Does Tooth Extraction and Perioperative Medication Affect PT-INR of Patients Taking Warfarin?

Background: Various antibiotics and analgesics have been reported to interact with warfarin. Reports that investigate the effects of medication taken for just a few days during tooth extraction on the prothrombin time-international normalized ratio (PT-INR) are rare. Methods: A total of 110 patients receiving long-term stable warfarin therapy underwent tooth extraction without interruption of warfarin treatment. INR values were measured one month before the tooth extraction, the day of the extraction, and one week after the extraction. We investigated the changes of INR values between the day of extraction and one week after the extraction, as well as the various risk factors for increases in INR values. Results: Before and after tooth extraction, the number of patients taking cefcapene pivoxil, amoxicillin, and azithromycin was 57, 36, and 8, respectively. Nine patients were administered ampicillin before tooth extraction and received amoxicillin after their tooth extraction. 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%). Conclusion: When a tooth extraction is performed in patients taking warfarin, certain factors could increase the INR, such as interaction between warfarin and antibiotics or analgesics, post-extraction inammation or infection, and eating disorders due to post-extraction pain. However, our results suggest that it has little effect on the INR values one week after extraction.


Background
Various antibiotics and analgesics have been reported to interact with warfarin [1][2][3][4][5]. For tooth extraction, patients are usually prescribed antibiotics in order to prevent surgical site infection (SSI) or Infective endocarditis (IE), and analgesics to decrease pain. These drugs may also interact with warfarin and produce a clinically signi cant alteration in anticoagulation status. However, most previous reports were on long-term treatment cases and cases where oral intake was not possible [1][2][3][4][5]. To our knowledge, there is only one report that investigated the effects of medication that was administered for just a few days for tooth extraction on the prothrombin time-international normalized ratio (PT-INR) [6]. This study investigated the effect of azithromycin (AZM) on INR values in patients taking warfarin [6].
In the present study, we retrospectively investigated the effects of various antibiotics and analgesics administered during tooth extraction on the INR values in patients who were on stable warfarin therapy.

Patients
In this study, inclusion criteria was set for patients above eighteen years old, and exclusion criteria was set for patients who hoped non-participate after the publication of this study. From January 2014 to December 2019, 110 patients taking warfarin underwent tooth extraction at Kakogawa Central City Hospital. Before tooth extraction, all patients consulted their primary physicians regarding their general medical status and the use of anticoagulants. If their INR values were over 3.0, they were advised to postpone the extraction, according to the Guidelines for Patients on Antithrombotic Therapy Requiring Dental Extraction'15 and the Guidelines for Pharmacotherapy of Atrial Fibrillation [7,8]. In the past, several studies reported that INR values increased beyond the therapeutic range one week after oral administration of antibiotics [9,10]. Based on these reports, our hospital routinely measures patients' INR values on the day of their tooth extraction when they are taking warfarin and are re-measured again one week after.

Medication
The types (e.g., cefcapene pivoxil [CFPN-PI], amoxicillin [AMPC], AZM), and dosages of antibiotics were chosen at the discretion of the physicians; these were taken one hour before tooth extraction and for a few days after extraction in order to prevent SSI. If the patients had a valvular disease, ampicillin (ABPC) was administered 30 minutes before extraction in order to prevent IE. This was in accordance with the Guidelines for Prevention and Treatment of Infective Endocarditis (Japanese Circulation Society 2008, 2017) [11]. For analgesics, only acetaminophen (APAP) was prescribed for several days.

Surgical procedures
All patients continued taking warfarin and were hospitalized from the day of their tooth extraction to the following day. Tooth extraction was performed under local anesthesia, administered as 1.8-3.6 mL of 2% lidocaine containing 1/80000 units of epinephrine. The teeth were extracted by a rotation and traction movement with forceps or elevators. If immediate hemostasis was not achieved with a dry gauze compression for 5 min, then a hemostat composed of oxidized cellulose (surgical; Ethicon, Somerville, NJ, USA), sutures with 3 − 0 absorbent thread, or a surgical splint was used at the surgeon's discretion.
After con rming hemostasis during the tooth extraction, all patients were instructed to bite down on the gauze for a few hours in each hospital room. In all patients, the presence of hemorrhage was checked by surgeons a few hours after the tooth extraction. If the hemorrhage required additional treatment such as re-suturing, we de ned it as a post-extraction hemorrhage.

Variables
We investigated the rates of the changes of the INR values beyond the therapeutic range one week after their tooth extraction. Additionally, the following variables from medical records were retrospectively reviewed: (1) medication-types; (2) patient details in terms of-sex, age, warfarin dose, diabetes mellitus, hypertension, cerebral infarction, antiplatelet therapy status (single or dual), preoperative nonsteroidal anti-in ammatory drugs (NSAIDs) being taken, serum creatinine levels, estimated glomerular ltration rates (eGFR), and alanine transaminase (ALT) levels; (3) surgical details including the-number of extracted teeth and whether thy had a post-extraction hemorrhage.

All patients
Before and after tooth extraction, the number of patients taking cefcapene pivoxil, amoxicillin, and azithromycin was 57, 36, and 8, respectively. Nine patients received ampicillin before-tooth extraction and received amoxicillin after-tooth extraction.

Patients who took CFPN-PI and APAP
From January 2014 to June 2016, CFPN-PI was the primary antibiotic used to prevent SSI. All 57 patients received 300 mg of CFPN-PI per day for three days before and after tooth extraction, followed by 1200-1800m of APAP per day for three days after tooth extraction. Seven out of the 57 patients underwent additional treatments due to post-extraction hemorrhages on the day of extraction.
The INR values increased beyond the therapeutic range in 1 out of 57 patients ( Fig. 1). We present this patient as Case A. Case A took 300 mg of CFPN-PI per day for three days, followed by 1800 mg per day for three days like the other patients, and had 12 teeth (the greatest number of teeth of the 57 patients) extracted. The patient's INR value was within the therapeutic range, but was the highest out of all 57 patients, with a value of nearly 3.0 one month before tooth extraction and on the day of the extraction (2.93, 2.81) (Fig. 1).

Patients who took AMPC and APAP
From July 2016 to December 2019, AMPC was the main antibiotic prescribed, as opposed to CFPN-PI.
Most of the 36 patients took AMPC at a dose of 750 mg/day for two days (two patients took if for three days) before and after tooth extraction, and APAP at a dose of 1200 mg/day for 3-7 days after tooth extraction. One patient underwent additional treatments due to post-extraction hemorrhages on the day of extraction.

Patients who took ABPC, AMPC and APAP
Most of the nine patients were treated with a single 2-g dose of ABPC the day before tooth extraction, and then took AMPC at a dose of 750 mg/day for two days (just one patient took it for four days), and 1200-1500 mg/day of APAP for 3-7 days after tooth extraction. Two out of the nine patients underwent additional treatments due to post-extraction hemorrhages on the day of extraction, and one out of two patients had a post-extraction hemorrhage after discharge.
One week after their tooth extraction, the INR value in one patient increased by more than twice as much (Fig. 1). We present this patient as Case B. Case B had two teeth extracted and was treated with a single 2-g dose of ABPC the day before tooth extraction, and then took AMPC at a dose of 750 mg/day for two days like the other patients. This patient had a post-extraction hemorrhage on the day of the extraction and visited our hospital due to re-post-extraction hemorrhage two days after tooth extraction as well.
After the patient's hemostasis was treated, they were prescribed AMPC for two days and APAP for three days. In addition, the patient's INR value was within the therapeutic range, but had a value close to 3.0 both one month before tooth extraction and on the day of the extraction (2.73, 2.73) (Fig. 1).

Patients who took AZM and APAP
AZM was mainly used for patients with impaired liver function or a penicillin allergy. All eight patients took AZM at a dose of 500 mg/day for three days before and after tooth extraction, and 1200-1500 mg/day for 3-7 days after tooth extraction. None of the patients had post-extraction hemorrhages.
One week after tooth extraction, a patient's INR value increased beyond the therapeutic range (Fig. 1). We present this patient as Case C. Case C had one tooth extracted and took AZM at a dose of 500 mg/day for three days, followed by 1200 mg/day of APAP for seven days. However, while Case C's INR was within the therapeutic range, it was the highest of all eight patients in this group, with a value close to 3.0 both one month before tooth extraction and on the day of the extraction (2.70, 2.90) (Fig. 1).

Discussion
In the present study, we investigated the effects that various antibiotics and analgesics taken during 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 postextraction hemorrhages in patients taking anticoagulants, and reported that the incidence of postextraction hemorrhages was 0-26% [12][13][14][15][16]. Our results were similar to those of other reports [12][13][14][15][16].  [1]. The mechanism by which antibiotics increase the action of warfarin is known to alter the intestinal ora 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 in ammation 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.  [18]. AZM in particular, which has a signi cantly long half-life, has been widely discussed in this context [6,10]. Glasheen  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

Conclusion
This is the rst report to investigate the effects that various antibiotics and analgesics taken for tooth All patients had oral informed consent regarding tooth extraction, and PT-INR measurements before and after tooth extraction. The PT-INR measurements before and after tooth extraction started more than ten years before by referring to the past reports [1][2][3][4][5]. It has been routinely done since then in our hospital. In this time, we conducted this retrospective observational study to examine the usefulness of the PT-INR measurements and whether it is meaningful to continue from now on. As this study is a retrospective study and planed after total cases nished, patients did not be given informed consent that their PT-INR measurements were for this study, when they had undergone tooth extraction. Instead, exclusion criteria were set for patients who chose not to participate after the publication of this study. This study has been