Gastroenterology & Hepatology
January 2016, Volume 12, Issue 1
Michelle A. Anderson, MD, MSc
Associate Professor
Internal Medicine
University of Michigan
Ann Arbor, Michigan
G&H Which antiplatelet agents are currently available, and what are their properties?
MA There are many antiplatelet agents available in the United States today. The most commonly used agents are aspirin and a class of drugs called thienopyridines (Figure 1). Aspirin has been around for many years, and it prevents platelet aggregation by irreversibly inhibiting platelet cyclooxygenase and, by that mechanism, the generation of thromboxane A2.
Within the thienopyridine group are clopidogrel, ticagrelor (Brilinta, AstraZeneca), prasugrel (Effient, Eli Lilly), and ticlopidine, all of which inhibit the adenosine diphosphate receptor inhibitors acting on platelet membranes to inhibit aggregation. With the exception of ticagrelor, all of these drugs are irreversible.
Older, less commonly used antiplatelet agents are dipyridamole and a combination of aspirin/dipyridamole. Dipyridamole prevents platelet aggregation by inhibiting adenosine reuptake.
G&H Which anticoagulant agents are currently available, and how do they work?
MA Warfarin, which was the only oral anticoagulant on the market for decades, inhibits all of the vitamin K–dependent, biologically active clotting factors (factors II, VII, IX, and X) and the anticlotting factors (proteins C, S, and Z) in the coagulation cascade.
The alternatives to warfarin are new oral anticoagulants (NOACs), which consist of dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Janssen), and apixaban (Eliquis, Bristol-Myers Squibb). There are also 3 anticoagulant agents that are given subcutaneously: enoxaparin, fondaparinux, and desirudin (Iprivask, Valeant Pharmaceuticals; Figure 2).
NOACs are much more precise than warfarin; they hit the coagulation pathway in very specific points. For instance, dabigatran only inhibits factor IIa, and rivaroxaban, apixaban, enoxaparin, and fondaparinux are factor Xa inhibitors. Desirudin is the only direct thrombin inhibitor.
G&H How common is the use of anticoagulant and antiplatelet agents?
MA The use of anticoagulant and antiplatelet agents in the general population is very common. Estimates for 2015 are still unknown because they are collected year to year by different organizations; however, data from 2012 show that more than 25 million prescriptions for warfarin were dispensed in the United States alone. NOACs are also being prescribed at an increasing rate. Since the approval of dabigatran in October 2010 until December 2013, over 6 million prescriptions were dispensed to more than 900,000 patients.
G&H What are the benefits and limitations associated with NOACs?
MA The main benefits of NOACs are that patients do not have to undergo a prothrombin time test due to predictable pharmacokinetics and the lower likelihood of diet or other medication interfering with the anticoagulation of the drug due to the specificity of the action of the drug.
However, NOACs are much more expensive than warfarin, and there are currently no medications available to reverse the anticoagulation that may cause complications with a NOAC.
G&H Which endoscopic procedures are safe to perform in the setting of antiplatelet therapy?
MA All endoscopic procedures, whether low risk (eg, upper endoscopy or colonoscopy with biopsy) or high risk (eg, endoscopic sphincterotomy), are safe on aspirin and all nonsteroidal anti-inflammatory drugs that are available in the United States.
Aggressive antiplatelet agents, such as clopidogrel, ticagrelor, and prasugrel, are typically held according to the half-life of the drug in patients undergoing high-risk procedures. For instance, if the drug has a half-life of 8 hours, most endoscopists recommend holding the drug for a minimum of 4 half-lives, or 32 hours.
G&H How significant is the risk of bleeding?
MA Bleeding is the primary adverse event associated with both anticoagulant and antiplatelet agents. Generally, rates of bleeding vary according to the type and dose of the drug and other concomitant medications that the patient may be on, as well as the age of the patient and comorbid conditions such as renal or liver failure.
Patients on warfarin have a 15% to 20% risk of bleeding annually, with a 1% to 2% risk of life-threatening or fatal bleeding for every year that they remain on the medication.
NOACs have a reduced risk for stroke, ischemic and intracranial bleeding, and death compared with warfarin; however, they have increased rates of gastrointestinal bleeding compared with warfarin.
G&H Are any other complications associated with anticoagulant agents?
MA The other major alternative adverse event to bleeding is a thromboembolic event, such as an ischemic or embolic stroke, which can occur when these medications are held or altered.
G&H Do certain endoscopic procedures present a higher risk of bleeding?
MA There are data on bleeding risk in patients who undergo endoscopic procedures while on antiplatelet and anticoagulant medications. Most of this information is on patients who undergo polypectomy while receiving clopidogrel. A 2013 meta-analysis of 5 studies involving 6000 patients found that patients who had polypectomy while actively taking clopidogrel had a risk ratio for postpolypectomy bleeding of 1.76 compared to patients who had their polyps removed without an antiplatelet agent. The same analysis found a nearly 5-fold increased risk ratio for delayed bleeding in patients who underwent polypectomy while on clopidogrel compared to the control group. These findings suggest an increased risk of bleeding for polypectomy in patients actively taking these medications while undergoing these procedures.
G&H Which patient populations present a higher risk of bleeding?
MA Patients with comorbid conditions, such as renal failure or liver disease, have a higher risk of bleeding when undergoing endoscopic procedures because their clotting cascade and ability to successfully form platelet aggregates have been affected.
Similarly, patients with left ventricular assist devices, especially newer devices, present an increased risk of bleeding because they have a propensity to form angiodysplastic lesions.
G&H What is currently considered the safe window for holding warfarin for procedures in high-risk individuals?
MA A 2008 study reported on patients who experienced a stroke when their anticoagulant medication, predominantly warfarin, was held for procedures. In many cases, these were endoscopic procedures. Patients who had their medications held for 5 days or fewer had a stroke proportion of 0.4% compared with the 2.2% stroke proportion in patients who had their medication held for 7 days or more, a nearly 6-fold increase.
A previous study published in 2003 found that patients who were off their anticoagulant medication for 9 days experienced a stroke compared with those who were off medication for 7 days and did not have a stroke. Thus, it appears that the length of time that the anticoagulant agent is held is critically important to whether that patient develops a complication such as a stroke. While there is no exact safe window for how long the medication can be held safely, it appears that 5 days may be the golden period, and anything beyond that could be dangerous.
G&H What is the role of the enoxaparin bridge?
MA The enoxaparin bridge is a method of keeping the patient anticoagulated up until the night before an endoscopic procedure so that the patient has as small of a window as possible of not being therapeutically anticoagulated. This is a controversial topic right now because data from cardiology studies have shown that patients who received bridging therapy were no less likely to have a thromboembolic event, but were 5 times more likely to have a bleeding event.
Because of that data, there are now 2 large trials sponsored by the National Institutes of Health—one completed this past February, and the other due to be completed in March 2017—addressing whether bridge therapy should ever be used. Expectations are that clinicians will cease bridging in the vast majority of patients.
G&H How soon after a major endoscopic intervention can anticoagulant and antiplatelet agents be safely restarted?
MA The simple answer is that no one knows for sure. One study reported that reinitiation of anticoagulant medication within 72 hours after endoscopic sphincterotomy was associated with an increased risk of bleeding (Figure 3). There are no similar findings that reinitiating anticoagulant medication after an endoscopic large polypectomy increases the risk of bleeding, and most endoscopists will restart warfarin within 24 hours because it takes so long to obtain a full therapeutic anticoagulation benefit in those patients.
With that said, endoscopists need to keep in mind that all of the NOACs and the subcutaneous anticoagulants have a rapid onset of action, within 1 to 3 hours. Therefore, if the drug that the patient will return to is one of these irreversible NOACs, the endoscopist may want to wait 48 hours following a high-risk procedure. This may be particularly true in patients who have a high risk for delayed bleeding and a low risk for a thromboembolic event.
G&H Does the use of anticoagulant and antiplatelet agents affect the timing of an elective endoscopic procedure?
MA Timing of the endoscopic procedure plays a role in patients who are on antiplatelet agents with drug-eluting stents in place. When endoscopists are evaluating those patients, it is important to recognize when the stent was placed, what type of stent was placed, and when it is safe for that patient to hold the antiplatelet agent, recognizing that the risk of clotting the drug-eluting stent is never 0%.
There is a recommendation from the American Heart Association and the American College of Cardiology that states that patients with drug-eluting stents should ideally undergo dual antiplatelet therapy for a minimum of 12 months following the placement of a stent. Thus, the endoscopist would ideally wait a minimum of 12 months in those patients before submitting them to an elective procedure.
G&H Are mechanical and thermal techniques reliable enough methods of hemostasis to allow antiplatelet agents to continue to be taken when an endoscopic procedure is planned?
MA There are no prospective, controlled data on thermal and mechanical hemostasis in patients undergoing endoscopic procedures while on active anticoagulant or antiplatelet therapy. All of the data are from case series or retrospective studies. However, in the data that are available, these techniques appear to be effective in preventing bleeding. The problem is that analyses have shown that the placement of more than 1 clip in a patient on anticoagulant agents is not cost-effective. Therefore, once 2 polyps have been removed and 2 clips have been placed, this approach is already not cost-effective.
G&H When bleeding is controlled via endoscopic hemostasis, what is the optimal timing of restarting antiplatelet or anticoagulant therapy?
MA This is an area with even less data, and no one truly knows the answer. Most experts recommend managing this scenario on a case-by-case basis using the patient’s risk for a thromboembolic event and his or her current status to guide reinitiation of therapy.
G&H What are the next steps of research?
MA We need studies to determine which patients are at the highest risk for anticoagulant-related harms, especially concerning NOACs, and how to best manage patients with severe bleeding episodes who are on newer medications. We also currently do not have good medications to reverse those patients.
I think that the data from the National Institutes of Health–sponsored trials should help us learn how to manage anticoagulation in patients in the periendoscopic period. I would like to see prospective data regarding the use of hemostatic approaches in patients who are taking active anticoagulant and antiplatelet agents and need to undergo endoscopy.
Dr Anderson has no relevant conflicts of interest to disclose.
Suggested Reading
ClinicalTrials.gov. Effectiveness of bridging anticoagulation for surgery (the BRIDGE study). https://clinicaltrials.gov/ct2/show/NCT00786474. Identifier: NCT00786474. Accessed December 23, 2015.
ClinicalTrials.gov. PERIOP 2 – a safety and effectiveness study of LMWH bridging therapy versus placebo bridging therapy for patients on long term warfarin and require temporary interruption of their warfarin. https://www.clinicaltrials.gov/ct2/show/NCT00432796. Identifier: NCT00432796. Accessed December 23, 2015.
Douketis JD, Spyropoulos AC, Kaatz S, et al; BRIDGE Investigators. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-833.
Gandhi S, Narula N, Mosleh W, Marshall JK, Farkouh M. Meta-analysis: colonoscopic post-polypectomy bleeding in patients on continued clopidogrel therapy. Aliment Pharmacol Ther. 2013;37(10):947-952.
Garcia DA, Regan S, Henault LE, et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med. 2008;168(1):63-69.