Atrial Fibrillation: Pathogenesis, Medical-Surgical Management and Dental Implications Arthur H. Friedlander, Thomas T. Yoshikawa, Donald S.

Chang, Zenaida Feliciano and Crispian Scully JADA 2009;140;167-177 The following resources related to this article are available online at jada.ada.org ( this information is current as of December 1, 2011):
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CLINICAL PRACTICE

CRITICAL REVIEW

Atrial fibrillation
Pathogenesis, medical-surgical management and dental implications
Arthur H. Friedlander, DMD; Thomas T. Yoshikawa, MD; Donald S. Chang, MD, MPH; Zenaida Feliciano, MD; Crispian Scully, CBE, MD, PhD, MDS, MRCS, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FRCPath, FMedSci, FHEA, DSc, DChD, DMed(HC)

trial fibrillation (AF) is a cardiac dysrhythmia that arises when electrical impulses normally generated by the sinoatrial (SA) node are replaced by disorganized and ineffective activity in the atria, leading to the irregular conduction of impulses to the ventricles (Figure). This often results in people complaining of an uncomfortable sensation of a rapid irregular heartbeat. The associated hemodynamic consequences of reduced cardiac output may lead to additional symptoms such as shortness of breath on exertion, lightheadedness and dizziness, hypotension-induced near-syncope and myocardial ischemiainduced angina pectoris.1 Large numbers of people with AF are, however, also asymptomatic. People who are symptomatic or asymptomatic are at high risk of experiencing an ischemic stroke arising from the development of a thrombus caused by impaired contraction of the left atrium and subsequent embolization and occlusion of a blood vessel in the brain. The resulting infarct usually is larger

ABSTRACT

CON
T

Background. Atrial fibrillation (AF) is a cardiac rhythm disturbance arising from disorganized electrical activity in the atria, and it is accompanied by an N irregular and often rapid ventricular response. It is the A U I N G E D U C 2 RT most common clinically significant dysrhythmia in the ICLE general and older population. Types of Studies Reviewed. The authors conducted a MEDLINE search using the key terms atrial fibrillation, epidemiology, pathophysiology, treatment and dentistry. They selected contemporaneous articles published in peer-reviewed journals and gave preference to articles reporting randomized controlled trials. Clinical Implications. The anticoagulant warfarin frequently is prescribed to prevent stroke caused by cardiogenic thromboemboli arising from stagnant blood in poorly contracting atria. Most dental procedures and a limited number of surgical procedures can be performed without altering warfarin dosage if the international normalized ratio value is within the therapeutic range of 2.0 to 3.0. Certain analgesic agents, antibiotic agents, antifungal agents and sedative hypnotics, however, should not be prescribed without consultation with the patients physician because these medications may alter the patients risk of hemorrhage and stroke. Conclusions. AF affects nearly 2.5 million Americans, most of who are older than 60 years. Consultation with the patients physician to discuss the planned dental treatment often is appropriate, especially for people who frequently have comorbid diseases such as coronary artery disease, congestive heart failure, diabetes and thyrotoxicosis, which are treated with multiple drug regimens. Key Words. Cardiovascular diseases; stroke; anticoagulation therapy. JADA 2009;140(2):167-177.
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Dr. Friedlander is associate chief of staff and the director of graduate medical education, VA Greater Los Angeles Healthcare System, the director of quality assurance, Hospital Dental Service, University of California Los Angeles Medical Center, and a professor of oral and maxillofacial surgery, School of Dentistry, University of California Los Angeles. Address reprint requests to Dr. Friedlander at VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail arthur.friedlander@med.va.gov. Address reprint requests to Dr. Friedlander. Dr. Yoshikawa is the Makinodan director, Geriatric Research Education and Clinical Center, VA Greater Los Angeles Healthcare System, an associate chief of staff, Geriatrics and Extended Care, VA Greater Los Angeles Healthcare System, a professor of medicine, David Geffen School of Medicine at UCLA, Los Angeles, and editor, Journal of the American Geriatrics Society. Dr. Chang is the director, Fellowship in Cardiovascular Medicine, UCLA-VA, VA Greater Los Angeles/San Fernando Valley Program, and an associate professor of medicine, David Geffen School of Medicine at UCLA, Los Angeles. Dr. Feliciano is cochief, Cardiac Electrophysiology, VA Greater Los Angeles Healthcare System, and an associate professor of medicine, David Geffen School of Medicine at UCLA, Los Angeles. Dr. Scully is the director (special projects), University College London Eastman Dental Institute, the codirector, WHO Collaborating Centre for Research, Education and Service in Oral Health, Disability and Culture, University College London Eastman Dental Institute, and a professor, Special Care Dentistry, University College London Eastman Dental Institute.

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Figure. Diagrammatic representation of pertinent anatomical and pathophysiological elements of atrial fibrillation. SA: Sinoatrial. AV: Atrioventricular.

than that seen in other types of strokes, is more disabling and is more likely to be fatal.2 In addition, impaired cognitive function may result from silent embolic strokes (multi-infarct dementia).3 Episodes of AF may be paroxysmal (spontaneously terminating usually within 24 hours), persistent (lasting more than seven days or requiring treatment to re-establish sinus rhythm) or permanent (the status when treatment fails to terminate the episode).4 Many patients with AF take anticoagulant medications to reduce their risk of stroke. When they require invasive dental procedures, consultation with their physician is advisable. We conducted a MEDLINE search using the key terms atrial fibrillation, epidemiology, pathophysiology, treatment and dentistry. We selected contemporaneous articles published in peer-reviewed journals and gave preference to articles reporting randomized controlled trials.
EPIDEMIOLOGY

aged 70 to 79 years the risk is essentially the same (men, 5.9 percent, and women, 5.8 percent).6 The disorder also commonly is seen in people who had myocardial infarction, coronary artery disease, congestive heart failure, valvular heart disease, cardiomyopathy, hypertension, diabetes, obesity and thyrotoxicosis.7 AF increases the risk of stroke four- to fivefold and is responsible for approximately 15 percent of all ischemic strokes and almost 25 percent of strokes occurring in people 80 years or older.8 It also increases by threefold the risk of congestive heart failure.9 People with AF and a concurrent second cardiovascular disease (for example, hypertension, coronary artery disease) have about a twofold increase in mortality, but it remains unclear if the increase is secondary to AF and the associated rapid ventricular rate or the underlying cardiovascular disease.10 During the next 40 years, the number of Americans diagnosed with AF is expected to rise to almost 16 million given
ABBREVIATION KEY. ADA CSA: American Dental Association Council on Scientific Affairs. AHA: American Heart Association. AF: Atrial fibrillation. ASA: Acetylsalicylic acid. AV: Atrioventricular. ECG: Electrocardiogram. INR: International normalized ratio. LMWH: Low-molecular-weight heparin. NSAID: Nonsteroidal anti-inflammatory drug. PV: Pulmonary veins. SA: Sinoatrial.

AF is the most common sustained cardiac dysrhythmia, and it affects nearly 2.5 million Americans.5 In the general population, the prevalence is 0.4 percent, but it increases with age such that 3.8 percent of people 60 years of age and 9.0 percent of those older than 80 years have the disorder. Men are at higher risk of experiencing AF (5.8 percent) than are women (2.8 percent) in the group aged 65 to 69 years, but in the group
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the expected aging of the population and the concomitant increase in chronic illnesses associated with its development.11-13
CARDIAC PHYSIOLOGY

The SA node, a small mass of tissue with the characteristics of both muscle and nerve that is situated in the right atrial wall, generates (depolarizes) nerve impulses that initiate each heartbeat. The fibers of the SA node fuse with the surrounding atrial muscle fibers so that the action potential generated in the nodal tissue spreads rapidly, evenly and uniformly throughout both atria and produces atrial contractions (that is, the atrial component of systole). This electrical wave front does not immediately pass into the ventricles because they are insulated from the atria by fibrous heart valves. Interspersed among the atrial muscle fibers, however, are several internodal fiber bundles that conduct the impulse to the atrioventricular (AV) node, which is located in the lower part of the interatrial septum. In the AV node, there is a short delay in the transmission of the impulse to the ventricles, which permits the atria to complete their contractions (consistent with the P wave on the electrocardiogram [ECG]) and empty their blood into the ventricles that already are partially filled with blood that had passively drained from the large veins (vena cava on the right side and the pulmonary veins [PVs] on the left side) into the atria during diastole. Once the impulse leaves the AV node, it descends in the interventricular septum via the bundle of His and terminates in the Purkinje fibers of the ventricle walls, causing them to contract (that is, the ventricular component of systole), as noted on the ECG by the presence of the QRS complex.
CARDIAC PATHOPHYSIOLOGY

The pathophysiology of AF is highly diverse and spans the spectrum from a dysrhythmia developing in response to structural and functional remodeling as a consequence of a pre-existing illness such as hypertension, congestive heart failure, lung disorder and thyroid disease, to a primary electrical disturbance. For example, hypertension commonly is accompanied by increased atrial stiffness and compensatory changes in the left ventricle, including hypertrophy and diastolic dysfunction. The resultant increase in left ventricular diastolic pressure is transmitted to the left atrium and pulmonary

vasculature causing structural and functional changes. These changes include atrial dilatation, atrial fibrosis and atrial myocyte degeneration. Such changes result in altered atrial electrophysiology, resulting in multiple chaotic electrical discharges that form wavelets instead of the classic P wave and originate from atrial components other than the SA node.14-16 These abnormal discharges are rapid (350-600 impulses per minute) and irregular, and they spread throughout the atria in a random pattern that depolarizes only small islets of myocardium and result in only localized minicontractions. Thus, the atrial chambers quiver rather than synchronously contract as a whole. The atrial blood that should have been propelled into the already partially filled ventricles contributing to cardiac output remains in both atria. The loss of this additional contribution to ventricular filling (termed atrial kick) results is as much as a 20 to 30 percent loss of cardiac output.17 Furthermore, the residual atrial blood hinders blood from leaving the lungs and traveling to the left atrium. This results in excess fluid in the lungs (pulmonary edema) and leads to shortness of breath. The residual atrial blood also hinders the return of blood from the systemic circulation to the right atrium and results in fluid accumulation (edema) in the ankles and abdominal organs. The presence of both pulmonary and ankle edema often is categorized as congestive heart failure. The residual atrial blood (most specifically, that in the left atrial appendage, a small cul-de-sac in the atrial chamber) is relatively stagnant and prone to form thrombi. These thrombi can embolize into the systemic circulation, in which they may occlude any number of vessels, including, most disastrously, a cerebral artery, causing an ischemic stroke.18 The rapid irregular electrical discharges from atrial sites other than the SA node then pass through the AV node at random, causing the ventricles to contract irregularly and usually rapidly (greater than 130 beats per minute). The increased effort from rapid ventricular contractions requires that the heart muscle be supplied with additional oxygenated blood. However, because of the rapidity of ventricular contractions, there is inadequate time for them to fill with blood completely. Suboptimal emptying of the atria compounds this problem. Consequently, less blood is pumped into the systemic circulation with each contraction, and this blood is less than optimally
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oxygenated because its flow was impaired when it passed through the lungs initially. The increased heart rate also compromises flow into the coronary arteries that supply the heart muscle during diastole. When the oxygen demand of the cardiac muscle exceeds the ability of the coronary arteries to supply the heart with oxygen-rich blood, the patient develops angina. Other groups of patients with AF are those with ectopic foci located in the narrow band of tissue that surrounds the openings of the four PVs in which they enter the left atrium. The juxtaposition of two types of tissuethat is, PV endothelium and atrial endocardium with differing electrical propertieslikely predisposes patients to the development of AF.19,20 AF also may occur in people younger than 60 years with no clinical or echocardiographic evidence of cardiopulmonary disease and is referred to as lone AF. Some researchers believe this is brought about during stress and fatigue or with excessive use of coffee, alcohol and cigarettes. In addition, there are numerous people with the disorder who remain asymptomatic (termed silent AF) and do not receive a diagnosis until they have a stroke.
DIAGNOSIS

problem. In these cases, the patient is asked to wear an ambulatory ECG monitoring device, which records the hearts rhythm over a prolonged period. The persistent form of AF, which lasts until it is treated, is diagnosed more easily. Physicians can recognize the abnormal beats by taking the patients pulse and can hear the rapid and irregular heartbeats using a stethoscope. Because of the varying stroke volumes resulting from varying periods of diastolic filling, not all ventricular beats recognized by auscultating the heart with a stethoscope produce a palpable peripheral pulse. Confirmation of the diagnosis is obtained with a standard ECG. The chaotic electrical activity produces irregular fibrillatory waves (rapid oscillations), which replace the recognizable P waves of atrial depolarization. These deflections vary in size, shape and timing, and they are accompanied by the irregular occurrence of normal-appearing QRS complexes of ventricular depolarization with a rate that usually ranges between 100 and 160 beats per minute. In elderly patients, the ventricular rate often is slower.
MEDICAL MANAGEMENT

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The initial evaluation of a patient who may be experiencing the first AF episode begins by taking a detailed history and conducting a physical examination. The history focuses on the symptoms associated with AF. The first step during the examination is palpation of the pulse for any irregularity (with or without an accompanying tachycardia). Consistent with AF is an irregularly irregular pulse. In patients 60 years and older, this finding has a sensitivity of 94 percent but a specificity of 72 percent and requires further diagnostic testing.21 Further physical examination focuses on signs of atherosclerosis and heart failure, including arterial bruits and jugular venous distension, and a detailed heart examination. A standard 12-lead ECG is performed to evaluate the patients heart rhythm and is a key step in the diagnosis of AF. The blood is tested for thyroid, renal and hepatic function, and a chest radiograph is obtained to evaluate the lung parenchyma and pulmonary vasculature. The paroxysmal form of AF, lasting just minutes or hours with the heart rate spontaneously returning to normal between episodes, is difficult to diagnose. The ECG performed at the initial visit to the physicians office may not show the
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Medical experts have determined that administering medications that slow the ventricular rate in combination with other drugs to prevent thrombus formation is associated with fewer drug-related adverse events. There also is no loss in survival advantage when these medications are compared with those that restore and maintain sinus rhythm in patients older than 60 years who have the persistent form of the disease.22-24 These medications slow the ventricular rate by retarding the conduction of electrical impulses through the AV node. Beta-blockers (atenolol, carvedilol, metoprolol, propranolol) and calcium channel blockers (diltiazem, verapamil) are the medications prescribed most frequently because they control the patients heart rate during both rest and activity. Few patients are prescribed digoxin, which is effective in slowing the heart rate only when the patient is not physically active. A combination of agents may be used for rate control. Slowing the rate of ventricular contractions enhances cardiac output, as more time is available for atrial contraction and ventricular filling. This often results in relief from symptoms of dizziness, weakness and shortness of breath. The determination of stroke risk caused by car-

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CLINICAL PRACTICE CRITICAL REVIEW

diogenic thombi often is guided by the CHADS2 score, which is an acronym for an index that gives 1 point each for Congestive heart failure, Hypertension, Age 75 years or older and Diabetes mellitus, as well as two points for a prior Stroke or transient ischemic attack. Patients with a score of zero are treated with aspirin (81-325 milligrams), owing to the low stroke rate. Those with a score of 1 are prescribed either aspirin or the anticoagulant warfarin sodium (Coumadin, DuPont Pharmaceuticals, Wilmington, Del.) depending on the patients preferences, bleeding risk and access to good international normalized ratio (INR) monitoring. Warfarin inhibits the biologically active forms of the vitamin Kdependent factors II (prothrombin), VII, IX and X, as well as the regulatory factors protein C, protein S and protein Z. It is recommended that patients with a score 2 or higher receive warfarin therapy owing to the high stroke risk.25 Warfarin decreases the risk of ischemic stroke by 68 percent, but it is associated with an increased risk of hemorrhagic stroke and extracranial bleeding in such sites as the gastrointestinal tract.26,27 The dosage level is titrated so that it takes the blood approximately two and one-half times (range, two to three times) the normal amount of time to clot, which equates to a prothrombin time expressed as an INR of 2.5.28 A number of risk factors for bleeding while receiving anticoagulation therapy have been identified, such as an INR greater than 3, adverse drug interactions (see below), poorly controlled hypertension, liver disease, chronic renal failure and being 65 years and older, as well as psychosocial risk factors associated with nonadherence (such as substance abuse including excessive use of alcohol and psychiatric illness).29 Patients who are unable or unwilling to monitor their INR levels sometimes are prescribed antiplatelet medications such as aspirin, clopidogrel or both, but these therapies are less effective than warfarin in preventing embolic strokes.30 The process of resetting the heart to sinus rhythm, known as cardioversion, often is used to reduce symptoms such as exercise intolerance and may improve left ventricular function (ejection fraction).31 Cardioversion can be accomplished by administering antidysrhythmic medications or delivering an electrical shock to the heart. Most antidysrhythmic medications (amiodarone, sotalol, dofetilide, flecainide, propafenone) approved by the U.S. Food and Drug

Administration convert AF to sinus rhythm by blocking the channels in the walls of cells through which ions travel (sodium, potassium and calcium channels and beta-adrenergic channels), thereby slowing the electrical conduction velocity and delaying repolarization. Restoration of sinus rhythm also controls and regularizes the ventricular rate.32 These medications are effective in 50 to 60 percent of patients, but because they often fail, anticoagulant agents usually are prescribed continuously to reduce the stroke risk. These medications also have numerous adverse systemic side effects.33 Of specific concern to dentists is that amiodarone interacts with warfarin, thereby increasing the anticoagulation effect.34 Sotalol may cause or exacerbate lung disease, thus compromising the safety of inhalation anesthesia. Cardioversion also can be performed by transmitting a low voltage (nontissue-destroying amounts) of electrical current to the heart through paddles applied to the external surface of the chest wall. The electric shock, synchronized to the R wave on the patients ECG, stops the abnormal electrical activity of the heart briefly, permitting the SA node to resume its role as the primary pacemaker. This process is successful in more than 95 percent of patients, but in approximately 75 percent of these people, AF returns in 12 to 24 months. Anticoagulant agents also usually are prescribed for these patients because rhythm therapy may fail without warning. AF ablation can be accomplished by destroying the tissues (arrhythmogenic foci) that cause aberrant electrical discharges known as hot spots. These sites, which are identified during the electrophysiological mapping process, are destroyed by radio frequency energy (or cryoenergy, lasers, microwaves or ultrasound) delivered by catheters threaded up toward the heart from the blood vessels in the groin. The catheter is inserted percutaneously into the femoral vein and then advanced into the inferior vena cava and then into the right atrium. From here, left atrium access is accomplished by means of an interarterial septal puncture.35 Hot spots frequently are located in the narrow band of tissue (a sleeve of myocardium) that surrounds the openings of the four PVs where they enter the left atrium.36 Encircling and isolating these sites with catheter-produced scars prevents transmission of these PV foci to the rest of the heart and corrects AF in 80 percent of patients. During cardiac surgery, a maze procedure can be performed in which a series of
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mazelike incisions or radio frequency burns are made in the atria in an attempt to eliminate AF. Other patients cardiac situations require that radio frequency energy be applied to the AV node to destroy small components of tissue. This prevents the atria from sending too many electrical impulses to the ventricles and impairing ventricular function. However, a permanent pacemaker then must be implanted under the skin, usually below the clavicle. Electrodes from the pacemakers generator are threaded through veins, which return to the heart. Small electrical impulses are sent along these leads to the heart to establish ventricular sinus rhythm. This procedure almost always improves the patients quality of life, but because the atria continue to fibrillate, anticoagulant medications still are required.
DENTAL CONSIDERATIONS

Most patients with AF can be treated safely in the dental office when specific precautions are taken (Table 1). Consultation with the patients physician to discuss the safest venue for providing dental treatment often is appropriate, especially for people who have advanced comorbid diseases that are treated with multiple drug regimens. Patients requiring general anesthesia are treated best in a hospital or fully equipped ambulatory surgical care center. Patients deemed appropriate to undergo treatment in a dental office should have an experience that minimizes stress and anxiety. Premedication with a short-acting benzodiazepine the night before the appointment and one hour before the appointment is appropriate. Supplementation with nitrous oxideoxygen inhalation also may be helpful but should be discussed with the patients physician. Profound local anesthesia and hemostasis are best achieved using agents containing a vasoconstrictor (for example, 1:100,000 epinephrine). The dental literature presents conflicting information as to the potential danger posed by ultrasonic scalers and electrosurgical units, as they may produce electromagnetic interference, which can impair pacemaker function. In 1998, Miller and colleagues37 conducted an in vitro test and found that ultrasonic scalers and electrosurgical units did interfere with pacemaker function. Furthermore, in a 2000 position paper, the American Academy of Periodontology advised that practitioners avoid using magnetostrictive ultrasonic
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scalers (but not piezoelectric scalers) owing to the potential deleterious effects that they may have on pacemaker function.38 In 2005, however, Patel and colleagues39 conducted an in vivo test and found that ultrasonic scalers and electronic pulp testers did not adversely affect pacemaker function. Similarly, in 2007, Brand and colleagues40 found that ultrasonic tooth scalers and electrosurgical units did not impair pacemaker function. Further confounding this issue are articles in the medical literature that suggest that patients with pacemakers are at risk from electrosurgical units, be they monopolar units in which the electric current spreads out and penetrates the patients entire body or bipolar units in which electric current flows only to the spot between the tips of the instrument.41-43 In view of the conflicting information in the scientific literature, the various types of implantable pacemakers, the many types of ultrasonic scalers and electrosurgical units on the market and the various venues in which dentists practice (that is, dental office operatories, ambulatory surgical clinics and main operating rooms of hospitals), it would be prudent for dentists to use hand instruments for scaling and root planing and a scalpel for incising tissue when treating patients with permanent implantable pacemakers. Minor dental proceduressuch as administering infiltration local anesthetic, placing restorations, fabricating fixed and removable prosthetic appliances and supragingival scaling and polishingusually do not require that dentists consider the patients INR, but prudent dentists will consult with the physician responsible for the patients warfarin therapy before performing more invasive procedures. The discussion between practitioners should include the patients recent INR values, access to the patients INR value on the day of surgery,44 plans to optimize blood pressure control to minimize intraoperative bleeding, and an assurance that the patient is not also receiving antiplatelet agents (such as aspirin, clopidogrel or both).45 Although it is common for physicians to concur with or support the American Heart Association (AHA) guidelines that permit interruption of anticoagulation therapy for up to one week for surgical procedures that carry a risk of bleeding,46 dentists should make physicians aware of the American Dental Association Council on Scientific Affairs (ADA CSA) guidelines that recognize that, while the AHA guidelines may be germane for patients undergoing general surgery, orthopedic surgery

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TABLE 1 and so forth, they are not applicable for Dental implications and treatment modifications for patients undergoing patients with atrial fibrillation. dentoalveolar 47 surgery. FurtherCOMPONENTS OF DENTAL TREATMENT MODIFICATION IF INDICATED more, dentists should New Patient With Multiple Comorbidities Consult physician for required precautions (For Example, Prior Myocardial Infarction, note that the ADA Congestive Heart Failure, Hypertension) CSA, the British Complexity of Treatment Requires Admit patient to hospital or fully equipped Dental Association General Anesthesia ambulatory surgical care center and the Haemostasis Stress Reduction Indicated Premedicate with short-acting benzodiazepine and Thrombosis Task and supplement with nitrous oxideoxygen Force of the British inhalation Committee for StandUse of Local Anesthetic Containing a Aspirate, inject slowly and obtain profound Vasoconstrictor anesthesia; intraligamentary and intrapapillary ards in Haematology48 injections are preferred to regional blocks if have reviewed the sciINR* greater than 3.0 49-55 entific literature Use of Electrosurgical Units and Best to avoid these devices and use a scalpel for and have concluded Ultrasonic Tooth Scalers incising tissue and hand instruments for scaling and root planing that warfarin therapy should not be disconPatients Receiving Warfarin and No change in INR required Requiring Local Anesthesia or Restoration tinued for patients Placement, Fabrication of Fixed undergoing routine Appliances or Supragingival Scaling dentoalveolar surgery Patients Receiving Warfarin With an INR Consult with the patients physician before if their INR is 4 or Between 2 and 3 and Requiring One to surgery to ascertain that blood pressure is being Three Simple Dental Extractions optimally controlled and that the patient is not less. This is because of also receiving antiplatelet agents (aspirin, clopithe difficulty in predogrel or both); then inform the physician that local hemostatic measures can control bleeding dicting the drop in the and that no change in the warfarin regimen is INR value in any indicated given patient and Complex Exodontia (For Example, Limit number of teeth to be extracted at one sitRetained Roots, Impacted Teeth) ting and section teeth to limit ostectomies; because the risk of a remove all granulation tissue, place resorbable patients experiencing gelatin or oxiodized cellulose materials in socket, compress wound and place tight mula thromboembolism tiple interrupted sutures (which may be lethal) Complex Maxillofacial Surgical Perform procedures in hospital setting and in clearly outweighs the Procedures for Patients Currently concert with patients physician; determine need Receiving Warfarin Therapy to change warfarin regimen and possibly instirisk of a patients tute bridging anticoagulation by adminisexperiencing excessive trating subcutaneous low-molecular-weight heparin postoperative oral bleeding. These con* INR: International normalized ratio. clusions should be reassuring to physicians, because this level of anticoagulation limit intraoperative and postoperative hemortherapy is in excess of the 2.0 to 3.0 range (2.5 rhaging in patients who are receiving warfarin target) typically prescribed for patients with AF therapy when undergoing oral surgery. They and, thus, provides an even greater margin of found that administration of local anesthetic safety.56 Most of these studies, however, evaluagents containing vasoconstrictors helps maintain ated patients having up to five simple tooth a dry surgical field and that intraligamentary and extractions (with most patients having between intrapapillary injections are preferred to regional one and three extractions) and there are no blocks if the patients INR is greater than 3.0 studies to date involving significant numbers of because of an anecdotal risk of bleeding into the patients having more extensive surgeries such as floor of the mouth and fascial planes of the neck, six or more extractions, removal of impacted which can lead to obstruction of the airway. teeth, alveolectomies or tori removal.57 To minimize the risk and extent of postoperaIn a literature review, Scully and Wolff 58 identive bleeding, the number of teeth extracted at tified certain procedures or precautions that may one sitting should be limited, and, when required,

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teeth should be sectioned to limit the need for ostectomies.59 When ostectomies are required, subperiosteal-tensionfree flaps should be developed and minimal bone should be removed to preserve the elements of the sockets bony walls to enhance clot stabilization. All granulation tissue should be curetted from the surgical site, resorbable gelatin or oxidized cellulose materials should be placed in the socket, the bony wound should be compressed, soft tissues should be apposed closely and tight multiple interrupted sutures should be placed. Patients should be asked to bite on saline-soaked gauze compresses for 30 minutes after surgery. Some clinicians augment the above procedures by also having patients rinse their mouths with an antifibrinolytic agent such as epsilon-aminocaproic acid (or tranexamic acid), four times per day for two minutes.60,61 The AHAs guidelines may be applicable when dentists are planning more complex and invasive maxillofacial surgical procedures, such as an extraoral open reduction of facial fractures that is associated with extensive bleeding in patients without a history of stroke, transient ischemic attack, systemic embolisms or a mechanical heart valve.62 Patients warfarin therapy should be managed in cooperation with the patients physicians, and patients INRs must be evaluated on the day of surgery. Older people are slower to normalize an elevated INR and may experience warfarin-related bleeding at lower INRs than do younger people.63-65 In some instances, physicians may prescribe bridging anticoagulation of subcutaneous low-molecular-weight heparin (LMWH) to shorten the time that the patient is unprotected from thromboembolisms.66-68 Typically, the last preoperative dose of LMWH is administered 24 hours before surgery. The first postoperative dose is given no earlier than 24 hours after surgery, commonly on the second postoperative day when hemostasis has been secured.69 Warfarin therapy may be reinstituted on the evening of surgery if hemostasis has been assured; if not, then it is started 24 hours postoperatively.
MEDICATION INTERACTIONS WITH WARFARIN

Medications prescribed with warfarin that may alter the risk of experiencing hemorrhage, irrespective of whether they directly alter the INR value, are shown in Table 2. These interactions are relatively rare, but they are unpredictable and may vary depending on dosage, duration, inter174 JADA, Vol. 140 http://jada.ada.org February 2009

mittent versus long-term use and other factors.70-72 Concomitant adjustments in warfarin dosage may need to be made by patients physicians to maintain the desired degree of anticoagulation therapy and to minimize the risk of bleeding. Certain analgesics increase patients risk of experiencing postoperative bleeding and of hemorrhaging from sites that did not undergo surgery and are distant to the oral cavity. Patients taking warfarin and aspirin (acetylsalicylic acid [ASA]) simultaneously or warfarin and a nonselective nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen simultaneously are at an increased risk of experiencing gastrointestinal bleeding even though these drug combinations do not increase INR values. The hemorrhaging is believed to occur because both ASA and the NSAIDs cause gastric erosions, which under normal circumstances usually remain asymptomatic but in the presence of warfarin are more likely to bleed significantly.73,74 Of greater significance is the increased risk of patients experiencing intracranial hemorrhage from the concurrent administration of warfarin and aspirin,75 probably because aspirin impairs platelet aggregation. Acetaminophen should be avoided because a study has shown that taking four regular strength (325 mg) tablets of acetaminophen per day for longer than one week significantly increases the risk of markedly elevating the INR value.76 This occurs because one of acetaminophens metabolites inhibits a key enzyme in the vitamin K cycle required for the livers production of coagulation factors.77 Certain medications, when taken over a number of days with warfarin, may increase the patients INR value and risk of hemorrhage unless the warfarin dosage is adjusted.78 This occurs because warfarin prevents the metabolism of vitamin K to its active form, which is needed in the livers synthesis of specific clotting factors. This effect is amplified by certain antibiotics (tetracyline, ampicillin and amoxicillin plus clavulanic acid), which further decrease available vitamin K because they destroy some of the normal intestinal bacteria that produce it.79-82 The patients INR and risk of hemorrhage also may be increased by medications such as metronidazole and the macrolides (erythromycin, azithromycin, clarithromycin) because they inhibit the normal metabolism of warfarin.83,84 Similarly, azole antifungal agents such as ketoconazole, fluconazole

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and itraconazole may increase the patients INR by inhibiting the metabolism of warfarin.56,85 However, a single dose of an antibiotic such as amoxicillin, ampicillin, azithromycin or clarithromycin is unlikely to have any significant effect on the patients INR.86 If a full antibiotic course is indicated, the narrow-spectrum penicillin V (or clindamycin for those allergic to penicillin) is the preferred medication.87 Other medications that may interact adversely with the therapeutic agents used to treat AF and render them less effective include dicloxacillin, nafcillin, phenobarbital and chloral hydrate, which can induce enzyme systems to rapidly metabolize warfarin.88 NSAIDs prescribed for more than three weeks can impair the effectiveness of -blockers to limit the heart rate, and erythromycin and tetracycline can induce digitalis toxicity.89,90
CONCLUSION

TABLE 2

Dental therapeutic agents prescribed with warfarin and their concomitant influence on risk of experiencing hemorrhage and stroke.
CLASS AND TYPE OF MEDICATION Analgesic Agent Aspirin Nonselective nonsteroidal antiinflammatory drugs (for example, ibuprofen) Acetaminophen in excess of four 325 milligram tablets a day for seven days or more Antifungal Agent Ketoconazole Fluconazole Itraconazole Antibiotic Agent Tetracycline Broad-spectrum penicillin (for example, amoxicillin, ampicillin) Macrolide (for example, erythromycin, azithromycin, clarithromycin) Metronidazole Dicloxacillin Nafcillin Sedative-Hypnotic Agent Chloral hydrate Phenobarbital * INR: International normalized ratio. 2007;30(9):1121-1128. 3. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348(13):1215-1222. 4. Miyasaka Y, Barnes MF, Petersen RC, et al. Risk of dementia in stroke-free patients diagnosed with atrial fibrillation: data from a community-based cohort. Eur Heart J 2007;28(16):1962-1967. 5. Go AS. The epidemiology of atrial fibrillation in elderly persons: the tip of the iceberg. Am J Geriatr Cardiol 2005;14(2):56-61. 6. Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol 1994;74(3):236-241. 7. Lakshminarayan K, Anderson DC, Herzog CA, Qureshi AI. Clinical epidemiology of atrial fibrillation and related cerebrovascular events in the United States. Neurologist 2008;14(3):143-150. 8. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics: 2007 updatea report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115(5):e69-e171. 9. Gottdiener JS, Arnold AM, Aurigemma GP, et al. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol 2000;35(6):1628-1637. 10. Friberg L, Hammar N, Pettersson H, Rosenqvist M. Increased mortality in paroxysmal atrial fibrillation: report from the Stockholm Cohort-Study of Atrial fibrillation (SCAF). Eur Heart J 2007;28(19): 2346-2353. 11. Lip GY, Tse HF. Management of atrial fibrillation. Lancet 2007;370(9587):604-618. Not documented Not documented Depressed Depressed Ischemic Ischemic Increased Increased Increased Increased Not documented Not documented Elevated Elevated Elevated Elevated Depressed Depressed Not documented Not documented Not documented Hemorrhagic Ischemic Ischemic Increased Increased Increased Elevated Elevated Elevated Not documented Not documented Not documented Increased (secondary to platelet effect) Increased (secondary to platelet effect) Increased Unchanged Unchanged Hemorrhagic Not documented RISK OF HEMORRHAGE INR* VALUE TYPE OF STROKE RISK

Elevated

Not documented

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As the population in the developed world ages, an increasing number of patients with AF will be treated with invasive dental interventions. Dentists must be familiar with the pathophysiology of AF and the medical treatment options. Some of these therapeutic regimens can affect dental treatment with regard to the surgical risk of hemorrhage and the need for consultation with the patients physician when prescribing medications that may alter the effects of anticoagulant agents.
Disclosure. None of the authors reported any disclosures. 1. Raghavan AV, Decker WW, Meloy TD. Management of atrial fibrillation in the emergency department. Emerg Med Clin North Am 2005;23(4):1127-1139. 2. Tagawa M, Takeuchi S, Chinushi M, et al. Evaluating patients with acute ischemic stroke with special reference to newly developed atrial fibrillation in cerebral embolism. Pacing Clin Electrophysiol

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12. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114(2):119-125. 13. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of newonset atrial fibrillation. JAMA 2004;292(20):2471-2477. 14. Tsang TS, Miyasaka Y, Barnes ME, Gersh BJ. Epidemiological profile of atrial fibrillation: a contemporary perspective. Prog Cardiovasc Dis 2005;48(1):1-8. 15. Saffitz JE. Connexins, conduction, and atrial fibrillation. N Engl J Med 2006;354(25):2712-2714. 16. Vergara P, Picardi G, Nigro G, et al. Evaluation of thyroid dysfunction in patients with paroxysmal atrial fibrillation. Anadolu Kardiyol Derg 2007;7(suppl 1):104-106. 17. Falk RH. Atrial fibrillation. N Engl J Med 2001;344(14):10671078. 18. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 2007;69(6):546-554. 19. Hassaguerre M, Jas P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339(10):659-666. 20. Gillinov AM, Wolf RK. Surgical ablation of atrial fibrillation. Prog Cardiovasc Dis 2005;48(3):169-177. 21. Cooke G, Doust J, Sanders S. Is pulse palpation helpful in detecting atrial fibrillation? A systematic review. J Fam Pract 2006;55(2):130-134. 22. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347(23):1834-1840. 23. National Collaborating Centre for Chronic Conditions. Atrial Fibrillation: National Clinical Guideline for Management in Primary and Secondary Care. London: Royal College of Physicians; 2006. 24. Snow V, Weiss KB, LeFevre M, et al; AAFP Panel on Atrial Fibrillation; ACP Panel on Atrial Fibrillation. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2003;139(12):1009-1017. 25. Goldstein LB, Adams R, Alberts MJ, et al; American Heart Association; American Stroke Association Stroke Council. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group (published correction appears in Circulation 2006;114[22]:e617). Circulation 2006;113(24):e873-e923. 26. Saxena R, Koudstaal PJ. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack. Cochrane Database Syst Rev 2004;(4):CD000187. 27. Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007;120(8):700-705. 28. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146(12):857-867. 29. Schauer DP, Moomaw CJ, Wess M, Webb T, Eckman MH. Psychosocial risk factors for adverse outcomes in patients with nonvalvular atrial fibrillation receiving warfarin. J Gen Intern Med 2005;20(12):1114-1119. 30. Bajorek BV, Krass I, Ogle SJ, Duguid MJ, Shenfield GM. Optimizing the use of antithrombic therapy for atrial fibrillation in older people: a pharmacist-led multidisciplinary intervention. J Am Geriatr Soc 2005;53(11):1912-1920. 31. Mead GE, Elder AT, Flapan AD, Kelman A. Electrical cardioversion for atrial fibrillation and flutter. Cochrane Database Syst Rev 2005;(3):CD002903. 32. Wyse DG. Rate control vs. rhythm control strategies in atrial fibrillation. Prog Cardiovasc Dis 2005;48(2):125-138. 33. Ziv O, Choudhary G. Atrial fibrillation. Prim Care 2005;32(4): 1083-1107. 34. Singh BN, Singh SN, Reda DJ, et al; Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) Investigators. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352(18):1861-1872. 35. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation for the

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