Practical application of anticoagulation therapy af and vte april 12

8,991 views

Published on

Published in: Healthcare, Health & Medicine
0 Comments
7 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
8,991
On SlideShare
0
From Embeds
0
Number of Embeds
22
Actions
Shares
0
Downloads
153
Comments
0
Likes
7
Embeds 0
No embeds

No notes for slide
  • This slide must be visually presented to the audience AND verbalized by the speaker.
  • This slide must be visually presented to the audience AND verbalized by the speaker.
  • This slide must be visually presented to the audience AND verbalized by the speaker.
  • Atrial fibrillation (AF) is characterized by irregular and ineffective atrial contraction. After an initial diagnosis of paroxysmal AF, there is a slow but steady progression to chronic AF, with baseline ECG variables, age, cardiomyopathy, and heart rate being independently associated with progression to chronic AF. AF worsens over time, producing changes in atrial function and structure (remodeling) that promote the occurrence of arrhythmias.
  • Atrial fibrillation (AF) is a common arrhythmia that affects about 1% of the population, and is the most common type of cardiac arrhythmia requiring medical care. About 350,000 Canadians are affected by AF, and one in six strokes occurs in patients with AF. The prevalence of AF increases with age, and is increasing in the community due to an increasingly elderly population. Lifetime risks for developing the condition are 1 in 4 for men and women ≥ 40 years of age.
  • Irregular and ineffective atrial contraction in AF can lead to thrombus formation in the left atrial appendage, which may in turn embolize and enter the systemic circulation to cause infarction involving the brain, kidney, gastrointestinal tract or limbs. Thus AF is associated with increased morbidity and mortality, and is an important risk factor for stroke. Stroke risk is increased 4-5-fold in patients with AF, increasing from 1.5% at age 50-59 years to 23.5% at age 80-89 years. One in six strokes occurs in patients with AF. About 40% of AF patients in primary care may be at high risk of stroke. AF is also associated with higher rates of heart failure and death. Patients with AF have an impaired quality of life (QoL), but QoL can improve to normal levels with treatment.
  • d) 3.James has hypertension, diabetes, and CHF, for each of which he gets 1 point. He does not have the other risk factors considered for the CHADS2 score, i.e., age ≥75 years and history of TIA/stroke
  • Much of the morbidity and mortality associated with AF results from thromboembolism. Therefore all AF patients should be evaluated for thromboembolic risk. The CHADS2 score (C = CHF, H = hypertension, A = age, D = diabetes, S = stroke) can help to quantify the patient’s stroke risk and may aid in selection of antithrombotic therapy for risk reduction. To calculate the CHADS2 score, 1 point each is assigned for the presence of the following risk factors: recent CHF, hypertension, age ≥ 75 years and diabetes; and 2 points are assigned for a history of prior stroke or TIA. Higher scores are associated with greater risk (see Tables below).
  • Another scheme for assessing stroke risk is the CHA2DS2-VASc score, [14] which considers additional factors, i.e., vascular disease (myocardial infarction, peripheral arterial disease and/or aortic atherosclerosis, 1 point), age 65-74 years (age 65-74 years, 1 point; age ≥ 75 yrs, 2 points) and gender (female, 1 point). The CHA2DS2-VASc score is particularly useful for identifying patients with risk factors of stroke, but whose CHADS2 score is 0. As per the CHA2DS2-VASc scheme, patients with one definitive risk factor or a CHA2DS2-VASc score of ≥ 1 could be considered for oral anticoagulation, but a patient with a CHA2DS2-VASc score of 0 is truly low risk and could be managed with no antithrombotic therapy. Patients with a CHA2DS2-VASc score of ≥ 2 have sufficient stroke risk to justify use of an anticoagulant
  • a) YesAnticoagulant therapy should be considered for patients at high risk of stroke (CHADS2 ≥ 2) and for most patients at intermediate risk (CHADS2 = 1). The CHA2DS2-VASc score is another scheme for assessing stroke risk, and can help in identifying patients with risk factors of stroke, but whose CHADS2 score is 0. Many patients with a CHADS2 score of 0 but a CHA2DS2-VASc score of 1, and all patients with a CHA2DS2-VASc score of ≥ 2, have sufficient risk to justify the use of oral anticoagulant therapy.
  • Treatment strategies for AF involve rate control and/or rhythm control (aimed at aim at controlling ventricular rate and/or restoring sinus rhythm), and antithrombotic therapy (aimed at prevention of thromboembolism). Antithrombotic therapy in AF involves the use antiplatelet agents or anticoagulants. The ACTIVE-W trial showed that oral anticoagulant therapy is superior to clopidogrel plus acetyl salicylic acid (ASA) for prevention of vascular events in patients with AF at high risk of stroke, and the ACTIVE-A study showed that clopidogrel plus ASA, as compared with ASA alone, reduced the rate of major vascular events among patients with AF who were at increased risk for stroke but for whom a vitamin K antagonist (VKA) was unsuitable.
  • The Canadian Cardiovascular Society (CCS) recommends that CHADS2 be used to assess thromboemboic risk and that oral anticoagulant therapy should be considered for patients at high risk of stroke (CHADS2 ≥ 2) and for most patients at intermediate risk (CHADS2 = 1).Many patients with a CHADS2 score of 0 may also have elevated stroke risk. Among these patients, most patients with a CHA2DS2-VASc score of 1, and all patients with a CHA2DS2-VASc score of ≥ 2 have sufficient risk to justify the use of oral anticoagulant therapy. Newer agents, i.e., dabigatran, rivaroxaban and apixabanare preferred over warfarin for stroke prevention in patients with AF.
  • Anticoagulant therapy for stroke prevention in AF is associated with bleeding risk. Therefore, the decision to initiate anticoagulant therapy in a particular patient would involve an assessment bleeding risk in that patient. The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol) bleeding score is a practical tool to assess the individual bleeding risk with warfarin of real-world patients with AF. A HAS-BLED score of ≥ 3 indicates that the patient is at increased risk of major bleeding.
  • In a meta-analysis involving 6 randomised controlled trials (2900 participants) comparing warfarin and placebo or no treatment in patients with nonvalvular AF, warfarin was associated with a 64% reduction in the incidence of stroke. By contrast, antiplatelet agents (8 trials, 4876 participants) reduced stroke risk by only 22%. Thus anticoagulation with warfarin was shown to be substantially more efficacious than antiplatelet therapy.Reference: Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have NonvalvularAtrial Fibrillation.Ann Intern Med 2007;146(12):857-867.
  • The optimal target with anticoagulant therapy is to achieve and maintain an International Normalized Ratio (INR) of 2.0-3.0. However, the degree of INR prolongation with a given dose of warfarin is unpredictable, and INR measurements are required at least monthly to maintain a safe and effective INR. Even with careful monitoring, it is difficult to achieve therapeutic range INRs > 65% of the time, and AF patients typically experience major bleeding at a rate of about 3.0 % per year. [1]The limitations of warfarin therapy include several food and drug interactions, which result in INR fluctuations, necessitating adjustments in its dosage. Furthermore, the efficacy of antithrombotic therapy for stroke prevention must be balanced against the risk of major hemorrhage, particularly cerebral hemorrhage – which is often fatal. Concerns about bleeding risk associated with VKAs and the need for frequent blood monitoring and dose adjustments may make both patients and healthcare providers reluctant to employ warfarin therapy in a large proportion of AF patients, [2] and several studies [3-5] have shown that warfarin therapy has been underused in clinical practice. However, a subtherapeutic INR (< 2.0) is associated with a greater risk of thrombotic events, and the relative risk of ischemic stroke is 3.3 times higher in patients with INR 1.5 than in those with an INR 2.0, [6] emphasizing the need for tight control of anticoagulation at INR 2.0-3.0, with an aim to be as close as possible to an INR of 2.5. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 Update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention and Rate/Rhythm Control.Can J Cardiol 2012;28(2):125-136.Kuzniatsova N, Lip GYH. Prevention of Thromboembolism in Atrial Fibrillation Patients. European Cardiology 2011;7(1):37-43.Stafford RS, Singer DE. Recent National Patterns of Warfarin Use in Atrial Fibrillation. Circulation 1998;97(13):1231-1233.Cohen N, Almoznino-Sarafian D, Alon I, et al. Warfarin for Stroke Prevention Still Underused in Atrial Fibrillation. Stroke 2000;31(6):1217-1222.Gage BF, Boechler M, Doggette AL, et al. Adverse Outcomes and Predictors of Underuse of Antithrombotic Therapy in Medicare Beneficiaries With Chronic Atrial Fibrillation. Stroke 2000;31(4):822-827.Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation.Am Fam Physician 1999;59(3):635-46.
  • The limitations of warfarin therapy include several food and drug interactions, which result in INR fluctuations, necessitating adjustments in its dosage.
  • Although warfarin is highly effective for stroke prevention in AF patients, it is underused and medication adherence is suboptimal. In one study, [1] only 40% of high risk patients presenting with a first ischemic stroke were taking warfarin for primary prevention before admission. Even among the highest risk group, i.e., those with a history of ischemic stroke or TIA, 43% were not taking warfarin. In addition to physician reluctance to prescribe warfarin, patient factors for the underuse of warfarin include individual preferences and inadequate knowledge about their disease and its treatment. While adherence is crucial for anticoagulation control, [2] persistence and discontinuation with warfarin in patients with AF is similar to that in other chronic diseases, with persistence decreasing over time for most users. [3] Factors influencing long term medication adherence include the complexity of the regimen, with several studies [4-6] showing patient preferences to include once daily dosing. In a large population-based study [4] that compared adherence rates to chronic medications in AF patients, the likelihood of adherence with a once daily dosing regimen was approximately 26% higher compared with a twice daily regimen.References1. Gladstone DJ, Bui E, Fang J, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke 2009;40(1):235-240.2.Davis NJ, Billett HH, Cohen HW, et al. Impact of Adherence, Knowledge, and Quality of Life on Anticoagulation Control. Ann Pharmacother 2005;39(4):632-636.3. Song X, Sander SD, Varker H, Amin A. Patterns and predictors of use of warfarin and other common long-term medications in patients with atrial fibrillation. Am J Cardiovasc Drugs 2012;12(4):245-53.4. LalibertéFo, Nelson W, Lefebvre P, et al. Impact of Daily Dosing Frequency on Adherence to Chronic Medications Among NonvalvularAtrial Fibrillation Patients. 5. Flack JM, Nasser SA. Benefits of once-daily therapies in the treatment of hypertension. Vasc Health Risk Manag 2011;7:777-87.6. Coleman CI, Roberts MS, Sobieraj DM, et al. Effect of dosing frequency on chronic cardiovascular disease medication adherence. Curr Med Res Opin 2012;28(5):669-80.
  • 10,697 adult patients newly initiated on diabetes or hypertension medication with a diagnosis of non-valvular AF8,256 patients were prescribed medications OD and 2,441 were prescribed medications BID (patients were excluded if they were receiving both OD and BID medications concurrently)Patients receiving OD medication had a 26% higher probability of being compliant compared to those receiving BID medicationIn those aged ≥65 years, OD medication was associated with a 52% higher probability of being compliant compared to those receiving BID medication
  • c)Newer agents, i.e., dabigatran, rivaroxaban and apixabanare preferred over warfarin for stroke prevention in patients with AF. There have been no head-to-head studies comparing one newer anticoagulant and another. Differences in study designs and patient populations in published trials make any indirect comparisons difficult. In comparative studies with warfarin, all these agents have demonstrated efficacy that is noninferior or superior to warfarin for stroke risk reduction.
  • In ROCKET-AF, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism in AF patients.Dabigatran was not evaluated in the ROCKET-AF trial. However, in the RE-LY trial, the 110 mg dose of dabigatran was noninferior to warfarin, while the 150 mg dose was associated with lower rates of stroke and systemic embolism.Apixaban was not evaluated in the ROCKET-AF trial. However, in the ARISTOTLE trial apixaban was superior to warfarin in preventing stroke or systemic embolism.
  • The underuse of anticoagulation in AF patients can result in consequences that include ischemic stroke and other adverse outcomes. Some of the limitations of warfarin can be overcome by the new oral anticoagulants dabigatran, rivaroxaban and apixaban. Following oral administration, maximal blood levels and anticoagulant effects are quickly achieved. The absorption and elimination of these agents is largely unaffected by food or other medications. They can be administered in fixed daily doses, and anticoagulation monitoring is not required. Due to the short serum and receptor inhibition half-lives of these agents, their anticoagulant effects diminish quickly after drug discontinuation. CCS 2012 guidelines recommend that when oral anticoagulant therapy is indicated, all AF and atrial flutter (AFL) patients should receive dabigatran, rivaroxaban or apixaban in preference to a VKA. ReferenceSkanes AC, Healey JS, Cairns JA, et al. Focused 2012 Update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention and Rate/Rhythm Control.Can J Cardiol 2012;28(2):125-136.
  • Notes: Dosing information refers to Stroke Prevention in Atrial Fibrillation indication. References:Pradax ® Canadian product monograph January 27, 2012Xarelto® Canadian Product Monograph, February 13, 2012ELIQUIS® Canadian Product Monograph, 13 December 2011Eikelboom and Weitz. Circulation 2010;121;1523-1532Granger CB et al. N Engl J Med. 2011 Sep 15;365(11):981-92.
  • ReferencesPatel MR et al. N Engl J Med 2011;365:883–891Connolly SJ et al. N Engl J Med 2009;361:1139–1151.Lopes RD et al. Am Heart J 2010;159:331–339.Granger CB et al N Engl J Med 2011; 365: 981-92.
  • While different studies have compared the efficacy and safety of the newer anticoagulants with warfarin, no (“head-to-head”) study has compared one newer anticoagulant and another. Furthermore, differences in study designs and patient populations in published trials make any indirect comparisons difficult.
  • While different studies have compared the efficacy and safety of the newer anticoagulants with warfarin, no (“head-to-head”) study has compared one newer anticoagulant and another. Furthermore, differences in study designs and patient populations in published trials make any indirect comparisons difficult. One indirect comparison study [39] found no profound significant differences between dabigatranetexilate (both doses), rivaroxaban and apixaban for preventing stroke and systemic embolism. Major bleeding was significantly lower with apixaban compared with dabigatran 150 mg BID and rivaroxaban, but not significantly different from dabigatran 110 mg BID. In another review, [40] a higher risk for myocardial infarction was noted with direct thrombin inhibitors than with factor Xa inhibitors. A systematic review and meta-analysis [41] of randomized controlled trials evaluated the efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban and apixaban) compared to warfarin in patients with AF. The new oral anticoagulants were associated with a decreased risk for all-cause stroke and systemic embolism, ischemic and unidentified stroke, hemorrhagic stroke, all-cause mortality, and vascular mortality. New oral anticoagulants were also associated with a lower risk for intracranial bleeding. Data regarding the risks for major bleeding and gastrointestinal bleeding were inconclusive. References1. Lip GYH, Larsen TB, Skjøth F, et al. Indirect Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety When Used for Stroke Prevention in Atrial Fibrillation. J Am CollCardiol 2012;60(8):738-746.2. Adam SS, McDuffie JR, Ortel TL, et al. Comparative Effectiveness of Warfarin and New Oral Anticoagulants for the Management of Atrial Fibrillation and Venous Thromboembolism: A Systematic Review. Ann Intern Med 2012.3. Miller CS, Grandi SM, Shimony A, et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) Versus Warfarin in Patients With Atrial Fibrillation. Am J Cardiol 2012;110(3):453-460.
  • a) 0.Linda does not have the risk factors considered for the CHADS2 score, i.e., age ≥75 years, diabetes, and history of heart failure or TIA/stroke.
  • b) 2.Linda gets 1 point each for female gender and age 65-74 years, for a total CHA2DS2-VASc score of 2.
  • b)Although Linda has CHADS2 = 0, she should receive anticoagulation because she has additional risk factors, i.e., age ≥ 65 years and female sex.
  • a) The new anticoagulants dabigatran, rivaroxaban and apixaban have demonstrated efficacy that is either noninferior or superior to warfarin.
  • Notes:1. In practice, CrCl may be calculated using MDRD or CKD-epi, but the trials used Cockroft-Gault. Hence the results are often very disparate. 2. Dabigatran 110 mg BID dosage is also recommended for patients aged ≥ 75 years with other risk factor(s) for bleeding. Also assess renal function
  • Note: If new anticoagulants are used in patients with CrCl30-40 mL/min, rivaroxaban or apixaban may be better choices than dabigatran because the degree of renal excretion for the factor Xa inhibitors is less than that for dabigatran.Reference: Weitz JI, Gross PL. New oral anticoagulants: which one should my patient use? Hematology Am Soc HematolEduc Program 2012;2012(1):536-540.
  • Venous thromboembolism (VTE) is the third most common cardiovascular disease after coronary artery disease and stroke. [1] The annual incidence of diagnosed VTE is 1-2 events per 1000 of the general population. [2,3] VTE is very uncommon before age 20 years, but after 40 years of age, the incidence about doubles with each decade. [2] References1. Douketis JD. Treatment of deep vein thrombosis: what factors determine appropriate treatment? Can Fam Physician 2005;51(2):217-23.2. Kearon C. Epidemiology of venous thromboembolism.SeminVasc Med 2001;1(1):7-26.3. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: A 25-year population-based study.Arch Intern Med 1998;158(6):585-593.
  • VTE may be provoked or unprovoked. Provoked VTE may relate to transient/reversible factors (e.g., surgery, hospitalization) or continuing/irreversible factors (e.g., cancer). Unprovoked (“idiopathic”) VTE has no identifiable cause. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT has an annual incidence of 48 per 100,000 population, [1] and is estimated to affect 45,000 individuals in Canada each year. [2]PE has an estimated annual incidence of 69 cases per 100,000 population. [1] Acute PE can be fatal. Approximately 10% of hospital deaths are attributed to PE. [3]References1. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: A 25-year population-based study.Arch Intern Med 1998;158(6):585-593.2. Douketis JD. Treatment of deep vein thrombosis: what factors determine appropriate treatment? Can Fam Physician 2005;51(2):217-23.3. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):338S-400S.
  • DVT usually starts in the calf veins, from where it may extend to the proximal veins, and subsequently embolize to the pulmonary arteries and cause PE. Calf DVTs often resolve spontaneously within 72 hours, and only about one-sixth extend to involve the proximal vein. Thus on ultrasound, the majority of thrombi are detected in the proximal veins. [1]DVT resolves slowly with anticoagulant treatment, but can recur after discontinuation of therapy. Patients with a history of VTE have a higher risk of recurrence than the general population, therefore necessitating secondary prophylaxis. [2] The risk of recurrence following a first episode of VTE associated with a major transient risk factor (i.e., provoked DVT) is ≈ 3% per year. The risk of recurrence is higher at ≈ 10% per year for a patient with no reversible risk factor (i.e., unprovoked DVT) or for one who has cancer. [3] The risk of recurrence of VTE is highest in the first 6-12 months. At 5 years, the cumulative rate of recurrence is about 25%, and at 10 years, it is 30%. [2]ReferencesKearon C. Epidemiology of venous thromboembolism.SeminVasc Med 2001;1(1):7-26.Zhu T, Martinez I, Emmerich J. Venous Thromboembolism: Risk Factors for Recurrence. Arteriosclerosis, Thrombosis, and Vascular Biology 2009;29(3):298-310.Kearon C. Natural History of Venous Thromboembolism. Circulation 2003;107(23 suppl 1):I-22-I-30.
  • Source: Scarvelis D, Wells PS. Diagnosis and treatment of deep-vein thrombosis.CMAJ 2006;175(9):1087-92.
  • d)UFH, LMWH and rivaroxaban may be used for the initial management of DVT.
  • b) Patients receiving rivaroxaban have reported improved treatment satisfaction compared with enoxaparin/VKA, particularly in reducing patient-reported anticoagulation burden. Dabigatran is not approved for the treatment of VTE. Warfarin has an unpredictable dose response and a narrow therapeutic window; thus, patients must be monitored closely when receiving this agent.
  • Several factors contribute to VTE risk. These risk factors are generally cumulative, e.g., VTE risk is high in a patient with hip fracture because of (usually) advanced age, proximal lower extremity injury and its operative repair, and marked reduction in mobility for weeks after surgery. If cancer is present, the risk is further increased.ReferenceGeerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest 2004;126(3 Suppl):338S-400S.
  • The probability of DVT can be assessed with Wells prediction rule for DVT.ReferenceWells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management.Lancet 1997;350(9094):1795-1798.
  • PE is major cause of death in patients with VTE, and the Wells’ prediction rule can help in identifying patients at risk for PE. ReferenceWells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.ThrombHaemost 2000;83(3):416-20.
  • For acute DVT or PE, the American College of Chest Physicians (ACCP) guidelines [1] recommend initial parenteral anticoagulant therapy or oral anticoagulation with rivaroxaban. Thereafter, the duration of treatment depends on whether the DVT is provoked or unprovoked. Long term (i.e., 3 months) anticoagulant therapy is recommended for provoked VTE, and extended therapy (i.e., > 3 months) may be recommended for unprovoked VTE. All patients receiving extended anticoagulant therapy should be reassessed periodically, e.g., annually. Patients treated with a vitamin K antagonist (VKA) should be maintained in the International Normalized Ratio (INR) range of 2.0-3.0. Agents approved for long term or extended prevention of recurrent thrombosis include a VKA, rivaroxaban or low molecular weight heparin (LMWH). Reference1. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest 2012;141(2 Suppl):e419S-94S.
  • Rivaroxaban is the only new oral anticoagulant indicated for DVT treatment. In the dose-finding ODIXa-DVT study, [1] rivaroxaban demonstrated efficacy and safety in the treatment of proximal DVT across a dosing range of 20-60 mg/day. The EINSTEIN-DVT study [2] compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg daily), to enoxaparin followed by VKA for 3, 6 or 12 months, in patients with acute symptomatic DVT. The results showed that rivaroxaban was noninferior in efficacy for prevention of symptomatic recurrent DVT, and was associated with similar rates of bleeding compared to enoxaparin/VKA. Patients receiving rivaroxaban reported improved treatment satisfaction compared with enoxaparin/VKA, particularly in reducing patient-reported anticoagulation burden. In the EINSTEIN-extension study, [3] patients who received 6-12 months of rivaroxaban treatment after completing their standard VTE treatment had a significantly reduced risk of recurrent VTE, suggesting that rivaroxaban can be an alternative to warfarin for long term secondary prevention of VTE.In EINSTEIN-PE, [4] rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg daily) was compared with standard therapy (enoxaparin 40 mg twice daily followed by VKA) for 3, 6 or 12 months in patients with acute symptomatic PE with or without symptomatic DVT. The fixed-dose regimen of rivaroxaban was noninferior to standard therapy for the initial and long-term treatment of PE and had a potentially improved benefit-risk profile.References1. Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of Proximal Deep-Vein Thrombosis With the Oral Direct Factor Xa Inhibitor Rivaroxaban (BAY 59-7939): The ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) Study. Circulation 2007;116(2):180-187.2. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010;363(26):2499-2510.3. Romualdi E, Donadini MP, Ageno W. Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-Extension study). Exp Rev CardiovasTher 2011;9(7):841-844.4. The EINSTEIN-PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med;366(14):1287-1297.
  • Although some patients who have been stabilized on warfarin may prefer to continue this medication, others may like to switch to the newer anticoagulants for their benefits of convenience and reduced risk of intracranial bleeding. DabigatranSwitching from warfarin to dabigatran can be done when the patient’s INR is < 2.0. To switch from dabigatran to another anticoagulant, the other anticoagulant should be started when the next scheduled dose of dabigatran would have been due. [1,2] RivaroxabanA switch from warfarin to rivaroxaban can be done if the INR is ≤ 2.5. If the INR is > 2.5, starting rivaroxaban should be delayed until the INR is ≤ 2.5. To switch from rivaroxaban to warfarin, rivaroxaban should be continued concurrently with warfarin until the INR is ≥ 2.0. Rivaroxaban can be discontinued when the INR is >2.0. [3]ApixabanTo switch from warfarin to apixaban, warfarin should be discontinued and apixaban should be started when the INR is < 2.0. Switching from apixaban to warfarin involves beginning warfarin therapy while continuing apixaban until the INR is ≥ 2.0. [4]References1. Advisory Committee Briefing Document. Available from: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm226009.pdf. [Accessed October 17, 2012].2. Wartak SA, Bartholomew JR. Dabigatran: Will it change clinical practice? Cleveland Clinic Journal of Medicine 2011;78(10):657-664.3. XARELTO® Product Monograph. Available from: http://www.bayer.ca/files/XARELTO-PM-ENG-18JUL2012-154961.pdf?#. [Accessed October 17, 2012].4. Eliquis 2.5 mg film-coated tablets. Available from: http://www.medicines.org.uk/emc/medicine/24988. [Accessed December 18, 2012].
  • Fromrivaroxaban to warfarin: For first 2 days, give warfarin at usual starting dose without INR testing; continue rivaroxaban with warfarin until INR is ≥2.0; discontinue rivaroxaban when INR is >2.0. Test INR at least 24 hours after the last dose of rivaroxaban to know anticoagulant effect of warfarin.Fromapixaban to warfarin: Start warfarin therapy while continuing apixaban for at least 2 days. After 2 days of coadministration, obtain an INR prior to next scheduled dose of apixaban. Continue coadministration of apixaban and warfarin until INR is ≥ 2.0.Fromdabigatran to warfarin: Adjust warfarin starting time according to CrCl: ≥50 ml/min: Start warfarin 3 days before discontinuing dabigatran 30- <50 ml/min: Start warfarin 2 days before discontinuing dabigatranUse INR to assess anticoagulant effect of warfarin, not dabigatran; INR will not reliably reflect anticoagulant effect of warfarin until ≥2 days after discontinuation.
  • Patients undergoing elective surgery or other invasive procedures may require temporary interruption of oral anticoagulant therapy (commonly warfarin), which may place them at increased risk for arterial thromboembolic events. In such cases, clinicians may empirically use bridging anticoagulation, often with low-molecular-weight heparin (LMWH), before and after surgery. However, clinician practices vary. There is debate on the need for bridging anticoagulation because of the short time period for which warfarin is withheld. Furthermore, it is costly, and administering it close to the time of surgery may increase the risk for bleeding. Good quality evidence is lacking, and there is inconsistency between various recommendations. [1-4]Manufacturers’ recommendations for dabigatran and rivaroxaban are to discontinue these drugs at least 1 day before the procedure. Longer times may be considered for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required, or who have moderate renal impairement. ReferencesManaging Anticoagulation in the Perioperative Period: ACCP Guidelines, 9th Ed, 2012. Available from: http://pulmccm.org/2012/outpatient-pulmonology-review/how-to-manage-anticoagulation-perioperative-surgery-accp-9th-edition-recommendations-guideline/. [Accessed November 1, 2012].Douketis JD. Perioperative management of patients who are receiving warfarin therapy: an evidence-based and practical approach. Blood 2011;117(19):5044-5049.Wysokinski WE, McBane RD. Periprocedural Bridging Management of Anticoagulation. Circulation 2012;126(4):486-490.BRIDGE Study Overview. Available from: https://bridge.dcri.duke.edu/Study%20Overview%2013Apr2010.pdf. [Accessed November 1, 2012].
  • A suggested approach to interrupting dabigatran or rivaroxaban before a procedure, and according to the patient’s renal function. ReferenceSchulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012;119(13):3016-3023.
  • Weitz JI, Gross PL. New oral anticoagulants: which one should my patient use? Hematology Am Soc HematolEduc Program 2012;2012(1):536-540.
  • Major bleeding rates with the newer anticoagulants are generally low and comparable to or lower than those with warfarin. [1] Nevertheless, due to their relatively long half-lives (dabigatran 8-15 hours; rivaroxaban 5-13 hours; apixaban 12 hours), prolonged bleeding may occur. On the other hand, the half-life of warfarin is even longer at 40 hours. [2] Up to ∼ 3% of patients may develop major bleeding while on therapy with the new anticoagulants. Key factors contributing to increased bleeding risk include, among others, increased age and the presence of renal impairment. [3] No effective antidotes are known for bleeding associated with the newer anticoagulants. INR testing is an unreliable measure of anticoagulation levels with these agents, and is not used. The activated partial thromboplastin time (aPTT) and prothrombin time (PT) also do not provide precise information on their anticoagulant effects, but may be useful as a qualitative indicator of drug presence. [4]ReferencesSiegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. European Heart Journal 2012.Weitz JI, Gross PL. New oral anticoagulants: which one should my patient use? Hematology Am Soc HematolEduc Program 2012;2012(1):536-540.Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. Journal of Thrombosis and Haemostasis 2009;7:107-110.Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012;119(13):3016-3023.
  • A suggested approach for the management of acute bleeding in patients taking novel oral anticoagulants.ReferenceSiegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants.European Heart Journal 2012.
  • Practical application of anticoagulation therapy af and vte april 12

    1. 1. Practical Applications of Anticoagulation Therapy Atrial Fibrillation and Venous Thromboembolism An Accredited Continuing Medical Education Program Developed by: George Dresser, MD, PhD, FRCPC Lorne Gula, MD, FRCPC Peter L. Gross, MD, FRCPC David Dixon, MD, MCISc(FM), CCFP, FCFP Murray Awde, MD, CCFP, FCFP Sol Stern, BSc, MSc, MD, MCFP
    2. 2. Faculty/Presenter Disclosure • Faculty: Dr. John Ward: MD, CCFP(EM), FRCPC (Med), Clinical Associate Professor, Dept of Emergency Medicine, UBC • Relationships with commercial interests: • Grants/Research Support: n/a • Speakers Bureau/Honoraria: Astra Zenica, Bayer, Pfizer • Consulting Fees: n/a • Other: n/a CFPC CoI Templates: Slide 1
    3. 3. Disclosure of Commercial Support • This program has received financial support from Bayer HealthCare in the form of an unrestricted educational grant. • Potential for conflict(s) of interest: • Dr. John Ward has received honorarium from Bayer HealthCare. CFPC CoI Templates: Slide 2
    4. 4. Mitigating Potential Bias • The speaker had provided a full disclosure in advance of the program. The scientific content of the program is evidence based and all content related to pharmacotherapy is within product label. The program has been peer reviewed and is nationally accredited by the College of Family Physicians of Canada. CFPC CoI Templates: Slide 3
    5. 5. Accreditation This program has been accredited by the College of Family Physicians of Canada for up to 1 Mainpro-M1 credit.
    6. 6. Learning objectives Upon completion of the program, participants will be able to: • Describe the role of anticoagulation for stroke prevention in atrial fibrillation (AF), and for the treatment of venous thromboembolism (VTE) • Evaluate stroke risk in patients with AF • Discuss the indications for anticoagulation therapy in patients with AF • Discuss new oral anticoagulant treatment options for patients with AF and VTE • Determine how to most effectively implement the new oral anticoagulants for the prevention of stroke in patients with AF and the treatment of VTE into clinical practice
    7. 7. Atrial Fibrillation
    8. 8. Atrial fibrillation • Irregular, ineffective atrial contraction • Worsens over time, leads to atrial remodeling1 • Slow but steady progression to chronic AF after initial paroxysmal AF2 1. Allessie M et al. Cardiovascular Research 2002;54(2):230-246. 2. Kerr CR et al. Am Heart J 2005;149(3):489-496.
    9. 9. Atrial fibrillation: Epidemiology • Affects about 1% of population - about 350,000 Canadians1,2 • Most common cardiac arrhythmia requiring medical care1 • Lifetime risk 1 in 4 for age ≥ 40 years3 • Prevalence increases with age; hence increasing due to increasingly elderly population2 1. Go As. et al. JAMA 2001;285(18):2370-2375. 2. Brembilla-Perrot B et al.. Pacing and Clinical Electrophysiology 2004;27(3):287-292. 3. Lloyd-Jones DM et al. Circulation 2004;110(9):1042-1046.
    10. 10. Stroke risk in AF • 4-5 fold increase in stroke risk in AF; 1 in 6 strokes occurs in AF patients1,2 • Stroke risk in AF increases from 1.5% at age 50-59 to 23.5% at age 80-891 • About 40% of AF patients in primary care may be at high risk of stroke3 1. Kannel WB et al. Am J Cardiol 1998;82(7):2N-9N. 2. Mattle HP. Cerebrovascular Diseases 2003;16(Suppl. 1):3-8. 3. Carroll K, Majeed A. Br J Gen Pract 2001;51(472):884-6, 889-91.
    11. 11. Case study: James • James, 72-year male, newly diagnosed with AF • H/o hypertension and diabetes, no H/o TIA or stroke • Had MI 2 years ago; since then has had intermittent CHF with exacerbation 1 month ago • He is now assessed for stroke risk, and considered for antithrombotic therapy
    12. 12. Case study: James (contd.) 1. What is this patient’s CHADS2 score? 1) 0 2) 1 3) 2 4) 3 5) 4 6) 5 7) 6
    13. 13. CHADS2 score and stroke risk Risk factor Points C - Congestive heart failure 1 H - Hypertension 1 A - Age >75 years 1 D - Diabetes 1 S - Prior Stroke or TIA 2 CHADS2 score Stroke rate per 100 patient- years 0 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 12.5 6 18.2 Gage BF et al. JAMA 2001;285(22):2864-2870.
    14. 14. CHA2DS2-VASc score Risk Factor Score C - Congestive heart failure 1 H - Hypertension 1 A - Age ≥ 75 yrs 2 D - Diabetes mellitus 1 S2 - Prior stroke or TIA 2 V - Vascular disease 1 A - Age 65-74 years old 1 Sc - Sex category (female) 1 Lip GYH, Halperin JL. Am J Med 2010;123(6):484-488.
    15. 15. Case study: James (contd.) 2. Should James receive anticoagulation for reducing his risk of stroke? a) Yes b) No
    16. 16. Antithrombotic therapy in AF • Aims at preventing thromboembolism • ACTIVE-W: Oral anticoagulant therapy was superior to clopidogrel plus ASA for preventing vascular events in AF patients at high risk of stroke1 • ACTIVE-A: Clopidogrel plus ASA, compared with ASA alone, reduced major vascular events in AF patients at increased risk for stroke but for whom VKA was unsuitable2 1. Lancet 2006;367(9526):1903-1912. 2. N Engl J Med 2009;360(20):2066-2078.
    17. 17. Skanes AC et al. Can J Cardiol 2012;28(2):125-136. CCS recommendations Note: Newer agents, i.e., dabigatran, rivaroxaban and apixaban, are preferred over warfarin for stroke prevention in AF
    18. 18. HAS-BLED score Condition Points H - Hypertension 1 A - Abnormal renal or liver function (1 point each) 1 or 2 S - Stroke 1 B - Bleeding 1 L - Labile INRs 1 E - Elderly (> 65 years) 1 D - Drugs or alcohol (1 point each) 1 or 2 HAS-BLED score Bleeds per 100 patient- years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 12.5 Pisters R et al. Chest 2010;138(5):1093-1100. Note: HAS-BLED has been validated for warfarin, but not for the new anticoagulants.
    19. 19. Warfarin • Traditional choice for anticoagulation in AF • Superior to antiplatelet therapy1 • Reduction in stroke risk1 • Warfarin 64% • Antiplatelet agents 22% • However, use is suboptimal2 1. Hart RG et al. Ann Intern Med 2007;146(12):857-867. 2. Verhovsek M et al. BMC Geriatrics 2008;8(1):13.
    20. 20. Limitations of warfarin • Unpredictable INR prolongation; monthly (sometimes weekly) measurements needed to maintain INR 2.0-3.01 • Food/drug interactions cause INR fluctuations necessitating dosage adjustments • Difficulty achieving therapeutic INR range >65% of time1 • Major bleeding 3.0%/year approx1 • Patient and HCP reluctance to employ warfarin2 1. Skanes AC et al. Can J Cardiol 2012;28(2):125-136. 2. Kuzniatsova N, Lip GYH. Eur Cardiol 2011;7(1):37-43. 3. Horton JD, Bushwick BM. Am Fam Physician 1999;59(3):635-46.
    21. 21. Warfarin: Food and drug interactions Increase anticoagulation Decrease anticoagulation Foods St. John’s Wort Ginseng Garlic Gingko biloba Avocado Spinach Brocolli Drugs Acetaminophen Amiodarone Androgens Allopurinol Aspirin (high dose) Cimetidine Clofibrate Chloramphenicol Disulfiram Dipyridamole Erythromycin Fluconazole Fluoxetine HCl Glucagon Indomethacin Liquid paraffin Metronidazole Phenylbutazone Phenytoin Probenecid Phenformin Quinidine Sulfinpyrazone Tamoxifen Tolbutamide Thyroid hormone Trimethoprim- sulfamethoxazole Antithyroid drugs Barbiturates Carbamazepine Cholestyramine Gluthimide Griseofulvin Oral contraceptive Rifampicin Sucralfate Gogna A, Arun S. Oral Anticoagulation in Clinical Practice. JIACM 2005;6(1):53-66
    22. 22. Underutilization of anticoagulation in high risk AF patients Gladstone DJ, et al. Stroke. 2009;40:235-40. Warfarin subtherapeutic Warfarin therapeutic Single antiplatelet agent No antithrombotics Dual antiplatelet therapy In addition, only 18% of AF patients who had a previous stroke had a therapeutic INR of warfarin at the time of stroke Preadmission treatment in patients with known AF admitted with acute ischemic stroke and classified as high risk for systemic emboli according to published guidelines (n=597) 29% 29% 30% 10% 2%
    23. 23. Need for medication adherence • Risk of subtherapeutic INR with warfarin: Relative risk of stroke with INR 1.5 is 3.3 times higher than with INR 2.01 • Findings in stroke patients2: • High risk patients: Only 40% of were taking warfarin for primary prevention before first stroke • Highest risk patients (with history of stroke/TIA): 43% were not taking warfarin • Adherence is related to complexity of regimen • 26% higher adherence with once daily regimen than with twice daily regimen3 1. Horton JD, Bushwick BM. Am Fam Physician 1999;59(3):635-46. Gladstone DJ et al. Stroke 2009;40(1):235-240. 3. Laliberté Fo, et al. Adv Ther 2012;29(8):675-690.
    24. 24. Once-Daily Dosing Is Associated With Higher Adherence Rates Than Twice-Daily Dosing 60 65 70 75 80 Total Population ≥ 65 years old OD BID Adherence to Chronic Medications in Non-valvular AF patients Laliberté F et al. Adv Ther (2012) 29(8):675-690.
    25. 25. Case study: James (contd.) 3. Which one of the following statements about the choice of anticoagulant therapy most correctly reflects the CCS recommendations? a) Warfarin is the first line choice for stroke risk reduction in AF; newer anticoagulants should only be considered if warfarin is contraindicated. b) The efficacy of new anticoagulants for stroke risk reduction in AF is dabigatran > rivaroxaban > apixaban. c) When oral anticoagulant therapy is indicated, AF patients should receive dabigatran, rivaroxaban or apixaban in preference to a VKA. James is being considered for anticoagulant therapy.
    26. 26. Case study: James (contd.) 4. In the ROCKET-AF trial: a) Dabigatran was inferior to warfarin in preventing stroke or systemic embolism. b) Rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism in AF patients. c) Apixaban was inferior to warfarin in preventing stroke or systemic embolism.
    27. 27. Newer anticoagulants (apixaban, dabigatran, rivaroxaban) • Quickly achieve maximal blood levels and anticoagulant effects following oral administration • Absorption and elimination largely unaffected by food or other medications. • Administered in fixed daily doses • Anticoagulation monitoring not required • Relatively short serum and receptor inhibition half- lives; anticoagulant effects diminish quickly after discontinuation Skanes AC et al. Can J Cardiol 2012;28(2):125-136.
    28. 28. Novel Oral Anticoagulants – Pharmacological Properties Characteristic Apixaban Dabigatran Rivaroxaban Target Factor Xa Factor IIa Factor Xa Prodrug No Yes No Dosing BID BID OD Bioavailability, % 50% 6.5% 80-100%* Half-life 8-15 h 12-14 h 5-13h Renal clearance (unchanged drug) 27% 85% ~33% Cmax 3-4 h 1-2 h 2-4 h Drug interactions Potent inhibitors of both CYP3A4 and P- gp P-gp inhibitors Potent inhibitors of both CYP3A4 and P-gp * When the 15mg and 20mg dose is taken with food
    29. 29. Trials Comparing New Anticoagulants vs. Warfarin ARISTOTLE1,2 RE-LY3 ROCKET AF4 No. of patients 18,201 18,113 14,264 CHADS2 score 2.1 2.1 3.5 Statistical objective Non-inferiority Non-inferiority Non-inferiority Study drugs Double-blind apixaban Two doses of double- blind dabigatran Double-blind rivaroxaban Control Double-blind warfarin (INR 2–3) Open-label warfarin (INR 2–3) Double-blind warfarin (INR 2–3) Primary Dose(s) Studied 5 mg BID 110 mg BID and 150 mg BID 20 mg OD Adjusted Dose Studied 2.5 mg BID For patient with any two of the following: - Age ≥80 years - Body weight ≤60 kg - Serum creatinine ≥1.5 mg/dl (133 µmol/l) (27% renal excretion) None (~85% renal excretion) 15 mg OD For patients with CrCl = 30-49 mL/min (~33% renal excretion) 1. Lopes RD et al, 2010; 2.Granger CB et al, 2011; 3. Connolly SJ et al, 2009; 4. Patel MR et al, 2011.
    30. 30. Comparison of new anticoagulants • No head-to-head comparative studies comparing new anticoagulants with each other • Different study designs and patient populations; hence indirect comparisons are difficult
    31. 31. Indirect comparison/meta-analysis of new anticoagulants 1. Lip GYH et al. J Am Coll Cardiol 2012;60(8):738-746. 2. Adam SS et al. Ann Intern Med 2012. 3. Miller CS et al. Am J Cardiol 2012;110(3):453-460. Lip1 • No significant differences between new anticoagulants for preventing stroke and systemic embolism • Less major bleeding with apixaban than dabigatran 150 mg BID and rivaroxaban, but not significantly different from dabigatran 110 mg BID Adam2 Higher MI risk with direct thrombin inhibitors than with factor Xa inhibitors Miller3 • New anticoagulants decreased risk for stroke, systemic embolism, all-cause mortality, and vascular mortality • Also lower risk for intracranial bleeding • Inconclusive data on risks for major bleeding and GI bleeding
    32. 32. Case study: Linda • Linda, a 73-year old female with AF and moderate renal impairment • No H/o hypertension, diabetes, heart failure or TIA/stroke • Prescribed warfarin to reduce stroke risk; however, she has a busy lifestyle and her INRs are regularly out of range
    33. 33. Case study: Linda 1. What is this patient’s CHADS2 score? a) 0 b) 1 c) 2 d) 3 e) 4 f) 5 g) 6
    34. 34. Case study: Linda (contd) 2. What is Linda’s CHA2DS2-VASc score? a) 0 b) 2 c) 4 d) 6 e) 8 f) 10
    35. 35. Case study: Linda (contd) 3. As per CCS guidelines, should Linda receive anticoagulation? a) Linda`s CHADS2 = 0, and hence she should not receive anticoagulation. b) Although Linda has CHADS2 = 0, she should receive anticoagulation because she has additional risk factors, i.e., age ≥ 65 years and female sex.
    36. 36. Case study: Linda (contd) Linda is being considered for a switch from warfarin to a newer anticoagulant for stroke risk reduction. 4. Which of the following statements is correct? a) Warfarin therapy is associated with INR fluctuations, and measurements of INR are required at least monthly to maintain a safe and effective INR. b) Compared to warfarin, the newer anticoagulants dabigatran, rivaroxaban and apixaban are less effective for stroke risk reduction.
    37. 37. New anticoagulants in AF CHADS2 score HAS- BLED score CHADS2 ≥2 CHADS2 ≥1 Consider anticoagulation for all patients New AF patient Balance stroke risk against bleeding risk. HAS-BLED score of ≥ 3 indicates increased risk of major bleeding Consider anticoagulation for most patients
    38. 38. Starting a new oral anticoagulant in a new patient Apixaban Dabigatran Rivaroxaban Usual dosage 5 mg BID 150 mg BID 20 mg OD Take with food? - - Yes Renal impairment CrCl ≥ 30 mL/min: No dose adjustment CrCl 15-30 ml/min: Use with caution CrCl <15 ml/min: not recommended CrCl 30-50 ml/min: No dose adjustment (consider 110 mg dosage); use with caution; assess renal function at least twice a year and with changes in clinical status CrCl <30 ml/min: contraindicated CrCl 30-49 mL/min: 15 mg OD CrCl <30 ml/min: not recommended Other Age ≥75 with other risk factor(s) for bleeding: 110 mg BID; also assess renal function
    39. 39. Patient has risk factor for stroke Estimate CrCl ≥25 mL/min 5 mg BID2.5 mg BID <15 mL/min Not recommended Recommended dose Apixaban Check Age Check Weight Check Serum Creatinine ≥ 80 years ≤ 60 kg ≥ 133 micromol/L If ≥ 2 features If ≤ 1 features Figure adapted from Huisman et al. Thromb Haemost 2012: 107: 838-847, Eliquis® PM November 27, 2012. Canadian Dosing Recommendations for Stroke Prevention in AF ≥15 - 24 mL/min No dosing recommendation can be made
    40. 40. Patient has risk factor for stroke Estimate CrCl <30 mL/min 30-49 mL/min >50 mL/min Elderly and/or risk factors for bleeding Age <75 years Age 75- 80 years Age >80 years 110mg BID 150mg BID 150mg BID 110mg BID 110mg BID150mg BID Contra- indicated One other risk factor for bleeding Recommended dose Dose can be considered Dabigatran Canadian Dosing Recommendations for Stroke Prevention in AF Figure adapted from Huisman et al. Thromb Haemost 2012: 107: 838-847, Pradaxa ® PM November 12, 2012.
    41. 41. Patient has risk factor for stroke Estimate CrCl 30-49 mL/min >50 mL/min 20 mg OD15 mg OD <30 mL/min Not recommended Rivaroxaban Figure adapted from Huisman et al. Thromb Haemost 2012: 107: 838-847, Xarelto® PM, July 18, 2012. Recommended dose Canadian Dosing Recommendations for Stroke Prevention in AF
    42. 42. Key learning points • AF is associated with 4-5-fold increase in stroke risk, and with increased morbidity and mortality • Oral anticoagulant therapy should be considered for patients at high risk of stroke (CHADS2 ≥2) and for most patients at intermediate risk (CHADS2 1). CHA2DS2-VASc score can identify patients with stroke risk factors not identified by CHADS2 • Warfarin has been in use for several years, but has many limitations. • Apixaban, dabigatran and rivaroxaban overcome many of warfarin’s limitations. Their absorption and elimination is largely unaffected by food or other medications, they can be administered in fixed daily doses, and anticoagulation monitoring is not required
    43. 43. Venous Thromboembolism
    44. 44. Venous thromboembolism (VTE) • Third most common cardiovascular disease after coronary artery disease and stroke1 • Diagnosed VTE: 1-2 events/1000 population/year2,3 • Uncommon before age 20, but incidence about doubles with each decade after age 402 1. Douketis JD. Can Fam Physician 2005;51(2):217-23. 2. Kearon CSemin Vasc Med 2001;1(1):7-26. 3. Silverstein MD et al. Arch Intern Med 1998;158(6):585-593.
    45. 45. Types of VTE • VTE may be: • Provoked • Transient/reversible factors, e.g., surgery, hospitalization • Continuing/irreversible factors, e.g., cancer • Unprovoked: No identifiable cause • VTE includes: • Deep vein thrombosis (DVT) • Incidence 48 cases/100,000 population/year1 • Estimated to affect 45,000 individuals/year in Canada2 • Pulmonary embolism (PE) • Incidence: 69 cases/100,000 population/year1 • Can be fatal; accounts for 10% of hospital deaths3 1. Silverstein MD et al. Arch Intern Med 1998;158(6):585-593. 2. Douketis JD. Can Fam Physician 2005;51(2):217-23. 3. Geerts WH et al. Chest 2004;126(3 Suppl):338S-400S.
    46. 46. Deep vein thrombosis (DVT) • Usually starts in calf veins, extends to proximal veins, embolizes to pulmonary arteries (PE) • Calf DVT often resolves spontaneously in 72 hours; only 1/6 involve proximal vein • DVT resolves with anticoagulant treatment, but can recur after discontinuation of therapy. • Highest risk in first 6-12 months • Cumulative recurrence: 25% at 5 years, 30% at 10 years • 33-50% of DVT patients develop post-thrombotic syndrome; higher with recurrent DVT 1. Kearon C. Semin Vasc Med 2001;1(1):7-26. 2. Kearon C. Circulation 2003;107(23 suppl 1):I-22-I-30.
    47. 47. Leg veins Scarvelis D, Wells PS. CMAJ 2006;175(9):1087-92.
    48. 48. Pulmonary Embolism (PE) • Estimated annual incidence: 69 cases per 100,000 population 1 • Acute PE can be fatal. Approximately 10% of hospital deaths are attributed to PE 2 • In about 5% of patients, poor resolution of PE or recurrent PE leads to development of pulmonary hypertension 3,4,5 1. Silverstein MD et al. Arch Intern Med 1998;158(6):585-593. 2. Geerts WH et al. Chest 2004;126(3 Suppl):338S-400S. 3. Kearon C. Circulation 2003;107(23 suppl 1):I-22-I-30. 4. de Perrot M et al. CMAJ 2006;174(12):1706. 5. Hoeper MM et al. Circulation 2006;113(16):2011-2020.
    49. 49. Recurrence • Rates of recurrent VTE 1 • At 1 month: 4% • At 1 year 11% 1. Spencer F et al. Arch Intern Med 2008;168:425-43.
    50. 50. Case study: Jack • Jack, 55-year old male, develops pain, swelling and redness in his left leg • On investigation, diagnosed as having DVT involving superficial femoral vein
    51. 51. Case study: Jack (contd.) 1. As per American College of Chest Physicians (ACCP) 2012 recommendations, any of the following anticoagulants can be employed for the initial (0 to ~7 days) management of VTE, except for a) Unfractionated heparin (UFH) b) Low molecular weight heparin (LWMH) c) Rivaroxaban d) Warfarin
    52. 52. Case study: Jack (contd.) 2. Which of the following statements regarding anticoagulation for the treatment of VTE is correct? a) INR monitoring is not needed if warfarin is used for anticoagulation. b) Patients receiving rivaroxaban report improved treatment satisfaction compared with those using traditional anticoagulants such as enoxaparin/VKA. c) Dabigatran is the drug of choice for acute treatment of VTE.
    53. 53. Risk factors for VTE • Surgery • Trauma (major or lower extremity) • Immobility, paresis • Malignancy • Cancer therapy (hormonal, chemotherapy, radioth erapy) • Previous VTE • Increasing age • Pregnancy, postpartum period • Estrogen-containing oral contraception, hormone replacement therapy • Selective estrogen receptor modulators • Acute medical illness • Heart or respiratory failure • Inflammatory bowel disease • Nephrotic syndrome • Myeloproliferative disorders • Paroxysmal nocturnal hemoglobinuria • Obesity • Smoking • Varicose veins • Central venous catheterization • Inherited or acquired thrombophilia Geerts WH et al. Chest 2004;126(3 Suppl):338S-400S.
    54. 54. Wells Prediction Rule for DVT Clinical variable Score Active cancer (treatment ongoing or within previous 6 months, or palliative) 1 Paralysis, paresis, or immobilization of lower extremity 1 Bedridden for > 3 days or major surgery within previous 12 weeks requiring general or regional anesthesia 1 Localized tenderness along distribution of deep veins 1 Swelling of entire leg 1 Calf swelling at least 3 cm larger than asymptomatic leg (10 cm below tibial tuberosity) 1 Pitting edema confined to symptomatic leg 1 Collateral superficial veins (non-varicose) 1 Previously documented DVT 1 Alternative diagnosis as least as likely as DVT -2 Clinical risk (probability) Total High >2 Moderate 1-2 Low <1 Wells PS et al. Lancet 1997;350(9094):1795-1798.
    55. 55. Wells Prediction Rule for PE Clinical variable Score Clinical signs and symptoms of DVT (minimum leg swelling and pain with palpation of deep veins) 3 PE as or more likely than an alternative diagnosis 3 Heart rate > 100 beats/minute 1.5 Immobilization or surgery within previous 4 weeks 1.5 Previous DVT or PE 1.5 Hemoptysis 1 Malignancy (on treatment, treated in the last 6 months or palliative) 1 Clinical risk (probability) Total High >6 Moderate 2-6 Low <2 Wells PS et al.Thromb Haemost 2000;83(3):416-20.
    56. 56. Antithrombotic Therapy for VTE • Initial (0 to ~7 days): Parenteral anticoagulant or oral rivaroxaban • Thereafter • Provoked VTE: Long term (i.e., 3 months) therapy – VKA, LMWH, dabigatran (not approved) or rivaroxaban • Unprovoked VTE: Extended therapy (i.e., > 3 months) – VKA, LMWH, dabigatran (not approved), apixaban (not approved) or rivaroxaban Kearon C et al. Chest 2012;141(2 Suppl):e419S-94S.
    57. 57. Choice of therapy Injectable • UFH: IV route; unpredictable dose response, narrow therapeutic window; needs close monitoring • LMWHs: More predictable pharmacokinetics , greater bioavailability than UFH • Fondaparinux (factor Xa inhibitor): SC route; similar efficacy to UFH, but may be higher risk for bleeding Oral - warfarin Several food and drug interactions, INR fluctuations needing dosage adjustments and associated with bleeding risk Oral - new anticoagulants • Quickly achieve maximal blood levels and anticoagulant effects • Absorption, elimination largely unaffected by food or other medications • Fixed daily doses • Anticoagulation monitoring not required • Reduced doses (especially for dabigatran) considered in reduced renal function, advanced age (> 75 years), or low BMI • Relatively short half-lives, hence effects diminish quickly after discontinuation • Only rivaroxaban is approved for VTE treatment and prevention of recurrent VTE in Canada
    58. 58. Clinical trials with apixaban Study Main methods Main Results BOTTICELLI DVT1 • Phase 2 dose-ranging study to assess efficacy and safety of three different doses of apixaban vs. treatment with LMWH or fondaparinux and VKA • Treatment of acute symptomatic DVT Apixaban is suitable for fixed-dose administration AMPLIFY- EXT2 • Apixaban treatment dose (5 mg) and thromboprophylactic dose (2.5 mg) • Extended anticoagulation for VTE Apixaban reduced risk of recurrent VTE compared to placebo, without increasing rate of major bleeding 1. Buller H et al. Journal of Thrombosis and Haemostasis 2008;6(8):1313-1318. 2. Agnelli G et al.. N Engl J Med 2012. Note: Apixaban and dabigatran are not currently approved for VTE treatment
    59. 59. Clinical trials with dabigatran Study Main methods Main Results RE-COVER 11 & RE-COVER 2 2 • Dabigatran 150 mg BID vs adjusted dose warfarin (INR 2- 3) • Treatment of acute VTE • Dabigatran 150 mg BID is as effective as adjusted dose warfarin • Safety profile similar to warfarin, and without the need for laboratory monitoring • RE-COVER 2 confirmed dabigatran is non-inferior to warfarin, with lower risk for bleeding RE-MEDY3 • Dabigatran 150 mg twice daily vs. warfarin (6-36 months) • Patients who had received anticoagulant therapy for acute VTE • Dabigatran is as effective as warfarin for preventing recurrent VTE, with lower risk for bleeding, but higher incidence of acute coronary event RE-SONATE4 • Dabigatran vs. Placebo • Patients who had received anticoagulant therapy for acute VTE 92% relative risk reduction with dabigatran in recurrent VTE compared to placebo, no significant difference in the incidence of major bleeding 1. Schulman S et al. N Engl J Med 2009;361(24):2342-2352. 2. Schulman S et al. ASH 2011 Annual Meeting. Abstract 205. 3. Schulman S et al. XXIII Congress of ISTH, 2011. Abstract O-TH-033, 4. Schulman S et al. XXIII Congress of ISTH, 2011. Abstract O-MO-037. Note: Apixaban and dabigatran are not currently approved for VTE treatment
    60. 60. Clinical trials with rivaroxaban Study Main methods Main Results EINSTEIN- DVT1 • Rivaroxaban (15 mg BID x 3 weeks followed by 20 mg daily) vs. enoxaparin followed by VKA for 3, 6 or 12 months • Patients with acute symptomatic DVT • Rivaroxaban is noninferior for prevention of symptomatic recurrent DVT; similar rates of bleeding compared to enoxaparin/VKA • Improved patient satisfaction with rivaroxaban compared with enoxaparin/VKA, particularly in reducing anticoagulation burden EINSTEIN-PE2 • Rivaroxaban (15 mg BID x 3 weeks followed by 20 mg daily) vs. enoxaparin 40 mg BID followed by VKA for 3, 6 or 12 months • Patients with acute symptomatic PE with/without symptomatic DVT Rivaroxaban is noninferior to standard therapy for initial and long-term treatment of PE, with potentially improved benefit-risk profile, and significantly reduced the number of major bleeding events EINSTEIN- extension1 • VTE patients who had completed their standard treatment course • Rivaroxaban 20 mg once daily for additional 6 or 12 months compared with placebo • Rivaroxaban significantly reduced the risk of recurrent VTE 1. N Engl J Med 2010;363(26):2499-2510. 2. N Engl J Med;366(14):1287-1297.
    61. 61. Starting rivaroxaban in a new patient Usual dosage 15 mg BID for 3 weeks (one 15 mg tablet in the morning and one in the evening with food), followed by 20 mg once daily. Maximum daily dose 30 mg in the first 3 weeks; 20 mg thereafter Renal impairment CrCL < 30 ml/min: not recommended
    62. 62. Key learning points • VTE is the third most common cardiovascular disease after coronary artery disease and stroke. Complications include PE and post-thrombotic syndrome • Risk factors for VTE include hip/lower limb fractures, marked reduction in mobility after major surgery. Risk increases with advanced age and/or cancer • VKA, LMWH, UFH, fondaparinux and rivaroxaban are indicated in VTE. However, traditional anticoagulants are associated with concerns about bruising and bleeding, lifestyle limitations, and need for regular monitoring • Rivaroxaban – the only new anticoagulant currently approved for VTE treatment and prevention of recurrent VTE – offers greater convenience, and may provide better clinical outcomes than with VKA or LMWH therapy
    63. 63. Practical Usage New Anticoagulants in AF and VTE
    64. 64. Switching from warfarin to new anticoagulant 1. Advisory Committee Briefing Document. 2. Wartak SA, Bartholomew JR. Cleveland Clin J Med 2011;78(10):657-664. 3. XARELTO® Product Monograph. 4. Eliquis 2.5 mg film-coated tablets information. To apixaban Discontinue warfarin and start apixaban when INR is <2.0 To dabigatran Start dabigatran only after warfarin has been discontinued and INR is < 2.0 To rivaroxaban Stop warfarin and determine INR • INR ≤2.5: Start rivaroxaban at usual dose • INR >2.5: Delay start rivaroxaban until INR is ≤2.5
    65. 65. Switching from new anticoagulant to warfarin 1. Advisory Committee Briefing Document. 2. Wartak SA, Bartholomew JR. Cleveland Clin J Med 2011;78(10):657-664. 3. XARELTO® Product Monograph. 4. Eliquis 2.5 mg film-coated tablets information. From apixaban • Start warfarin and continue apixaban for ≥2 days • After 2 days, obtain INR prior to next apixaban dose • Continue coadministration until INR is ≥ 2.0 From dabigatran Start warfarin according to CrCl: • ≥50 ml/min: 3 days before discontinuing dabigatran • 30- <50 ml/min: 2 days before discontinuing dabigatran INR not reliable to assess warfarin effect till ≥2 days after discontinuation From rivaroxaban • First 2 days: give warfarin at usual starting dose; no INR testing • Continue rivaroxaban till INR ≥2.0; then discontinue • INR ≥24 hours after last dose of rivaroxaban for warfarin effect
    66. 66. Switching from parenteral anticoagulant to new anticoagulant To apixaban Done at the next scheduled dose To dabigatran Initiate dabigatran 0-2 hours before next dose of other agent is due, or at time of discontinuation in case of continuous treatment To rivaroxaban Start rivaroxaban when heparin is stopped, or 0-2 hours before next scheduled injection of full-dose of LMWH or fondaparinux. If receiving prophylactic anticoagulant, start rivaroxaban ≥6 hours after the last dose
    67. 67. Switching from new anticoagulant to parenteral anticoagulant From apixaban Done at the next scheduled dose From dabigatran For prevention of VTE after hip- or knee- replacement surgery, wait 12 hours after last dose of dabigatran before switching From rivaroxaban Discontinue rivaroxaban; give first dose of parenteral anticoagulant when next rivaroxaban dose was scheduled
    68. 68. Bridging anticoagulation • Bridging anticoagulation with LMWH is often used empirically, before and after surgery • Debate on need for bridging anticoagulation1-4 • Manufacturers’ recommendations for dabigatran and rivaroxaban: • Discontinue these drugs at least 1 day before the procedure • Consider longer times if major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, where complete hemostasis may be required, or if moderate renal impairment 1. ACCP Guidelines 2012. 2. Douketis JD. Blood 2011;117(19):5044-5049. 3. Wysokinski WE, McBane RD. Circulation 2012;126(4):486-490. 4. BRIDGE Study Overview.
    69. 69. Interruption of dabigatran or rivaroxaban before surgery or invasive procedures Schulman S, Crowther MA. Blood 2012;119(13):3016-3023.
    70. 70. Renal impairment Renal impairment - a risk factor for bleeding with anticoagulants Apixaban Dabigatran Rivaroxaban Renal clearance 25%1 80%1 33%1 Severe impairment Not recommended for CrCl <15 ml/min 3-5 Contraindicated 2 Not recommended for CrCl <15 ml/min 3-5 Other Less affected than dabigatran, preferred in moderate impairment 3-5 Lower dose if age ≥75 with risk factors for bleeding 2 Less affected than dabigatran, preferred in moderate impairment 3-5 1. Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program 2012;2012(1):536-540. 2. PradaxTM Product Monograph. 3. Eliquis 2.5 mg film-coated tablets information. 4. Harder S. J Clin Pharmacol 2012;52(7):964-975. 5. Eliquis Product Monograph.
    71. 71. Choice of anticoagulant Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program 2012;2012(1):536-540.
    72. 72. Bleeding with new anticoagulants • Up to ∼3% of patients may develop major bleeding • Major bleeding rates comparable/lower than with warfarin • Factors for increased risk: ↑ age, renal impairment • No effective antidotes known • INR is unreliable for new anticoagulants • No precise information with aPTT, PT; but may be qualitative indicator of drug presence 1. Siegal DM, Crowther MA. Eur Heart J 2012. 2. Weitz JI, Gross PL. Hematology Am Soc Hematol Educ Program 2012;2012(1):536-540. 3. Crowther MA, Warkentin TE. J Thrombosis Haemostasis 2009;7:107-110. 4. Schulman S, Crowther MA. Blood 2012;119(13):3016-3023
    73. 73. Managing bleeding with new anticoagulants Siegal DM, Crowther MA. Eur Heart J 2012.
    74. 74. Useful resources • CCS guidelines for AF: 2012 update • ACCP 2012 guidelines: Antithrombotic Therapy for VTE

    ×