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10/22/2012

OBJECTIVES

ANTITHROMBOTIC THERAPY GUIDELINES 2012: A FAMILY MEDICINE PERSPECTIVE

• Review the new CHEST recommendations for antithrombotic therapy • Rank by strength of evidence the most useful recommendations • Briefly examine the studies which were used to create the recommendations • Briefly review non-Vitamin K inhibitors which will may replace VKI for some indications

DISCLOSURES

ANTICOAGULATION THERAPY

• I have nothing to disclose.

• Antithrombotic therapy are medications used for the following conditions: • Treatment for venous thromboembolism (VTE) • Prevention of systemic embolism associated with • Atrial fibrillation • Prosthetic heart valves

• Prevention of stroke and recurrent myocardial infarction in select patients Du Breuil

INTRODUCTION 1

LEVELS OF EVIDENCE

• The Levels of Evidence presented here derive from the Centre For Evidence Based Medicine (CEBM) located at Oxford University

• 1A: Systematic Review (SR) of Randomized Control Trials (RCTs) • 1B: Individual RCT with a narrow Confidence Interval • 2A: SR (with homogeneity) of cohort studies • 2B: Individual cohort study +/- low quality RCT: e.g., 80% follow-up • 2C: “Outcomes” Research, Ecological Studies

• Only 2 recommendations for anti-thrombotic therapy in the Chest guidelines had ffi i t evidence id tto supportt Grade G d 1 sufficient recommendations • The other recommendations are 2B and 2C levels • The following slide will be repeated after some of the recommendations to remind the viewer

• • • •

3A: SR (with homogeneity) of case-control studies 3B: Individual Case-Control study 4: Case series (and poor quality cohort and case-control studies) 5: Expert Opinion, or based on physiology, bench research

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INTRODUCTION 2 ƒ Antithrombotic therapy is used for a variety of conditions:

PHYSIOLOGY

Warfarin Extrinsic Pathway

Extrinsic Pathway=II,VII,IX,X

IXa

• Treatment of venous thromboembolism (VTE) • Prevention of systemic embolism associated with:

X

X

Xa 2+

prothrombin

¾ Stroke ¾ Recurrent myocardial infarction in some patients Du Breuil

LMWH

Ca PL

¾ atrial fibrillation ¾ Use of prosthetic heart valves

• Prevention of:

Va Thrombin

Fibrinogen Cross-linked fibrin clot

HARRISON

XIIIa

Fibrin polymer

V

Antithrombin III

Fibrin monomer

PHARMACOLOGY

PHARMACOGENETIC TESTING

• Warfarin interferes with the cyclic interconversion of vitamin K and vitamin K epoxide. This results in the reduction of clotting factors II, VII, IXa and X. • Heparin binds to antithrombin III which catalyzes the inactivation off th thrombin factors. i ti ti bi and d other th clotting l tti f t • Low-molecular-weight-heparin (LMWH) are smaller heparin fragments which do not bind well to plasma proteins leading to a more predictable anticoagulant effect.

• For patients initiating VKA therapy, we recommend against the routine use of pharmacological testing for guiding doses of VKA (Grade 1B) • This study determined whether pharmacologic-guided dosing reduced the percent of out-of-range out of range INRs. INRs • There was no difference between the pharmacologicalguided dosing versus a standard empirical dosing treatment

Anderson Jeffrey L

LEVELS OF EVIDENCE

WARFARIN THERAPEUTIC RANGE

• 1A: Systematic Review (SR) of Randomized Control Trials (RCTs) • 1B: Individual RCT with a narrow Confidence Interval • 2A: SR (with homogeneity) of cohort studies • 2B: Individual cohort study +/- low quality RCT: e.g., 80% follow-up • 2C: “Outcomes” Research, Ecological Studies

• For patients treated with VKAs, we recommend a therapeutic range of 2.0 to 3.0 (target INR of 2.5) rather than the lower (INR<2) or higher (INR 3.0-5.0) range (Grade 1B)

• • • •

3A: SR (with homogeneity) of case-control studies 3B: Individual Case-Control study 4: Case series (and poor quality cohort and case-control studies) 5: Expert Opinion, or based on physiology, bench research

T RCT showed h d conflicting fli ti lt One O h d increased i d • Two RCTs results. showed recurrent VTEs and increased bleeding and one showed a reduced number of VTEs and decreased bleeding • A systematic review of 4 studies showed 115 more VTEs per thousand patients with slightly fewer deaths from bleeding

Chest

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TESTING FREQUENCY

LEVELS OF EVIDENCE

• For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks (Grade 2B)

• 1A: Systematic Review (SR) of Randomized Control Trials (RCTs) • 1B: Individual RCT with a narrow Confidence Interval • 2A: SR (with homogeneity) of cohort studies • 2B: Individual cohort study +/- low quality RCT: e.g., 80% follow-up • 2C: “Outcomes” Research, Ecological Studies

St bl INR d tto adjust dj t VKA dosing d i f att least l t • Stable INRs mean no need for 3 months. • Among 3 RCTs, none showed a difference in rates of thromboembolism, bleeding, or INR control. Chest

• • • •

SELF-TESTING AND SELFMANAGEMENT • For patients treated with VKAs who are motivated and can demonstrate competency in self-management strategies, including the self-testing equipment, we suggest patient self-management rather than usual p g (Grade ( ) outpatient INR monitoring 2B). • In Patient Self-Testing (PST), patients perform their own INR testing and adjust their anticoagulant dose.

3A: SR (with homogeneity) of case-control studies 3B: Individual Case-Control study 4: Case series (and poor quality cohort and case-control studies) 5: Expert Opinion, or based on physiology, bench research

THERAPEUTIC RANGE FOR HIGH-RISK GROUPS • Patients with antiphospholipid syndrome with previous arterial or venous thromboembolism, we suggest VKA therapy in the INR range (2.0-3.0) rather than higher intensity INR (3.0-4.5) (Grade 2B) • The bestt RCT showed higher Th b h d hi h mortality t lit secondary d tto major bleeding

• The largest study The Home INR Study (THINRS)Matchar • No improvement in clinical outcome • Modest improvement in patient satisfaction.

• Frequency of INR testing much higher compared to the usual laboratory-based monitoring Garcia-Alamino

HIGH INRS WITHOUT BLEEDING • For patients taking VKAs with INRs between 4.5 and 10 with no evidence of bleeding, we suggest against the routine use of Vitamin K (Grade 2B) • 4 RCTs support the evidence, but all had very wide confidence intervals Crowther #2

• For patients taking VKAs with INRs > 10 and with no evidence of bleeding, we suggest that oral vitamin K be administered. (Grade 2C) • No RCT trials showed decreased bleeding compared to placebo.

Crowther

CLINICAL PREDICTION RULES • For patients initiating VKA therapy, we suggest against the use of clinical prediction rules as the sole criteria to withhold VKA therapy. (Grade 2C) • High risk was defined as patients with • • • • • • •

Age > 65 History of stroke GI bleed within the last 2 weeks Recent MI Hct < 30% Creatinine > 1.5 mg/dL Diabetes mellitus

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LEVELS OF EVIDENCE

LOADING DOSE

1A: Systematic Review (SR) of Randomized Control Trials (RCTs) 1B: Individual RCT with a narrow Confidence Interval 2A: SR (with homogeneity) of cohort studies 2B: Individual cohort study +/- low quality RCT: e.g., 80% followup • 2C: “Outcomes” Research, Ecological Studies

• For patients sufficiently healthy to be treated as outpatients we suggest initiating VKA therapy with warfarin 10 mg daily for the first 2 days followed by dosing based on INR measurements. (Grade 2C)

• • • •

• 3A: SR (with homogeneity) of case-control studies • 3B: Individual Case-Control study • 4: Case series (and poor quality cohort and case-control studies) • 5: Expert Opinion, or based on physiology, bench research

INITIATION OVERLAP FOR HEPARIN AND VKA • For patients with acute VTE, we suggest that VKA therapy be started on day 1 or 2 of LMWH or UFH therapy rather than waiting for several days to start (Grade 2C). 4 studies 10 • Late start defined as days 3 3-10 • No difference for outcomes • Recurrent VTE • Major bleeding • Death

• Patient’s assigned to early initiation in one study focusing on hospital utilization spent a mean of 4 fewer days in the hospital. • Major problem with studies were lack of blinding and very wide confidence interval.

Th largest l t recentt study t d consisted i t d off 201 outpatients. t ti t The Th • The 10 mg group achieved a therapeutic INR in 4.2 days versus 5.6 days for the 5 mg group. Ebell,kovacs • There was no difference in the percentage of patients with a super therapeutic INR > 5

• Two other smaller poorly done studies showed no difference in the time to therapeutic INR levels.

MANAGEMENT OF SINGLE OUT-OFRANGE INR • For patients taking VKAs with previously stable therapeutic INRs who present with a single out-ofrange INR of < 0.5 below or above therapeutic, we suggest continuing the current dose and testing the INR within 1 to 2 weeks (Grade 2C) • No difference noted between group with a reduced or boosted dose and group with an unchanged dose. • Problem with the two studies was the small sample size and lack of blinding.

BRIDGING FOR LOW INRS

VITAMIN K SUPPLEMENTATION

• For patients with stable therapeutic INRs presenting with a single sub therapeutic INR value, we suggest against routinely administering bridging with heparin (Grade 2C) I one retrospective t ti t d there th i ifi t • In study was no significant difference in thromboembolic events between the two groups, but only addresses a single low INR.

• For patients taking VKAs, we suggest against routine use of Vitamin K supplementation (Grade 2C) • Both studies showed no benefit to using Vitamin K • Both studies which examined this had very wide confidence events intervals due to a low number of events.

• No studies addressed what to do if there were more than one low INR

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ANTICOAGULATION MANAGEMENT SERVICES FOR VKAS • We suggest that health-care providers who manage oral anticoagulation therapy should do so in a systematic and coordinated fashion, incorporating patient education, systematic INR testing, tracking, follow-up, and good patient communication of results and dosing decisions. • 4 RCTs compared usual care with the care of Anticoagulation Management Services (AMS) • AMS defined as having a designated, trained staff member using a standardized doing nomogram • Usual care is that provided by the patient’s personal physician • Not one study showed the benefit of an AMS • None of the RCTs were blinded and all four had major problems. • Several low-quality observational studies showed better outcomes in those patients managed by an AMS

DISCONTINUATION OF THERAPY • For patients eligible to discontinue treatment with VKA, we suggest abrupt discontinuation rather than gradual tapering of the dose (Grade 2C) • Gradual discontinuation is more confusing and inconvenient for the patient • 4 RCTs were very small and had very large confidence intervals.

THERAPEUTIC DOSE OF LMWH IN PATIENTS WITH DECREASED RENAL FUNCTION • For patients receiving therapeutic LMWH who have severe renal insufficiency (creatinine clearance < 30 mL/min), we suggest a reduction of the dose rather than using standard doses (Grade 2C). A i LMWH iis primarily i il eliminated li i t d th h renall excretion ti • Again through • The renal dose is 1 mg/kg every 24 hours.GLOBALRPh

• All studies were of poor quality.

DOSING DECISION SUPPORT • For dosing decisions during maintenance VKA therapy, we suggest using a validated decision support tools (paper nomograms or computerized RB1 dosing programs) rather than no decision support 2C) (Grade 2C). • Inexperienced prescribers may be more likely to improve prescribing with the use of decision support tools than experienced providers. • Studies subject to bias and had very wide confidence intervals.

DOSE MANAGEMENT OF SUBCUTANEOUS (SC) UFH • For outpatients with VTE treated with SC UFH, we suggest weight-adjusted dosing (first dose 333 units/kg, then 250 units/kg without monitoring rather than fixed or weigh-adjusted dosing with monitoring • Relevant with LMWH would R l t for f those th ith severe CKI where h ld nott be recommended. • The studies did not use blinding, were not powered and had very wide confidence intervals.

TREATMENT OF ANTICOAGULANTRELATED BLEEDING • For patients with VKA-associated major bleeding, we suggest reversal of anticoagulation with the four-factor prothrombin concentrate rather than with plasma (Grade 2C) • Plasma has the disadvantage of potential allergic reaction, infection fluid overload and preparation time transmission of infection, time. • The four-factor concentrate major disadvantage is their high cost.

• We suggest the additional use of vitamin K 5 to 10 mg by slow IV rather than reversal with coagulation factors alone (Grade 2C-because few trials with large numbers) • Vitamin K sustain the effects of the PT concentrate which have short half-lives.

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Robert Beck, 9/23/2012


10/22/2012

REFERENCES 1. Du Breuil AL, Umland EM. Outpatient Management of Anticoagulation Therapy. Am Fam Physician. 2007 75(7):1031-1042. 2. Harrison's™ vPRINCIPLES OF INTERNAL MEDICINE Eighteenth Edition. Copyright © 2012, 2008, 2005, 2001, 1998, 1994, 1991, 1987, 1983, 1980, 1977, 1974, 1970, 1966, 1962, 1958 by The McGraw-Hill Company. Chapter 116. Figure 116.1 3. Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical 2012;141;e152S-e184S Practice Guideline. Chest 2012;141;e152S e184S 4. Anderson Jeffrey L., Horne Benjamin D., Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation. Circulation. 2007; 116: 2563-2570 5. Matchar DB , Jacobson A , Dolor R , et al ; THINRS Executive Committee and Site Investigators . Effect of home testing of international normalized ratio on clinical events . N Engl J Med . 2010 ; 363 ( 17 ): 1608 - 1620 . 6. Crowther MA , Ginsberg JS , Julian J , et al . A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome . N Engl J Med . 2003 ; 349 ( 12 ): 1133 – 1138 7. Crowther MA , Garcia D , Ageno W , et al . Oral vitamin K effectively treats international normalised ratio (INR) values in excess of 10. Results of a prospective cohort study .Thromb Haemost . 2010 ; 104 ( 1 ): 118 - 121 . 175 . Gunther KE , Conway G , Leibach L , Crowther MA .

REFERENCES 8.

9. 10.

11.

Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial . Ann Intern Med . 2003; 138( 9): 714- 719. Ebell, MH. Evidence-Based Initiation of Warfarin (Coumadin) Am Fam Physician. 2005 Feb 15;71(4):763-765. Garcia-Alamino JM, Ward AM, Alonso-Coello P, et al. Self-monitoring and selfti l ti C h D t b S t Rev. R managementt off orall anticoagulation. Cochrane Database Syst 2010;14(4):CD003839. GLOBALRPh. The Clinicians Ultimate Reference.

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Beck's presentation