Continuous oral anticoagulation therapy has been used for many years to decrease the incidence of thromboembolism in at-risk patients. Dental surgical treatment for patients who are receiving anticoagulation therapy is controversial. Some clinicians recommend no change in anticoagulation therapy for dental surgical treatment, whereas others recommend withdrawal of oral anticoagulation therapy a few days before the surgical procedure, as well as administration of unfractionated heparin for high-risk patients undergoing high-risk procedures.1–4 More recently, the literature reported studies showing that no serious bleeding problems resulted from dental surgery in patients receiving therapeutic levels of warfarin when meticulous surgical techniques were used.2,3 In spite of this, there remains a great deal of variability among physicians recommending alteration of anticoagulant therapy before dental surgery.5
The physician and dentist need to weigh the risks of hemorrhage from dental procedures against the risks of emboli from ceasing administration of anticoagulation medication.
Together, the physician and dentist need to weigh the risks of hemorrhage from dental procedures against the risks of emboli from ceasing administration of anticoagulation medication. Dentists should become aware of an emerging anticoagulant alternative: the low-molecular-weight heparin, or LMWH.
In the past several years, LMWHs have been used in the medical community. They are agents formulated from chemical or enzymatic depolymerization of unfractionated heparin to lower-molecular-weight fragments. This is the type of heparin that most dentists are familiar with from dental school or residency training. LMWHs have been used to prevent deep venous thrombosis, or DVT, and pulmonary emboli.6–12 In addition, they are used to treat unstable angina; non–Q-wave myocardial infarctions, or MIs; and embolism prophylaxis before major orthopedic and abdominal surgeries.6–12 More recently, LMWHs have been used as a substitute for warfarin in dental procedures.13 As an alternative to unfractionated heparin, LMWHs provide successful anticoagulation, require little monitoring, and reduce the duration and cost of hospital admissions for dental procedures.14–17
In the following case report, we describe the use of LMWHs in a patient receiving anticoagulation therapy treated in an outpatient dental clinic.
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CASE REPORT
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A 72-year-old man with a medical history significant for DVT, hypertension and diabetes mellitus, presented at the University of Illinois at Chicago Medical Center, or UICMC, with severe chronic periodontal disease and carious dentition. He started taking warfarin (2.5 milligrams) after DVT occurred four months earlier. His international normalized ratio, or INR,18 was maintained at 2.5 to 3.5 (1.0 is normal). He needed to have 19 teeth extracted and an alveoloplasty. After healing, full dentures were to be fabricated and fit.
After consulting with the patient’s physician, we decided that he could not discontinue warfarin therapy without using another form of anticoagulation while we waited for his INR to decrease to a more desirable level. We offered the LMWH therapy of 30 mg of subcutaneous enoxaparin to the patient, which he accepted. We then initiated a protocol often recommended at our institution, the UICMC.19
Four days before the procedure, the patient was instructed to discontinue the warfarin. He began a series of 30-mg subcutaneous enoxaparin injections every 12 hours on an outpatient basis, three days before the dental procedure. In this case, the actual times were 9 a.m. and 9 p.m., the protocol used by UICMC. Staff at the outpatient hematology clinic at UICMC instructed the patient and his son on how to administer the enoxaparin injections. The patient was instructed to lie down and grasp a fold of skin on his abdomen between his thumb and forefinger. The syringe needle then was to be inserted to the full depth and the plunger depressed. The patient’s son administered the injections.
When we discontinued the patient’s warfarin, his INR was allowed to normalize, while the enoxaparin provided anticoagulation. We instructed the patient to discontinue the enoxaparin injections the evening before the surgery, as the surgery was scheduled for 9 a.m. the following day. On the morning of the surgery, we checked the patient’s INR and found that it was 1.1. We performed the extractions and alveoloplasty while the patient was under local anesthesia. We packed the sites with absorbable gelatin sponges and sutured them with primary closure. The LMWH was continued for three days, and warfarin therapy was restarted that evening to allow the patient’s INR to return to a therapeutic level. After the three days, the enoxaparin injections were discontinued. Healing occurred uneventfully with minimal oozing at the time the INR became therapeutic.
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DISCUSSION
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Concerns with anticoagulation therapy.
Patients receiving anticoagulation therapy can pose many difficulties for dentists. The possibility of postsurgical hemorrhage is a concern for clinicians who perform surgery on patients receiving anticoagulation therapy. Patients who are receiving long-term warfarin therapy often are managed by stopping or decreasing the drug two to four days before surgery; however, there are some documented cases of embolic complications in patients whose warfarin therapy was discontinued for dental treatment.2,3,17 There also is evidence that thrombosis may be more likely to occur as a result of hypercoagulability that can occur after cessation of oral anticoagulation therapy.2,17–22 After warfarin is discontinued, it can take as many as five or six days for the clotting process to return to normal. Drugs such as common analgesics (nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, acetaminophen and cyclooxygenase-2 inhibitors), antibiotics (amoxicillin, erythromycin, Bactrim [Roche Laboratories, Nutley, N.J.] and macrolides) and alcohol can interact adversely with warfarin.23
As a result of these concerns, researchers have investigated whether alteration of the anticoagulant therapy is necessary. A recent study24 found no correlation between the appearance of postoperative bleeding and the INR value measured on the day of the extraction. Postoperative bleeding was local and could be controlled easily by local hemostasis with tranexamic acid or gelatin sponges and sutures. The authors found that local hemostasis with gelatin sponges and sutures appeared to be sufficient after meticulous curettage of the extraction site. Other studies also have indicated that warfarin need not be discontinued or altered to safely perform oral surgery.25–29
Patients who are at high risk of developing a thromboembolism and who are receiving oral anticoagulants also can have their oral anticoagulants substituted with unfractionated heparin. Unfractionated heparin is a mixture of glycosaminoglycans of different molecular weights. It has an onset of action within minutes and a short half-life (50 to 90 minutes). Heparin potentiates the action of antithrombin III and thereby inactivates active prothrombin (factor IIa), as well as factors IX, X, XI and XII and plasmin. Heparin also prevents the conversion of fibrinogen to fibrin. The antidote is protamine sulfate. With unfractionated heparin there is a potential for drug-induced thrombocytopenia and thromboembolic disease.6–12
Low-molecular-weight heparins can serve as an effective alternative to unfractionated heparin for patients who are at a high risk of developing thromboembolism.
In cases in which patients receive unfractionated heparin, the patient usually is admitted to the hospital a few days before the surgical procedure, oral anticoagulation therapy is discontinued, and intravenous, or IV, heparin therapy is initiated. Intensive monitoring of partial thromboplastin time, or PTT, is required. Approximately four to six hours before the procedure, the IV heparin therapy is discontinued. Depending on the type and extent of the procedure, heparin therapy and oral anticoagulants are reinitiated shortly after surgery.
LMWHs.
Although LMWHs have been used considerably in the medical community, there have been only two reported cases of their use in dentistry.13,30 Until the debate over the need to modify oral anticoagulation therapy is resolved, LMWHs can serve as an effective alternative to unfractionated heparin for patients who are at a high risk of developing thromboembolism. The development of LMWHs was prompted by the shortcomings of unfractionated heparin and numerous clinical observations showing that they have less antifactor IIa activity relative to their factor Xa activity. LMWHs’ half-life is three to five hours, with the maximum effect occurring after two to four hours; time of elimination before dental procedures is about 12 to 24 hours8; PTT monitoring is not required; and INR readings are ineffective, because of LMWHs’ reduced protein binding, which allows for the production of a more stable and predictable level of anticoagulation.6
LMWH fragments are too small to bind to prothrombin, which reduces nonspecific binding to plasma proteins and results in improved predictability of the dose-response relationship. There also is a reduced binding to macrophages and endothelial cells, resulting in an increased elimination half-life and a reduced binding to platelets and platelet factor 4, which may relate to a lower frequency of heparin-induced thrombocytopenia observed with unfractionated heparin. LMWHs exert their anticoagulant effect by binding to antithrombin III, which causes a conformational change in the antithrombin III molecule that instantly and markedly increases its ability to inactivate factor Xa and prothrombin (factor II). The depolymerization process, however, decreases LMWHs’ ability to inhibit prothrombin to a much greater degree than the ability to inhibit factor Xa.31
Collectively, the following summarize LMWHs’ advantages over unfractionated heparin2,6:
- – subcutaneous administration with no IV access required, which allows for outpatient administration by the patient, a family member or a nurse;
- – increased bioavailability at low doses, caused by decreased binding to endothelial cells;
- – decreased incidence of heparin-induced thrombocytopenia, caused by decreased platelet activation and affinity, which allows for less frequent need to monitor for platelet counts;
- – more predictable and consistent anticoagulation response, caused by a decreased binding to plasma proteins and to proteins released from endothelial cells and activated platelets, which, in turn, clinically reduces the need for monitoring of anticoagulant effect;
- – longer plasma half-life, caused by a decreased binding to and clearance by endothelial cells and macrophages.
The U.S. Food and Drug Administration, or FDA, has approved three LMWHs: enoxaparin, dalteparin and ardeparin. The drugs tinzaparin and danaparoid also have been approved. The FDA-approved agents are used for prophylaxis of venous thromboembolism. Enoxaparin is the only one approved to treat non–Q-wave MIs and unstable angina and for prophylaxis before major surgery.8 None of the LMWHs are FDA-approved to treat atrial fibrillation or to prevent coagulation on mechanical heart valves. As physicians familiarize themselves with LMWHs, off-label uses are becoming common for prophylaxis and treatment of thrombotic disorders during pregnancy, as adjunctive therapy for complicated percutaneous coronary interventions and as anticoagulation therapy for mechanical prosthetic heart valves to minimize the duration of hospitalization. LMWHs are being used for off-label therapy for patients who have mechanical heart valves and for whom warfarin needs to be discontinued temporarily for surgery or dental procedures.8
Cost-effectiveness and convenience may play major roles in choosing to use a low-molecular-weight heparin instead of unfractionated heparin.
There are two cases reported in the literature of LMWH treatment failure resulting in thrombosed prosthetic heart valves.9 In one case, a 29-year-old woman who had an artificial mitral valve replacement had her warfarin therapy substituted with subcutaneous enoxaparin. She was admitted in the 35th week of pregnancy after 32 weeks of treatment with enoxaparin, with acute pulmonary edema and severe hemodynamic decompensation. The patient underwent mitral valve replacement and a large, organized thrombus was found on the old prosthesis. In the second case, a 72-year-old patient who had an artificial aortic valve had a cerebral hemorrhage. Treatment with warfarin was changed to enoxaparin. After 37 weeks of treatment, the patient presented with severe pulmonary congestion. Urgent aortic valve replacement was performed, and the surgeons found that the artificial valve was severely obstructed with an organized thrombus.9 Other literature, however, reports on the success of anticoagulation therapy with LMWH for patients who have artificial heart valves.8
Cost-effectiveness and convenience may play major roles in choosing to use an LMWH instead of unfractionated heparin. Anticoagulant outcomes for LMWHs are similar to those for inpatient heparin therapy, but at a lower cost. The analysis that produced this finding was conducted by researchers in Canada and incorporated data from 300 patients randomly assigned to receive twice-daily subcutaneous injections of enoxaparin, administered primarily at home or through a continuous infusion of heparin administered in a hospital.13 The analysis considered costs related to the provision of healthcare, patients’ treatment-related travel time and work absences. The overall mean treatment cost in Canadian dollars per patient was $5,323 for inpatient heparin therapy and $2,278 for outpatient enoxaparin therapy, a difference of $3,045. When researchers substituted U.S.–dollar figures for hospitalization costs and the price of enoxaparin, they predicted a difference of $2,750.13
We obtained cost data from UIC’s hospital pharmacy. The retail cost of 5 mg of warfarin was $24 for 30 tablets. The retail cost of 12 syringes of 30 mg of enoxaparin was $665; our patient used a total of 12 syringes of 30 mg of enoxaparin. The cost of hospitalization (room and bed) was $840 per day. The cost of one bag of IV heparin is $90. On average one bag is used per day, but this can vary depending on the patient’s INR. The total cost of heparinization and hospitalization for one week is $6,510. Clearly, reducing the dosage of warfarin to lower INR levels and coupling that with other management tools—such as tranexamic acid, absorbable gelatin sponges and sutures—is the most cost-effective method. The use of an LMWH, however, is more cost-effective and convenient than hospitalization and heparinization.
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CONCLUSION
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The development of LMWH may affect the way dentists manage their patients who are receiving anticoagulation therapy and who require discontinuation of warfarin and additional anticoagulation while they wait for their INR to return to acceptable levels. Some physicians may recommend this alternative to their patients, and dentists should be aware of this possibility. The use of LMWH is much more convenient for the patient and more cost-effective than the use of unfractionated heparin and its associated requirement for hospitalization. No matter which form of anticoagulant therapy is used, there is no substitute for meticulous surgical technique. Although LMWH use in dentistry is fairly new, it is becoming a new option for patients receiving anticoagulation therapy who require dental surgery and alteration of their coagulation status.
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ABSTRACT
CASE REPORT
