Response to Letter to the Editor: Antiplatelet Therapy Should Not Be Stopped
We thank Dr. Kempen for his letter highlighting the challenges of caring for patients with coronary drug-eluting stents (DES). We have discussed some of his questions and other issues related to perioperative management of patients with coronary stents with noted national experts in this area from cardiology. Below is a synopsis of the perspective of Cindy L. Grines, MD, FACC, and chair of the 2007 AHA/ACC/SCAI/ACS/ADA Science Advisory committee report on stent management, with her permission.
The purpose of the 2007 AHA/ACC/SCAI/ ACS/ADA Science Advisory was to alert both patients and healthcare professionals that stent thrombosis (ST) is a serious medical issue.1 The guidelines for dual antiplatelet therapy have been changed to say emphatically that patients should receive a minimum of 12 months of dual antiplatelet therapy—and the minimum means, in many cases—physicians may want to go even further than that period of time. There are several patient subsets that would likely benefit much longer than 12 months. These include patients with acute coronary syndromes, long stents, multiple stents, overlapping stents, diabetes, renal failure, all of which are additional risk factors for stent thrombosis. In these patients, indefinite clopidogrel (Plavix®) use may be recommended. The guidelines were co-written by the American Heart Association, the American College of Cardiology, as well as the American College of Physicians, Surgeons and Dentistry. The Science Advisory was an attempt to avoid the premature discontinuation of dual antiplatelet therapy; providers must realize stopping antiplatelet therapy in patients with DES without discussing it with their cardiologist could result in their patients having a fatal heart attack. The leading adverse event associated with early discontinuation of antiplatelet therapy is ST. Stent thrombosis occurs in up to 29% of patients who discontinue antiplatelet therapy early. The mortality rate in patients with ST ranges from 20-45%.1,2 Premature discontinuation of dual antiplatelet therapy is the greatest predictor of ST. In a single-site study of 652 patients treated with sirolumis DES, premature discontinuation of clopidogrel was associated with a 30-fold greater risk of ST, with >25% of patients who discontinued clopidogrel therapy within the first month suffering ST.1,3 In a study of 500 patients who received DES after an acute myocardial infarction (MI), the death rate over the next 11 months was 7.5% for those who stopped taking their thienopyridine medication compared with 0.7% in those who had not stopped therapy.1,4
With regard to antithrombin agents, if you look at the studies done on comparing aspirin with warfarin compared to aspirin with thienopyridine, the warfarin is a big loser. I mean, a 5-fold increased risk of ST; so in my mind, I’ve extrapolated other antithrombin agents to the warfarin situation . . . . I tend to lean more in the camp of the antiplatelet agents. But again, I would rather just keep the patient on the aspirin and the clopidogrel because I’m very concerned about the abrupt stopping of the antiplatelet agent, and then at the same time you’re inciting an inflammatory and hypercoagulable state by performing surgery.
Discontinuation of dual antiplatelet therapy with clopidogrel and aspirin does occur because of cost, perceived risk of bleeding, patients and physicians unaware of the benefits and time of therapy required, and the discontinuation of these drugs by physicians, dentists, surgeons, or their staff before surgical procedures. We avoid elective surgery for more than 1 year after DES, more than 3 months after bare metal stents (BMS), as the risk of ST in both stent types remains high during the postoperative period. With more urgent procedures, if any provider—a physician, dentist, or surgeon—feels that stopping the antiplatelet medicines is absolutely necessary, then there should first be a consultation with the patient’s cardiologist. We have changed our practice to never allow the discontinuation of aspirin within the first year of a DES, and would probably extend that to longer duration in stents at high-risk of thrombosis. Importantly, clopidogrel should be restarted as soon as possible. In general, we see more surgeons willing to operate on dual antiplatelet therapies, or at least aspirin. If dual antiplatelet therapy has been discontinued for whatever reason, aspirin should be restarted immediately. Non-enteric coated aspirin (4 baby aspirins) may be given, and the patient should have antiplatelet effects within 2 hours.
Drug-eluting stents prevent the tissue growth that causes restenosis and reduce the need for angioplasty or bypass surgery, but it should be noted that the reduced tissue growth means the stent is exposed to blood for a longer time; this increases the risk of clotting. Dual antiplatelet therapy is also important in patients receiving bare metal stents, but the risk of thrombosis in these procedures remains high for only 1 to 3 months. Consideration should be given to using a bare metal stent if patients are noncompliant with medications, or cannot afford to take clopidogrel for the full year, or if they absolutely cannot postpone an elective surgery.
Following is a summary of additional commentary from Deepak Bhatt, MD, FACC, associate director at the Cleveland Clinic Foundation and A. Michael Lincoff, MD, FACC, vice chairman of Cardiovascular Medicine at the Cleveland Clinic Foundation.
Although there are no evidence-based data supporting the perioperative use of a short-acting glycoprotein (GP) IIb/IIIa platelet inhibitor (“bridging therapy”), there appears to be a role for this use. There are instances in which the only option perioperatively is fast-acting parenteral antiplatelet inhibition with a GP IIb/IIIa antagonist. There are patients for whom there is increased risk of stent thrombosis (ST); for example, a patient had a complex DES procedure a month ago, and then needed hip surgery after falling and breaking their hip, and the surgeon just absolutely refused to operate. This patient was brought into the hospital and started on a short-acting intravenous IIb/IIIa inhibitor. Though practically speaking it means bringing these patients in hospital, there are many patients for whom that extra 4-day hospitalization is worth it. One has to balance the risks and look at the consequences of thrombosis. In those instances, go ahead and proceed with bridging therapy.5 Another option is cangrelor, which is being tested in Phase III trials. An intravenous short-acting ADP receptor antagonist, cangrelor may conceptually be a future option in the perioperative period.
We are in agreement with Grines et al.: procedures should only be performed on patients with DES in institutions where 24-hour interventional cardiology coverage is present in the event that immediate percutaneous coronary intervention (PCI) is needed for perioperative ST.6 Almost all case reports to date have cited ST occurring postoperatively, most commonly in the Post Anesthesia Care Unit, and manifesting as a ST-elevation MI (STEMI). Thus, the importance of having immediate access to a coronary catheterization laboratory must be emphasized. McFadden et al. reported ST and STEMI occurring preoperatively after premature discontinuation of dual antiplatelet therapy, or aspirin, in cases where the patient had completed their prescribed course of clopidogrel.7 Stent thrombosis and its sequelae occur acutely. Therefore, it would be unlikely that a patient with ST would be asymptomatic. However, in all cases, the anesthesiologist (or a member of the anesthesia care team) and surgeon should speak with the patient’s cardiologist in order to reach a consensus as to what the safest course of treatment may be. We agree with Dr. Kempen that all patients with coronary stents undergo preoperative screening a week before scheduled surgery to ensure that the appropriate care has been coordinated, dual antiplatelet therapy has been appropriately managed, and all appropriate parties are involved in this very complex care.
Ideally, patients who have clopidogrel and aspirin discontinued for more than 5 days prior to a procedure who are asymptomatic should have aspirin reinstituted for 3-5 days to achieve steady-state before proceeding with surgery. We have cancelled a number of cases over the past few months because of premature discontinuation of dual antiplatelet therapy. If aspirin has been discontinued for 3-5 days, we have given 325 mg of non-enteric coated aspirin, and proceeded with surgery later that day to allow platelet inhibition to take effect. Studies have shown that 160 mg of aspirin will inhibit platelet function.8 The same effect can be achieved with aspirin 75-81 mg over 3-5 days.
We also agree with Dr. Grines that aspirin should never be discontinued in the perioperative period. However, in cases where the surgeon absolutely refuses to operate with the patient on aspirin, then it is imperative that communication occur between the patient’s cardiologist, surgeon, and anesthesia provider, and the risks of ST versus major bleeding be carefully weighed. Again, the risk of ST is 29%, and the mortality rate from ST ranges from 20-45%. The surgeon must be made acutely aware of this when considering whether to operate while the patient remains on aspirin.
The use of platelet infusions intraoperatively should be avoided except in the instance where there is life-threatening bleeding. There are certain states (acute MI, unstable angina, trauma, surgery), in which platelet aggregation and activity are enhanced even without an increase in platelet counts.9 This phenomenon occurs as a consequence of sympathetic activation and cytokine release.10,11 Inflammatory activation from endothelial damage, as in PCI and surgery, exacerbates the prothrombotic state, making the patient highly susceptible for thromboembolic events. Autopsy results have shown this mechanism is responsible for at least half of all perioperative infarctions.12,13 Theoretically, apheresis platelets administered to patients with stents who have serum levels of clopidogrel and aspirin may not develop antiplatelet effects to provide adequate protection from ST for hours to days. Also, activation of the transfused platelets may occur, further increasing the risk of ST, MI, and death. Direct and autologous donation of any blood component is being discouraged by blood banks at many institutions, including our own, because of increased cost and no proven safety benefit over homologous donation.
The controversy and concern surrounding coronary artery stents, especially in the case of DES, illustrate the importance of instituting a multidisciplinary approach in the care of these patients.
Lisa Newsome, MD
Roger Royster, MD
Richard Prielipp, MD
- Grines CL, Bonow RO, Casey DE Jr; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. 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.
- Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293:2126-30.
- Jeremias A, Sylvia B, Bridges J, et al. Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 2004;109:1930-2.
- Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation 2006;113:2803-9.
- Rabbat MG, Bavry AA, Bhatt DL, Ellis SG. Understanding and minimizing late thrombosis of drug-eluting stents. Cleve Clin J Med 2007;74:129-36.
- Brilakis ES, Banerjee S, Berger PB. Perioperative management of patients with coronary stents. J Am Coll Cardiol 2007;49:2145-50.
- McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519-21.
- Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287-94.
- Neumann FJ, Ott I, Gawaz M, Puchner G, Schomig A. Neutrophil and platelet activation at balloon-injured coronary artery plaque in patients undergoing angioplasty. J Am Coll Cardiol 1996;27:819-24.
- Mangano DT. Perioperative cardiac morbidity. Anesthesiology 1990;72:153-84.
- Cohen MC, Aretz TH. Histological analysis of coronary artery lesions in fatal postoperative myocardial infarction. Cardiovasc Pathol 1999;8:133-9.
- Dawood MM, Gutpa DK, Southern J, et al. Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention. Int J Cardiol 1996;57:37-44.
- Poldermans D, Schouten O, Vidakovic R, et al. A clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: the DECREASE-V Pilot Study. J Am Coll Cardiol 2007;49:1763-9.