If there is moderate renal impairment, NOACs should be used with caution and, in most cases, dosages need to be reduced. Compliance Compliance and adherence to treatment is crucial, especially as these drugs have a relatively short half-life. Antiplatelet medications that are used commonly in Australia include, aspirin, clopidogrel, prasugrel and ticagrelor.
Management of patients on DAPT who are referred for surgical procedures depends on the level of emergency and the thrombotic and bleeding risk of the individual patient. Current recommendations for DAPT range from 4 weeks in patients undergoing elective stenting with bare metal stents BMS to up to 12 months in patients with drug-eluting stents DES or for patients undergoing coronary stenting for acute coronary syndrome.
Premature cessation of DAPT is thought to be one of the most important causes of stent thrombosis, which can have fatal consequences. The current guidelines recommend that elective non-cardiac surgeries be postponed for at least 6 weeks ideally 3 months following angioplasty with BMS and for 12 months after DES, 15 as the risk of thrombosis is highest within 6 weeks after the placement of a bare-metal stent and within 3—6 months after the placement of a DES.
Perioperative continuation of aspirin increases bleeding risk slightly but does not increase the risk for bleeding that requires medical or other interventions and therefore can usually be continued. If there were concerns about increased risk of bleeding, then the best approach would be to stop the rivaroxaban 24 hours prior to the procedure and taking the next dose the morning after the procedure.
Mr Smith does not need cessation of his dual antiplatelet therapy. His angioplasty was performed only 2 weeks prior and as the risk of bleeding is low, DAPT should be continued. If the risk of bleeding in his procedure were deemed to be high on DAPT, then the procedure is best postponed until a time when it is deemed safe to stop his clopidogrel.
General practitioners GPs undeniably have a major role to play in the management of patients on oral anticoagulants who have to undergo an invasive procedure. Most patients having minor procedures can continue to take an anticoagulant, provided that they are closely monitored.
Patients at high risk of bleeding should be considered for a more aggressive perioperative management strategy with bridging therapy. Antiplatelet therapy is usually safe to continue in procedures with a low risk of bleeding. Generally, drugs such as clopidogrel, prasugrel and ticagrelor should be stopped about 5—7 days before any procedure where the risk of bleeding is deemed to be high.
The timing of any non-urgent procedure and stopping of antiplatelet therapy depends on the time frame between insertion of stents and the planned procedure and on the type of stent used. Early, effective and ongoing communication between GPs and specialists is required to maximise patient safety during perioperative transitions of anticoagulation. Involvement of an accredited pharmacist via a home medicines review may be helpful to facilitate optimal use of anticoagulants at this time of risk.
Competing interests: None. Provenance and peer review: Not commissioned, externally peer reviewed. Australian Family Physician. Search for: Search AFP. Filter Relevance Date. Issues by year. Volume 43, Issue 12, December Background The strategy of whether to continue anticoagulation and antiplatelet agents during surgery depends on an evaluation of the throm-boembolic risk and haemorrhagic risk of the individual patients.
Procedures that carry a significant risk of bleeding may require tem-porary cessation of the medication. Objective We briefly review the use of common oral anticoagulant and antiplatelet agents, including clinical indications and limitations associated with those agents. We also discuss the risks of thromboembolism, and balancing bleeding risk in patients receiving oral anticoagulation therapy, temporary interruption of such therapy and management of such patients undergoing an elective surgical procedure.
Discussion Generally, patients at high risk of thromboembolism should be considered for a more aggressive perioperative management strategy with bridging therapy. Current recommendations for dual antiplatelet treatment range from 4 weeks in patients undergoing elective stenting with bare metal stents, up to 12 months in patients with drug-eluting stents or patients undergoing coronary stenting for acute coronary syndrome.
If a patient is to undergo high-bleeding-risk surgery and an antiplatelet effect is not desired, clopidogrel, prasugrel and ticagrelor should be discontinued 5—7 days before the procedure. Table 1. Table 2. High-bleeding-risk procedures The strategy for perioperative anticoagulation in patients undergoing major, high-bleeding-risk surgery is based on the assessment of the risk of thromboembolism versus the risk of haemorrhage Table 5.
Perioperative management Anticoagulants 7—10 1 Evaluate the thromboembolic risk and hemorrhagic risk of the individual patients 2 Consider temporary cessation of the drug in procedures that carry a significant risk of bleeding 3 Low thromboembolism and bleeding risk Warfarin may be continued with relatively low INR 1. Factors to consider before switching from warfarin to NOAC after surgery The NOACs so far tested in clinical trials have all shown non-inferiority when compared with VKAs, as well as better safety, consistently reducing the number of intracranial haemorrhages.
Therefore, factors to consider before switching from warfarin to a NOAC after surgery are: Renal function Before switching from warfarin to NOAC, one of the most important considerations should be renal function. Perioperative management of antiplatelet therapy Dual antiplatelet therapy DAPT following percutaneous coronary stenting and acute coronary syndrome ACS is common.
Conclusion General practitioners GPs undeniably have a major role to play in the management of patients on oral anticoagulants who have to undergo an invasive procedure. References Australian Government Department of Health. PBS Information. Available at www. Periprocedural bleeding and thromboembolic events with dabigatran compared to warfarin: results from the RE-LY Randomized Trial.
Circulation ;— Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
JAMA ;— Can the CHADS2 score predict postoperative stroke risk in patients with chronic atrial fibrilation who are having elective non-cardiac surgery? Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. If possible, discontinue use of aspirin products 2 weeks before surgery. Nonsteroidal anti-inflammatory drugs such as Advil Motrin, ibuprofen , Aleve Naprosyn, naproxen , and Indocin indomethacin also inhibit platelet function and should be held for 2 weeks before surgery if possible.
Coumadin warfarin blocks the production of blood clotting factors. Vitamin K is an anti-dote. Coumadin is the most difficult anticoagulant to manage and close physician supervision is required.
Xarelto rivaroxiban , Eliquis apixaban , and Savaysa edoxaban inhibit blood clotting factor Xa. They can be stopped days before major surgery and held one day before minor surgery. These can be resumed the day after surgery if there is no bleeding.
Pradaxa dabigatran directly inhibits thrombin from activating the clotting cascade. It can be held days before major surgery and one day before minor surgery. Pradaxa can be resumed the day after surgery if there is no bleeding. If unable to take oral medication following surgical intervention, consider bridging with a parenteral low molecular weight heparin LMWH. Rivaroxaban can be restarted at the same prior dose after hemostasis has been reached; however, in high bleeding risk procedures, it is recommended to reinitiate rivaroxaban after 48—72 hours.
During such gap without anticoagulation, bridging with LMWH may be required in high and very high thromboembolic risk patients. Apixaban, known by the brand name Eliquis, is an oral anticoagulant that acts on the same mechanism as rivaroxaban and edoxaban.
All three of these drugs directly and selectively inhibit factor Xa, which occupies a pivotal role converting prothrombin to thrombin. This is significant because thrombin is needed both to activate platelets and to produce fibrin from fibrinogen for clot formation. The ultimate goal of both the extrinsic and intrinsic pathways is to activate factor X to become factor Xa in order to perpetuate the cascade.
By interfering with this important step, apixaban achieves a state of anticoagulation. Apixaban is administered orally and displays a more prolonged absorption than dabigatran or rivaroxaban. With repeated dosing, the half-life of apixaban is 12 hours. Apixaban is mostly metabolized by CYP3A4. It is a substrate of P-glycoprotein and breast cancer-resistant protein.
To prevent deep venous thrombosis, apixaban is prescribed in 10 mg doses twice daily for seven days, which is later tapered down to 5 mg twice a day. A dose of 2. Apixaban also offers protection from stroke and systemic embolism in patients with nonvalvular atrial fibrillation with a dose of 5 mg twice daily. However, if a patient has two of the following characteristics, a dose of 2.
The other indications do not need renal dose adjustments. Apixaban is not recommended in severe liver dysfunction Child-Pugh C. Treatment for PE with apixaban requires first 10 mg twice daily for seven days and later 5 mg twice daily, whereas reducing recurrence requires just 2.
Much like rivaroxaban, apixaban is metabolized by the CYP3A4 enzyme. It also weakly inhibits CYP2C This will then cause the levels of apixaban to accumulate in the blood. Strong CYP3A4 inhibitors are also categorized as Risk C, and this category includes the following: cobicistat, darunavir, itraconazole, ketoconazole, lopinavir, ombitasvir, paritaprevir, ritonavir, saquinavir, and telaprevir. Grapefruit juice is also known to dramatically increase levels of apixaban and must be consumed with caution when taking this drug.
Some of the drugs that act as inducers on cytochrome P include the following: carbamazepine, phenytoin, rifampin, and barbiturates. Some of the other drugs that are categorized as Risk X with apixaban include anticoagulants with the exception of acenocoumarol and warfarin , dabigatran etexilate, edoxaban, hemin, omacetaxine, St.
Bleeding and severe hypersensitivity are major contraindications for the administration of apixaban. Some side effects include bleeding 1. Apixaban, like the other DOACs, has a lower thromboembolic risk and major bleeding risk. Thromboembolic risk determined in the ARISTOTLE trial apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation noted 16 thromboembolic events day postprocedural evaluation for stroke or any VTE out of 4, procedures 0.
Bleeding risk for patients receiving apixaban was not significant in the preoperative period and patients can safely resume anticoagulation with apixaban, once hemostasis is achieved. Limited data comparing risks and benefits of apixaban continuation or cessation exist, and thus, every decision is made on a case-by-case basis.
Novel factor Xa inhibitors have a rapid onset of action in the blood stream as noted by pharmacokinetics with maximum concentration three to four hours after ingestion of apixaban. Preoperatively, patients should be assessed for risk of stroke and thrombosis while off anticoagulation for high bleeding risk procedures.
Edoxaban, known by the brand name Savaysa, reduces blood coagulation by directly inhibiting factor Xa, much like rivaroxaban and apixaban. In the simplest sense, all three of these drugs decrease thrombin generation, and in doing so, decrease the formation of thrombi, which produces a state that opposes coagulation.
Edoxaban impacts multiple coagulation tests, namely, partial thromboplastin time and anti-Xa assay, which have both been shown to accurately indicate drug levels within the plasma. Edoxaban is administered orally, and it takes between one and two hours for it to reach peak plasma concentration. The half-life of edoxaban ranges from 10 to 14 hours, and in the plasma, it is most often found in the form of unchanged edoxaban.
Edoxaban is a substrate of the P-glycoprotein transporter. About half of it is renally cleared, and when excreted via the urine, it is predominately done so in the form of unchanged drug. Edoxaban is used to protect against stroke and systemic embolism in instances of nonvalvular atrial fibrillation. It is also indicated after a hip or knee arthroplasty for the prevention of venous thrombotic events. Another crucial use of edoxaban is to treat DVT and PE in those who received a parenteral anticoagulant 5 to 10 days prior.
More specifically, in patients given warfarin, the rate of systemic emboli was 1. Edoxaban, an oral medication that can be taken without food, is available in 15, 30, and 60 mg tablets. For DVT or PE treatment following use of a parenteral anticoagulant, a dose of 60 mg orally daily is recommended in patients weighing greater than 60 kg, and one of 30 mg orally daily in those weighing less than 60 kg. Edoxaban is minimally metabolized by hydrolysis, conjugation, and oxidation involving CYP3A4.
It is also a substrate of P-glycoprotein. However, edoxaban is also listed as a Risk X with the following medications: anticoagulants excluding acenocoumarol and warfarin , apixaban, dabigatran, omacetaxine, rifampin, rivaroxaban, urokinase, and vorapaxar. This means that edoxaban should not be used in conjunction with any of these medications. For instance, certain organ tissues and cells the brain, T-lymphocytes, and testes possess P-glycoprotein in larger amounts.
These same areas will have comparatively less edoxaban in the presence of an inducer than will other areas. For this reason, P-glycoprotein inducers are categorized as Risk C and must be monitored closely when administered with edoxaban.
Additionally, P-glycoprotein inhibitors cause the opposite effect and run the risk of high serum levels of edoxaban. Since this might produce too much anticoagulation, P-glycoprotein inhibitors are categorized as Risk D, which means that it is important to consider therapy modification. For example, in patients taking edoxaban for VTE, a dose reduction is recommended if the patient also takes a P-glycoprotein inhibitor.
A dose adjustment is not recommended, however, in patients taking edoxaban for atrial fibrillation, even if they are also taking an inhibitor.
It is recommended that dosage be adjusted in patients with mild hepatic impairment Child-Pugh class A and that the drug be avoided entirely in those with moderate-to-severe hepatic impairment Child-Pugh classes B and C. Additionally, since molecule size of these oral anticoagulants is small, they can pass through the placenta and must be avoided in pregnancy. Edoxaban in particular is pregnancy category C drug, along with dabigatran and rivaroxaban.
As with most anticoagulants, including the new oral anticoagulants, the greatest risk is for bleeding, which makes sense given their fundamental mechanism of action. Thus, an obvious contraindication to edoxaban and other oral anticoagulants is active pathological bleeding. Despite this adverse effect, edoxaban has still been shown to be preferable to warfarin with regard to reducing major bleeding events. At the same time, those treated with edoxaban developed fewer bleeding complications, at a rate of 8.
However, at the same time, they have been found to produce more gastric bleeding than warfarin. Other side effects of edoxaban include abnormal liver function tests 4. Very limited data exist in the literature regarding the perioperative risk of interrupting edoxaban use. Likely due to the recent FDA approval of edoxaban on January 8, , and various black box warnings associated with the medications, it has not been widely integrated into general practice of clinicians.
In the ENGAGE AF-TIMI 48 trial, comparing edoxaban and warfarin for stroke prevention in atrial fibrillation population, 3, patients had drug interruption discontinued apixaban 4—10 days prior to procedure and 4, patients continued apixaban discontinuation of apixaban, 3 days or less prior to procedure.
Analysis of the perioperative period did not show any statistical significance in both studied arms with similar outcomes in terms of stroke or systemic embolism, whether the drugs were discontinued or not. Bleeding risk is increased if anticoagulation is not interrupted in the perioperative period, and such bleeding risk did not differ from forms of anticoagulation whether it is a vitamin K antagonist or factor Xa inhibitor such as edoxaban.
Patients were further split into 30 and 60 mg of edoxaban based on dose reductions due to renal function, and again evaluations of the interrupted and uninterrupted population were performed. Patients who received 30 mg of edoxaban had 12 out of 1, events in the interrupted arm and 35 out of 1, events in the uninterrupted arm.
Edoxaban 60 mg exhibited similar results, 11 out of 1, events noted in the interrupted population and 47 out of 1, in the uninterrupted population. In patients with increased risk of thromboembolism, bridging with shorter acting anticoagulants such as unfractionated heparin is recommended. In high bleeding risk procedures, edoxaban should be discontinued 72 hours prior.
Edoxaban is recommended to be discontinued at least 24 hours prior to low bleeding risk procedures, irrespective of renal functional status. In high-risk thromboembolic patients, bridging of edoxaban is recommended prior to procedure; however, due to the rapid onset of edoxaban, bridging postoperatively is usually not required. It requires the assessment of thromboembolic event risk while off anticoagulation compared to the relative risk of bleeding if such drug is continued.
DOACs may be successfully managed in the perioperative period with consideration given to the pharmacokinetics of the DOAC, renal function of patients, risk of bleeding with respective to the procedure or surgery, and thromboembolic risk of the patient.
The common pitfalls in this rapidly changing field of DOACs include improper timing of either stopping or restarting the medications periprocedure. This review serves as a concise resource that would aid a practicing clinician in making an informed decision.
Additional large randomized, prospective studies are needed to further characterize the safety and management of newer DOACs in the perioperative period.
Future research in the area of DOACs could also probably entail development of protocols for monitoring anticoagulation status and development of specific antidotes for reversal. Paper subject to independent expert single-blind peer review.
All editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties.
Author Contributions. Analyzed the data: TS and EO. Wrote the first draft of the manuscript: TS and EO. All the authors reviewed and approved the final manuscript. National Center for Biotechnology Information , U.
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