Artículo de Revisión

Hans Fred Garcia Araque*, Darío Oliveros Acosta**

* Anestesiólogo Cardiovascular, Profesor asociado Universidad Militar, Servicio de Anestesiología, Hospital Militar Central, Bogotá, Colombia. Correspondencia: Transversal 3ª No. 49-00, Bogotá, Colombia. Correo electrónico: hafregar@gmail.com.

** Anestesiólogo, Hospital del Tunal, E.S.E. Bogotá, Colombia. Correspondencia: Carrera 67 No. 169A-82 Apto 402, int. 2, Bogotá, Colombia

Recibido: junio 20 de 2010. Enviado para modificaciones: agosto 1 de 2010. Aceptado: agosto 23 de 2011.

Objective. To review the indications and perioperative management considerations for anti-platelet aggregation (APT) therapy.

Methodology. Using “non-cardiac surgery”, “APT” and “apirine-clopidogrel” as key words, a non-systematic search was conducted in the PubMed/Medline and SciELO databases.

Results. APT is used frequently for the management of cardiovascular and non-cardiovascular medical entities. It is important to adopt a clear stance regarding the continuation, change or withdrawal of this therapy in the perioperative context. That decision must be based on a judicious assessment of the risk of bleeding and the risk of perioperative complications secondary to the withdrawal of the antiplatelet agent that has offered the patient adequate management before surgery.

Conclusion. In most cases of non-cardiac surgery, withdrawal of aspirin in patients with coronary heart disease, cerebral or peripheral vascular disease must be avoided if the risk of bleeding is considered low or moderate.

It is not uncommon to find in clinical practice that people stop the use of aspirin before elective surgery in order to reduce the risk of bleeding-related complications, whereas in emergency cases, precautions required in patients receiving antiplatelet therapy are not clear.

In order to arrive at an objective way to determine whether antiplatelet (APT) therapy must be withdrawn or not, this research group presents a review of the indications and perioperative management considerations based on a non-systematic search of the literature in the PubMed/MedLine and SciELO databases.

The key words used were “non-cardiac surgery”, “APT” and “aspirin-clopidogrel”. The search was limited to publications between 2005 and 2011. Publications prior to 2005 were included only when referenced in the text of articles that were selected two or more times during the search; only articles in Spanish or English were included.

The authors selected the 50 papers considered most relevant by the authors, mainly meta-analyses, review articles, updates, randomized double-blind trials and clinical guidelines. The abstracts of all the articles found were read, and full texts were downloaded only for the 50 papers selected, using information technology tools offered by Nueva Granada Military University.

Why use antiplatelet therapy?

The role of aspirin in the treatment of cardiovascular diseases is well documented (1-7), and it is accepted as a secondary prevention strategy in all patients with moderate-to-high risk for cardiovasular disease (8). Aspirin reduces non-fatal myocardial infarction by one third; non-fatal cerebrovascular events by one fourth; and vascular mortality by one sixth, in patients with a high annual risk of a cardiovascular event (1). On the other hand, in a dual antiplatelet therapy with thienopyridine, aspirin is superior than when used as monotherapy in patients with a history of symptomatic atherothrombosis (2), acute coronary syndromes (3,4), and in patients in whom it is critical to prevent a serious complication associated with coronary artery stent thrombosis (9).

Despite the proven efficacy of the dual antiplatelet therapy, patients stop the therapy either because of medical recommendations or because of other issues such as financial difficulties, lack of family support when they require assistance with medication intake, low education, the fact of not seeking healthcare or just because of sheer negligence (10-13).

Several studies have shown the adverse cardiovascular consequences of withdrawing antiplatelet therapy in various patient populations (6,7,14-16). In a prospective study with 1,358 patients presenting with acute coronary syndromes to the emergency department, with a 30-day follow-up, 5.4 % (n = 73) had stopped taking their oral antiplatelet agent 3 weeks before the acute episode, and the majority (64 %) had done so on the doctor’s orders because of an upcoming elective procedure. Patients who had stopped their aspirin therapy had a two-fold increase in the risk of dying or suffering a myocardial infarction after 1 month, compared to those who continued their aspirin therapy. In average, the acute event occurred in these patients by the eleventh day after withdrawing the oral antiplatelet agent (15).

These findings were confirmed later by a meta-analysis of 50,279 patients: it was shown that withdrawal of, or non compliance with, the aspirin therapy was associated with almost a three-fold increase in the risk of adverse events (HR: 3.14 (1.75-5.61); p 0,0001) in patients with a moderate-to-high risk of acute coronary syndrome. The risk is magnified in patients with coronary stents, with an OR = 89.78 (29.9 - 269.6) (7).

As to non-coronary vascular diseases, it is important to consider cerebrovascular and peripheral vascular disease. Acute ischemia of the extremities has often been associated with the withdrawal of aspirin, and is a red flag for thrombosis in patients with severe occlusive disease taken to diagnostic or surgical procedures without the use of aspirin (17).

Perioperative period

Virchow proposed vascular lesions and venous stasis as factors associated with thrombosis, and as fundamental elements of its classical triad. Surgery itself is associated with platelet activation, high levels of procoagulant factors and diminished fibrinolysis. This thrombotic state may increase the risk of atherothrombotic events in patients with atherosclerotic vascular disease (18). Effective APT reduced the risk of such events, as well as the probability of adverse outcomes (19,20).

It is indisputable that antiplatelet therapy is associated with a high risk of perioperative bleeding (21). A recent meta-analysis (22) suggests that the use of aspirin before invasive procedures may increase the overall risk of bleeding by 50 %, although this does not have a direct influence either on treatment success or morbidity and mortality.

Abnormal bleeding is almost always the reason for deciding to withdraw aspirin during the preoperative period. Abnormal bleeding occurs in patients taking aspirin before general surgery, gynecological surgery (22), urologic surgery (23,24) dermatological procedures (25), orthopedic surgery (26) or diagnostic procedures such as gastrointestinal biopsies (27), among others. Notwithstanding the above, the risk of bleeding complications is considered low according to international management guidelines (28,29). An analysis of 41 studies including 49,590 patients showed that, although the risk of bleeding increases, the use of aspirin is not associated with a higher number of complications, except in cases of intracranial or spinal surgery, tonsilectomy and posterior chamber ophthalmological surgery (22,28).

Dual antiplatelet aggregation therapy is associated with an increased risk of bleeding, beyond the risk associated with aspirin only (4,9). It has been shown that patients with stents who receive dual therapy and are taken to non-cardiac surgery without withdrawing the therapy during the preoperative period are at a higher risk of bleeding when compared to patients receiving only aspirin as anti-aggregation therapy (30).

Very few publications describe the risk of bleeding associated with the use of clopidogrel in non-cardiac surgery. It has been demonstrated in small series that the risk of bleeding increases when clopidogrel is used together with aspirin (31). As far as the group of researchers is aware, there are no studies comparing bleeding associated with clopidogrel versus aspirin in the perioperative setting, although there are animal studies that have shown clearly that clopidogrel is associated with prolonged, more abundant bleeding when compared to aspirin (32).

Despite the widespread notion of bleeding complications in patients receiving aspirin, the vast majority of procedures may be undertaken safely, without the need to stop aspirin in the perioperative period (28,33). Moreover, in patients offered spinal or peridural anesthesia, aspirin by itself does not increase the risk of hematoma formation as a result of the anesthetic procedure (34,35). When assessing the effect of aspirin on the risk of hematoma in the neural axis, the incidence of complications is 1 in 150,000 peridural anesthetic procedures, and of 1 in 22,000, with subaracnoidal anesthesia (36).

On the other hand, the use of aspirin before surgery as monotherapy does not increase bleeding complications in patients undergoing certain ophthalmological procedures such as vitreous, retinal or cataract surgery (37,38).

Periopera tive managementin patients with stents

Drug-eluting stents have partially replaced standard stents in modern clinical practice following the demonstrated drop in intra-stent stenosis and successful revascularization (39-41); however, late thrombosis has been observed months or years after implantation of drug-eluting stents (42-44), associated with an incomplete intimal coverage, characteristic of drug-eluting stents (45).

The goals of perioperative anesthetic management of patients with stents include optimization of antiplatelet therapy in order to minimize the risk of stent thrombosis. Although management options are not widely accepted, a French task force working with the perioperative management of antiplatelet agents in patients with coronary stents has proposed the following options (46):

a. continue antiplatelet therapy with no changes;

b. withdraw antiplatelet therapy (or at least stop dual therapy and continue with aspirin only);

c. withdraw the dual antiplatelet therapy a few days before the procedure, and reinstitute it as soon as possible.

At present there is no consensus or evidence-based guideline that determines when one option is better than another.

Patients with a high risk of stent thrombosis are not candidates for withdrawing antiplatelet aggregation therapy and, whenever possible, all invasive diagnostic or surgical procedures must be postponed (Table 1) (10).

If it is not possible to cancel or postpone a procedure that entails the risk of bleeding, the suggestion is to withdraw the antiplatelet therapy totally or partially. Depending on the case, it is recommended to make the management decision from a multidisciplinary perspective, in order to make and in-depth assessment of the risk of thrombosis and bleeding.

Managementrec ommendations

It is important to know exactly how long to postpone a surgical procedure after stenting, and the time for mandatory dual antiplatelet therapy. If an elective surgery was scheduled before stent placement, the decision to implant a standard stent versus a drug-eluting stent will influence the time to perform the procedure.

In the clinical situation where surgery must be performed within a 12-month period, the recommendation is to select a drug-eluting stent as the device of choice (28,47). In contrast, if the surgery may be postponed beyond the 12-month period, the use of a drug-eluting stent is not appropriate. However, the risk of very late stent thrombosis must be considered if the APT is interrupted if the need arises to perform the surgical procedure sooner (30, 42).

A review of the current literature does not show sufficient evidence supporting a clear approach regarding the management of these patients (24); this research group has based its work on the American Heart Association guidelines regarding preoperative assessment for non-cardiac surgery that determine that the elective procedure should be postponed until the antiplatelet therapy is completed (47).

The ACC/AHA guidelines for the preoperative assessment in non-cardiac surgery recommend that all non-cardiac procedures must be postponed at last 4 weeks (preferably 6) after standard stent placement (47). Regarding drug-eluting stents, the minimum time period between stenting and surgery is more difficult to establish, but since there are no hard data to support one approach over another (5), the consensus suggests that the time period should be no less than 12 months, and even longer in high risk patients.

Aspirin users must only stop the therapy whenever the risk of bleeding associated with the surgical procedure is greater that the risk of thromboembolic complications (48). There are no guidelines to help with the greater bleeding that may occur during the treatment with APT. However, it is suggested that the incidence of major complications due to aspirin-related bleeding is low; and in cases of intraoperative or postoperative bleeding clearly associated with APT, platelet transfusion must be considered (one unit of platelets for every 7 kg of body weight) (8,28).

Management in patients without coronary artery stenting

Patients with coronary heart disease managed with or without stenting are not the sole chronic users of aspirin: patients with cerebrovascular disease, chronic arterial occlusive disease, rheumatoid arthritis, rheumatic fever, gout, patients after carotid endarterectomy and stents (and who are allergic to warfarin), patients with complications related to autoimmune disorders (such as systemic lupus erythematosus or antiphospholipid syndrome) are also chronic users of aspirin. These patients need to be assessed with the same care as those patients with stents, and sometimes they may benefit from non withdrawal of their medication before a surgical procedure.

Perioperative management of antiplatelet therapy in patients without coronary artery stenting usually follows the same principles described previously. Aspirin must be given in the perioperative period with the goal of reducing atherothrombotic events or preventing a worsening of the underlying disease, whenever possible. Depending on the type of procedure, aspirin-related bleeding complications range between 0% (skin incisions, cataract surgery) and 75 % (transurethral prostate resection and neurosurgery) (22).

It is always good to remember that the patient is not totally unprotected during the surgical procedure in terms of antiaggregation capability, considering that aspirin only blocks one of the many pathways involved in platelet activation, and there is a high incidence of resistance to aspirin and clopidrogel - 5 % to 45 %, and 4 % to 30 %, respectively (49). These and other circumstances require careful analysis of whether the clinical context may add a new factor for abnormal bleeding during the postoperative period and may warrant one or the other approach.

There are no studies with level 1 evidence to date (without taking into consideration the population of surgical patients with drug-eluting stents) comparing patients taken to non-cardiac surgery with APT versus placebo, although there is at least one -the French STRATAGEM study- that has completed recruitment and will be available soon (50).

Although the exact incidence of adverse events directly associated with APT withdrawal is not know, it is clear that aspirin is an important therapeutic component in several cardiovascular and non-cardiovascular diseases. Unfortunately, APT is not risk-free, and it is associated with increased intraoperative and postoperative bleeding, but not so with major bleeding complications in most situations.

Perioperative management of this therapy is a complex medical problem requiring careful assessment of individual risk factors for thrombotic complications and bleeding associated with elective invasive or surgical procedures. Routine withdrawal of APT before non-cardiac surgical procedures is unnecessary and must be rejected.

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