Anticoagulation & Stroke Prevention in Nonvalvular Atrial Fibrillation (NVAF) PDF

Anticoagulation I. STROKE PREVENTION IN NONVALVULAR ATRIAL FIBRILLATION A. Introduction 1. Atrial fibrillation (AF) is the most common sustained cardiac dysrhythmia, affecting 2.7–6.1 million Americans. Overall prevalence of AF is 0.4%–1%. 2. Incidence increases with advancing age. a. Around 1% o...

Anticoagulation I. STROKE PREVENTION IN NONVALVULAR ATRIAL FIBRILLATION A. Introduction 1. Atrial fibrillation (AF) is the most common sustained cardiac dysrhythmia, affecting 2.7–6.1 million Americans. Overall prevalence of AF is 0.4%–1%. 2. Incidence increases with advancing age. a. Around 1% of patients with AF are younger than 60. b. Around 12% of patients with AF are 75–84 years of age. c. More than 33% of patients with AF are 80 or older. 3. A F accounts for more than 450,000 hospitalizations annually in the United States and significant health care costs. B. Pathophysiology 1. Etiology a. Typically related to structural heart disease such as coronary artery disease, valvular heart disease, heart failure, or other cardiogenic issues such as hypertension b. Noncardiogenic causes: Hyper- or hypothyroid disease, acute infection, excessive alcohol intake, after surgery, and PE 2. Thrombosis a. Incomplete conduction of supraventricular impulses creates a lack of atrial contraction. b. Incomplete emptying of the cardiac chambers during systole increases the rate of blood pooling in the atria, most notably in the left atrial appendage. c. 90% of thromboses occur in the left atrial appendage and 10% in the left atrium. d. Blood stasis is associated with increased formation of mural thrombi, which may cause arterial embolization, or stroke, if dislodged by a return to normal sinus rhythm or by the shearing forces from turbulent blood flow through the chambers. C. N  onvalvular AF (NVAF): When discussing the role of direct oral anticoagulants (DOACs), NVAF represents patients without moderate to severe mitral stenosis and those with a mechanical heart valves. D. Stroke 1. NVAF increases the risk of stroke by 5-fold compared with patients without AF. 2. AF is responsible for 15% of all strokes. 3. Risk stratification (only for patients with NVAF) a. CHADS2 score i. Maximum score of 6 based on risk factors (Table 1) ii. Risk of ischemic stroke is 1.9%–18.2%, depending on score (Table 2). iii. Limited by ability to determine who is truly at low or intermediate risk because scores of 0 or 1 suggest a risk of almost 2%–3% (see Table 2) b. CHA 2DS2-VASc score i. Maximum score of 9 based on risk factors (Table 1) ii. Compared with CHADS2 , adds risk factors of age 65–74, female sex, and history of other vascular disease iii. Improves predictive value of patients who are truly at low risk (score of 0 = 0% risk) and intermediate risk (score of 1 = 1.3% risk) iv. Guidelines from the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS); European Society of Cardiology; and American College of Chest Physicians recommend using the CHA 2DS2-VASc score to determine the need for anticoagulant therapy in patients with NVAF (Table 3; Table 4). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-133 Anticoagulation Table 1. Risk Stratification for Ischemic Stroke in Patients with NVAF CHADS2 Score Congestive heart failurea Hypertension Age ≥ 75 Diabetes Previous stroke, TIA, TE 1 1 1 1 2 CHA 2DS2 -VASc Score Congestive heart failurea Hypertension Age ≥ 75 Diabetes Previous stroke, TIA, TE Vascular disease (prior MI, PAD, aortic plaque) Age 65–74 Sex category (female) 1 1 2 1 2 1 1 1 Heart failure as a risk factor represents patients with an ejection fraction ≤ 40%. MI = myocardial infarction; PAD = peripheral artery disease; TE = thromboembolism; TIA = transient ischemic attack. a Table 2. Adjusted Stroke Rate per Year Based on CHADS2 and CHA2DS2-VASc Scores Score 0 1 2 3 4 5 6 7 8 9 CHADS2 Adjusted Stroke Rate (%/yr) 1.9 2.8 4.0 5.9 8.5 12.5 18.2 — — — CHA2DS2-VASc Adjusted Stroke Rate (%/yr) 0 1.3 2.2 3.2 4.0 6.7 9.8 9.6 6.7 15.2 Risk Category Low Intermediate High Table 3. AHA/ACC/Heart Rhythm Society Guideline Recommendations for Antithrombotic Therapy in Patients with NVAF Based on CHA2DS2-VASc Score CHA2DS2-VASc Score of 0 in Men or 1 in Women Reasonable to omit anticoagulant therapy CHA2DS2-VASc Score = 1 in Men or 2 in Women May consider oral anticoagulation CHA2DS2-VASc Score ≥ 2 in Men or 3 in Women Oral anticoagulant therapy is indicated. DOAC over warfarin in DOAC-eligible patientsa a Exclusions include moderate to severe mitral stenosis or mechanical heart valve. DOAC = direct oral anticoagulant. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-134 Anticoagulation Table 4. AHA/ACC/HRS Guideline for the Treatment of Patients with AFa Recommendation Recommend assessment of stroke risk in patients without valvular AF. Recommend use of the CHA 2DS2-VASc score Oral anticoagulant therapy recommended for patients with AF and a CHA 2DS2-VASc score ≥ 2 in a male or ≥ 3 in a female Dabigatran (LOE: B), rivaroxaban (LOE: B), apixaban (LOE: B), and edoxaban (LOE: B-R) are recommended over warfarin in eligible patients with AF In patients with AF who have a mechanical heart valve, warfarin is the recommended anticoagulant In patients treated with warfarin, an INR should be assessed weekly upon initiation and at least monthly when INR is stable (e.g., INR in range) Selection of anticoagulation should be based on risk of TE and regardless of AF pattern (e.g., paroxysmal, persistent, or permanent) In patients with AF who are unable to maintain a stable therapeutic INR with warfarin, use of a DOAC is recommended Patients with AF or atrial flutter ≥ 48 hr or unknown duration undergoing electrical or pharmacologic cardioversion should receive therapeutic anticoagulation with well-managed VKA (INR 2.0–3.0) or DOAC for at least 3 wk before and at least 4 wk after cardioversion regardless of CHA 2DS2-VASc Patients with AF ≥ 48 hr or unknown duration undergoing immediate cardioversion for hemodynamic instability should receive therapeutic anticoagulation as soon as possible and for at least 4 wk after successful cardioversion unless contraindicated Regardless for AF of any duration, long-term anticoagulation therapy should be based on thromboembolic and bleeding risk profile after cardioversion Level of Evidence B A A B A B C-EO B-R C C-EO Recommendations listed only include those considered class I or strong by AHA/ACC/HRS. AF = atrial fibrillation; DOAC = direct oral anticoagulant; LOE = level of evidence; TE = thromboembolism; VKA = vitamin K antagonist. a c. HAS-BLED score (Table 5) i. 9-point scale to assess risk of major bleeding in patients being considered for anticoagulation ii. H AS-BLED score of 3 or greater indicates a high bleeding risk. Less than 10% of patients have a score of 3 or greater. iii. Compared with other scoring systems (e.g., ATRIA or HEMORRHAGES), HAS-BLED more effectively discriminates risk. iv. Should not be used to determine who does not receive therapy, but more to balance the risk of stroke with the risk of bleeding. v. Predictive value is inconsistent and unreliable with DOACs. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-135 Anticoagulation Table 5. Components and Bleeding Rates of the HAS-BLED Score Risk Factors Hypertension (systolic blood pressure > 160 mm Hg) Abnormal renal or liver function (1 point each)a History of stroke Bleeding tendency or predispositionb Labile INRsc (for patients taking warfarin) Older adults (age > 65) Drugs or alcohol excess (1 point each)d Score 0 1 2 3 4 5 >5 Points 1 1 or 2 1 1 1 1 1 or 2 Risk of Major Bleeding/Year 1.1% 1.0% 1.9% 3.7% 8.7% 12.5% Undetermined Renal = chronic dialysis, renal transplantation, or SCr ≥ 2.26 mg/dL; liver = chronic hepatic disease (e.g., cirrhosis), bilirubin > 2 × the upper limit of normal (ULN), in association with AST/ALT/ALP > 3 × the ULN. b History of bleeding or predisposition to bleeding such as a bleeding diathesis or anemia. c Unstable/high INRs or time in therapeutic range < 60%. e Drugs include antiplatelet drugs or NSAIDs; alcohol use is ≥ 8 alcoholic drinks/wk. . a E. Anticoagulant Therapy 1. Warfarin a. Vitamin K antagonist (VKA) – Racemic mixture of S- and R-isomers i. Inhibits vitamin K recycling by competitively inhibiting vitamin K epoxide reductase. Ultimately, this prevents the γ-carboxylation of clotting factors II, VII, IX, and X, leaving these factors to bind to phospholipid membranes and unable to take part in coagulation. ii. Also inhibits carboxylation and activation of natural anticoagulants, protein C, protein S. iii. S-warfarin is about 4-fold more potent than R-warfarin. b. Several trials have shown a 70%–80% relative risk reduction in stroke and systemic embolism with warfarin therapy compared with placebo. c. Dosing for NVAF is based on requirements to achieve an INR goal of 2.0–3.0. Time to pharmacologic effect of warfarin requires consideration of the elimination half-life of inhibited clotting factors: factor VII = 6 hours; factor IX = 24 hours; factor X = 36 hours; factor II = 72 hours. Functional clotting factors already produced must “run their course” and cannot be inhibited with higher doses, regardless of the INR. d. Initial starting dose is typically 5 mg orally daily, but doses of up to 10 mg daily may be required depending on patient-related factors (e.g., concomitant medication use that induces the metabolism of warfarin). A lower starting dose (2–3 mg orally daily) should be considered in patients with the following: advanced age, low body weight (less than 45 kg), drug interactions, malnutrition, heart failure, hyperthyroid state, low albumin or liver disease, certain ethnic groups (e.g., Asian populations) i. Dosing algorithms are available to help with initiating therapy. In the outpatient setting, an INR should be measured at least weekly until the INR stabilizes. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-136 Anticoagulation ii. U  sing pharmacogenomic data can achieve a faster therapeutic INR and fewer INRs of 4 or less but has not reduced thrombotic or bleeding events. Therefore, using pharmacogenomic data is not part of standard of care. iii. In patients receiving a parenteral direct thrombin inhibitor or in lupus cases when the INR is not reflective of dosing, a factor VII or X concentration has been used with some success. A chromogenic factor X assay is likely most reliable for measuring the anticoagulant activity of warfarin in these patients, especially those with INR values greater than 3.0. e. Follow-up INR monitoring i. I NR values on a specific day are the result of warfarin doses taken over the previous 3–4 days, and dosing changes made on a specific day are not fully represented in the INR for 3–5 days. It takes 5–7 days to see the full effect of a stable warfarin dose. ii. If the INR is out of the therapeutic range in the outpatient setting, the total weekly dose should be increased or decreased by 5%–20%, depending on the INR; if the INR is greater than 4.0, the clinician should consider holding one or two doses before resuming the agent at the reduced maintenance dose. iii. If the INR was previously stable or therapeutic and a single out-of-range INR is 0.5 or less above or below the therapeutic range, current dosing can be continued; the INR should be rechecked within 1–2 weeks. iv. In general, no need to adjust dose if INR is within 0.1 of goal, but would monitor more closely (especially if below goal). v. If the INR decreases to 1.8 or less, the risk of ischemic stroke in AF increases by 60%, whereas the risk of bleeding does not significantly increase until the INR is greater than 4.0. vi. VKA therapy is well managed when the individual patient’s time in therapeutic range (TTR) is greater than 65%–70%. If this level of TTR is not achieved, strategies should be implemented to improve the patient’s TTR (e.g., more regular INR tests, education/counseling to better control diet, alcohol, drug interactions, medication adherence referral to a dedicated anticoagulation clinic). f. Drug-drug interactions i. S-warfarin mainly metabolized by CYP2C9 > CYP3A4. ii. R-warfarin mainly metabolized by CYP1A2, CYP3A4 > CYP2C19 iii. Enzyme induction will produce a reduced INR and warfarin effect, increasing the risk of thrombosis (e.g., phenytoin, phenobarbital, carbamazepine, rifampin, St. John’s wort). iv. Enzyme inhibition will produce an increased INR and warfarin effect, increasing the risk of bleeding. (a) S -warfarin – CYP2C9 > CYP3A4 (e.g., metronidazole, trimethoprim/sulfamethoxazole, fluconazole, isoniazid, fluoxetine, sertraline, amiodarone) (b) R-warfarin – CYP1A2 and CYP3A4 > CYP2C19 (e.g., clarithromycin, erythromycin, azole antifungals, fluoxetine, amiodarone, cyclosporine, sertraline, grapefruit juice, ciprofloxacin, protease inhibitors, diltiazem, verapamil, isoniazid, metronidazole) v. A ntiplatelet agents through a pharmacodynamic effect (e.g., aspirin, P2Y12 inhibitors, NSAIDs, fish oil, gingko, garlic) vi. Agents that compete for renal clearance (e.g., amiodarone, propafenone, cimetidine) vii. Agents that reduce vitamin K synthesis in the intestinal flora (e.g., antibiotics) viii. Reduced warfarin absorption (e.g., cholestyramine, sucralfate) g. Drug-disease interactions i. Increased clotting factor consumption (e.g., hyperthyroid state, fever) ii. Reduced warfarin metabolism (e.g., heart failure, liver disease, acute alcohol ingestion) iii. Increased warfarin metabolism (e.g., chronic alcohol ingestion, tobacco use) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-137 Anticoagulation 2. iv. Reduced clotting factor production (e.g., liver disease) v. Increased sensitivity to warfarin (e.g., acute infection, inflammation) h. Drug-food interactions i. Consistent dietary intake of vitamin K is recommended because ingested vitamin K will bypass the vitamin K epoxide reductase inhibited by the VKA and reduce INR. ii. Wide variety of vitamin K in various foods, with some green, leafy vegetables containing very high concentrations (greater than 200 mcg) of vitamin K (e.g., spinach, kale, collard greens, brussel sprouts, swiss chard) iii. In the setting of continuous enteral feeding, consider holding the feeds 1 hour before and after the dose. Dabigatran a. Direct thrombin (IIa) inhibitor (Table 6) b. Recommended dosing: 150 mg orally twice daily. Reduced dose of 75 mg twice daily has not been evaluated in clinical trials. Reduced dose of 110 mg twice daily is not indicated for patients with NVAF in the United States but is used in Canada and Europe. c. Evaluated in the RE-LY trial compared with dose-adjusted warfarin: Dabigatran at a dose of 150 mg orally twice daily was associated with a significantly lower rate of stroke and systemic embolism with similar rates of major hemorrhage compared with warfarin. d. In addition to bleeding, dyspepsia is a common adverse effect, occurring in about 10% of patients and contributing to significantly higher rates of drug discontinuation at 1 year and 2 years in the RE-LY trial. e. Drug interactions are based on P-glycoprotein (P-gp) (Table 7). f. Stability: Once the bottle is opened, the medication should be used within 4 months to maintain appropriate potency, and capsules cannot be placed in a pillbox. g. Capsules should not be opened because this results in a 75% increase in bioavailability. h. Converting to and from dabigatran to and from other anticoagulants (Box 1) Table 6. Direct Oral Anticoagulant Pharmacologic Properties Mechanism of action Bioavailability Onset of anticoagulant activity (hr) Half-life (hr)a Renal clearance Protein binding Removed by dialysis P-gp transport Hepatic metabolism a Dabigatran Rivaroxaban Direct IIa inhibitor Factor Xa inhibitor 3%–7% 66% without food, 80%–100% with food 1–2 2–4 Apixaban Edoxaban Factor Xa inhibitor Factor Xa inhibitor 50% 62% 3–4 1–2 12–17 80% 35% Yes Yes None 12 27% 87% No Yes CYP3A4/5 10–14 50% 55% No Yes Minimal (4% CYP3A4/5) 5–9 36% 90% No Yes CYP3A4/5 and CYP2J2 Half-life can be increased in patients with advanced age and/or severe illness with renal and/or hepatic failure. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-138 Anticoagulation Table 7. Dosing of DOACs in NVAF Agent Dabigatran Standard Dose Adjustmenta Dosing 150 mg BID 75 mg BID • CrCl 15–30 mL/min • CrCl 30–50 mL/min with systemic ketoconazole or dronedarone (P-gp inhibitors) Rivaroxaban 20 mg once daily with meals 15 mg once daily with meals • CrCl 15–50 mL/min • Dialysisb Apixaban 2.5 mg BID • Two of three criteria (age ≥ 80, weight ≤ 60 kg, or SCr ≥ 1.5 mg/dL) • Use with strong CYP3A4 and P-gp inhibitorsd 5 mg BID • Dialysisb,e Edoxaban 60 mg once daily 30 mg once daily • CrCl 15–50 mL/min Avoid Usea • CrCl < 15 mL/min • Dialysis • CrCl 15–30 mL with amiodarone, verapamil, ketoconazole, dronedarone, and clarithromycin (P-gp inhibitors) • P-gp inducers (e.g., rifampin) • Chemotherapy agents – Vinblastine, doxorubicin, imatinib, crizotinib, vandetanib, sunitinib, abiraterone, and enzalutamide • Strong CYP3A4 and P-gp inducersc • Strong CYP3A4 and P-gp inhibitorsd • Chemotherapy agents – Vinblastine, doxorubicin, imatinib, crizotinib, vandetanib, sunitinib, abiraterone, and enzalutamide • Strong CYP3A4 and P-gp inducersc (e.g., rifampin, phenytoin, carbamazepine, St. John’s wort) • If indicated for 2.5 mg BID and concomitant strong CYP3A4 and P-gp inhibitorsd • Chemotherapy agents – Vinblastine, doxorubicin, imatinib, crizotinib, vandetanib, sunitinib, abiraterone, and enzalutamide • CrCl > 95 mL/min • CrCl < 15 mL/min • Dialysis • P-gp inducers (e.g., rifampin) • Chemotherapy agents – Vinblastine, doxorubicin, imatinib, crizotinib, vandetanib, sunitinib, abiraterone, and enzalutamide CrCl in the DOAC trials was calculated using the Cockcroft-Gault equation with total body weight. Data in the package label for dosing for rivaroxaban and apixaban in the setting of dialysis are from eight-patient single-dose pharmacokinetic studies, with no data supporting safety or efficacy available. c Strong CYP3A4 and P-gp inducers include rifampin, phenytoin, carbamazepine, St. John’s wort. d Strong CYP3A4 and P-gp inhibitors include protease inhibitors, itraconazole, ketoconazole, conivaptan. e The apixaban package label suggests a dose of 5 mg BID in patients receiving dialysis with age < 80 and weight > 60 kg. A study with several days of apixaban administration in patients receiving dialysis showed about a 2-fold increase in Cmax and AUC using 5 mg BID and suggested that the 2.5-mg BID dose can be considered. BID = twice daily; DOAC = direct oral anticoagulant. a b ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-139 Anticoagulation Box 1. Dabigatran Conversion Strategies to and from Oral and Parenteral Anticoagulants Converting from Dabigatran to Warfarin Dependent upon calculated creatinine clearance (mL/min): • For patients with a CrCl ≥ 50 mL/min, initiate warfarin 3 days before discontinuing dabigatran • For patients with a CrCl 31–50 mL/min, initiate warfarin 2 days before discontinuing dabigatran • For patients with a CrCl 15–30 mL/min, initiate warfarin 1 day before discontinuing dabigatran • For patients with a CrCl < 15 mL/min, no dosing recommendations are available. Reasonable to initiate warfarin 1 day before discontinuing dabigatran Converting from Warfarin to Dabigatran Discontinue warfarin and initiate dabigatran when the INR is < 2.0a Converting Between Dabigatran and Parenteral Anticoagulants • Initiate dabigatran 0–2 hr before the next dose of the parenteral drug was to have been administered (e.g., LMWH) or when a continuously administered parenteral drug is discontinued (e.g., IV UFH) • For patients currently taking dabigatran, wait 12 hr (CrCl > 30 mL/min) or 24 hr (CrCl < 30 mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant • Note: High dabigatran concentrations can occur in severe renal impairment, and effects last for several days. A thrombin time can be used to determine when the effects of dabigatran are dissipating Because dabigatran can contribute to an increased INR, the INR will better reflect warfarin’s effect after dabigatran has been discontinued for at least 2 days. INR = international normalized ratio; IV = intravenous(ly); LMWH = low-molecular-weight heparin; UFH = unfractionated heparin. a 3. Rivaroxaban a. Factor Xa inhibitor (see Table 6) b. Recommended dosing: 20 mg orally once daily with the evening meal. Reduced dose of 15 mg once daily is available and should be taken with food. Used in around 20% of patients in the ROCKET-AF trial c. Compared with dose-adjusted warfarin in the ROCKET-AF trial: Rivaroxaban, compared with warfarin, was noninferior for the prevention of stroke and systemic embolism and associated with a significantly reduced rate of intracranial hemorrhage and fatal bleeding. d. Drug interactions i. Strong CYP3A4 and P-gp inhibitors and inducers (see Table 7) ii. The package insert for rivaroxaban has a warning for use of moderate CYP3A4 and P-gp inhibitors (e.g., amiodarone, verapamil, diltiazem, erythromycin, dronedarone, cimetidine) in patients with a CrCl of 15–80 mL/minute due to risk for increased rivaroxaban concentrations, as demonstrated in pharmacokinetic studies. An analysis of patients receiving these agents with rivaroxaban with this level of renal function from the ROCKET-AF trials did not show an increased risk of bleeding. e. Oral bioavailability of rivaroxaban 20 mg increased with food; otherwise, around 66% in the fasting state f. Converting to and from rivaroxaban to and from other anticoagulants (Box 2) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-140 Anticoagulation Box 2. Rivaroxaban Conversion Strategies to and from Oral and Parenteral Anticoagulants Converting from Rivaroxaban to Warfarin Discontinue rivaroxaban and initiate both a parenteral anticoagulant and warfarin when the next dose of rivaroxaban would have been taken. Discontinue the parenteral anticoagulant when INR > 2.0 Converting from Rivaroxaban to Anticoagulants (with rapid onset) Other than Warfarin Discontinue rivaroxaban, and administer the first dose of the other anticoagulant (oral or parenteral; other than warfarin) when the next rivaroxaban dose would have been taken Converting from Warfarin to Rivaroxaban Discontinue warfarin and initiate rivaroxaban once INR < 3.0 Converting from Anticoagulants (with rapid onset) Other than Warfarin to Rivaroxaban Initiate rivaroxaban 0–2 hr before the next scheduled evening administration of the drug (e.g., LMWH or nonwarfarin oral anticoagulant), and do not administer the other anticoagulant. For UFH administered by continuous infusion, discontinue the infusion and initiate rivaroxaban at the same time INR = international normalized ratio; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin. 4. Apixaban a. Factor Xa inhibitor (see Table 6) b. Recommended dosing: 5 mg orally twice daily. Reduced dose of 2.5 mg twice daily is available and was used in about 5% of patients in the ARISTOTLE trial. Of note, apixaban 2.5 mg orally twice daily was used in the landmark trial in individuals with two or more of the following: age 80 or older, weight 60 kg or less, and/or SCr 1.5 mg/dL or greater. c. Evaluated in the ARISTOTLE trial compared with dose-adjusted warfarin: Apixaban was associated with a significantly lower incidence of stroke, systemic embolism, major bleeding, hemorrhagic stroke, and death from any cause compared with warfarin. d. Drug interactions are associated with strong CYP3A4 and P-gp inhibitors and inducers (see Table 7). e. Converting to and from apixaban to and from other anticoagulants (Box 3) Box 3. Apixaban Conversion Strategies to and from Oral and Parenteral Anticoagulants Converting from Apixaban to Warfarin Discontinue apixaban, and initiate both a parenteral anticoagulant and warfarin when the next dose of apixaban would have been taken. Discontinue the parenteral anticoagulant when INR > 2.0 Converting from Apixaban to Anticoagulants (with rapid onset) Other than Warfarin Discontinue apixaban, and initiate the new anticoagulant (oral or parenteral; other than warfarin) at the usual time of the next dose of apixaban Converting from Warfarin to Apixaban Warfarin should be discontinued and apixaban initiated when INR < 2.0 Converting from Anticoagulants (with rapid onset) Other than Warfarin to Apixaban Initiate apixaban 0–2 hr before the next scheduled administration of the drug (e.g., LMWH or non-warfarin oral anticoagulant), and do not administer the other anticoagulant. For UFH administered by continuous infusion, discontinue the infusion and initiate apixaban at the same time INR = international normalized ratio; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-141 Anticoagulation 5. Edoxaban a. Factor Xa inhibitor (see Table 6) b. Recommended dosing: 60 mg orally once daily in patients with a CrCl greater than 50 to 95 mL/ minute or less (see Table 6). Reduced dose of 30 mg once daily is available. Used in around 25% of the patients in the ENGAGE-AF trial c. Evaluated in the ENGAGE-AF TIMI 48 trial compared with dose-adjusted warfarin: Edoxaban, compared with warfarin, was noninferior for the prevention of stroke or systemic embolism and associated with significantly lower rates of major bleeding and death from cardiovascular causes. d. Drug interactions are associated with P-gp (see Table 7). e. Converting to and from edoxaban to and from other anticoagulants (Box 4) Box 4. Edoxaban Conversion Strategies to and from Oral and Parenteral Anticoagulants Converting from Edoxaban to Warfarin Oral option: For patients taking 60 mg of edoxaban, reduce the dose to 30 mg and initiate warfarin concomitantly. For patients receiving 30 mg of edoxaban, reduce the dose to 15 mg and initiate warfarin concomitantly. INR must be measured at least weekly and just before the daily dose of edoxaban to minimize the influence of edoxaban on INR measurements. Once a stable INR ≥ 2.0 is achieved, edoxaban should be discontinued and warfarin continued Parenteral option: Discontinue edoxaban, and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose. Once a stable INR ≥ 2.0 is achieved, the parenteral anticoagulant should be discontinued and warfarin continued Converting from Edoxaban to Anticoagulants (with rapid onset) Other than Warfarin Discontinue edoxaban, and initiate the new anticoagulant (oral or parenteral; other than warfarin) at the usual time of the next dose of edoxaban Converting from Warfarin to Edoxaban Discontinue warfarin and initiate edoxaban when the INR is ≤ 2.5 Converting from Anticoagulants (with rapid onset) Other than Warfarin to Edoxaban Discontinue the other oral anticoagulant (other than warfarin) or LMWH, and initiate edoxaban at the usual time of the next dose of the other anticoagulant. For UFH administered by continuous infusion, discontinue the infusion and initiate edoxaban 4 hr later INR = international normalized ratio; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin. 6. DOAC vs. warfarin in AF a. Primary efficacy end point – stroke or systemic embolism (for all DOAC trials) i. All agents were noninferior to warfarin. ii. Dabigatran and apixaban were superior to warfarin in the intention-to-treat analysis. iii. Rivaroxaban and edoxaban were superior to warfarin in the per-protocol analysis. b. Hemorrhagic stroke – All agents showed a significantly lower rate of hemorrhagic stroke than warfarin. This is a key benefit of a DOAC over warfarin across all trials. c. Ischemic stroke – Dabigatran was the only DOAC that significantly reduced ischemic stroke at a dose of 150 mg orally twice daily, as shown in the unblinded RE-LY trial. d. Major bleeding i. Apixaban and edoxaban showed a statistically significant reduction in major bleeding compared with warfarin. ii. Dabigatran and rivaroxaban had safety outcomes similar to warfarin. e. All-cause mortality: All agents reduced mortality by approximately 10%, but apixaban was the only agent to show a statistically significant reduction in mortality compared with warfarin (p=0.01). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-142 Anticoagulation 7. Controversies and considerations a. Major differences in the trials (Table 8) prevent concluding that one agent has superior efficacy or safety over any other. The AHA/ACC/HRS, European Society of Cardiology, and American College of Chest Physicians guidelines do not prefer one DOAC to another. b. Patient risk i. Varied results may be due to varying risks of patients compared with using a different DOAC. c. TTR was greater than 60% in all trials except for ROCKET AF (55%). This trial had patients at the highest risk (mean CHADS2 score 3.5) and was the only trial that did not provide the investigators with a protocol to follow (wanted to evaluate real-world practice). Regardless, analysis has shown that TTR with warfarin did not influence the study outcomes for any of the agents other than perhaps dabigatran. Table 8. Comparison of Trial Characteristics of Direct Oral Anticoagulants vs. Warfarin Study drug Study size Double-blind Previous VKA use (%) CHADS2 score Mean 0 or 1 (%) 2 (%) 3–6 (%) Previous stroke or TIA (%) Protocol to manage INR Mean TTR (%) Median TTR (%) Median follow-up (yr) RE-LY Dabigatran 18,113 (three arms) No 50 ROCKET AF Rivaroxaban 14,264 (two arms) Yes 62 ARISTOTLE Apixaban 18,201 (two arms) Yes 57 ENGAGE AF-TIMI 48 Edoxaban 21,105 (three arms) Yes 59 2.1 32 36 32 20 Yes 64 NR 2.0 3.5 0 13 87 55 No 55 58 1.9 2.1 34 36 30 19 Yes 62 66 1.8 2.8 — 77 (≤ 3) 23 (4–6) 28 Yes 65 68 2.8 NR = not reported; TIA = transient ischemic attack; TTR = time in therapeutic range; VKA = vitamin K antagonist. 8. General warnings regarding DOACs and special populations: a. Because of limited safety in pregnancy, it is recommended to avoid DOACs. b. Evidence has confirmed the presence of DOACs in breast milk, or it is not known. In addition, safety data are limited; therefore, DOACs are not recommended for use in patients who are breastfeeding. An alternative mechanism of anticoagulation will be needed during breastfeeding. c. Avoid DOACs in patients with moderate to severe hepatic dysfunction (Child-Pugh class B or C) because of lack of data. These patients have been excluded from the phase III clinical trials. d. Avoid DOACs in patients with antiphospholipid syndrome. i. Two studies with DOACs showed worse clinical outcomes than with warfarin in patients with triple-positive antiphospholipid syndrome (lupus anticoagulant, anticardiolipin, and anti– β2-glycoprotein I antibodies). ii. Although patients with single- or double-positive antiphospholipid syndrome were not included in these studies, it would be prudent to avoid DOACs until more data are available. e. Patients with obesity i. Although the use of DOACs was originally cautioned in patients with AF and class 3 (severe) obesity (BMI 40 kg/m 2 or greater) because of concern for potential underdosing of the anticoagulant, additional outcomes studies and post hoc analyses evaluating DOACs across BMI categories including class 3 obesity suggest maintenance of efficacy and safety of treatment. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-143 Anticoagulation f. g. F. ii. N  o dose adjustments are recommended when using apixaban, rivaroxaban, and dabigatran for AF using on the basis of obesity status. iii. Edoxaban has limited data showing safety and efficacy outcomes. Therefore, it is recommended to avoid use in class 3 obesity. Patients undergoing bariatric surgery: All DOACs have unpredictable pharmacokinetics in these patients and should therefore be avoided. Patients with low body weight: Data are very limited, but are most supportive of apixaban and rivaroxaban, followed by edoxaban and dabigatran. Although no dose adjustment is recommended, these patients have an increase in concentration that may expose them to a higher risk of bleeding. Antiplatelet Therapy 1. Aspirin a. Before the 2019 ACC/AHA/HRSA guideline publication, aspirin may have been considered in individuals with a CHA 2DS2-VASc score of 1. b. Data that led to changes in the role of aspirin in NVAF included a meta-analysis that consisted of eight trials and a total of 4876 participants comparing aspirin with placebo or no treatment. The primary outcome was incidence of stroke. Aspirin dosages ranged from 25 mg twice daily to 1300 mg once daily. i. Primary prevention aspirin had an absolute reduction of 0.8%. ii. Secondary prevention aspirin had an absolute reduction of 2.5%. iii. Benefit of aspirin from one trial (SPAF-1) drives these results. c. SPAF (Stroke Prevention in Atrial Fibrillation)-1 trial showed a benefit of aspirin in reducing the risk of ischemic stroke in patients with NVAF. i. Dose was 325 mg daily. ii. Effectiveness was shown in patients older than 75. d. Apixaban 5 mg twice daily was compared with aspirin (81 mg daily or 324 mg daily) in patients who were unsuitable for therapy with a VKA in the AVERROES trial. i. 64% of patients received an aspirin dose of 81 mg daily, and only 7% received an aspirin dose of 324 mg. ii. Trial was terminated early because of the superiority of apixaban in reducing the occurrence of stroke or systemic embolism compared with aspirin. iii. No difference in major bleeding (HR with apixaban, 1.13; 95% CI, 0.74–1.75; p=0.57) 2. Aspirin plus clopidogrel – Evaluated in two ACTIVE trials (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events). Patients with NVAF and at least one risk factor for stroke a. ACTIVE W (compared with dose-adjusted warfarin) i. Aspirin 75–100 mg daily plus clopidogrel 75 mg daily was compared with dose-adjusted warfarin to an INR of 2.0–3.0. ii. Trial was terminated early because of the superior efficacy of warfarin. iii. Aspirin and clopidogrel proved inferior to warfarin (5.6% vs. 3.9%; p<0.001) for stroke, systemic embolism, myocardial infarction (MI), and vascular death. iv. No difference in major bleeding, but significantly more minor bleeding with aspirin and clopidogrel than with warfarin b. ACTIVE A (compared with aspirin monotherapy) i. Aspirin 75–100 mg daily plus clopidogrel 75 mg daily compared with aspirin alone if patients were not candidates for, or refused anticoagulation with, warfarin. ii. Aspirin plus clopidogrel was superior to aspirin alone in reducing composite outcome of stroke, MI, non–central nervous systemic embolism, or death from vascular causes (6.8% vs. 7.6%; p=0.01). Primary composite outcome driven by reduction in ischemic stroke. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-144 Anticoagulation iii. S  ignificant increase in major and minor bleeding with use of dual antiplatelet therapy (p<0.001) iv. Subgroup analysis identified that patients 65–74 years of age and at intermediate risk of stroke (CHADS2 score 1) had the most benefit from adding clopidogrel to aspirin. G. P  atients with NVAF Who Need Percutaneous Coronary Intervention (PCI) (require triple antithrombotic therapy) 1. Optimal antithrombotic therapy for patients with both AF requiring oral anticoagulation and PCI with stent(s) requiring dual antiplatelet therapy has been called “triple therapy” and deemed challenging in balancing efficacy in reducing complications such as stent thrombosis and stroke while minimizing risk of bleeding. 2. Although the risk of major bleeding with warfarin therapy in patients with AF is around 2% per year, patients receiving warfarin, aspirin, and clopidogrel have a major bleeding rate of around 8% per year. 3. Clinical approaches for patients with a need for both oral anticoagulants and antiplatelet therapy have been evaluated to reduce the risk of ischemic/thrombotic events and bleeding risk. Table 9 summarizes the landmark trials that support recommendations in the 2020 ACC expert consensus decision pathway. Table 9. Summarized Landmark Trials of Oral Anticoagulation and Antiplatelet Therapy for AF and PCI Trial WOEST Patients enrolled (n) 572 Inclusion criteria Adults with indication for oral anticoagulant who underwent PCI Follow-up (mo) Treatment groupsa P2Y12 inhibitor Primary outcome Primary outcome event rate (HR; 95% CI) Primary ischemic/ thrombotic end point PIONEER AF-PCI 2124 Adults with NVAF who underwent PCI RE-DUAL PCI 2725 Adults with NVAF who underwent PCI AUGUSTUS 4614 Adults with NVAF with recent ACS or PCI and planned use of P2Y12 inhibitor for ≥ 6 mo 12 12 14 6 VKA + P2Y12 Rivaroxaban Dabigatran Apixaban inhibitor (15 mg daily) + (110 mg twice daily) + (5 mg twice daily) + 2. VKA + aspirin + P2Y12 inhibitor P2Y12 inhibitor P2Y12 inhibitor P2Y12 inhibitor Rivaroxaban Dabigatran Apixaban (2.5 mg twice daily) (150 mg twice daily) + (5 mg twice daily) + + aspirin + P2Y12 inhibitor aspirin + P2Y12 inhibitor P2Y12 inhibitor VKA + aspirin (1–3 mo) + VKA + aspirin + VKA + P2Y12 inhibitor P2Y12 inhibitor P2Y12 inhibitor VKA + aspirin + P2Y12 inhibitor Clopidogrelb (88%) Clopidogrelb (100%) Clopidogrelb (93%) Clopidogrele (93%) Ticagrelorc (5%) Ticagrelorc (12%) Ticagrelore (6%) Prasugreld (2%) Prasugrele (1%) Any bleeding Clinically significant Major bleeding or Major bleeding or bleeding CRNM CRNM Apixaban vs. VKA: Group 1 vs. 3: 19.4% vs. 44.4% Group 1 vs. 3: 10.5% vs. 14.7% 15.4% vs. 26.9% (0.36; 0.26–0.5) 16.8% vs. 26.7% (0.69; 0.58–0.81) (0.52; 0.42–0.63) (0.59; 0.47–0.76) Aspirin vs. placebo: Group 2 vs. 3: Group 2 vs. 3: 16.1% vs. 9% 20.2% vs. 25.7% 18% vs. 26.7% (1.89; 1.59–2.24) (0.72; 0.58–0.88) (0.63; 0.5–0.8) Death or ischemic Death from CV Death, MI, stroke, Death, MI, stroke, event (MI, stroke, causes, MI, stroke systemic embolism, target vessel stent thrombosis, or unplanned revascularization, revascularization) revascularization and stent thrombosis ENTRUST-AF PCI 1506 Adults with NVAF who underwent PCI 12 Edoxaban (60 mg daily) + P2Y12 inhibitor VKA + aspirin + P2Y12 inhibitor Clopidogrelb Major bleeding or CRNM 17% vs. 20% (0.83; 0.65–1.05; p=0.001 for NI) Death from CV causes, stroke, systemic embolic event, MI, or stent thrombosis ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-145 Anticoagulation Table 9. Summarized Landmark Trials of Oral Anticoagulation and Antiplatelet Therapy for AF and PCI (Cont’d) Trial Primary ischemic/ thrombotic event rate (HR; 95% CI) WOEST PIONEER AF-PCI RE-DUAL PCI AUGUSTUS ENTRUST-AF PCI 7% vs. 6% Apixaban vs. VKA: Group 1 vs. 3: 11.1% vs. 17.6% (0.6; Group 1 vs. 3: (1.06; 0.71–1.69) 6.7% vs. 7.1% 15.2% vs. 13.4% 0.38–0.94) 6.5% vs. 6% (0.93; 0.75–1.16) (1.13; 0.9–1.43) (1.08; 0.69–1.68) Aspirin vs. placebo: Group 2 vs. 3: Group 2 vs. 3: 6.5% vs. 7.3% 11.8% vs. 12.8% 5.6 vs. 6% (0.89; 0.71–1.11) (0.89; 0.67–1.19) (0.93; 0.59–1.48) a Low-dose aspirin orally daily (75–100 mg). b Clopidogrel dosing at 75 mg orally daily. c Ticagrelor dosing at 90 mg orally twice daily. d Prasugrel dosing at 10 mg orally once daily. e Dosages not reported. ACS = acute coronary syndrome; AF = atrial fibrillation; CRNM = clinically relevant nonmajor (bleeding); CV = cardiovascular; MI = myocardial infarction; NI = noninferiority; NVAF = nonvalvular atrial fibrillation; PCI = percutaneous coronary intervention; VKA = vitamin K antagonist. 4. 2020 ACC expert consensus decision pathway a. Recommends against routine use of triple therapy b. Recommends a default strategy after PCI of an anticoagulant and a P2Y12 inhibitor i. DOAC recommended over warfarin ii. Clopidogrel recommended over ticagrelor and prasugrel c. Durations after PCI i. Discontinue aspirin at hospital discharge for PCI, but may continue up to 30 days in patients at high risk of thrombosis and low risk of bleeding. If aspirin is used in combination with an anticoagulant, the dose should not exceed 100 mg daily. ii. PCI for stable ischemic heart disease: Patients should receive an anticoagulant and a P2Y12 inhibitor for 6 months, then an anticoagulant and a P2Y12 inhibitor or aspirin for an additional 6 months, then an anticoagulant alone long term. iii. PCI for an acute coronary syndrome should receive an anticoagulant and a P2Y12 inhibitor for 12 months, then an anticoagulant alone. iv. Limiting use of antiplatelet therapy to only 3 months in patients receiving PCI for stable ischemic heart disease, or only 6 months in patients receiving PCI for an acute coronary syndrome, can be considered in patients at high risk of bleeding. Patient Case Questions 1–4 pertain to the following case. B.D. is a 73-year-old male (height 175 cm, weight 80 kg) with newly diagnosed NVAF. He also has a history of hypertension, dyslipidemia, stable ischemic heart disease, and systolic heart failure. His medications include aspirin 81 mg orally daily, enalapril 10 mg orally daily, atorvastatin 80 mg orally daily, metoprolol succinate 200 mg orally daily, furosemide 40 mg orally daily, spironolactone 25 mg orally daily, and amlodipine 10 mg orally daily. His heart rate is 72 beats/minute and blood pressure is 122/72 mm Hg. His laboratory values include K 4.9 mEq/L, stable SCr 1.9 mg/dL, and blood glucose 101 mg/dL. 1. Which best depicts B.D.’s CHA2DS2-VASc score? A. 2. B. 3. C. 4. D. 5. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-146 Anticoagulation Patient Case (Cont’d) 2. W hich is most accurate regarding DOAC therapy for reducing the risk of stroke in patients with NVAF such as B.D.? A. All the DOACs significantly reduced ischemic stroke in the phase III trials compared with warfarin. B. All the DOACs significantly reduced hemorrhagic stroke in the phase III trials compared with warfarin. C. A  pixaban is more effective than rivaroxaban because apixaban was superior to warfarin in the ARISTOTLE trial and rivaroxaban was only noninferior to warfarin in the ROCKET-AF trial. D. D  abigatran was studied in patients with highest risk across the phase III trials and should not be used in patients with a CHADS2 score less than 3. 3. Which is the most appropriate regimen for reducing B.D.’s risk of stroke? A. Dabigatran 75 mg orally twice daily. B. Rivaroxaban 20 mg orally once daily. C. Apixaban 5 mg orally twice daily. D. Edoxaban 60 mg orally once daily. 4.  ix months later, B.D. elects to undergo PCI for the management of his coronary artery disease. He has had S no medication changes, and his vital signs and laboratory information remain consistent. Which is the best available evidence-based approach to B.D.’s antithrombotic therapy? A. Rivaroxaban 10 mg orally daily plus clopidogrel 75 mg orally daily. B. Apixaban 2.5 mg orally twice daily plus clopidogrel 75 mg orally daily. C. A  djusted-dose warfarin to an INR of 2.0–3.0 plus aspirin 81 mg orally daily plus clopidogrel 75 mg orally daily. D. Edoxaban 15 mg orally once daily plus aspirin 81 mg orally daily plus clopidogrel 75 mg orally daily. II. ANTICOAGULATION IN VALVULAR HEART DISEASE A. Risk of TE: Can be 20-fold higher for patients with valve disease than for patients without this disease B. T  he 2020 ACC/AHA guidelines on the management of valvular disease provide the most up-to-date information on the role of anticoagulation with valvular heart disease. C. Bioprosthetic Heart Valves 1. The first 3 months is the highest-risk period of TE after bioprosthetic heart valve implantation, especially with mitral valves. 2. Bioprosthetic heart valves have a lower long-term risk of TE than mechanical heart valves. 3. Risk of TE is higher with mitral valves than with aortic valves because of the larger diameter and therefore slower flow of the mitral valve compared with the smaller diameter and faster flow of the aortic valve. 4. Surgical aortic bioprosthetic valve a. Lifelong low-dose aspirin (75–100 mg orally daily) for patients without another indication for oral anticoagulation (class 2a recommendation) b. Patients at low risk of bleeding can receive initial anticoagulation with warfarin to a target INR of 2.5 (±0.5) for at least 3 months and for up to 6 months (class 2a recommendation). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-147 Anticoagulation 5. 6. 7. Transcatheter aortic valve implantation a. Lifelong low-dose aspirin (75–100 mg orally daily) for patients without another indication for oral anticoagulation (class 2a recommendation) b. Patients at low risk of bleeding may receive initially one of the following for 3–6 months (class 2b recommendation): i. Low-dose aspirin (75–100 mg) orally daily and clopidogrel 75 mg orally daily ii. Warfarin at a target INR of 2.5 (±0.5) Mitral bioprosthetic valve a. Lifelong low-dose aspirin for patients without another indication for oral anticoagulation (class 2a recommendation) b. Patients at low risk of bleeding can receive warfarin to a target INR of 2.5 (±0.5) for at least 3 months and for up to 6 months (class 2a recommendation). Patients with concomitant AF a. If bioprosthetic valve placement was more than 3 months ago, a DOAC is an effective alternative to warfarin, and use should be based on the patient’s CHA 2DS2-VASc score (class 1 recommendation). b. If AF onset is within 3 months of bioprosthetic valve placement, warfarin should be used. Optimal duration of anticoagulation is not well defined. Repeat evaluation for recurrence of arrythmia is recommended, and evaluation of CHA 2DS2-VASc score is encouraged (class 2a recommendation). i. The RIVER trial (n=1005) evaluated rivaroxaban 20 mg daily and warfarin (INR 2.0–3.0) in patients with AF and a bioprosthetic mitral valve. ii. Rivaroxaban was noninferior to warfarin (median TTR of 65.5%) with respect to the mean time until the primary outcome of death, major CV events, or major bleeding at 12 months. iii. Thrombotic events or CV death with rivaroxaban was 3.4% compared with 5.1% with warfarin (HR 0.65; 95% CI, 0.35–1.20). iv. Stroke was significantly lower with rivaroxaban (0.6% vs. 2.4%). Major bleeding with rivaroxaban was 1.4% compared with 2.6% with warfarin (HR 0.54; 95% CI, 0.21–1.35). v. In the 20% of patients enrolled within 3 months of valve placement, thrombotic events or CV death was significantly reduced with rivaroxaban compared with warfarin (6.4% vs. 18.9%), suggesting a role for use of a DOAC within the first 3 months of valve placement. D. Mechanical Heart Valves 1. Warfarin therapy should be used regardless of the valve position to prevent valve thrombosis and TE events (class 1 recommendation). 2. Aortic mechanical heart valve a. Patients with a bileaflet or current-generation single-tilting disk valve and no risk factors for TE should have a target INR of 2.5 (±0.5) (class 1 recommendation). b. Patients with risk factors for TE (i.e., AF, prior TE, left ventricular systolic dysfunction, hypercoagulable state) or those with an older-generation valve (e.g., ball-in-cage) should have a target INR of 3.0 (±0.5) (class 1 recommendation). c. Low-dose aspirin should only be added for patients with an indication for antiplatelet therapy and a low risk of bleeding (class 2b recommendation). d. Patients receiving an On-X aortic valve and having no risk factors for TE should have a target INR of 2.5 (±0.5) for the first 3 months, followed by a target INR of 1.5–2.0 with low-dose aspirin (class 2b recommendation). 3. Mitral mechanical heart valve a. Patients should receive warfarin therapy with a target INR of 3.0 (±0.5) (class 1 recommendation). b. Low-dose aspirin should only be added for patients with an indication for antiplatelet therapy and a low risk of bleeding (class 2b recommendation). 4. Aortic and mitral heart valves – Patients should receive warfarin therapy with a target INR of 3.0 (±0.5). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-148