Disclosure. Anticoagulation Safety. I have no financial relationships with pharmaceutical companies that make anticoagulant medications 1/19/2016

Transcription

1 Anticoagulation Safety Ian Gordon M.D., Ph.D. Clinical Professor of Surgery University of California Irvine Chief of Vascular Surgery VAMC Long Beach Disclosure I have no financial relationships with pharmaceutical companies that make anticoagulant medications My brain? That s my second favorite organ. Woody Allen 1

2 Goals of Presentation Discuss risk for stroke in atrial fibrillation (AF) and the CHADS 2 and CHA 2 DS 2 Vas C scales Describe current guidelines for anticoagulation in AF Discuss the pertinent biochemistry of coagulation and pharmacology of warfarin and the New Oral Anticoagulants (NOACs) Explain risks of bleeding with anti coagulation in relation to the risk for stroke Identify barriers to physicians appropriately treating AF and methods to overcome them Describe potential of team approaches to AF Classification of AF AF CATEGORY First detected Characteristic Features only one diagnosed episode Paroxysmal Persistent Permanent recurrent episodes that spontaneously stop < 7 days recurrent episodes that last more than 7 days an ongoing long term episode Classification of AF Lone AF: Absence of other CV disease (HTN, COPD, Left Atrial enlargement, and age < 60 years Nonvalvular AF: Absence of rheumatic mitral valve disease, prosthetic heart valve, or hx mitral valve repair Secondary AF: result of acute MI, cardiac surgery, pericarditis, hyperthyroidism, PE or other conditions associated with AF 2

3 EPIDEMIOLOGY OF STROKE Cerebrovascular disease used to be 2 cd commonest cause of death in US according to WHO it remains the 2cd commonest cause of death worldwide Has fallen to 4 th cause of death in US ~ 130,000 deaths in 2011 [CDC] 2/3 strokes in those older than 65, and risk rises exponentially with age above 30 Men are 25% more likely to have stroke than women, but 60% of stroke deaths are in women EPIDEMIOLOGY OF ATRIAL FIBRILLATION (AF) Approximately million American AF pts Incidence increases with age, 18% of >80 have AF AF accounts for 6 24% of all ischemic strokes After a TIA or stroke, ~ 11% have new AF 15% of strokes occur in those with AF AF increases the risks for stroke 5 fold, strokes tend to be worse In mitral regurgitation AF increases risk 20x vs sinus rhythm Hylek Semin Thromb Hemost 2013;39: Vallakati et al. Postgrad Med DOI 10:1080/ ANTICOAGULATION FOR STROKE IN AF Adjusted dose warfarin reduces risk for stroke in AF patients 68% compared to no therapy Aspirin (ASA) reduces the risk of stroke 20% Between warfarin was the drug that led to the greatest number of hospital admissions in US in the elderly ¼ ½ of AF patients eligible for anticoagulation are not receiving therapy Those on warfarin are out of the therapeutic range almost half the time Hylek Semin Thromb Hemost 2013;39: Hart Ann Int Med 2007; 146:

4 CHADS 2 SCALE CONDITION POINTS C Congestive Heart Failure 1 H Hypertension 1 A Age > 75 years 1 D Diabetes Mellitus 1 S 2 Prior Stroke, TIA, or Thromboembolism 2 Annual Stroke Risk CHADS 2 CHADS 2 SCORE STROKE RISK % 95% CI Gage BF et al. Validation of clinical classification schemes for predicting stroke JAMA 285; Therapy Recommendations Based on CHADS 2 Score SUGGESTED SCORE RISK THERAPY 0 Low None or ASA 1 Moderate Oral anticoagulant or ASA 2 High Oral Anticoagulant 4

5 Therapy Recommendations Based on CHADS 2 Score SUGGESTED SCORE RISK THERAPY 0 Low None or ASA 1 Moderate Oral anticoagulant or ASA 2 High Oral Anticoagulant CHA 2 DS 2 VAS C SCALE CONDITION POINTS C Congestive Heart Failure 1 H Hypertension 1 A 2 Age > 75 years 2 D Diabetes Mellitus 1 S 2 Prior Stroke, TIA, or Thromboembolism 2 V Vascular Dz (PAD,MI, Aortic plaque) 1 A Age S C Sex Category (Female) 1 Only add point for female sex if other risk factor(s) are present Annual Stroke Risk CHADS 2 VAS C SCALE CHA 2 DS2 VAS C STROKE RISK % 95% CI ??

6 Therapy Recommendations Based on CHADS 2 Score SUGGESTED SCORE RISK THERAPY 0 Low None or ASA 1 Moderate Oral anticoagulant or ASA 2 High Oral Anticoagulant OVERVIEW OF HEMOSTASIS Platelet activation: platelet surface promotes the assembly of both key clotting factor complexes Clotting cascade: intrinsic and extrinsic pathways to factor X activation Generation of tenase and prothrombinase Xa (with Va, calcium, phospholipid) cleaves II to release IIa thrombin Thrombin cleaves fibrinogen to form fibrin monomer Key Role of Thrombin Cleaves fibrinogen to fibrin self assembing monomer > polymer lattice Activates platelets Stimulates positive feedback in cascade Activates factor VIII to VIIIa which promotes crosslinking of fibrin lattice: stabilizes clot 6

7 Activation of prothrombin by factor Xa in the prothormbinase complex is localized to negatively charged membrances by the calcium binding Domains of these vitamin K-dependent factors. Factor Va localizes to the membrane via its light chain. Factor Xa is a serine protease and Factor Va is not enzymatically active. FVa HC - factor Va heavy chain; FVa LC - factor Va light chain; FXa cat catalytic domain of factor Xa 7

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9 Thrombin as a target for anticoagulation Deep grove on one side of molecule contains active site cleaves fibrinogen [direct thrombin inhibitors] Exosites I binds thrombin receptor, fibrinogen, factor V, protein C and thrombomodulin Exosite II binds with heparin and heparin sulfates complexes with antithrombin (AT) 9

10 ONLINE 17.2 Warfarin Developed at University of Wisonsin [Wisconsin Research Foundation] Observation was Canadian cattle bleeding to death after eating moldy hay Biochemists isolated dicoumerol prototype for Coumadin (warfarin) Inhibits vitamin K dependent γ glutamyl carboxylation of amino acids inhibits clotting factors II, VII, IX, X Warfarin for AF Well established efficacy in multiple trials: 64% reduction in risk for stroke vs ASA or no therapy in pts with CHADs scores of 1 or more, especially 2 or higher Ideal therapy is INR of 2 3 Requires close clinical monitoring Time in therapeutic range (TTR) in clinical trials ranges between 55% and 66%, guidelines are for monthly Vallakati et al. Postgrad Med DOI 10:1080/

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12 Problems with warfarin Delay in onset, long half life of action Need for routine monitoring resources Difficult to reverse Interactions with many other drugs due to liver enzyme inhibition or induction Need for dietary restrictions Antibiotics which affect bowel flora cause fluctuations in available vit K Protein C and protein S interactions Most common cause of drug related hospitalization in the elderly Warfarin Drug Interactions 728 drug interactions on website 194 considered major Metronidazole and macrolide antibiotics decrease metabolism increase INR Many antibiotics decrease bowel flora that produce vitamin K azithromycin, levofloxacin, trrimethoprim/sulfamethoxazole (TMP/SMX))increase INR 12

13 Warfarin Antidotes Fresh Frozen Plasma in large volumes (2 10 L) difficult but achievable hour window Vitamin K takes days [very slow] Prothrombinase Complex Concentrates (PCCs) replaces VKA sensitive factors very fast USA available PCCs: Profilnine, Bebulin Factor VII replacement Activated PCCs have more clotting factors 4 instead of 3, probably more effective, not generally available Warfarin Antidotes Fresh Frozen Plasma in large volumes (2 10 L) difficult but achievable hour window Vitamin K takes days [slow] Prothrombinase Complex Concentrates (PCCs) replaces VKA sensitive factors USA available PCCs: Factor 7 concentrate, Factor 9 concentrate Profilnine, Bebulin FDA approved Kcentra in 2014 contains Factors II, VII, IX, X, Proteins C and S, and Antithrombin 13

14 Direct Thrombin Inhibitors New class of anticoagulants that directly inactivate IIa by binding to proteolytic site Hirudin from leeches described in 1882 Leprudin = recombinant hirudin Bivalirudin = bivalent hirudin derivative Melagatran (Ximelagatran) dipeptide that binds to active site only Argatroban arginine derivative that binds to active site Dabigatran (Pradaxa ) first FDA approved oral DTI DABIGATRAN ETEXILATE 1 st new anti coagulant class approved in USA in > 50 years Oral anti thrombin inhibitor absorbed as prodrug, converted by cytochrome P 450 to active drug cleared by renal metabolism RE LY: 18,113 subjects with nonvalvular Afib randomized to Dabigatran (110 or 150 mg BID) or warfarin (INR 2 3) Endpoint was new CVA or embolism Dabigatran was superior: 1.11%/yr vs. 1.71%/yr incidence of stroke or embolism 14

15 DABIGATRAN ETEXILATE Indications and precautions Indication: Reduce the risk of stroke and systemic embolism in non valvular atrial fibrillation Contraindications: Bleeding, allergy to dabigatran Dose adjust for severe renal failure(gfr 30 ml) Precautions: Permeability glycoprotein (P gp) inducers (rifampin) exposure to drug, should be avoided P gp inducers (ketaconazole, verapamil) do not significantly exposure, and dose adjustment is not usually needed Dabigatran Pharmacokinetics RE LY trial data plasma concentrations in 9522 subjects on either 110 or 150 mg bid were analyzed in this study Age, sex, Cr clearance, CHF, South Asian ethnicity all influenced drug excretion/clearance PPIs, amiodarone and verapamil affected bioavailability Except for Cr clearance < 30 ml/min, none of the other factors affected plasma levels > 26% Adjustment of dose for GFR < 30 ml/min is necessary suggest 75 mg BID Liesenfeld et al. J Thrombosis and Haemostasis 2011;9:

16 RE-LY Patient flow diagram. Eikelboom J W et al. Circulation Copyright American Heart Association 2011;123: RE LY TRIAL Kaplan-Meier curves for each of the 3 treatment groups MAJOR BLEEDING Eikelboom J W et al. Circulation 2011;123:

17 Kaplan-Meier curves for each of the 3 treatment groups for GI BLEEDING Eikelboom J W et al. Circulation 2011;123: Kaplan-Meier curves for each of the 3 treatment groups for the outcome of intracranial bleeding. Eikelboom J W et al. Circulation 2011;123: Copyright American Heart Association Increased Risk for MI and ACS with Dabigatran January 2012 Authors performed meta analysis of 7 clinical trials where Dabigatran was compared to either lovenox or dose adjusted warfarin Signficantly higher risk of MI or ACS in Dabigatran group vs control 237/20,000 vs 83/10,514 (1.19 % vs 0.79%) OR 1.27, 95% CI , p = 0.03 Uchino, K. et al. Arch Intern Med 2012;0:archinternmed v

18 Risk of myocardial infarction and acute coronary syndrome across 7 studies, including original long-term Anticoagulant Therapy (RE-LY) results Uchino, K. et al. Arch Intern Med 2012;0:archinternmed v1-6. Copyright restrictions may apply. Incidence of new MI/ACS-RE-LY DABIGATRAN Until very recently no approved antidote and still no monitoring test Charcoal if ingested < 2 hours Dialysis reportedly clears 60% in 3 hours [no clinical data to confirm efficacy Prothrombinase complex concentrates (PCC) : factor VII or IX preparations (e.g., Profilnine) which reverse warfarin do not work for Dabigatran No US approved monitoring test kits are marketed in Canada and EU 18

19 DABIGATRAN Antidote for dabigatran: idarucizumab (Praxbind ) Just last month FDA approved idarucizumab monoclonal antibody which binds to and rapidly inactivates dabigatran shown to work in normal volunteers Prothrombinase Complex Concentrate Inhibitors do not work for dabigatran Pollack CV et al. NEJM;373: There is a test for Dabigatran plasma levels 19

20 if PTT > 80, increased bleeding aptt Rivaroxaban (Xarelto ) Indications and precautions Indication: DVT/PE prophylaxis in joint replacement surgery, non valvular atrial fibrillation, treatment of PE and DVT Contraindications: Bleeding, allergy, epidural catheters Dose adjust for severe renal failure (GFR 30 ml) Cytochrome P450 and P gp inhibitors exposure Rifampin (P gp inducer) exposure RIVAROXABAN (XARELTO ) 1 st oral Xa inhibitor approved in USA Initially approved for DVT/PE prophylaxis in joint replacement surgery, later for non-valvular Afib and treatment of DVT/PE Blocks Factor Xa but does not require AT Rapid absorption: C max reached in 2 to 4 hours Half-life of 5 to 9 hours in healthy subjects, ages 20 to 45; 11 to 13 hours in the elderly Afib dose is 20 mg qd, orthopedic surgery dose is 10 mg qd 20

21 Rivaroxaban Pharmacokinetics Oral one compartment model Age, renal function, body weight are significant factors There is a strong correlation with PT and plasma levels Useful for monitoring??? Low variability between individuals Highly predicable and reliable effect Xu et al. Br J Clin Pharmacol 2012; epub January13 Rivaroxaban vs.warfarin in non-valvular AF Rocket Trial 21

22 Rivaroxaban vs.enoxaparin after joint replacement RECORD TRIALS RIVAROXABAN 22

23 Antidotes for oral factor Xa inhibitors No currently FDA approved antidote Prothrombinase Complex Concentrate Inhibitors do work in normal volunteers, no published reports in pateints New drug andexanet alfa reverses effects of rivaroxaban, apixaban, adoxaban is inactive version of factor Xa which binds these drugs with high affinity to stop their inhibition of native Xa. FDA approval expected very soon Siegel DM et al. NEJM 2015 DOI: /NEJMoa No approved antidote for Rivaroxaban or Apixaban No antidote: drug is primarily renal excretion: can institute diuresis, dialysis not likely to help as drug is highly protein bound Can give charcoal into the gut to reduce absorption One recent study in normal volunteers showed prothrombinase complex concentrate to rapidly reverse rivoraxaban effect on PT [Eerenberg et al. Circulation 2011] Effect of Rivaroxaban on post MI mortality 23

24 Rivaroxaban Does not have the MI/ACS problem of dabigatran Once day dosing PT monitoring may be very helpful Recent data suggests PCCs can probably reverse effects not and FDA approved indication APIXABAN (ELIQUIS ) 2 cd oral Xa inhibitor approved in USA 2012 Now approved for prevention of thrombembolism in nonvalvular Afib Like Rivoraxaban - blocks Factor Xa but does not require AT Rapid absorption: C max reached in 3 to 4 hours Half-life of hours Elimination 25% renal, 75% fecal Dose is 5 mg BID, reduce to 2.5 mg BID if 2/3 present (age>80, Cr > 1.5, or weight<60kg) APIXABAN (ELIQUIS ) Strong CYP3A4 and P-gp inhibitors (e.g., ketoconazole) increases AUC and effects recommendation to use 2.5 mg dose Strong CYP3A4 and P-gp inducers (e.g., rifampin) lead to decreased AUC and activity No dose adjustment for diltiazem and napraxen 24

25 Edoxaban (Savaysa ) Edoxaban (Savaysa ) 60 mg/day approved in US in January 2015, previously available In Japan as Lixiana INDICATIONS SAME AS DABIGATRAN 1] Reduce risk for stroke and systemic embolism risk in non valvular atrial fibrillation EXCEPT WHEN GFR> 95 ml/min) 2] treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5 10 days 3] to reduce the risk of recurrent DVT and PE Kaplan Meier Curves for the Primary Efficacy and Principal Safety End Points. Giugliano RP et al. N Engl J Med 2013;369:

26 Kaplan Meier Curves for the Primary Efficacy and Principal Safety End Points. Giugliano RP et al. N Engl J Med 2013;369: AHA/ACC Recommendations for AF CHA 2 DS 2 VAS c recommended to assess stroke risk Warfarin recommended for mechanical valves. With prior stroke, TIA, or CHA 2 DS 2 VAS c C 2, oral anticoagulants recommended warfarin, dabigatran, rivaroxaban, or apixoban. With warfarin, determine INR at least weekly during initiation and monthly when stable Evaluate renal function prior to starting direct thrombin or factor Xa inhibitors, and re evaluate when clinically indicated and at least annually AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation, Journal of the American College of Cardiology (2014), doi: /j.jacc AHA/ACC Recommendations for AF For atrial flutter, antithrombotic therapy is recommended as for AF With nonvalvular AF and CHA 2 DS 2 VAS c score of 0, it is reasonable to omit antithrombotic therapy With CHA 2 DS 2 VAS c score 2 and end stage CKD (CrCl <15 ml/min) or on hemodialysis, it is reasonable to prescribe warfarin for oral anticoagulation With nonvalvular AF and a CHA 2 DS 2 VAS c score of 1, no antithrombotic therapy or treatment with an oral anticoagulant or ASA may be considered AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation, Journal of the American College of Cardiology (2014), doi: /j.jacc

27 2014 AHA/ACC Recommendations for AF With moderate to severe CKD and CHA 2 DS 2 VAS c of 2, reduced doses of direct thrombin or factor Xa inhibitors may be considered For coronary interventions, bare metal stents may be considered to minimize duration of dual anti platelet therapy Following coronary revascularization in patients with CHA 2 DS 2 VAS c score of 2, it may be reasonable to use clopidogrel concurrently with oral anticoagulants, but without aspirin AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation, Journal of the American College of Cardiology (2014), doi: /j.jacc AHA/ACC Recommendations for AF Direct thrombin, dabigatran, and factor Xa inhibitor, rivaroxaban, are not recommended with AF and end stage CKD or on hemodialysis because of the lack of evidence from clinical trials regarding the balance of risks and benefit Direct thrombin inhibitor, dabigatran, should not be used with a mechanical heart valve AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation, Journal of the American College of Cardiology (2014), doi: /j.jacc Challenges in Management of AF AF pts have many severe comorbidites: CHF, CAD, PAD, often frail, may be at risk for falling 20% of AF pts with high risk not on oral ACs More than ¼ stop ACs within 1 year Primary reason for underutilization is fear of physicians concern for bleeding and falls Anticoagulation if appropriately employed for high risk pts without contraindications would prevent 50,000 new strokes annually in US at a cost savings of 8 billion dollars Vallakati et al. Postgrad Med DOI 10:1080/

28 Can bleeding risk be reliable predicted? HAS BLED: hypertension, Abnormal kidney or hepatic function, Stroke, Bleeding tendency or history, Labile INR, Elderly, Drugs/alcohol ATRIA :Hypertension (1pt), previous bleed(1 pt), age>75 (1pt), anemia (3 pts), severe renal impairment (3 pts) HEMORR 2 HAGES includes fall risks, platelet count or function, malignancy, genetic factors Scores do identify high risk pts who need more monitoring (INR) but have low positive predictive value Not recommended for use in current ACC/AHA guidelines Vallakati et al. Postgrad Med DOI 10:1080/ Why underuse of ACs? 25 of 29 studies report undertreatment for AF pts with high risk <70% of high risk patients (+ hx CVA or TIA) are on AC With CHADS 2 based criteria only 55% of score of 2 were on AC (Pinnacle Registry) Similar results in European studies 51 75% utilizatoin for high risk pts, worse utilization in Asia ~ 60% 50% physician choice Factors advanced age Dementia fall risk Fall risk Less utilization in paroxysmal AF Vallakati et al. Postgrad Med DOI 10:1080/ Why underuse of ACs? Some role for antiplatelet agents: US guidelines suggest them for CHADs score = 1, European for score 1 in pts who refuse AC Doctors underestimate benefit of ACs in high risk pts and overestimate risk for bleeding Study of 465 Canadian MDs average estimate of relative risk reduction with ACs for stroke was 53% vs clinical trial data = 68% Canadian MDs estimated risk of major bleeding as 10% per year vs, actual rate of ~ 1% Bungard TJ et al. CMAJ 2001;165: Kakkar AK et al. Plos One 2013;(5):e

29 GARFIELD REGISTRY Kakkar AK et al. Plos One 2013;(5):e63479 Effect of caring for AF patients with bleeding or stroke on subsequent prescriptions Choudhry NJK et al. BMJ Clinical Research Ed. 2006;332: Relative efficacy and risk for bleeding with warfarin vs NOACs for AF stroke prevention Many post market reports of bleeding with dabigatran per FDA database: bleeding rates are similar or less than warfarin. Similar data not yet developed for factor Xa inhibitors For all NOACs risk for intracranial hemorrhage (ICH) is less than with warfarin based on large trials this is widely accepted Quality adjusted life years gained with NOACs are substantially higher with NOACs than warfarin due to greater efficacy in preventing stroke and lower ICH In some analyses NOACs, despite cost of drug, are still cost effective because monitoring not indicated Recent Cochrane Meta analysis: risks of NOACs for events and bleedings not significantly different than warfarin Robertson L et al. Cochrane Database of Systemic reviews 2015; Issue 12 article No. CD Vallakati et al. Postgrad Med DOI 10:1080/

30 Canadian Government Meta analysis Reviewed 28 RCTs looking at warfarin versus new oral anticoagulants (NOACs) as well as ASA or ASA + clopidogrel Absolute differences between warfarin and NOACs were small fewer than 10 events per 1,000 pt years Anticoagulants consistently better than antiplatelet drugs alone (subgroups including age >70, age <70, CHADS 2 =1, CHADS 2 2) Canadian Agency for Drugs and Technologies in Health Antithrombotic Agents for the Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation Vol 1, Issue 1B, March 2013 REDUCTION IN AND EMBOLISM RISK Apixaban vs. dose adjusted warfarin odds ratio = fewer events/1000 pt yr Dabigatran 150 vs. dose adjusted warfarin odds ratio = fewer events/1000 pt yr Low dose ASA and clopidogrel + low dose ASA vs. warfarin or NOACs odds ratio = 1.9 Rivaroxaban vs. warfarin or other NOACs no significant differences Canadian Agency for Drugs and Technologies in Health Antithrombotic Agents for the Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation Vol 1, Issue 1B, March 2013 Cochrane Database Meta analysis M eta analysis of clinical trials of warfarin vs NOACs for pulmonary embolism Many reported episodes of bleeding with dabigatran per FDA Mini Sentinal database: bleeding rates are similar or less than warfarin. No similar data for other NOACs For all NOACs risk for intracranial hemorrhage (ICH) is less than with warfarin Quality adjusted life years gained with NOACs are substantially higher than with warfarin due to greater efficacy in preventing stroke and lower ICH In some analyses NOACs, despite cost of drug, are still cost effective because monitoring not indicated Robertson L et al. Cochrane Database of Systemic reviews 2015; Issue 12 article No. CD

31 Stroke Risk Assessment for Atrial Fibrillation (SRAAF): hospital-based stroke assessment and intervention Australian hospital: pharmacist led program with advisory panel of hematologist, geriatrician, family practitioner cardiologist, 2 pharmacists SRAAF team made recommendations for therapy for AF based on risk for CVA and presence of contraindications for warfarin anticoagulation Compared rates of anticoagulation therapy for AF pts with high risk for stroke vs low risk at admission versus discharge based on evaluations by SRAAF team Compared rates of anticoagulation at discharge before and after development of program Jackson SL et al. J Clin Pharm and Therapeutics. 2011;36:71-79 STROKE RISK ASSESSMENT FORM Stroke Risk Assessment for Atrial Fibrillation (SRAAF): hospital-based stroke assessment and intervention ON WARFARIN n ((%) PREINTERVENTION INTERVENTION AT ADMISSION HIGH RISK 76 (31) 47 (44) MODERATE RISK 22 (30) 6 (50) AT DISCHARGE HIGH RISK 76 (30) 65 (57) MODERATE RISK 22 (30) 13 (80) 31

32 Can we improve compliace with guidelines for management of AF with anticoagulation? EDUCATION, EDUCATION, EDUCATION Educational meetings, internet training, posters Get With the Guidelines (GWTG): AHA program to increase adherence to guidelines for CV diseases includes treatment for CHF, CAD, smoking cessation New GWTG AFIB module in 2013 Individual hospitals that achieve 85% compliance with guidelines receive Performance Achievement Awards Possibly as better results with NOACs are generally appreciated increase utilization will result Jackson SL et al. J Clin Pharm and Therapeutics. 2011;36:71-79 Interdisciplinary Nurse Coordinated Atrial Fibrillation Expert Programmes Goals of Program stroke prevention, controlling symptoms, improve quality of life, morbidity and mortality, admissions to hospital and ER, cost effectiveness Convert guidelines into practical workflow models that are applied to to individual patient care Berti D et al. European Heart Journal 2013;34: Berti D et al. European Heart Journal 2013;34:

33 Berti D et al. European Heart Journal 2013;34: Dabigatran: how the drug company withheld important analyses (BMJ2014; July 2014) Deborah Cohen, investigations editor, The BMJ The recommendations for use of new generation oral anticoagulants may be flawed because regulators did not see evidence showing that monitoring drug plasma levels could improve safety. The company also withheld analyses that calculated how many major bleeds dose adjustment could prevent. Conclusions NOACs will slowly but surely take over role of warfarin, especially when drugs become generic, and due to development of approved antidotes An important factor for improving safety of therapy is monitoring with simple lab tests: PT/INR peak and trough levels for Xa inhibitors, and possibly PTT like test for direct thrombin inhibitors Other trend to improve management is focused guidelines like those employed for VTE prophylaxis (I can hear the groans) 33