For Immediate Release
Date: Jan 4th, 2011
Contact: Dr. Robert Henry
Dental Management of Patients Taking Antiplatelet Medications
A discussion of the scientific rationale for managing patients on antiplatelet agents, with management guidelines for dental clinicians.
Antiplatelet medications are drugs that decrease platelet aggregation and inhibit thrombus (clot) formation.1 They are widely used in primary and secondary prevention of thrombotic cerebrovascular or cardiovascular disease. The most common antiplatelet medications are the cyclooygenase inhibitors (aspirin) and the adenosine disphosphate (ADP) receptor inhibitors clopidogrel (Plavix) and ticlopidine (Ticlid). The dental management of patients taking these drugs is reviewed here.
Key words or phrases: Aspirin, Clopidogrel, dental management, antiplatelet, antithrombotic agent.
Antiplatelet medications are drugs that decrease platelet aggregation and inhibit thrombus (clot) formation.1 They are widely used in primary and secondary prevention of thrombotic cerebrovascular or cardiovascular disease. The most common antiplatelet medications are the cyclooygenase inhibitors (aspirin) and the adenosine disphosphate (ADP) receptor inhibitors clopidogrel (Plavix) and ticlopidine (Ticlid). With millions of patients now taking some form of antithrombotic agent, the potential risk for bleeding to occur during dental treatment has increased dramatically. This article discusses the scientific rationale for managing patients on antiplatelet agents and provides dental clinicians with management guidelines.
Aspirin, also known as acetylsalicylic acid, is a salicylate drug and is one of the most commonly used drugs in the world today. In 2005, in the United States, almost one-fifth (19.3 percent) of adults (about 43 million) reported taking aspirin every day or every other day. More than half (53.9 percent) of those who were ever told by a doctor that they have indicators of heart disease reported taking aspirin every day or every other day. Aspirin use also increases with age. Almost half (48.5 percent) of those age 65 and over reported taking aspirin every day or every other day, as compared with about one-fourth (27.0 percent) of those age 45 to 64.2
Aspirin is often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, as an anti-inflammatory medication, and as an antiplatelet agent used in long-term, low doses to prevent heart attacks, strokes, and blood clot formation in people at high risk for developing blood-clots.3 It has also been shown that low doses of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue.4, 5
Aspirin works by suppressing the production of prostaglandins and thromboxanes.6 Prostoglandins are local hormones produced in the body and have diverse effects in the body, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute myocardial infarction. The major side-effect of aspirin use is that excessive bleeding may result because of the ability of blood to clot is reduced.
Aspirin also irreversibly inhibits cyclooxygenase (COX)-1, and modifies the enzymatic activity of COX-2. These two enzymes (COX-1 and COX-2) contribute to the balance between vasoconstriction-vasodilation and platelet aggregation, and are altered to varying degrees by aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), smoking, and during disease states associated with high platelet turnover (i.e., immune thrombocytopenia, peripheral blood stem cell transplantation).7
COX-1 is highly sensitive to low doses of aspirin (40-80 mg daily).8 Complete inactivation of platelet COX-1 as well as maximum inhibition of collagen-induced platelet aggregation is achieved at 160 mg of aspirin taken daily.9 The antiplatelet action of aspirin is effective up to 320 mg daily, which is much lower than dosages required for anti-inflammatory and analgesic functions needed for the COX-2 pathways.10 Doses of aspirin higher than 320 mg daily may be less effective as an antithrombotic because of inhibition of prostacyclin production.11
For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin resistance or insensitivity. One study has suggested that women are more likely to be resistant than men.12 Another study of 2,930 patients found 28 percent to be resistant.13 The appearance of aspirin resistance can also occur as a result of nonadherence to daily dosing and the presence of comorbid conditions.14
Contraindications and adverse effects
Aspirin should not be taken by people who are allergic to ibuprofen or naproxen, or to have salicylate intolerance or to a more generalized drug intolerance to NSAIDs, and caution should be exercixed in those with asthma or NSAID-precipitated bronchospasm.15,16,17 Due to its effect on the stomach lining, manufactuers recommend that people with peptic ulcers, mild diabetes, or gastritis seek medical advice before using aspirin.18 There is an increased risk of stomach bleeding, even in the absence of these conditions, when aspirin is taken with alcohol or warfarin.
Patients with hemophilia or other bleeding tendencies should not take aspirin or other salicylates.19 Aspirin is known to cause hemolytic anemia in people who have the genetic disease glucose 6-phosphate dehydrogenase deficiency (G6PD), particularly in large doses and depending on the severity of the disease.20 People with kidney disease, hyperuricemia, or gout should not take aspirin because aspirin inhibits the kidneys’ ability to excrete uric acid and thus may exacerbate these conditions. Aspirin should not be given to children or adolescents to control cold or influenza symptoms as this has been linked with Reye’s syndrome.21
Adverse effects include gastrointestinal, central effects, Reye’s syndrome, and other effects and are summarized in Table 1 on page 16.
Dental bleeding from patients on aspirin
The fear of uncontrolled bleeding has caused dental practitioners to tell their patients to stop aspirin intake for seven to 10 days before any dental surgical procedure. However, in a recent review of the literature, Brennen et al. present evidence suggesting low-dose aspirin should be continued during dental surgical procedures.28
Three recent clinical trials were reviewed that demonstrated limited impact of aspirin on post-extraction bleeding. In one study, 36 patients were randomized to 325 mg of aspirin or placebo for two days before and two days after a single tooth extraction. No association between aspirin use and post-op bleeding problems was identified.29 In another study, 39 patients were randomized either to 100 mg of aspirin per day or to no aspirin, before single or multiple dental extractions(s). One group resumed taking aspirin the day after surgery. Regardless of taking aspirin or not, there were no episodes of excessive intraoperative or postoperative bleeding in either group.30 Similar results were found in a cohort of 51 patients on 75 to 100 mg of aspirin per day before a wide range of invasive dental procedures including single-tooth and multiple extractions. In this last study, only a single patient experienced increased intraoperative bleeding that was adequately controlled with local measures.31 The conclusion reached from these studies was that low-dose aspirin therapy should not be stopped before dental surgical procedures. Local hemostatic measures (sutures, packing, or packing with 10 percent tranexamic acid) was sufficient to control bleeding in the few cases experiencing excessive bleeding.
Is it a problem to just discontinue aspirin to control potential bleeding?
In several studies, patients who discontinue aspirin use prior to surgery are likely to develop adverse events compared to those who did not stop aspirin therapy.32,33,34 In one study of 1,358 patients with acute coronary syndrome (ACS), Collet et al. followed prospectively 930 nonusers, 355 prior users and 73 recent withdrawers of oral antiplatelet agents. The recent withdrawers had higher 30-day rates of death or myocardial infarction -- 21.9 percent versus 12.4 percent and bleedings (13.7 percent versus 5.9 percent, P=0.03) than prior users.32 Five percent of the patients admitted with ACS had withdrawn aspirin (oral antiplatelet) within three weeks before admission. It was concluded that prior users of oral antiplatlet agents and patients with recent interruption of their antiplatelet medication displayed worse clinical outcomes than nonusers.32
In a study by Ferrari et al., 1,236 patients hospitalized for ACS were evaluated for the role of aspirin withdrawal.33 A total of 51 (4.1 percent) of these patients discontinued aspirin within one month of the ACS. Thirteen of these patients who discontinued daily aspirin use did so before a dental procedure. The mean delay between aspirin withdrawal and the acute coronary event was 10+ 1.9 days (range 4-17 days).33
Finally, Fischer et al. reported that discontinuation of aspirin by daily aspirin users may increase the risk of myocardial infarction (MI).34 Of the 8,688 patients who experienced first-time acute MI, the risk of acute MI was 1.52 times greater for subjects who stopped taking NSAIDs including aspirin from one to 29 days compared with nonusers.34 This study concluded that the risk of acute MI is increased during several weeks after cessation of NSAID therapy. Overall, the data support the conclusion that among ACS patients, discontinuing daily aspirin use, even for 7-10 days, increases the risk for adverse clinical cardiovascular outcomes during the first month after drug withdrawal.
Can laboratory tests predict if bleeding will occur?
Brennan et al. also reviewed studies that investigated the predictive value of laboratory tests to determine if excessive bleeding may occur from patients taking aspirin intra-operatively.28 In the past, the cutaneous bleeding time test has been commonly used as a reasonable measure of bleeding risk for patients who take aspirin.35 While this test can often reveal increased bleeding time results in patients who take aspirin, it does not predict increased blood loss from dental or even orthopedic surgery.36 Other tests, such as platelet aggregation tests, have not proven predictive for bleeding during or after invasive dental procedures.37
The guiding factors for dental clinicians performing dental surgery in patients taking antiplatelet agents does not include the cutaneous bleeding time as a screening test to determine the bleeding risk from aspirin.38 Rather, a thorough medical history that includes questions regarding excessive bleeding after trauma and/or previous surgeries is more important. Finally, knowledge of the number of platelets and concurrent medications that can influence bleeding are also very important to know in determining the risk for bleeding in patients taking aspirin.39
Clopidogrel (Plavix) and ticlopidine (Ticlid)
Clopidogrel and ticlopidine are antiplatelet drugs in the thienopyridiene family that are adenosine diposphate (ADP) receptor inhibiotors. The action of these two drugs is to inhibit one of the types of ADP receptors (P2Y12) found on the platelet membrane, which is important in platelet aggregation and the cross-linking of platelets by fibrin.40 Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose of 300 to 600 mg is usually administered.41
Clopidogrel is indicated for prevention of vascular ischemic events in patients with symptomatic atherosclerosis, acute coronary syndrome (ACS) without ST-segment elevation (NSTEMI), along with aspirin, and ST elevation MI (STEMI). It is also used, along with aspirin, for the prevention of thrombosis after placement of intracoronary stent. Consensus-based therapeutic guidelines recommend the use of clopidogrel, instead of aspirin, in patients requiring antiplatelet therapy but with a history of gastric ulceration, as inhibition of the synthesis of prostagladins by aspirin can exacerbate this condition.41
Ticlopidine (trade name Ticlid), an older drug than clopidogel, has largely been replaced in medical practice by clopidogrel/Plavix because of its increased risk of thrombotic thrombocytopenic purpura (TTP) and neutropenia. Because ticlopidine has the same pharmacologic profile as clopidogrel, but higher adverse effects profile, ticlopidine is rarely used in the United States today.42
In contrast, clopidogrel is marketed as clopidogrel bisulfate by Bristol-Meyers Squibb, Inc., under patent as Plavix, until November 2011. Plavix comes in 75 mg oral tablets, and is one of the top selling drugs in the world since 2007, with sales in the U.S. of $5.9 billion in 2005.43,44 Generic clopidogrel is also produced by several pharmaceutical companies in India at lower prices, as well as counterfeit Plavix, also in circulation until Plavix’s patent runs out in November 2011.
Adverse effects associated with clopidogrel
The most serious adverse drug reactions associated with clopidogrel therapy include:45
• Severe neutropenia (incidence: 1/2,000);
• thrombotic thrombocytopenic purpura (TTP) (Incidence: 4/1,000,000);
• hemorrhage (the incidence may be increased by co-using with aspirin);
• gastrointestinal hemorrhage (incidence: 2.0 percent);
• cerebral hemorrhage (incidence: 0.1 to 0.4 percent);
• use of non-steroidal anti-inflammatory drugs is discouraged due to increased risk of digestive tract hemorrhage.
Dual antiplatlet therapy: Using aspirin with clopidogrel
The combination of clopidogrel plus asprin is mainly used in patients with percutaneous coronary stent intervention (coronary stents), in order to prevent thrombotic complications following placement.46 While the combination of aspirin and clopidogrel has been associated with bleeding risk with coronary artery bypass graft (CABG) surgery, there have been no studies to examine whether an increased risk of bleeding exists in the dental setting following extractions compared to more invasive surgical procedures (such as a CABG).47 Of significance however, is that a recent Science Advisory from the American Heart Association, American College of Cardiology, American College of Surgeons and the American Dental Association recommended continuing aspirin and clopidogrel therapy for minor dental surgical procedures in patients who have coronary artery stents or delaying treatment until the prescribed antiplatelet regimen is completed and warned of the significant thrombotic risks if therapy was discontinued.48
Dental recommendations for patients taking antiplatelets
Bleeding complications from patients taking antiplatelets, while inconvenient, do not carry the same risk as thromboembolic (“throwing a clot”) complications. Patients are more at risk of permanent disability or even death if they stop antiplatelet medication prior to a surgical procedure, than if they continued these drugs.49 Published reviews of the literature advise that antiplatelet monotherapy (either aspirin or clopidogrel by themselves), and combination therapy (both aspirin and clopidogrel) should not routinely be stopped prior to dental surgical procedures.48
Patients with the following medical problems taking antiplatelet medications should probably not be treated in the general dentist’s office without medical advice or should be referred to a dental hospital or oral surgery practice for difficult, invasive, or extensive surgical care:50,51,52
• liver impairment and/or alcoholism;
• renal failure;
• thrombocytopenia, hemophilia, or other disorder of hemostatis;
• currently receiving a course of cytotoxic medication.
Minor surgical procedures can be safely carried out without altering the antiplatelet medication dose. The following would be classified as minor procedures: simple extraction of three teeth, gingival surgery, crown and bridge procedures, dental scaling and the surgical removal teeth.50 When more than three teeth need to be extracted, one recommendation would be to remove two to three teeth at a time, by quadrants, or singly, but having the patient return for multiple visits.49 Scaling and gingival surgery should initially be confined to a limited area to assess if bleeding is problematic.
Managing bleeding for patients on antiplatelets
Prevention of bleeding is key in managing patients on antiplatelet medications. Planned surgery should ideally be at the beginning of the day, which allows more time to deal with immediate re-bleeding problems. Similarly, planning surgery for early in the week allows for treating delayed re-bleeding episodes occurring after 24-48 hours during the workweek.49
A local anesthetic containing a vasoconstrictor should be administered by infiltration whenever practical. Regional nerve blocks should be avoided where possible but when necessary, the local anesthetic should be administered cautiously using an aspirating syringe.
Every effort should be made to make the procedure as atraumatic as possible and any bleeding should be managed using local measures. All granulation tissue and infection (abcesses/granulomas) must be removed from the socket or area. Sockets should be gently packed with an absorbable hemostatic dressing, in the absence of active infection. Options include: Gelfoam (resorbable gelatin sponge), surgical (oxidized cellulose) or Collacote/Collaplug (collagen sponge) for packing. If primary closure is possible, this should be done. Resorbable sutures are preferable as they attract less plaque.39 If non-resorbable sutures are used, they should be removed in four to seven days. Following closure, pressure should be applied to the sockets by using a gauze pad that the patient should bite on for 15 to 30 minutes. For persistent intraoperative areas which are bleeding, or if patients return with oozing from the site, re-packing the area or socket with additional sutures should be considered. In addition, a topical cyanoacrylate glue (Histocryl) can be placed over the approximated wound edges, as an effective, easily applicable local hemostatic for use in such patients.53
Patients should be given clear instructions regarding the management of the surgical site including to not smoke for 24 to 48 hours if possible, to avoid rinsing for 24 hours, to not suck hard or disturb the socket with the tongue, to avoid hot liquids and hard foods for a day, to avoid chewing on the affected side, and what to do if bleeding persists.
In the dental setting, continuing low-dose antiplatelet therapy in monotherapy (aspirin or clopidogrel) or dual therapy (in combination) is currently recommended for patients receiving dental care, including surgical procedures. Unless exceptions mentioned in this paper exist, bleeding following extractions can typically be managed by local hemostatic measures including pressure, packing, sutures, and cyanoacylate (Histocryl) glue (in reserve). As the population ages, the number of patients on antiplatelets will continue to increase. As long as aspirin and antiplatelet medications are effective in preventing myocardial infarction, ischemic stroke, and vascular death due to thrombotic events, the dental mangament of these patients will continue to be important for dentists in their day-to-day clinical practice.
This article was originally printed in the Texas Dental Journal: Tex Dent J (2009); 126(7): 608-616. Reprinted/used with permission from the Texas Dental Association.
Robert G. Henry, D.M.D., M.P.H., is chief, Dental Service, with the Department of Veterans Affairs Medical Center, in Lexington, KY, and clinical associate professor at the University of Kentucky College of Dentistry.
A full list of references are available upon request from the KDA office.