Aspirin (acetylsalicylic acid, ASA) has a long, remarkable history in the development of useful drugs from herbal or vegetable sources. In ancient times, extracts of willow (Latin: salix) tree bark were used for therapeutic purposes. Early documentation appears on a Sumerian tablet dating from ~2000 BCE. The first known documentation of willow bark as an analgesic appears in the Ebers Papyrus, a medical text written in about 1540 BCE. Later, Greeks, Romans, Arabs and Chinese used willow bark preparations for their anti-inflammatory properties.
Fast forward to the 1800s when chemists characterized the medicinally active substance of willow tree bark, called salicin. From this starting material, salicylic acid was created. The common meadowsweet flower (Spiraea ulmaria) contains a similar compound in abundance. Gastric side effects limited therapeutic use of salicylic acid. However, several chemists prepared a derivative, acetylsalicylic acid, which was much more clinically useful as a pain reliever and antipyretic. The Bayer chemical and pharmaceutical company marketed this substance named “Aspirin” (“A” for acetate, “spir” for Spiraea, with the ending “in” to facilitate enunciation). Aspirin played an important therapeutic role in the Spanish flu epidemic of 1918-1919 while becoming one of the most widely used drugs of the 20th century.
In the 1940s, California family physician Lawrence Craven observed excessive bleeding in tonsillectomy and adenoidectomy patients taking aspirin as an analgesic. In the conceptual context that thrombosis might be a cause of myocardial infarction (MI), Craven prescribed aspirin to his patients. He reported that in this cohort (no control group) receiving even small doses of prophylactic aspirin, the incidence of MI was reduced or eliminated. He also reported an apparent reduction in the occurrence of cerebrovascular events. These findings were not immediately introduced into routine practice until more definitive studies, including meta-analyses, produced comparable results.
Several investigators found that aspirin exerted antithrombotic effects by inhibiting platelet aggregation. The biochemical mechanism accounting for this action was subsequently identified: irreversible inhibition of cyclooxygenase-1 (COX-1), an essential enzyme in the pathway generating prostaglandins including thromboxane A2, a key factor in platelet activation and thrombus formation. Since platelets lack the cellular machinery to produce COX-1, restoration of platelet function depends on generation of new platelets. This process takes several days.
Fast forward again to the current era where aspirin, sometimes in conjunction with clopidogrel, is a mainstay in antiplatelet therapy to prevent thrombosis. Some patients considered to be at low risk for developing cardiovascular disease take aspirin to prevent new coronary or peripheral vascular thrombosis (primary prophylaxis). Patients with documented vascular disease (e.g., history of MI or stroke, peripheral vascular disease) take aspirin to prevent further events (secondary prophylaxis). In particular, patients with coronary stents take aspirin as secondary prophylaxis to prevent occlusion of the devices. Furthermore, patients with certain medical conditions (diabetes mellitus, congestive heart failure, renal insufficiency) are deemed to be at high risk for vascular disease; they also take aspirin as secondary prophylaxis.
Concern for increased bleeding led to a generally accepted practice of stopping antiplatelet therapy 5-10 days before a surgical or invasive procedure. While surgical bleeding may be increased with ongoing aspirin therapy, the risk of associated hemorrhagic morbidity and mortality remains modest for most procedures. Indeed, there is an enhanced risk of thrombosis with early withdrawal of antiplatelet therapy in medical patients following acute coronary syndromes, cerebrovascular accidents, or the insertion of vascular stents. In the setting of surgery, with attendant acute procoagulant and proinflammatory consequences, acute withdrawal of aspirin therapy may enhance the likelihood of thrombosis, thereby increasing the risk of cardiovascular morbidity and mortality.
We lack adequate studies for every procedure in every surgical specialty. However, except in some specific circumstances, the cardiovascular risk from acute aspirin withdrawal likely outweighs the risk of surgical complications from bleeding. Recent reviews conclude that aspirin should be continued up to the day of surgery for at risk patients, with few exceptions (intracranial neurosurgical procedures, intramedullary spine surgery, surgery of the middle ear or posterior eye, and possibly prostate surgery). Continuation of ASA is not viewed as a contraindication to neuraxial anesthesia. Stopping ASA therapy in secondary prophylaxis patients thus warrants thoughtful consideration in the interests of safe patient care. This decision should probably be made in conjunction with the patient’s cardiologist and/or vascular physician.
At our institution, a multidisciplinary group derived a set of guidelines for managing aspirin therapy in the perioperative period. These guidelines, based on the recent literature, are intended to provide the surgeon or procedural physician a conceptual framework to aid decision making about aspirin therapy (Box). A key feature of the guidelines is the expectation that clinical decisions to stop ASA for secondary prophylaxis patients will be made collaboratively with cardiologists, vascular medicine physicians, or primary care providers who know the patient well. This approach is similar to the suggestions of Douketis et al. for secondary (high risk) prophylaxis patients, but specifies several exceptions. In contrast to the suggestion of Douketis et al., our institutional guidelines generally recommend continuing ASA for the primary prophylaxis (low risk) patient, again specifying several exceptions but giving discretion to the surgeon or procedural physician to stop or continue ASA therapy. Our institutional guidelines also emphasize documentation of decision making.
An overview of aspirin’s history and the applications of this drug leaves several unanswered questions for safe patient management in the perioperative period:
- Do we have adequate criteria to define primary prophylaxis? Stated another way, are some patients currently taking aspirin for primary prophylaxis at higher risk for cardiovascular complications than other primary prophylaxis patients?
- Do we have adequate criteria to define secondary prophylaxis?
- Which surgical procedures are more likely to provoke inflammatory and hypercoagulable states than other interventions?
- For individual invasive procedures (in individual patients), how do we determine whether the risk of bleeding outweighs the risk of thrombotic complications? A corollary question is how to help surgeons and other procedural physicians, vascular medicine specialists, cardiologists, and anesthesiologists formulate an optimum management plan for a specific patient.
- What other drugs or preparatory measures might permit the withdrawal of aspirin as an antiplatelet agent without increasing the likelihood of perioperative thrombosis? A corollary question is how can the consequences of acute aspirin withdrawal be mitigated?
- How might anesthetic management (e.g., regional versus general anesthesia, the combinations of drugs used in general anesthesia) impact the propensity for perioperative thrombotic complications?
- What are the advantages/disadvantages of giving aspirin (and how much) immediately before anesthesia and surgery to a high risk patient who has stopped this therapy or who has never been on aspirin?
Even after 4000 years of medicinal use, and 2 centuries of detailed chemical, biochemical, and physiologic investigation, many questions remain about willow bark extract and its derivatives in patient care. The answers have important implications for daily clinical practice and safe patient care in the perioperative period. When should our patients take aspirin, and how much, as they are placed on call to the OR in the morning?
|MGH GUIDELINES FOR PERIOPERATIVE ASPIRIN ADMINISTRATION
Consensus Statement from the Departments of Anesthesia, Medicine, Cardiology and Surgery
Aspirin (ASA) is prescribed for primary and secondary prophylaxis to reduce adverse thrombotic events related to cardiovascular and cerebrovascular atherosclerotic disease.
prophylaxis can be defined as treatment with ASA in the absence of an established diagnosis of cardiovascular disease (by combination of history, exam, ECG or stress testing, ECHO, or cath lab testing). Example: an active 55-year-old male with a medical history limited to hypertension and hyperlipidemia, but no evidence of any other conditions, who takes ASA (81 mg) daily.
prophylaxis can be defined as treatment with ASA in the presence of overt cardiovascular disease or conditions conferring particular risk.
Examples of overt disease in the medical history or conditions conferring risk:
– atrial fibrillation
Management of ASA in the immediate perioperative period, based on recent literature1-4
PRIMARY prophylaxis patients:
ASA (81 – 325 mg) should be continued in the perioperative period up to and including the day of the procedure. ASA may be held for a few days at the discretion of the surgeon or procedural physician due to a possible heightened risk for perioperative bleeding. Hold ASA in specific circumstances: intracranial, middle ear, posterior eye or intramedullary spine surgery; possibly in prostate surgery. This decision should be documented.
SECONDARY prophylaxis patients:
ASA (81 – 325 mg) should be continued in the perioperative period up to and including the day of the procedure. Exceptions: intracranial neurosurgical procedures, intramedullary spine surgery, surgery of the middle ear, or posterior eye, and possibly prostate surgery.
Stopping ASA in patients receiving the drug for SECONDARY PROPHYLAXIS needs an explicit discussion with the patient’s primary care physician, cardiologist, or vascular physician.
The discussion should weigh the cardiovascular risks of stopping ASA versus the risk of bleeding from the procedure. This decision should be documented.
Robert Peterfreund, MD, is an Associate Professor of Anesthesia at Harvard Medical School and an Anesthetist at Massachusetts General Hospital in Boston, MA.
- Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e326S-e350S.
- Eberli D, Chassot P-G, Sulser T, et al. Urologicalsurgery and antiplatelet drugs after cardiac and cerebrovascular events. J Urol Surg 2010;183:2128-36.
- Gerstein NS, Shulman PM, Gerstein WH, et al. Should more patients continue aspirin therapy perioperatively? Clinical impact of the aspirin withdrawal syndrome. Ann Surg. 2012;In Press.
- Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol 2010;27:999-1015.
- Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacology and management in the perioperative period. Anesth Analg 2011;112:292-318.
- Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving antithrombotic thrombolytic therapy. Reg Anesth Pain Med 2010;35:64-101.
- Jeffreys D. Aspirin: The remarkable story of a wonder drug. New York, NY: Bloomsbury Publishing, 2005.
- Miner J, Hoffhines A. The discovery of aspirin’s antithrombotic effects. Texas Heart Institute Journal 2007;34:179-86.
- Mollman H, Nef HM, Hamm CW. Antiplatelet therapy during surgery. Heart 2010;96:986-91.
- Peter K, Myles PS. Perioperative antiplatelet therapy: a knife-edged choice between thrombosis and bleeding still based on consensus rather than evidence. Thromb Haem 2011;105:750-1.
- Servin FS. Is it time to re-evaluate the routines about stopping/keeping platelet inhibitor in conjunction with ambulatory surgery? Curr Opin Anesthesiol 2010;23:691-6.
- Steib A, Hadjiat F, Skibba W, et al. Focus on perioperative management of anticoagulants and antiplatelet agents in spine surgery. Orthop Traumatol Surg Res 2011;97(6 Suppl):S102-6.