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AHA/ACC/SCAI/ACS/ADA SCIENCE ADVISORY

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^_*

	Abstract

Top Abstract Dual Antiplatelet Therapy for... Premature Thienopyridine... Stent Thrombosis After... Factors Related to Premature... Summary and Recommendations Disclosures References

 
Abstract: Dual antiplatelet therapy with aspirin and a thienopyridine has been shown to reduce cardiac events after coronary stenting. However, many patients and healthcare providers prematurely discontinue dual antiplatelet therapy, which greatly increases the risk of stent thrombosis, myocardial infarction, and death. This advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent and educating the patient and healthcare providers about hazards of premature discontinuation. It also recommends postponing elective surgery for 1 year, and if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-risk patients with drug-eluting stents.

Key Words: AHA Scientific Statements • thrombosis • myocardial infarction • stents • myocardial stunning

	Dual Antiplatelet Therapy for Prevention of Ischemic Cardiovascular Events and Stent Thrombosis

Top Abstract Dual Antiplatelet Therapy for... Premature Thienopyridine... Stent Thrombosis After... Factors Related to Premature... Summary and Recommendations Disclosures References

Stent thrombosis most commonly occurs in the first month after stent implantation, and in this interval, it is referred to as "subacute stent thrombosis." However, numerous cases of "late" stent thrombosis, particularly in patients who have been treated with DES, have been described as occurring months or even years after stent implantation (19–21). In the majority of cases, stent thrombosis is a catastrophic event, resulting in life-threatening complications. In a pooled analysis of 6 trials and registries from the 1990s, the incidence of death or MI associated with angiographically documented stent thrombosis was found to be 64.4% (14). Mortality rates due to presumed or documented stent thrombosis range from 20% to 45% (19–21).

In the current era of dual antiplatelet therapy, the average reported occurrence of subacute stent thrombosis is 1% (16–22). The timing of thrombosis appears to be delayed in DES. Late (1 to 12 months) stent thrombosis was not readily apparent with bare-metal stents yet was reported to occur in 0.19% of patients in a large DES registry (18). Predictors of late stent thrombosis have included stenting of small vessels, multiple lesions, long stents, overlapping stents, ostial or bifurcation lesions, prior brachytherapy, suboptimal stent result (underexpansion, malapposition, or residual dissection), low ejection fraction, advanced age, diabetes mellitus, renal failure, acute coronary syndrome, and premature discontinuation of antiplatelet agents (Table 2) (9,13,18–21).

	Premature Thienopyridine Discontinuation and Stent Thrombosis

Top Abstract Dual Antiplatelet Therapy for... Premature Thienopyridine... Stent Thrombosis After... Factors Related to Premature... Summary and Recommendations Disclosures References

 
The premature discontinuation of thienopyridine therapy is associated with a marked increase in the risk of stent thrombosis and is the leading independent predictor for stent thrombosis in multivariate analyses. Although the number of actual stent thromboses reported in individual studies is modest, the findings are noteworthy.

In a large observational cohort study of patients treated with DES, stent thrombosis occurred in a striking 29% of patients in whom antiplatelet therapy was discontinued prematurely (9). This discontinuation of antiplatelet therapy was associated with a hazard ratio of 161 (95% confidence interval 26 to 998) for the occurrence of subacute stent thrombosis and a hazard ratio of 57 (95% confidence interval 15 to 220) for the occurrence of late (>30 days) stent thrombosis.

In a single-site study of 652 patients treated with sirolimus DES, premature discontinuation of clopidogrel was associated with an 30-fold greater risk of stent thrombosis, with >25% of patients who discontinued clopidogrel therapy within the first month suffering stent thrombosis (17). Park et al (13) reported on 1911 consecutive patients with DES followed up for a median of 19.4 months. Five (7.8%) of 64 patients with premature interruption of aspirin, clopidogrel, or both experienced stent thrombosis.

Spertus and colleagues (19) published an analysis from the PREMIER (Prospective Registry Evaluating Myocardial Infarction: Events and Recovery) registry of 500 patients with acute MI treated with DES. The mortality rate over the next 11 months of those who stopped thienopyridine therapy was 7.5% compared with 0.7% in those who had not stopped therapy (hazard ratio 9.0, P<0.0001). Although the rates of stent thrombosis were not reported, it is reasonable to presume that many of the deaths were related to coronary artery disease.

Pfisterer et al (20) randomized 746 patients (1133 lesions) to DES versus bare-metal stents. All patients received dual antiplatelet therapy for 6 months, after which aspirin alone was continued. At 30 days, rates of death or nonfatal MI were lower in the DES group (2.0% versus 4.69%, P=0.05); however, after discontinuation of clopidogrel at 6 months, late stent thrombosis (2.6% versus 1.3%) and death or nonfatal MI (4.9% versus 1.3%) occurred more frequently in the DES group.

Similarly, Eisenstein et al (21) reported an observational study in 4666 patients with follow-up at 6, 12, and 24 months after stenting. In patients treated with bare-metal stents, continued use of clopidogrel did not influence death or MI rates between 6 and 24 months. Conversely, in DES patients, extended use of clopidogrel at 6, 12, and 24 months was associated with reduced death or death/MI rates at all time intervals.

	Stent Thrombosis After Noncardiac Surgery

Top Abstract Dual Antiplatelet Therapy for... Premature Thienopyridine... Stent Thrombosis After... Factors Related to Premature... Summary and Recommendations Disclosures References

 
Several reports have specifically described incidents of stent thrombosis that occurred after the discontinuation of antiplatelet therapy for noncardiac surgery among patients recently treated with coronary stents (24–26). Kaluza et al (25) reported on 40 patients treated with bare-metal stents who underwent noncardiac surgery within 6 weeks of stent implantation. Seven patients had an MI, of which 6 were fatal. Stent thrombosis was presumed to be the cause of all MIs. In 5 of 7 cases, thienopyridine therapy (ticlopidine) had been withheld before surgery. In a similar analysis of 47 patients who underwent noncardiac surgery within 90 days of bare-metal stent implantation, 6 of the 7 patients in whom thienopyridine therapy was discontinued died "in a manner suggestive of stent thrombosis" (26).

	Factors Related to Premature Cessation of Thienopyridine Therapy

Top Abstract Dual Antiplatelet Therapy for... Premature Thienopyridine... Stent Thrombosis After... Factors Related to Premature... Summary and Recommendations Disclosures References

 
Premature cessation of thienopyridine may occur for several different reasons. The cost of clopidogrel (approximately $4 daily) has been cited as one reason patients discontinue (or do not renew) their therapy (27). It is unclear whether the introduction of modestly lower-cost generic clopidogrel will significantly affect this issue. In an analysis from the PREMIER registry (19), factors identified with premature discontinuation of thienopyridine therapy included older age, not having completed high school, not being married, not receiving discharge instructions for medication use, not being referred for cardiac rehabilitation, greater likelihood of having preexistent cardiovascular disease or anemia, and not seeking health care because of cost. The study authors concluded that "additional patient education about the rationale for and importance of continuing thienopyridine treatment may be needed—particularly for patients with less formal education."

Dual antiplatelet therapy is not without risk. Like all antithrombotic agents, both aspirin and clopidogrel increase the risk of bleeding compared with placebo. When compared with aspirin, clopidogrel may be associated with lower risk of GI bleeding (28). However, when clopidogrel was combined with aspirin and administered for prolonged duration (up to 28 months), randomized trials demonstrated an absolute increase (ranging from 0.4% to 1.0%) in major bleeding, compared with aspirin alone (28).

Antiplatelet therapy may be stopped at the instruction of physicians, dentists, and other healthcare providers who are to perform an invasive or surgical procedure on the patient because of misguided concerns about excessive procedure-related bleeding. Unfortunately, many patients are routinely instructed to stop "blood thinners" before such procedures without a thorough evaluation of the rationale for such therapy and without distinction between warfarin and antiplatelet agents. Many of these procedures (eg, minor surgery, teeth cleaning, and tooth extraction) can likely be performed at no or only minor risk of bleeding or could be delayed until the prescribed antiplatelet regimen is completed. Although there is a longstanding concern on the part of dental practitioners about the possibility of prolonged bleeding during and after invasive dental procedures on patients receiving antiplatelet drugs, a recent prospective study of single tooth extractions on patients randomized to aspirin versus a placebo failed to show a statistically significant difference in postoperative bleeding (29). Although there are no prospective studies of invasive dental procedures on patients taking a thienopyridine alone or in combination with aspirin, there are also no well-documented cases of clinically significant bleeding after dental procedures, including multiple dental extractions. Given the relative ease with which the incidence and severity of oral bleeding can be reduced with local measures during surgery (eg, absorbable gelatin sponge and sutures) and the unlikely occurrence of bleeding once an initial clot has formed, there is little or no indication to interrupt antiplatelet drugs for dental procedures (30).

The likelihood of increased bleeding and/or an increased requirement for blood transfusion in patients undergoing major noncardiac surgery can be inferred from reports of increased bleeding when cardiac surgery (including off-pump coronary bypass grafting) is undertaken in patients taking a thienopyridine drug. Independent documentation of the scope of this risk of increased bleeding during noncardiac surgery, however, is not available. If one must discontinue the thienopyridine drug before major surgery to reduce the risk of excessive bleeding, consideration should be given to continuing aspirin for its antiplatelet action to mitigate the risk of late stent thrombosis and to restarting the thienopyridine as soon as possible. Although some have attempted "bridging" stent patients with antithrombin agents, there is no evidence of a benefit of warfarin (Table 1) or other antithrombins, and there is an increased risk of bleeding (31). Similarly, there are no data to support the use of "bridging" glycoprotein IIb/IIIa agents.

	Summary and Recommendations

Top Abstract Dual Antiplatelet Therapy for... Premature Thienopyridine... Stent Thrombosis After... Factors Related to Premature... Summary and Recommendations Disclosures References

 
Thienopyridine therapy in combination with aspirin has become the mainstay antiplatelet treatment strategy for the prevention of stent thrombosis. Premature discontinuation of antiplatelet therapy markedly increases the risk of stent thrombosis, a catastrophic event that frequently leads to MI and/or death. Factors contributing to premature cessation of thienopyridine therapy include drug cost, physician/dentist instructions to patients to discontinue therapy before procedures, and inadequate patient education and understanding about the importance of continuing therapy.

To eliminate premature discontinuation of thienopyridine therapy, this advisory group gives the following recommendations.

1 Before implantation of a stent, the physician should discuss the need for dual antiplatelet therapy. In patients not expected to comply with 12 months of thienopyridine therapy, whether for economic or other reasons, strong consideration should be given to avoiding a DES.

2 In patients who are undergoing preparation for percutaneous coronary intervention and are likely to require invasive or surgical procedures within the next 12 months, consideration should be given to implantation of a bare-metal stent or performance of balloon angioplasty with provisional stent implantation instead of the routine use of a DES.

3 A greater effort by healthcare professionals must be made before patient discharge to ensure patients are properly and thoroughly educated about the reasons they are prescribed thienopyridines and the significant risks associated with prematurely discontinuing such therapy.

4 Patients should be specifically instructed before hospital discharge to contact their treating cardiologist before stopping any antiplatelet therapy, even if instructed to stop such therapy by another healthcare provider.

5 Healthcare providers who perform invasive or surgical procedures and are concerned about periprocedural and postprocedural bleeding must be made aware of the potentially catastrophic risks of premature discontinuation of thienopyridine therapy. Such professionals who perform these procedures should contact the patient's cardiologist if issues regarding the patient's antiplatelet therapy are unclear, to discuss optimal patient management strategy.

6 Elective procedures for which there is significant risk of perioperative or postoperative bleeding should be deferred until patients have completed an appropriate course of thienopyridine therapy (12 months after DES implantation if they are not at high risk of bleeding and a minimum of 1 month for bare-metal stent implantation).

7 For patients treated with DES who are to undergo subsequent procedures that mandate discontinuation of thienopyridine therapy, aspirin should be continued if at all possible and the thienopyridine restarted as soon as possible after the procedure because of concerns about late-stent hellothrombosis.

8 The healthcare industry, insurers, the US Congress, and the pharmaceutical industry should ensure that issues such as drug cost do not cause patients to prematurely discontinue thienopyridine therapy and to thus incur catastrophic cardiovascular complications.

	Disclosures

Top Abstract Dual Antiplatelet Therapy for... Premature Thienopyridine... Stent Thrombosis After... Factors Related to Premature... Summary and Recommendations Disclosures References

 

Writing Group Disclosures

Writing Group Member Organization Represented Employment Research Grant Other Research Support Speakers' Bureau/ Honoraria Ownership Interest Consultant/ Advisory Board Other Cindy L. Grines AHA Representative William Beaumont Hospital None None None None None None Robert O. Bonow AHA Representative Northwestern University None None None None None None Donald E. Casey, Jr ACP Representative Atlantic Health None None None None None None Timothy J. Gardner ACS Representative Christiana Care Health System None None None None None None Peter B. Lockhart ADA Representative Carolinas Medical Center None None None None None None David J. Moliterno SCAI Representative University of Kentucky None None None None None None Patrick O'Gara ACC Representative Brigham and Women's Hospital None None None None None None Patrick Whitlow ACC Representative Cleveland Clinic None None None None ICON Interventional Systems,* Medlogics* None * Modest.

AHA indicates American Heart Association; ACP, American College of Physicians; ACS, American College of Surgeons; ADA, American Dental Association; SCAI, Society for Cardiovascular Angiography and Interventions; and ACC, American College of Cardiology.

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be "significant" if (1) the person receives $10 000 or more during any 12-month period or 5% or more of the person's gross income; or (2) the person owns 5% or more of the voting stock or share of the entity or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition.

Reviewer Disclosures

Reviewer Employment Research Grant Other Research Support Speakers' Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Elliott M. Antman Brigham and Women's Hospital Eli Lilly* None None None None None None Gregory J. Dehmer Texas A&M University College of Medicine and Scott & White Clinic None None None None None None None T. Bruce Ferguson East Carolina University None None None None None None None Raymond J. Gibbons Mayo Clinic Radiant Medical, KAI Pharmaceuticals, TargeGen, TherOx None None None None Hawaii Biotech,* TIMI 37A* None Arthur H. Jeske University of Texas Health Science Center, Houston None None None None None None None Vincenza Snow American College of Physicians None None None None None None None * Modest. Significant.

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be "significant" if (1) the person receives $10 000 or more during any 12-month period or 5% or more of the person's gross income; or (2) the person owns 5% or more of the voting stock or share of the entity or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition.

	Footnotes

 
The American Heart Association, the American College of Cardiology, the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons, and the American Dental Association make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 21, 2006, by the American College of Cardiology on December 28, 2006, by the Society for Cardiovascular Angiography and Interventions on December 20, 2006, by the American College of Surgeons on December 16, 2006, and by the American Dental Association on December 17, 2006.

When citing this document, the American College of Cardiology Foundation requests that the following citation format be used: Grines C, Bonow RO, Casey DE, Jr., Gardner TJ, Lockhart PB, Moliterno DJ, O'Gara P, Whitlow P. 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. J Am Coll Cardiol 2007:49;734–9.

This article has been copublished with the American Heart Association and the Society for Cardiovascular Angiography and Interventions.

Copies: For copies of this document, please contact Elsevier Inc. Reprint Department, fax (212) 633-3820, e-mail reprints{at}elsevier.com.

Permissions: Modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.americanheart.org/presenter.jhtml?Identifier=4431. A link to the "Permission Request Form" appears on the right side of the page.

^_* Representation does not imply endorsement by the American College of Physicians.

	References

Top Abstract Dual Antiplatelet Therapy for... Premature Thienopyridine... Stent Thrombosis After... Factors Related to Premature... Summary and Recommendations Disclosures References

 

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				R. J. Applegate, M. T. Sacrinty, M. A. Kutcher, R. M. Santos, S. K. Gandhi, T. T. Baki, and W. C. Little "Off-label" stent therapy 2-year comparison of drug-eluting versus bare-metal stents. J. Am. Coll. Cardiol., February 12, 2008; 51(6): 607 - 614. [Abstract] [Full Text] [PDF]

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