Drug
Mode of action
Half-life
Onset of action
Duration of action
Aspirin
Irreversible inhibition of the enzyme COX-1
15–20 min
Few minutes
Platelet lifespana
Clopidogrel
Irreversible binding to the ADP P2Y12 receptor of the platelets
About 8 h (active metabolites after liver action)
2 h if given loading dose
Platelet lifespana
Prasugrel
Irreversible binding to the ADP P2Y12 receptor of the platelets
Fast conversion in active metabolites
About 30 min
Platelet lifespana
Ticagrelor
Reversible P2Y12 antagonist
Approximately 12 h
About 30 min after a loading dose
4–5 days
Cilostazol
Selective inhibition of phosphodiesterase IIIA (reversible inhibition of platelet aggregation)
Around 21 h
2–3 h
12–48 h
Although the management of the APA in the perioperative period is not easy, the main challenge for the anaesthesiologist and the thoracic surgeon is those patients receiving an APA with a coronary stent (mainly, drug-eluting coronary stents).
16.2.1 Rationale for the Recommendations
Some years ago, the most common practice with the APA was their withdrawal between 7 and 10 days before thoracic surgery. But, in the last years, several general documents recommending the maintenance of the APA have been published, whenever the haemorrhagic risk allows this continuation [1–7].
The perioperative management of APA must be based on the optimal assessment of benefit/risk relationship. This includes the stratification of the perioperative haemorrhagic risk associated with the continuation of antiplatelet agents throughout surgery and the stratification of the thrombotic risk associated with their discontinuation. In order to summarise all the information, you can find a summary in Table 16.2 [2, 4–8].
Table 16.2
Proposed stratification of the haemorrhagic risk related with the continuation of antiplatelet agents through the perioperative period and the thrombotic risk associated with their discontinuation
Haemorrhagic risk | Minor | Moderate | Major |
Transfusion usually not needed Minor plastic/general/OS surgery Biopsies, tooth extraction, surgery of the anterior segment of eye | Transfusion usually needed Cardiac surgery Major OS/visceral/ENT/urology or reconstructive surgery | Possible bleeding in an enclosed space Cranial surgery, spinal surgery, surgery of the posterior segment of eye. Transurethral prostatectomy | |
Thrombotic risk | Minor | Moderate | Major |
>6 months after AMI, CABG, percutaneous coronarography, BMS, coronary surgery, CVS (>12 months if high-risk patient or associated complications) | >12 months after DES 6–24 weeks after AMI, CABG, BMS, CVS (6–12 months if high-risk patient or associated complications) | <12 months after DES <6 weeks after AMI, CABG, BMS, CVS (<6 months if high-risk patient or associated complications) |
16.2.2 General Recommendations for Patients Scheduled for Thoracic Surgery
The practical guidelines for the management of APA on patients scheduled for elective thoracic surgery need the local agreement of a multidisciplinary team that includes anaesthesiologists and thoracic surgeons, with the participation and acceptance by haematologists, cardiologists and neurologists.
The decision to discontinue the antiplatelet therapy prior to surgery should be based on careful cardiovascular and thrombotic risk assessment of the patient and on the type of surgery and of bleeding risk. The recommendations about the perioperative management of antiplatelet therapy in these patients are not fully agreed, but they can be summarised as follows [1–8]:
In all cases, it is recommended that a low dose of aspirin (75–100 mg) be maintained throughout the perioperative period, unless the risk of bleeding clearly outweighs thrombotic risk.
In order to reduce the potential risk of bleeding, aspirin dose higher than 200 mg should be replaced by 75 or 100 mg.
The treatment should be substituted by low-dose aspirin in the case of patients treated with clopidogrel as monotherapy and where discontinuation is mandatory (unless contraindicated).
If antiplatelet therapy must be discontinued, it should be stopped the shortest time possible: 2 days for aspirin and 5 days for clopidogrel. Thereafter, treatment should be restarted as soon as possible following surgery after ensuring haemostasis, between 6 and 48 h during the postoperative period. Depending on the withdrawal time and in order to accelerate antiplatelet response, loading dose administration may be indicated as follows: aspirin 250 mg and clopidogrel 300 mg.
16.2.3 Current Antiplatelet Protocols in Patients with Drug-Eluting Stents
APAs are recommended in the treatment of patients who had undergone percutaneous coronary interventions (PCI) and have a coronary stent in place. After this, the current protocols of administration of APA could be summarised as follows [9]:
After stent implantation, the use of aspirin should be continued indefinitely. It is reasonable to use aspirin around 100 mg per day in preference to higher maintenance doses.
The duration of the therapy with a thienopyridine after stent implantation should generally be given for at least 12 months. Options could include clopidogrel 75 mg daily, prasugrel 10 mg daily and ticagrelor 90 mg twice daily.
If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of thienopyridine therapy after stent implantation, earlier discontinuation (e.g. <12 months) of thienopyridine therapy is reasonable.
Continuation of clopidogrel, prasugrel or ticagrelor beyond 12 months may be considered in patients undergoing placement of drug-eluting stent.
From this protocol in the treatment of patients with a coronary stent in place, the recommendations for their management have some special considerations [1–4, 7–10]:
Although there is not a valid algorithm for all situations, current trend is to delay all surgery that is not life threatening if the stent has high thrombotic risk. So, elective noncardiac surgery should not be performed in the 4–6 weeks after a bare-metal stent implantation or the 12 months after drug-eluting stent implantation in patients in whom the thienopyridine will need to be discontinued perioperatively. In spite of this recommendation, the evidence supporting this practice is scarce and limited, and major adverse cardiac events (MACE) in this kind of patients undergoing surgery could be related more with emergency surgery and advanced cardiac disease but not with stent type or timing of surgery beyond 6 months after stent implantation [11].
If surgery can’t be delayed, the continuation of the antiaggregation is essential to minimise the thrombotic risk of the stent. If it is not possible to maintain the APA due to a high bleeding risk, it is necessary to know that the withdrawal of the thienopyridine and the maintenance of the aspirin alone do not assure the elimination of the thrombotic risk. So the final decision in cases of surgeries that it is not possible to be delayed should be multidisciplinary and made individually.
In all cases, the administration of the APA treatment after surgery should be done as soon as possible. Main recommendation is to give it in the first 24 h after the end of surgery if the haemostatic competence of the patient is assured.
After the high-risk period, if the surgery is likely to cause little or no risk of bleeding, it is recommended not to stop antiplatelet therapy. Moreover, in general, the maintenance of the treatment with aspirin in patients with a coronary stent in place is the first option.
For patients with a coronary stent who must undergo urgent surgical procedures that mandate the discontinuation of dual antiplatelet therapy, it is reasonable to continue aspirin if possible and restart the thienopyridine as soon as possible in the immediate postoperative period.
16.3 Management of Anticoagulated Patients Scheduled for Thoracic Surgery
Many patients receive oral and chronic anticoagulation due to atrial fibrillation or a mechanical heart valve, although other indications for it include cerebrovascular pathology (repeated strokes) or prevention of recurrences of previous thromboembolic events. Nowadays, the anticoagulant therapy could be made by vitamin K antagonists (VKAs) or by any of new direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban or edoxaban, which are recently accepted or waiting their approval for these indications.
16.3.1 Management of Patients Under Vitamin K Antagonists
The perioperative management of VKAs is well established, and nearly no change has been done in the lately recommendations [2, 12–15]. Rational decisions are made depending on the risks of thrombosis and bleeding associated with the different alternatives. In general the interruption of VKAs is required to achieve normal or near-normal haemostasis at the time of surgery (INR 1.5 or below). After stopping VKAs, between 3 and at least 5 days will be required for most anticoagulant effect to be eliminated (with acenocoumarol 3 days seem to be enough, and with warfarin the delay should be up to 5 days). So, the main recommendation in patients scheduled for thoracic surgery that require temporary interruption of a VKA before the operation is to stop VKAs approximately 5 days before surgery in the case of warfarin [2], although with acenocoumarol, the recommended time could be shorter (3 days). After surgery, it is recommended resuming VKA 12–24 h postoperative, when oral intake is permitted and there is adequate haemostasis.
The temporary discontinuation of VKAs could expose patients to a risk of thromboembolism, although some controversies have been published for this topic [14–18], mainly for a possible tendency to increase bleeding with the bridging therapy without any decrease of thrombotic events. In general, current protocols recommend:
For patients with a mechanical heart valve, atrial fibrillation or VTE at high risk for thromboembolism, there is a need of bridging anticoagulation (administration of a short-acting anticoagulant) during the interruption of VKA therapy.
For patients at low risk for thromboembolism, the bridging can be avoided.
When there is a moderate risk for thromboembolism, the bridging or no-bridging approach chosen should be based on an assessment of individual patient- and surgery-related factors. If the surgery or procedure is a low risk for bleeding, the bridging may be considered, but if it is of high bleeding risk (major thoracic surgery), no bridging therapy may be better.
The best option for bridging therapy is, probably, the administration of sc LMWH. Again, the dose of the LMWH in this scenario is controversial, and the proposals go from prophylactic doses to therapeutic ones (high doses reserved only for patients at high thrombotic risk). In any case, the last dose should be given before surgery time, ensuring normal haemostasis (around 24 h for LMWH). After surgery, therapeutic-dose LMWH should be resumed 24 h postoperatively in non-high-bleeding-risk surgery. In patients who are undergoing high-bleeding-risk surgery, the resumption of therapeutic-dose LMWH should be delayed 48–72 h after surgery.
16.3.2 Management of Patients Under Direct Oral Anticoagulant
DOACs have in common that they are given orally and they do not need antithrombin for their action, but they are different drugs acting in different targets of the coagulation cascade: rivaroxaban, apixaban and edoxaban directly inhibit factor Xa; dabigatran is a direct inhibitor of factor IIa.
They can be used for thromboprophylaxis in patients scheduled for major orthopaedic surgery (total hip or knee arthroplasties), for the prevention of a stroke in patients with atrial fibrillation and for the treatment and secondary prevention in patients with venous thromboembolism [19].
As there is no experience enough about the perioperative management of DOACs, it is necessary to highlight some points:
Some antidotes have been developed for their reversal: idarucizumab for the reversal of dabigatran [20] and andexanet for the antagonization of xabans [21]. If the antidotes are not availables, some papers propose the adminsitration of PCC for the first line control of severe bleeding related with the administration of DOACs [19].
The dosage used for the chronic anticoagulation is quite different and higher than the dosage used for thromboprophylaxis.
The safety objective to be reached in patients receiving DOAC for “full” anticoagulation is, in these days, unknown. The safe preoperative objective has been defined for <30 ng/ml in any DOAC [22], but it is very difficult to control plasma levels in current practice. Moreover, there is a lack of relation between this plasma level and the results of standard coagulation tests.
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