeding according to TIMI criteria (pooled OR 0.51, 95% CI, 0.29-0.89, P = .02).8,26
Key points of the studies discussed above are as follows: 1) There is an increased risk of bleeds with L-DAPT versus S-DAPT; 2) L-DAPT results in a statistically significant reduction in thromboembolic events that is attenuated in patients with second-generation DES; and 3) both generations of DES showed similar mortality rates. It is important to differentiate between both generations of DES in order to determine treatment duration. Patients with second-generation DES can be treated with S-DAPT (3-6 months) to yield similar thrombosis risk-lowering and decreased bleeding events compared with L-DAPT. On the other hand, clinical judgment should be used to determine the risks and benefits of extending DAPT beyond 12 months or shortening it in patients with first-generation DES. Since studies show lower thromboembolic-event risk but increased bleeding risk and similar mortality rates in patients with first-generation DES, it would be advisable to extend therapy beyond 12 months in those at higher risk for thrombosis. Additional studies are required to determine the optimal duration of therapy after first-generation DES. Healthcare professionals can use the therapeutic outcomes presented above to guide clinical judgment until a formal consensus is reached.
1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-e322.
2. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58:e44-e122.
3. Abbott D, Cutlip D. Drug-eluting intercoronary stents: general principles. UpToDate. Waltham, MA: UpToDate; 2015. www.uptodate.com. Accessed October 21, 2015.
4. Shah PK. Inflammation, neointimal hyperplasia, and restenosis: as the leukocytes roll, the arteries thicken. Circulation. 2003;107:2175-2177.
5. Dangas G, Kuepper F. Restenosis: repeat narrowing of a coronary artery: prevention and treatment. Circulation. 2002;105:2586-2587.
6. Stefanini GG, Holmes DR Jr. Drug-eluting coronary-artery stents. New Engl J Med. 2013;368:254-265.
7. Levin T, Cutlip D. General principles of the use of intercoronary stents. UpToDate. Waltham, MA: UpToDate; 2015. www.uptodate.com. Accessed October 21, 2015.
8. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123:2736-2747.
9. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–st-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e426.
10. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of st-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e78–e140.
11. 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;345:494-502.
12. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527-533.
13. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411-2420.
14. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159-168.
15. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1607-1621.
16. Shishehbor MH, Topol EJ, Mukherjee D, et al. Outcome of multivessel coronary intervention in the contemporary percutaneous revascularization era. Am J Cardiol. 2006;97:1585-1590.
17. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-2619.
18. Helft G, Le Feuvre C, Georges JL, et al. Efficacy and safety of 12 versus 48 months of dual antiplatelet therapy after implantation of a drug-eluting stent: the OPTImal DUAL antiplatelet therapy (OPTIDUAL) trial: study protocol for a randomized controlled trial. Trials. 2013;14:56.
19. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155-2166.
20. Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2015;65:1298-1310.
21. Guptill JT, Mehta RH, Armstrong PW, et al. Stroke after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction: timing, characteristics, and clinical outcomes. Circ Cardiovasc Interv. 2013;6:176-183.
22. Giugliano RP, Braunwald E. The year in acute coronary syndrome. J Am Coll Cardiol. 2014;63:201-214.
23. Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med. 2010;362:1374-1382.
24. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125:2015-2026.
25. Rha SW. Duration of dual antiplatelet treatment in the era of next generation drug-eluting stents. World J Cardiol. 2014;6:148-153.
26. Pandit A, Giri S, Hakim FA, Fortuin FD. Shorter (≤6 months) versus longer (≥12 months) duration dual antiplatelet therapy after drug eluting stents: a meta-analysis of randomized clinical trials. Catheter Cardiovasc Interv. 2015;85:34-40.
To comment on this article, contact email@example.com.