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A retrospective review of clinical international normalized ratio results and their implications
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A retrospective review of clinical international normalized ratio results and their implications Moawia M. Kassab, Thomas W. Radmer, James W. Glore, Alexis Visotcky, Jared Robertson and Bradley Degroot JADA 2011;142(11):1252-1257 10.14219/jada.archive.2011.0109 The following resources related to this article are available online at jada.ada.org (this information is current as of July 6, 2014): Updated information and services including high-resolution figures, can be found in the online version of this article at: http://jada.ada.org/content/142/11/1252
This article cites 17 articles, 6 of which can be accessed free: http://jada.ada.org/content/142/11/1252/#BIBL Information about obtaining reprints of this article or about permission to reproduce this article in whole or in part can be found at: http://www.ada.org/990.aspx
Copyright © 2014 American Dental Association. All rights reserved. Reproduction or republication strictly prohibited without prior written permission of the American Dental Association.
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A retrospective review of clinical international normalized ratio results and their implications Moawia M. Kassab, DDS, MS; Thomas W. Radmer, DDS, MS; James W. Glore, DDS; Alexis Visotcky, MS; Jared Robertson, BS; Bradley Degroot, BS
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J Background. Warfarin is a key element in therapy ✷ ✷ ® for atrial fibrillation, deep venous thrombosis (DVT), stroke (cerebrovascular accident) and cardiac valve replacement. Often, patients’ warfarin blood levels are not tightly controlled with regard to accepted therapeu- A 2 RT I C LE tic ranges, by virtue of the drug’s unpredictable nature. Methods. The authors searched 16,017 active clinical charts for active patients of record from the three campuses of the School of Dentistry, Marquette University (MU), Milwaukee, for the years 2009 and 2010. Dental records of 315 patients contained entries including “INR,” the abbreviation for the term “international normalized ratio.” Only 247 of those records contained an indication of whether the patient’s INR values were within therapeutic range. The authors found that 1.96 percent of the total MU dental clinic patient population had a history of warfarin use. Results. When the authors compared the INR values for patients with diagnoses of atrial fibrillation, DVT, stroke and cardiac valve replacement, they found that INR values for 107 of the 247 patients (43.3 percent) were not within therapeutic range for the respective diagnoses. For example, only 50 percent of the patients being treated for atrial fibrillation presented themselves for surgical dental treatment while their INR values were in tight control. Conclusion. The INR values for a significant number of dental patients are not within the therapeutic range for their medical conditions. These patients need to seek follow-up care from their medical care providers. Clinical Implications. Screening for INR in the dental office— especially before invasive dental treatment such as periodontal surgery, tooth extraction and dental implant placement—can help prevent postoperative complications. It also can aid the clinician in evaluating whether a patient’s INR is within therapeutic range and, subsequently, whether the patient’s physician needs to adjust the warfarin dosage. Key Words. Extraction; periodontal surgery; warfarin; dental implant; international normalized ratio; prothrombin time; testing; point of care. JADA 2011;142(11):1252-1257. T
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arfarin is an oral anticoagulant commonly used to treat patients with conditions such as atrial fibrillation, deep venous thrombosis (DVT), stroke (cerebrovascular accident) and cardiac valve replacement. Warfarin affects the extrinsic clotting pathway by preventing the reduction of vitamin K into its active form. Its effectiveness in the patient is measured by means of a standardized prothrombin time (PT) test. PT and its derived ratios of prothrombin ratio (PR) and international normalized ratio (INR) all are measures of the extrinsic pathway of coagulation.1 The reference range for PT is about 11 to 16 seconds. The normal range for INR is 0.8 to 1.2. PT is measured by means of blood plasma, which is collected in a test tube containing citrate; the citrate acts as an anticoagulant and binds to the calcium in the sample. The blood is mixed and centrifuged to separate cells from the plasma. The separated plasma portion is infused with excess calcium,
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Dr. Kassab is an assistant professor, Department of Surgical Sciences, School of Dentistry, Marquette University, 1801 W. Wisconsin Ave., Milwaukee, Wis. 53201, e-mail “[email protected]”. Address reprint requests to Dr. Kassab. Dr. Radmer is an assistant professor, Department of Surgical Sciences, School of Dentistry, Marquette University, Milwaukee. Dr. Glore is a clinical associate professor, Department of Surgical Sciences, School of Dentistry, Marquette University, Milwaukee. Ms. Vistocky is a biostatistician, Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee. Mr. Robertson is a third-year dental student, School of Dentistry, Marquette University, Milwaukee. Mr. Degroot is a third-year dental student, School of Dentistry, Marquette University, Milwaukee.
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CLINICAL
thus neutralizing the citrate; this enables the sample to clot again. Tissue factor III is added, and the time the sample takes to clot is measured. The PR is the PT divided by results from a control sample. Because PT results may vary from laboratory to laboratory owing to equipment, different batches of tissue factor and reagents used to perform the tests, the INR was established by the World Health Organization, Geneva.2 Each manufacturer of tissue factor assigns an international sensitivity index (ISI) score to batches it produces by comparing the individual batch with an international standard established by a committee of the World Health Organization.2 The INR is the ratio of a patient’s PT to a normal control sample raised to the power of the ISI value for the analytical sample used.1 Each patient’s target therapeutic range of INR depends on the reason for treatment. Patients receiving warfarin for atrial fibrillation, DVT and stroke have a target INR of 2.0 to 3.0, whereas patients receiving warfarin after undergoing cardiac valve replacement surgery have a target range of 2.5 to 3.5.3-7 An INR below the therapeutic range increases the risk of a thrombotic event, and an INR above the therapeutic range increases the risk of a hemorrhagic event.3-8 Because it is based on PT, a patient’s INR can be elevated owing to other conditions that affect the extrinsic clotting pathway. These conditions include vitamin K deficiency, disseminated intravascular coagulation and liver failure. Conversely, patients whose clotting pathways are altered in other ways, such as those receiving aspirin (antiplatelet drugs) therapy and those with hemophilia (extrinsic pathway) or von Willebrand disease (platelet abnormality), will have unaffected PT results. Traditionally, patients underwent monthly blood testing by a physician to confirm that their INR values were within their target range. However, study findings have shown that more frequent testing results in tighter control of a patient’s INR values.8,9 The additional testing most often is achieved by means of home testing devices or point-of-care (POC) testing devices. The results of numerous studies have shown that POC testing devices, when used correctly, are able to give reliable INR results in 1 to 2 minutes.8-11 Many medical practitioners modify or stop a patient’s anticoagulation therapy before he or she undergoes dental treatment.12 However, myriad studies indicate that patients can maintain therapeutic levels of warfarin through rou-
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tine dental procedures without incurring increased risk of experiencing major bleeding complications.12-17 Beirne noted that “stopping warfarin with or without bridging for dentoalveolar surgery is not supported by clinical evidence when the INR is within or below the therapeutic range.”13 To minimize the patient’s potential risk of experiencing thromboembolism or hemorrhage, it is important that his or her INR is within therapeutic range on the day of treatment. For patients receiving anticoagulation therapy because they have a diagnosis of atrial fibrillation, DVT or stroke, there is no need to delay therapy if the INR is higher than 1.0 point above the therapeutic range for these three conditions (2.0-3.0). However, for those who receive anticoagulation therapy after undergoing cardiac valve replacement, increasing the acceptable level of INR beyond 4.0 may result in an exponential increase in the risk of a postoperative bleeding event. INR is an expression of a normalization value of PT expressed in seconds. Proceeding with invasive dentoalveolar treatment in a patient whose reported INR values are above 4.0 can lead to a significant increase in postoperative bleeding, even when the clinician undertakes local hemostatic measures. In a 2003 report, Jeske and Suchko18 found that dental treatment can be performed safely in patients whose INR is 4.0 or lower, regardless of their medical condition or why the warfarin has been prescribed. Brennan and colleagues16 suggested “that dentists should not rely on a patient’s previous INR test result as a reliable predictor of his or her current INR and that a new INR be obtained 24 to 48 hours before the patient undergoes an invasive dental procedure.” A review of the literature indicates several aspects of warfarin therapy that the dental practitioner should keep in mind, such as the importance of maintaining patients’ INR values in a narrow therapeutic window.3-8 The high prevalence of patients outside this window in a hospital setting and inconsistencies found between teaching practices in U.S. dental schools along with consistencies of medical evidence indicates a cause for concern for the dental professional.16,17 An analysis of the day-of-surgery INR values for dental patients receiving oral anticoagulants is ABBREVIATION KEY. AF: Atrial fibrillation. ASTDD: Association of State and Territorial Dental Directors. DVT: Deep venous thrombosis. INR: International normalized ratio. ISI: International sensitivity index. MU: Marquette University. POC: Point of care. PR: Prothrombin ratio. PT: Prothrombin time. JADA 142(11)
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Figure 1. INRatio PT Monitoring System Professional Kit (Alere, San Diego) with test strip. Image reproduced with permission of Alere.
Figure 2. Test strip for INRatio PT Monitoring System Professional Kit (Alere, San Diego) with adequate blood drop for testing. Image reproduced with permission of Alere.
indicated to determine whether POC testing should become customary care in a non–hospitalbased dental practice. METHODS
The institutional review board of Marquette University (MU), Milwaukee, approved our protocol for a retrospective review of clinical INR results at the MU School of Dentistry and their implications, along with a waiver of consent for the study and an authorization to use protected health information, in July 2010 (HR-2035). Our review was simplified by the fact that MU School of Dentistry began using axiUm (Exan Group, Coquitlam, British Columbia, Canada) to document medical records and provide electronic forms of progress notes in 2007. The software program allows for a search of key terms in the progress notes section of the electronic dental record. We searched 16,017 clinical charts for active patients of record from the three campuses in the MU School of Dentistry—comprising 1254 JADA 142(11)
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patients at the main clinic and those from the north and south community dental clinics in Milwaukee—for the years 2009 and 2010. Dental records of 315 patients contained entries including the term “INR.” Only 247 patient records had an indication of whether or not the patient’s INR values were within therapeutic range. Of the 247 patients whose records contained INR notations in the progress notes, 206 patients had one, 36 patients had two and five patients had three of the following conditions: atrial fibrillation, DVT, stroke or cardiac valve replacement. Sixty-eight records contained an INR entry without a provisional diagnosis. We manually inspected these records to retrieve information from the health history that would aid in determining the reason for the patient’s receiving warfarin therapy. The manual inspection did not yield information about a provisional diagnosis; therefore, we excluded these records from consideration. We identified 247 records that met all of the parameters we had established. The POC device used at the MU School of Dentistry is the INRatio PT Monitoring System Professional Kit (model +M304001000043Z) (Alere, San Diego). The INRatio involves the use of disposable test strips with a recombinant thromboplastin reagent as the reactive component. The meter detects clot endpoints by measuring the electrical impedance of a capillary blood sample. Each test strip incorporates two control channels that test high and low for each sample. Control results outside the accepted range result in an error message and no reported INR value. All testing was accomplished with capillary blood and performed under the manufacturer’s published protocol by faculty members and students of the MU School of Dentistry. (Students learned to use the POC device and conducted the testing under the direct supervision of members of the dental school’s faculty in the Department of Surgical Sciences.) By using the POC device, we performed INR testing in patients receiving anticoagulation therapy immediately before they underwent any invasive dental treatment. Of particular significance to this method of testing is the fact that a “hanging” drop of blood must enter the test chamber of the coded and calibrated strip for the test to be valid (Figures 1 and 2). RESULTS
We found that 1.96 percent of the total MU dental clinic patient population had a history of warfarin use. Records indicating a working
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TABLE 1 diagnosis for the warfarin therapy (n = 247) repreComparison of therapeutic range status for 247 sented 1.53 percent of the patients* whose clinical records contained an entry population visiting all MU dental facilities for patient regarding international normalized ratio.† care on the three MilDIAGNOSIS‡ NO. (%) OF PATIENTS, ACCORDING P VALUE waukee campuses. This perTO THERAPEUTIC RANGE STATUS centage, which is signifiNot Within Range Within Range cantly higher than the Any Diagnosis 107 (43.3) 140 (56.7) —§ national average, can be attributed to the relatively Atrial Fibrillation 37 (34.6) 70 (50) .020 aged and medically comproDeep Venous Thrombosis 59 (55.1) 59 (42.1) .054 mised population that conStroke 15 (14.0) 28 (20.0) .240 stitutes the MU School of Cardiac Valve 13 (12.1) 12 (8.6) .400 Dentistry patient base. Replacement When comparing patients * Patients drawn from among active patients of record at the three clinics of the School of Dentistry, with diagnoses of atrial fibMarquette University, Milwaukee. † Calculated according to Fisher exact test. rillation, DVT, stroke or car‡ Some patients had more than one diagnosis. diac valve replacement in § Not applicable. terms of therapeutic range, we found that 107 of the 247 dentistry really are at the “crossroads” with patients had INR values that were not within medicine, then a concentrated effort among all the therapeutic range for their diagnosis (Table health care providers to use all of the current 1). Patients included in this analysis had a diagtechnology to assess all of our patients’ health nosis of at least one of the following: atrial fibrilcare needs is critical.19,20 This goal includes edulation, DVT, stroke or cardiac valve replacement. cation of students regarding the use and clinical We evaluated patients with each diagnosis indiapplication of POC devices to assess warfarin vidually for therapeutic range. We found that therapy. In MU’s rural outreach programs, this the INRs of 34.6 percent of patients with atrial becomes more important because patients in fibrillation, of 55.1 percent of patients with DVT, those areas often have difficulty accessing priof 14.0 percent of patients with stroke and of mary care physicians. This training is a primary 12.1 percent of patients with cardiac valve goal of public health policies that appear on the replacement were not within therapeutic range. Association of State and Territorial Dental Table 1 lists the individual P value, calculated Directors’ (ASTDD’s) Web site.21 Certainly, we according to the Fisher exact test, for each diagcan emphasize assessment of patients who are nosis. Because the sample size was relatively receiving warfarin therapy in addition to develsmall, we used a Fisher exact test to determine oping policies regarding the first three items on significance. The range of INR values for any a list of public health issues that the ASTDD diagnosis, as reported in Table 2, was 0.2 to 7.0. identified as facing dentistry in 2006: methamTable 2 also reports individual ranges for each of phetamine use and “meth mouth,” tooth grills the four diagnoses; for example, the range of (removable cosmetic dental appliances and jewrecorded INR results for atrial fibrillation elry) and human papillomavirus. ranged from 1.0 to 6.6. Notwithstanding the fact We need to address the significance of the that any condition that requires anticoagulation results in Table 1, along with the challenge that therapy has the potential for a life-threatening those results reflect. Our null hypothesis was outcome when that therapy is modified, the conthat all patients receiving warfarin therapy who dition involving anticoagulation for cardiac valve reported to the MU School of Dentistry or to one replacement that could result in a thromboemof its community dental centers for invasive bolic event is the INR’s being below the theradental care had INRs that were controlled and peutic range. In this study, the values ranged within the targeted therapeutic range for from 1.1 to 3.8, which indicates that many of patients with atrial fibrillation, DVT, stroke or these patients were not in a state of therapeutic cardiac valve replacement. The P values for anticoagulation. patients with atrial fibrillation and DVT indiDISCUSSION cate a significant probability that the INRs of If one goal of dental education is to protect the patients seen were not within therapeutic public welfare, and if dental educators and all of range. In our review, we found that the INRs of JADA 142(11)
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TABLE 2
International normalized ratio values for 247 patients* whose clinical records contained an entry regarding INR.† INR† VALUE
DIAGNOSIS
Mean ± SD‡
Range
Any Diagnosis
2.37 ± 0.9
0.2-7.0
Atrial Fibrillation
2.46 ± 0.8
1.0-6.6
Deep Venous Thrombosis
2.35 ± 1.0
0.2-7.0
Stroke
2.34 ± 0.9
1.0-6.6
Cardiac Valve Replacement
2.52 ± 0.8
1.1-3.8
* Patients drawn from among active patients of record at three clinics of the School of Dentistry, Marquette University, Milwaukee. † INR: International normalized ratio. ‡ SD: Standard deviation.
12.1 percent of patients with valve replacement and of 14.0 percent of patients with stroke were not within therapeutic range. POC testing and teaching the value of testing to dental students are extremely important, because patients are not always aware of the results of their blood tests. The reported INR values are in themselves a cause for alarm. Patients with INR values higher or lower than the suggested therapeutic range (again, the range varies according to diagnosis; see Table 2) were informed of their INR number, then were referred to their physicians for management of their anticoagulation therapy and to bring the INR values within therapeutic range. As much as a patient with a higher INR value might experience significant postsurgical complications, including bleeding, patients with lower INR values, who might seem to have a better level of coagulation, such as that needed to undergo dental surgery, run the risk of developing thromboembolism. Referral to a physician and proper treatment can ensure that the patient’s INR is in therapeutic range before the initiation of invasive dental procedures. It is important for practitioners to be aware of their patients’ medical history and any anticoagulation therapy they might be receiving. If properly trained, dental practitioners can use a POC tester to confirm an appropriate INR value before beginning invasive dental procedures.22 It seems prudent for dental practitioners to adopt preoperative POC testing for invasive dental procedures to provide safer treatment for their patients. This also provides an avenue for collaboration with other health care professionals to yield more comprehensive care for patients. In evaluating INR testing for patients treated 1256
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in our institution, we found that the purchase of the INR testing machine provided a threefold benefit. First, it addressed anticoagulation therapy as a case selection criterion in evaluating the timing of invasive dentoalveolar procedures, as well as the concomitant need to provide appropriate hemostatic measures. Second, it introduced the concept of POC testing and monitoring to our students. Third, the device provided a service to patients who did not have day-of-surgery INR test results available at the time of their surgical appointment, thereby alleviating the problem of canceling surgery and rescheduling, as well as the inherent costs of such activity. The cost of such equipment is a factor in providing INR monitoring. In a large institution such as MU, the cost-benefit ratio is weighted heavily by the instructional value. That is not a factor in a private practitioner’s decisionmaking process. Fortunately, as of March 2008, the Center for Medicare and Medicaid Services expanded the Part B coverage for home PT/INR monitoring beyond that for people who have artificial heart valves. This reduction in out-ofpocket costs resulted in 3 million additional patients’ potentially conducting self-testing. Many private insurance companies have begun to follow through with coverage. The private practitioner may include INR testing in the preoperative protocol by instructing patients to bring their monitors to the dental office at the time of surgery. Available machines for home and office use include the feature of stored memory, thus providing access to prior results. CONCLUSION
INR testing should be incorporated into any dental practice in which invasive procedures are performed. POC devices provide valuable information comparable with that derived from laboratory-based testing. Either method should be incorporated into practice when a patient is exposed to the risk of bleeding or a thromboembolic event. ■ Disclosure. None of the authors reported any disclosures. The authors wish to thank Thomas Wirtz, Director of Dental Informatics, School of Dentistry, Marquette University, Milwaukee, for his assistance. 1. Hirsh J, Schulman S. Antithrombotic therapy. In: Cecil RL, Goldman L, Ausiello DA, eds. Cecil Medicine. 23rd ed. Philadelphia: Saunders Elsevier; 2008:197-206. 2. WHO Expert Committee on Biological Standardization. Annex 3: Requirements for thromboplastins and plasma used to control oral anticoagulant therapy (requirements for biological substances no. 30) (revised 1982). In: WHO Expert Committee on Biological Standardization. Thirty-third Report. Geneva: World Health Organization; 1983:81-105. Technical Report Series 687. 3. Garcia DA, Hylek E. Reducing the risk for stroke in patients
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CLINICAL who have atrial fibrillation. Cardiol Clin 2008;26(2):267-275, vii. 4. Friedlander AH, Yochikawa TI, Chang DS, Feliciano Z, Scully C. Atrial fibrillation: pathogenesis, medical-surgical management and dental implications. JADA 2009;140(2):167-177. 5. Singer DE, Albers GW, Dalen JE, et al; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 suppl):546S-592S. 6. Geerts WH, Bergqvist D, Pineo GF, et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 suppl):381S-453S. 7. Butchart EG, Gohlke-Bärwolf C, Antunes MJ, et al; Working Groups on Valvular Heart Disease, Thrombosis, and Cardiac Rehabilitation and Exercise Physiology, European Society of Cardiology. Recommendations for the management of patients after heart valve surgery (published online ahead of print Aug. 15, 2005). Eur Heart J 2005;26(22):2463-2471. doi:10.1093/eurheartj/ehi426. 8. Heneghan C, Alonso-Coello P, Garcia-Aamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 2006;367(9508):404-411. 9. Ryan F, O’Shea S, Byrne S. The reliability of point-of-care prothrombin time testing: a comparison of CoaguChek S and XS INR measurements with hospital laboratory monitoring (published online ahead of print Nov. 18, 2008). Int J Lab Hematol 2010; 32(1 part 1):e26-e33. doi:10.1111/j.1751-553X.2008.01120.x. 10. Gardiner C, Williams K, Mackie IJ, Machin SJ, Cohen H. Patient self-testing is a reliable and acceptable alternative to laboratory INR monitoring. Br J Haematol 2005;128(2):242-247. 11. Green TL, Mansoor A, Newcommon N, Stephenson ES, Hill MD. Reliability of point-of-care testing of INR in acute stroke. Can J Neurol Sci 2008;35(3):348-351. 12. Ward BB, Smith MH. Dentoalveolar procedures for the anticoagulated patient: literature recommendations versus current
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practice. J Oral Maxillofac Surg 2007;65(8):1454-1460. 13. Beirne OR. Evidence to continue oral anticoagulant therapy for ambulatory oral surgery. J Oral Maxillofac Surg 2005;63(4):540-545. 14. Sacco R, Sacco M, Carpenedo M, Mannucci PM. Oral surgery in patients on oral anticoagulant therapy: a randomized comparison of different intensity targets (published online ahead of print May 7, 2007). Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104(1):e18-e21. doi:10.1016/j.tripleo.2006.12.035. 15. Al-Mubarak S, Al-Ali N, Abou-Rass A, et al. Evaluation of dental extractions, suturing, and INR on postoperative bleeding of patients maintained on oral anticoagulant therapy (published online ahead of print Aug. 10, 2007). Br Dent J 2007;203(7):E15. doi:10.1038/bdj.2007.725. 16. Brennan MT, Hong C, Furney SL, Fox PC, Lockhart PB. Utility of an international normalized ratio testing device in a hospital-based dental practice. JADA 2008;139(6):697-703. 17. Linnebur SA, Ellis SL, Astroth JD. Educational practices regarding anticoagulation and dental procedures in U.S. dental schools. J Dent Educ 2007;71(2):296-303. 18. Jeske AH, Suchko GD. Lack of a scientific basis for routine discontinuation of oral anticoagulation therapy before dental treatment (published correction appears in JADA 2004;135[1]:28). JADA 2003;134(11):1492-1497. 19. Commission on Dental Accreditation. Standards for dental education programs. “www.ada.org/115.aspx”. Accessed Aug. 31, 2011. 20. Field MJ, ed. Dental Education at the Crossroads: Challenges and Change. Washington: National Academy Press; 1995. 21. Association of State & Territorial Dental Directors. Emergent issues for dental public health and oral health programs. “www. astdd.org/emergent-issues-for-dental-public-health-and-oralhealth-programs/”. Accessed Aug. 31, 2011. 22. Romney G, Glick M. An updated concept of coagulation with clinical implications. JADA 2009;140(5):567-574.
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A retrospective review of clinical international normalized ratio results and their implications Moawia M. Kassab, Thomas W. Radmer, James W. Glore, Alexis Visotcky, Jared Robertson and Bradley Degroot JADA 2011;142(11):1252-1257 10.14219/jada.archive.2011.0109 The following resources related to this article are available online at jada.ada.org (this information is current as of July 6, 2014): Updated information and services including high-resolution figures, can be found in the online version of this article at: http://jada.ada.org/content/142/11/1252
This article cites 17 articles, 6 of which can be accessed free: http://jada.ada.org/content/142/11/1252/#BIBL Information about obtaining reprints of this article or about permission to reproduce this article in whole or in part can be found at: http://www.ada.org/990.aspx
Copyright © 2014 American Dental Association. All rights reserved. Reproduction or republication strictly prohibited without prior written permission of the American Dental Association.
Downloaded from jada.ada.org on July 6, 2014
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PRACTICE
A retrospective review of clinical international normalized ratio results and their implications Moawia M. Kassab, DDS, MS; Thomas W. Radmer, DDS, MS; James W. Glore, DDS; Alexis Visotcky, MS; Jared Robertson, BS; Bradley Degroot, BS
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J Background. Warfarin is a key element in therapy ✷ ✷ ® for atrial fibrillation, deep venous thrombosis (DVT), stroke (cerebrovascular accident) and cardiac valve replacement. Often, patients’ warfarin blood levels are not tightly controlled with regard to accepted therapeu- A 2 RT I C LE tic ranges, by virtue of the drug’s unpredictable nature. Methods. The authors searched 16,017 active clinical charts for active patients of record from the three campuses of the School of Dentistry, Marquette University (MU), Milwaukee, for the years 2009 and 2010. Dental records of 315 patients contained entries including “INR,” the abbreviation for the term “international normalized ratio.” Only 247 of those records contained an indication of whether the patient’s INR values were within therapeutic range. The authors found that 1.96 percent of the total MU dental clinic patient population had a history of warfarin use. Results. When the authors compared the INR values for patients with diagnoses of atrial fibrillation, DVT, stroke and cardiac valve replacement, they found that INR values for 107 of the 247 patients (43.3 percent) were not within therapeutic range for the respective diagnoses. For example, only 50 percent of the patients being treated for atrial fibrillation presented themselves for surgical dental treatment while their INR values were in tight control. Conclusion. The INR values for a significant number of dental patients are not within the therapeutic range for their medical conditions. These patients need to seek follow-up care from their medical care providers. Clinical Implications. Screening for INR in the dental office— especially before invasive dental treatment such as periodontal surgery, tooth extraction and dental implant placement—can help prevent postoperative complications. It also can aid the clinician in evaluating whether a patient’s INR is within therapeutic range and, subsequently, whether the patient’s physician needs to adjust the warfarin dosage. Key Words. Extraction; periodontal surgery; warfarin; dental implant; international normalized ratio; prothrombin time; testing; point of care. JADA 2011;142(11):1252-1257. T
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arfarin is an oral anticoagulant commonly used to treat patients with conditions such as atrial fibrillation, deep venous thrombosis (DVT), stroke (cerebrovascular accident) and cardiac valve replacement. Warfarin affects the extrinsic clotting pathway by preventing the reduction of vitamin K into its active form. Its effectiveness in the patient is measured by means of a standardized prothrombin time (PT) test. PT and its derived ratios of prothrombin ratio (PR) and international normalized ratio (INR) all are measures of the extrinsic pathway of coagulation.1 The reference range for PT is about 11 to 16 seconds. The normal range for INR is 0.8 to 1.2. PT is measured by means of blood plasma, which is collected in a test tube containing citrate; the citrate acts as an anticoagulant and binds to the calcium in the sample. The blood is mixed and centrifuged to separate cells from the plasma. The separated plasma portion is infused with excess calcium,
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Dr. Kassab is an assistant professor, Department of Surgical Sciences, School of Dentistry, Marquette University, 1801 W. Wisconsin Ave., Milwaukee, Wis. 53201, e-mail “[email protected]”. Address reprint requests to Dr. Kassab. Dr. Radmer is an assistant professor, Department of Surgical Sciences, School of Dentistry, Marquette University, Milwaukee. Dr. Glore is a clinical associate professor, Department of Surgical Sciences, School of Dentistry, Marquette University, Milwaukee. Ms. Vistocky is a biostatistician, Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee. Mr. Robertson is a third-year dental student, School of Dentistry, Marquette University, Milwaukee. Mr. Degroot is a third-year dental student, School of Dentistry, Marquette University, Milwaukee.
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thus neutralizing the citrate; this enables the sample to clot again. Tissue factor III is added, and the time the sample takes to clot is measured. The PR is the PT divided by results from a control sample. Because PT results may vary from laboratory to laboratory owing to equipment, different batches of tissue factor and reagents used to perform the tests, the INR was established by the World Health Organization, Geneva.2 Each manufacturer of tissue factor assigns an international sensitivity index (ISI) score to batches it produces by comparing the individual batch with an international standard established by a committee of the World Health Organization.2 The INR is the ratio of a patient’s PT to a normal control sample raised to the power of the ISI value for the analytical sample used.1 Each patient’s target therapeutic range of INR depends on the reason for treatment. Patients receiving warfarin for atrial fibrillation, DVT and stroke have a target INR of 2.0 to 3.0, whereas patients receiving warfarin after undergoing cardiac valve replacement surgery have a target range of 2.5 to 3.5.3-7 An INR below the therapeutic range increases the risk of a thrombotic event, and an INR above the therapeutic range increases the risk of a hemorrhagic event.3-8 Because it is based on PT, a patient’s INR can be elevated owing to other conditions that affect the extrinsic clotting pathway. These conditions include vitamin K deficiency, disseminated intravascular coagulation and liver failure. Conversely, patients whose clotting pathways are altered in other ways, such as those receiving aspirin (antiplatelet drugs) therapy and those with hemophilia (extrinsic pathway) or von Willebrand disease (platelet abnormality), will have unaffected PT results. Traditionally, patients underwent monthly blood testing by a physician to confirm that their INR values were within their target range. However, study findings have shown that more frequent testing results in tighter control of a patient’s INR values.8,9 The additional testing most often is achieved by means of home testing devices or point-of-care (POC) testing devices. The results of numerous studies have shown that POC testing devices, when used correctly, are able to give reliable INR results in 1 to 2 minutes.8-11 Many medical practitioners modify or stop a patient’s anticoagulation therapy before he or she undergoes dental treatment.12 However, myriad studies indicate that patients can maintain therapeutic levels of warfarin through rou-
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tine dental procedures without incurring increased risk of experiencing major bleeding complications.12-17 Beirne noted that “stopping warfarin with or without bridging for dentoalveolar surgery is not supported by clinical evidence when the INR is within or below the therapeutic range.”13 To minimize the patient’s potential risk of experiencing thromboembolism or hemorrhage, it is important that his or her INR is within therapeutic range on the day of treatment. For patients receiving anticoagulation therapy because they have a diagnosis of atrial fibrillation, DVT or stroke, there is no need to delay therapy if the INR is higher than 1.0 point above the therapeutic range for these three conditions (2.0-3.0). However, for those who receive anticoagulation therapy after undergoing cardiac valve replacement, increasing the acceptable level of INR beyond 4.0 may result in an exponential increase in the risk of a postoperative bleeding event. INR is an expression of a normalization value of PT expressed in seconds. Proceeding with invasive dentoalveolar treatment in a patient whose reported INR values are above 4.0 can lead to a significant increase in postoperative bleeding, even when the clinician undertakes local hemostatic measures. In a 2003 report, Jeske and Suchko18 found that dental treatment can be performed safely in patients whose INR is 4.0 or lower, regardless of their medical condition or why the warfarin has been prescribed. Brennan and colleagues16 suggested “that dentists should not rely on a patient’s previous INR test result as a reliable predictor of his or her current INR and that a new INR be obtained 24 to 48 hours before the patient undergoes an invasive dental procedure.” A review of the literature indicates several aspects of warfarin therapy that the dental practitioner should keep in mind, such as the importance of maintaining patients’ INR values in a narrow therapeutic window.3-8 The high prevalence of patients outside this window in a hospital setting and inconsistencies found between teaching practices in U.S. dental schools along with consistencies of medical evidence indicates a cause for concern for the dental professional.16,17 An analysis of the day-of-surgery INR values for dental patients receiving oral anticoagulants is ABBREVIATION KEY. AF: Atrial fibrillation. ASTDD: Association of State and Territorial Dental Directors. DVT: Deep venous thrombosis. INR: International normalized ratio. ISI: International sensitivity index. MU: Marquette University. POC: Point of care. PR: Prothrombin ratio. PT: Prothrombin time. JADA 142(11)
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Figure 1. INRatio PT Monitoring System Professional Kit (Alere, San Diego) with test strip. Image reproduced with permission of Alere.
Figure 2. Test strip for INRatio PT Monitoring System Professional Kit (Alere, San Diego) with adequate blood drop for testing. Image reproduced with permission of Alere.
indicated to determine whether POC testing should become customary care in a non–hospitalbased dental practice. METHODS
The institutional review board of Marquette University (MU), Milwaukee, approved our protocol for a retrospective review of clinical INR results at the MU School of Dentistry and their implications, along with a waiver of consent for the study and an authorization to use protected health information, in July 2010 (HR-2035). Our review was simplified by the fact that MU School of Dentistry began using axiUm (Exan Group, Coquitlam, British Columbia, Canada) to document medical records and provide electronic forms of progress notes in 2007. The software program allows for a search of key terms in the progress notes section of the electronic dental record. We searched 16,017 clinical charts for active patients of record from the three campuses in the MU School of Dentistry—comprising 1254 JADA 142(11)
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patients at the main clinic and those from the north and south community dental clinics in Milwaukee—for the years 2009 and 2010. Dental records of 315 patients contained entries including the term “INR.” Only 247 patient records had an indication of whether or not the patient’s INR values were within therapeutic range. Of the 247 patients whose records contained INR notations in the progress notes, 206 patients had one, 36 patients had two and five patients had three of the following conditions: atrial fibrillation, DVT, stroke or cardiac valve replacement. Sixty-eight records contained an INR entry without a provisional diagnosis. We manually inspected these records to retrieve information from the health history that would aid in determining the reason for the patient’s receiving warfarin therapy. The manual inspection did not yield information about a provisional diagnosis; therefore, we excluded these records from consideration. We identified 247 records that met all of the parameters we had established. The POC device used at the MU School of Dentistry is the INRatio PT Monitoring System Professional Kit (model +M304001000043Z) (Alere, San Diego). The INRatio involves the use of disposable test strips with a recombinant thromboplastin reagent as the reactive component. The meter detects clot endpoints by measuring the electrical impedance of a capillary blood sample. Each test strip incorporates two control channels that test high and low for each sample. Control results outside the accepted range result in an error message and no reported INR value. All testing was accomplished with capillary blood and performed under the manufacturer’s published protocol by faculty members and students of the MU School of Dentistry. (Students learned to use the POC device and conducted the testing under the direct supervision of members of the dental school’s faculty in the Department of Surgical Sciences.) By using the POC device, we performed INR testing in patients receiving anticoagulation therapy immediately before they underwent any invasive dental treatment. Of particular significance to this method of testing is the fact that a “hanging” drop of blood must enter the test chamber of the coded and calibrated strip for the test to be valid (Figures 1 and 2). RESULTS
We found that 1.96 percent of the total MU dental clinic patient population had a history of warfarin use. Records indicating a working
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TABLE 1 diagnosis for the warfarin therapy (n = 247) repreComparison of therapeutic range status for 247 sented 1.53 percent of the patients* whose clinical records contained an entry population visiting all MU dental facilities for patient regarding international normalized ratio.† care on the three MilDIAGNOSIS‡ NO. (%) OF PATIENTS, ACCORDING P VALUE waukee campuses. This perTO THERAPEUTIC RANGE STATUS centage, which is signifiNot Within Range Within Range cantly higher than the Any Diagnosis 107 (43.3) 140 (56.7) —§ national average, can be attributed to the relatively Atrial Fibrillation 37 (34.6) 70 (50) .020 aged and medically comproDeep Venous Thrombosis 59 (55.1) 59 (42.1) .054 mised population that conStroke 15 (14.0) 28 (20.0) .240 stitutes the MU School of Cardiac Valve 13 (12.1) 12 (8.6) .400 Dentistry patient base. Replacement When comparing patients * Patients drawn from among active patients of record at the three clinics of the School of Dentistry, with diagnoses of atrial fibMarquette University, Milwaukee. † Calculated according to Fisher exact test. rillation, DVT, stroke or car‡ Some patients had more than one diagnosis. diac valve replacement in § Not applicable. terms of therapeutic range, we found that 107 of the 247 dentistry really are at the “crossroads” with patients had INR values that were not within medicine, then a concentrated effort among all the therapeutic range for their diagnosis (Table health care providers to use all of the current 1). Patients included in this analysis had a diagtechnology to assess all of our patients’ health nosis of at least one of the following: atrial fibrilcare needs is critical.19,20 This goal includes edulation, DVT, stroke or cardiac valve replacement. cation of students regarding the use and clinical We evaluated patients with each diagnosis indiapplication of POC devices to assess warfarin vidually for therapeutic range. We found that therapy. In MU’s rural outreach programs, this the INRs of 34.6 percent of patients with atrial becomes more important because patients in fibrillation, of 55.1 percent of patients with DVT, those areas often have difficulty accessing priof 14.0 percent of patients with stroke and of mary care physicians. This training is a primary 12.1 percent of patients with cardiac valve goal of public health policies that appear on the replacement were not within therapeutic range. Association of State and Territorial Dental Table 1 lists the individual P value, calculated Directors’ (ASTDD’s) Web site.21 Certainly, we according to the Fisher exact test, for each diagcan emphasize assessment of patients who are nosis. Because the sample size was relatively receiving warfarin therapy in addition to develsmall, we used a Fisher exact test to determine oping policies regarding the first three items on significance. The range of INR values for any a list of public health issues that the ASTDD diagnosis, as reported in Table 2, was 0.2 to 7.0. identified as facing dentistry in 2006: methamTable 2 also reports individual ranges for each of phetamine use and “meth mouth,” tooth grills the four diagnoses; for example, the range of (removable cosmetic dental appliances and jewrecorded INR results for atrial fibrillation elry) and human papillomavirus. ranged from 1.0 to 6.6. Notwithstanding the fact We need to address the significance of the that any condition that requires anticoagulation results in Table 1, along with the challenge that therapy has the potential for a life-threatening those results reflect. Our null hypothesis was outcome when that therapy is modified, the conthat all patients receiving warfarin therapy who dition involving anticoagulation for cardiac valve reported to the MU School of Dentistry or to one replacement that could result in a thromboemof its community dental centers for invasive bolic event is the INR’s being below the theradental care had INRs that were controlled and peutic range. In this study, the values ranged within the targeted therapeutic range for from 1.1 to 3.8, which indicates that many of patients with atrial fibrillation, DVT, stroke or these patients were not in a state of therapeutic cardiac valve replacement. The P values for anticoagulation. patients with atrial fibrillation and DVT indiDISCUSSION cate a significant probability that the INRs of If one goal of dental education is to protect the patients seen were not within therapeutic public welfare, and if dental educators and all of range. In our review, we found that the INRs of JADA 142(11)
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TABLE 2
International normalized ratio values for 247 patients* whose clinical records contained an entry regarding INR.† INR† VALUE
DIAGNOSIS
Mean ± SD‡
Range
Any Diagnosis
2.37 ± 0.9
0.2-7.0
Atrial Fibrillation
2.46 ± 0.8
1.0-6.6
Deep Venous Thrombosis
2.35 ± 1.0
0.2-7.0
Stroke
2.34 ± 0.9
1.0-6.6
Cardiac Valve Replacement
2.52 ± 0.8
1.1-3.8
* Patients drawn from among active patients of record at three clinics of the School of Dentistry, Marquette University, Milwaukee. † INR: International normalized ratio. ‡ SD: Standard deviation.
12.1 percent of patients with valve replacement and of 14.0 percent of patients with stroke were not within therapeutic range. POC testing and teaching the value of testing to dental students are extremely important, because patients are not always aware of the results of their blood tests. The reported INR values are in themselves a cause for alarm. Patients with INR values higher or lower than the suggested therapeutic range (again, the range varies according to diagnosis; see Table 2) were informed of their INR number, then were referred to their physicians for management of their anticoagulation therapy and to bring the INR values within therapeutic range. As much as a patient with a higher INR value might experience significant postsurgical complications, including bleeding, patients with lower INR values, who might seem to have a better level of coagulation, such as that needed to undergo dental surgery, run the risk of developing thromboembolism. Referral to a physician and proper treatment can ensure that the patient’s INR is in therapeutic range before the initiation of invasive dental procedures. It is important for practitioners to be aware of their patients’ medical history and any anticoagulation therapy they might be receiving. If properly trained, dental practitioners can use a POC tester to confirm an appropriate INR value before beginning invasive dental procedures.22 It seems prudent for dental practitioners to adopt preoperative POC testing for invasive dental procedures to provide safer treatment for their patients. This also provides an avenue for collaboration with other health care professionals to yield more comprehensive care for patients. In evaluating INR testing for patients treated 1256
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in our institution, we found that the purchase of the INR testing machine provided a threefold benefit. First, it addressed anticoagulation therapy as a case selection criterion in evaluating the timing of invasive dentoalveolar procedures, as well as the concomitant need to provide appropriate hemostatic measures. Second, it introduced the concept of POC testing and monitoring to our students. Third, the device provided a service to patients who did not have day-of-surgery INR test results available at the time of their surgical appointment, thereby alleviating the problem of canceling surgery and rescheduling, as well as the inherent costs of such activity. The cost of such equipment is a factor in providing INR monitoring. In a large institution such as MU, the cost-benefit ratio is weighted heavily by the instructional value. That is not a factor in a private practitioner’s decisionmaking process. Fortunately, as of March 2008, the Center for Medicare and Medicaid Services expanded the Part B coverage for home PT/INR monitoring beyond that for people who have artificial heart valves. This reduction in out-ofpocket costs resulted in 3 million additional patients’ potentially conducting self-testing. Many private insurance companies have begun to follow through with coverage. The private practitioner may include INR testing in the preoperative protocol by instructing patients to bring their monitors to the dental office at the time of surgery. Available machines for home and office use include the feature of stored memory, thus providing access to prior results. CONCLUSION
INR testing should be incorporated into any dental practice in which invasive procedures are performed. POC devices provide valuable information comparable with that derived from laboratory-based testing. Either method should be incorporated into practice when a patient is exposed to the risk of bleeding or a thromboembolic event. ■ Disclosure. None of the authors reported any disclosures. The authors wish to thank Thomas Wirtz, Director of Dental Informatics, School of Dentistry, Marquette University, Milwaukee, for his assistance. 1. Hirsh J, Schulman S. Antithrombotic therapy. In: Cecil RL, Goldman L, Ausiello DA, eds. Cecil Medicine. 23rd ed. Philadelphia: Saunders Elsevier; 2008:197-206. 2. WHO Expert Committee on Biological Standardization. Annex 3: Requirements for thromboplastins and plasma used to control oral anticoagulant therapy (requirements for biological substances no. 30) (revised 1982). In: WHO Expert Committee on Biological Standardization. Thirty-third Report. Geneva: World Health Organization; 1983:81-105. Technical Report Series 687. 3. Garcia DA, Hylek E. Reducing the risk for stroke in patients
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CLINICAL who have atrial fibrillation. Cardiol Clin 2008;26(2):267-275, vii. 4. Friedlander AH, Yochikawa TI, Chang DS, Feliciano Z, Scully C. Atrial fibrillation: pathogenesis, medical-surgical management and dental implications. JADA 2009;140(2):167-177. 5. Singer DE, Albers GW, Dalen JE, et al; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 suppl):546S-592S. 6. Geerts WH, Bergqvist D, Pineo GF, et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 suppl):381S-453S. 7. Butchart EG, Gohlke-Bärwolf C, Antunes MJ, et al; Working Groups on Valvular Heart Disease, Thrombosis, and Cardiac Rehabilitation and Exercise Physiology, European Society of Cardiology. Recommendations for the management of patients after heart valve surgery (published online ahead of print Aug. 15, 2005). Eur Heart J 2005;26(22):2463-2471. doi:10.1093/eurheartj/ehi426. 8. Heneghan C, Alonso-Coello P, Garcia-Aamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 2006;367(9508):404-411. 9. Ryan F, O’Shea S, Byrne S. The reliability of point-of-care prothrombin time testing: a comparison of CoaguChek S and XS INR measurements with hospital laboratory monitoring (published online ahead of print Nov. 18, 2008). Int J Lab Hematol 2010; 32(1 part 1):e26-e33. doi:10.1111/j.1751-553X.2008.01120.x. 10. Gardiner C, Williams K, Mackie IJ, Machin SJ, Cohen H. Patient self-testing is a reliable and acceptable alternative to laboratory INR monitoring. Br J Haematol 2005;128(2):242-247. 11. Green TL, Mansoor A, Newcommon N, Stephenson ES, Hill MD. Reliability of point-of-care testing of INR in acute stroke. Can J Neurol Sci 2008;35(3):348-351. 12. Ward BB, Smith MH. Dentoalveolar procedures for the anticoagulated patient: literature recommendations versus current
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practice. J Oral Maxillofac Surg 2007;65(8):1454-1460. 13. Beirne OR. Evidence to continue oral anticoagulant therapy for ambulatory oral surgery. J Oral Maxillofac Surg 2005;63(4):540-545. 14. Sacco R, Sacco M, Carpenedo M, Mannucci PM. Oral surgery in patients on oral anticoagulant therapy: a randomized comparison of different intensity targets (published online ahead of print May 7, 2007). Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104(1):e18-e21. doi:10.1016/j.tripleo.2006.12.035. 15. Al-Mubarak S, Al-Ali N, Abou-Rass A, et al. Evaluation of dental extractions, suturing, and INR on postoperative bleeding of patients maintained on oral anticoagulant therapy (published online ahead of print Aug. 10, 2007). Br Dent J 2007;203(7):E15. doi:10.1038/bdj.2007.725. 16. Brennan MT, Hong C, Furney SL, Fox PC, Lockhart PB. Utility of an international normalized ratio testing device in a hospital-based dental practice. JADA 2008;139(6):697-703. 17. Linnebur SA, Ellis SL, Astroth JD. Educational practices regarding anticoagulation and dental procedures in U.S. dental schools. J Dent Educ 2007;71(2):296-303. 18. Jeske AH, Suchko GD. Lack of a scientific basis for routine discontinuation of oral anticoagulation therapy before dental treatment (published correction appears in JADA 2004;135[1]:28). JADA 2003;134(11):1492-1497. 19. Commission on Dental Accreditation. Standards for dental education programs. “www.ada.org/115.aspx”. Accessed Aug. 31, 2011. 20. Field MJ, ed. Dental Education at the Crossroads: Challenges and Change. Washington: National Academy Press; 1995. 21. Association of State & Territorial Dental Directors. Emergent issues for dental public health and oral health programs. “www. astdd.org/emergent-issues-for-dental-public-health-and-oralhealth-programs/”. Accessed Aug. 31, 2011. 22. Romney G, Glick M. An updated concept of coagulation with clinical implications. JADA 2009;140(5):567-574.
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