In the present study, we investigated the effects that various antibiotics and analgesics taken during tooth extraction had on the INR values of patients taking warfarin. One week after tooth extraction, the INR values increased beyond the therapeutic range in 3 out of 110 patients (2.7%). The INR values before tooth extraction in these three patients were close to 3.0. The INR value increased by more than twice as much in 1 of 110 patients (0.9%).
According to the Guidelines for Patients on Antithrombotic Therapy Requiring Dental Extraction 15, tooth extraction can be safely performed without interrupting warfarin when the INR value is below 3.0 [7]. In the present study, when the INR values were below 3.0 in all patients, there were no cases of hemorrhages that required systemic treatment (e.g., vitamin K or clotting factor), or thrombosis (e.g., cerebral embolisms). Post-extraction hemorrhage which required additional treatment such as re-suturing, were observed in seven out of 110 patients (6.4%) (Table 1). In the past, many reports have investigated post-extraction hemorrhages in patients taking anticoagulants, and reported that the incidence of post-extraction hemorrhages was 0–26% [12–16]. Our results were similar to those of other reports [12–16].
Table 1
Variables | |
Types of antibiotics | CFPN-PI | 57 (51.8) |
| AMPC | 36 (32.7) |
| ABPC + AMPC | 9 (8.2) |
| AZM | 8 (7.3) |
Sex | Male | 73 (66.4) |
| Female | 37 (33.6) |
Age | Mean ± SD | 72.5 ± 9.1 |
| < 75 | 59 (53.6) |
| ≥ 75 | 51 (46.4) |
Warfarin dose (mg) | Mean ± SD | 2.72 ± 1.10 |
Diabetes mellitus | No | 85 (77.3) |
| Yes | 25 (22.7) |
Hypertension | No | 57 (51.8) |
| Yes | 53 (48.2) |
Cerebral infarction | No | 93 (84.5) |
| Yes | 17 (15.5) |
With antiplatelet therapy | No | 82 (74.5) |
| Single | 27 (24.5) |
| Dual | 1 (1.0) |
Preoperative NSAIDs | No | 106 (96.4) |
| Yes | 4 (0.6) |
Serum creatinine (mg/dl) | Mean ± SD | 0.93 ± 0.30 |
eGFR (mL/min/1.73 m2) | Mean ± SD | 60.0 ± 16.9 |
ALT (IU/L) | Mean ± SD | 21.2 ± 13.8 |
Number of extracted teeth | Mean ± SD | 2.3 ± 2.2 |
| Single tooth | 54 (49.1) |
| Multiple teeth | 56 (50.9) |
Post-extraction hemorrhage | No | 103 (93.6) |
(having additional treatment) | Yes | 7 (6.4) |
It is widely known that an increased age (> 75 years old), high doses of warfarin, renal failure or liver failure, diarrhea, and drug interactions can all cause increases in INR values [17]. Rice et al. conducted a review of many reports and reported that many antibiotics increased INR values, although the duration of administration varied [1]. The mechanism by which antibiotics increase the action of warfarin is known to alter the intestinal flora and decrease the production of vitamin K, thereby enhancing the action of warfarin. Antibiotics also inhibit cytochrome P-450 (CYP) in the liver, increasing the concentration of warfarin in the blood [1]. Several studies have shown that infection and inflammation decrease the expression and activity of CYP, resulting in decreased drug clearance [1, 3]. Other studies have reported that infection itself affects the metabolism of warfarin [3, 4]. In the present study, Case B, whose INR value more than doubled one week after their tooth extraction, was the only one who underwent additional treatments for two post-extraction hemorrhages. Case B might have been the most invasive case, and had evidence of an infection accompanied by necrotic tissue and delayed wound healing one week after tooth extraction.
Several reports have investigated the relationship between various antibiotics and INR values [6, 9, 10, 18]. Ghaswalla et al. reported that there was a significant interaction between time and antibiotics on the INR values of elderly (> 65 years old) patients who were on stable warfarin therapy (AMPC, AZM, levofloxacin [LVFX]) [18]. AZM in particular, which has a significantly long half-life, has been widely discussed in this context [6, 10]. Glasheen et al. reported that INR value increased beyond the therapeutic range in 31% of AZM cases and 33% of levofloxacin LVFX cases one week after oral administration. This was seen in patients on stable warfarin therapy [10]. On the other hand, Kusafuka et al. reported that changes in INR values one week before and after tooth extraction were not statistically significant (2-factor analysis of variance, Not Significant [NS]) when 18 patients taking warfarin were administered AZM [6]. In the present study, changes in INR values throughout the study were not statistically significant (2-factor analysis of variance, NS) for all antibiotics, including AZM. However, in 3 patients whose INR values were close to 3.0 before tooth extraction, the INR values increased beyond the therapeutic range. This result indicates that surgeons have to take attention of medication when the INR value is close to 3.0 before their tooth extraction.
Although most NSAIDs are known to enhance the action of warfarin [5], APAP also requires discussion [19]. Cardeira et al conducted a review of many reports and reported that taking APAP was associated with a mean 0.62 INR increase compared to placebo, for patients taking warfarin [19]. However, in all reports used in this review, the duration of the APAP treatment was longer than four weeks. Because in the present study the APAP treatment was just for 3–7 days after tooth extraction, there may have been no significant association between APAP and the increase in the INR values one week after extraction. Surgeons need to be wary about prescribing APAP long term.
This study has some limitations. First, there is a possibility of unknown confounding factors and factors not studied (e.g., the presence of diarrhea) due to the retrospective nature of this study. Next, the number of patients was small depending on the antibiotics prescribed. Frequent PT-INR frequent measurements are highly invasive for patients, so we have to make criteria of measurements by patients. In the present study, the INR value increased beyond the therapeutic range in 3 out of 110 patients (2.7%). The INR values were close to 3.0 before tooth extraction in these three patients. Our results suggest that surgeons have to take precautions before performing tooth extraction when INR values are close to 3.0. In addition, in those cases, measuring of INR values one week later may be useful.