Atrial Fibrillation Current State of Management with Importance to Newer Anticoagulants and Devices

Transcription

1 Atrial Fibrillation Current State of Management with Importance to Newer Anticoagulants and Devices Garland Green, MD Interventional Cardiologist Cardiovascular Institute of the South

2 Atrial fibrillation Atrial fibrillation (AF) is an atrial tachyarrhythmia characterised by predominantly uncoordinated atrial activation with consequent deterioration of atrial mechanical function On the ECG, there is an absence of consistent P waves; instead there are rapid oscillations or fibrillatory waves that vary in size, shape and timing

3 Atrial Fibrillation

4 Atrial Fibrillation

5 Etiology Cardiac causes of AF Common cardiac causes: Ischemic heart disease Rheumatic heart disease Hypertension Sick sinus syndrome Pre-excitation syndromes (e.g. Wolff-Parkinson-White syndrome) Less common cardiac causes: Cardiomyopathy or heart muscle disease Pericardial disease (including effusion and constrictive pericarditis) Atrial septal defect Atrial myxoma

6 Etiology Non-cardiac causes of AF Acute infections, especially pneumonia Electrolyte depletion Lung carcinoma Other intrathoracic pathology (e.g. pleural effusion) Pulmonary embolism Thyrotoxicosis

7 Atrial Fibrillation -- Prevalence --

8 Risk Factors In the Framingham study, the development of AF was associated with increasing age diabetes hypertension and valve disease. It is also commonly associated with, and complicated by, congestive heart failure and strokes. Dietary and lifestyle factors have also been associated with AF Excessive alcohol Caffeine Emotional and physical stress. Post-op AF is associated with a greater risk of mortality and morbidity, and post-op AF predisposes a significantly increased risk of stroke and thromboembolism.

9 Classification of AF Terminology Clinical features Pattern Initial event (first detected episode) Paroxysmal Persistent Permanent ( accepted ) Symptomatic Asymptomatic Onset unknown Spontaneous termination <7 days and most often <48 hours Not self-terminating Lasting >7 days or prior cardioversion Not terminated Terminated but relapsed No cardioversion attempt May or may nor reoccur Recurrent Recurrent Established

10 Treatment for persistent AF Two main treatment strategies: Rate-control involves the use of chronotropic(rate control ie beta blockers, calcium blockers, digoxin) drugs or electrophysiological/surgical interventions Rhythm-control involves the use of electrical or pharmacological cardioversion for persistent AF, or suppression of recurrent (e.g. paroxysmal) AF There is still the need for appropriate antithrombotic therapy if a rhythm-control strategy is chosen

11 Rate-control strategy Try rate control first for patients with persistent AF: Over 65 With coronary artery disease With contraindications to antiarrhythmic drugs Unsuitable for cardioversion Without congestive heart failure

12 Rhythm-control strategy Try rhythm-control first for patients with persistent AF: Who are symptomatic Who are younger Presenting for the first time with lone AF Secondary to a treated/corrected precipitant With congestive heart failure

13 Other management strategies AV nodal ablation with PPM Afib Ablation Maze procedure

14 Stroke risk was equivalent with intermittent and sustained NVAF in SPAF trials1

15 CHA2DS2-VASc Congestive heart failure 1 Hypertension 1 Age > 75 2 Diabetes 1 Stroke/TIA/TE 2 Vascular disease (MI, PAD, aortic plaque) 1 Age Female sex 1

16 CHA2DS2-VASc Stroke rate %/year 0 0% 1 1.3% 2 2.2% 3 3.2% 4 4.0% 5 6.7% 6 9.8% 7 9.6% 8 6.7% %

17 Score Risk Anticoagulation Considerations 0 Low Aspirin ( mg) daily or none 1 Moderate Aspirin daily or warfarin (INR to ) or dabigatran (Pradaxa) or rivaroxaban (Xarelto) or apixaban (Eliquis), depending on factors such as patient preference 2 or greater Moderate or High Warfarin (INR ) or dabigatran (Pradaxa) or rivaroxaban (Xarelto) or apixaban (Eliquis) or edoxaban (Savaysa)

18 HAS-BLED score for bleeding risk on oral anticoagulation in atrial fibrillation Feature Score if present Hypertension (Systolic 160mmHg) 1 Abnormal renal function 1 Abnormal liver function 1 Age 65 years 1 Stroke in past 1 Bleeding 1 Labile INRs 1 Taking other drugs as well 1 Alcohol intake at same time 1

19 Novel Oral Anticoagulants Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa)

20 Pradaxa (dabigatran) Direct, specific, competitive thrombin inhibitor X TF/VIIa IX Half-life hours Uses P-gp transporter with bowel absorption VIIIa Va IXa Clearance : 80% renal excretion Not a substrate of CYP 450 enzymes Xa II Dabigatran Oral, twice daily dosing without need for coagulation monitoring Fibrinogen IIa Fibrin Adapted from Weitz et al, 2005; 2008

21 PRADAXA 150 mg twice daily was significant in reducing the risk of stroke and systemic embolism an additional 35% vs warfarin PRADAXA= DABIGATRAN

22 Significant risk reduction of both ischemic stroke and hemorrhagic stroke vs warfarin

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27 An Immediate and Specific Reversal Agent for PRADAXA --PRAXBIND specifically binds to dabigatran and its acylglucuronide metabolites, neutralizing their anticoagulant effect immediately after administration --Binds with higher affinity than dabigatran to thrombin --Has no effect on other anticoagulant or antithrombotic therapies

28 Managing anticoagulant effects of PRADAXA in cases of hemorrhagic complications

29 Rivaroxaban (Xarelto) TF/VIIa Direct, specific, competitive factor Xa inhibitor Half-life 5-13 hours Clearance : 1/3 direct renal excretion X VIIIa Va Xa IXa IX Rivaroxaban 2/3 metabolism via CYP 450 enzymes Oral, once daily dosing with largest meal without need for coagulation monitoring II IIa Fibrinogen Fibrin Adapted from Weitz et al, 2005; 2008

30 Cumulative event rate (%) Primary Efficacy Outcome Stroke and non-cns Embolism Event Rate Rivaroxaban Warfarin Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: < No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Days from Randomization

31 Primary Safety Outcomes Major and non-major Clinically Relevant Rivaroxaban Event Rate Warfarin Event Rate HR (95% CI) P- value (0.96, 1.11) Major (0.90, 1.20) Non-major Clinically Relevant (0.96, 1.13) Event Rates are per 100 patient-years Based on Safety on Treatment Population

32 Bleeding Sites GI (upper, lower, and rectal) CrCl ml/min Riva 15 mg (N = 1474) Warfarin (N=1476) P- value Riva 20 mg (N=5637) CrCl 50 ml/min Warfarin (N=5640) P- value Intracranial Macroscopic haematuria Bleeding associated with non-cardiac surgery Intra-articular Epistaxis *Major bleeding per 100 pt-yrs of follow-up

33 XARELTO (rivaroxaban) Is Administered With Once-daily Dosing CrCl (ml/min) Recommended Once-daily Dose of XARELTO >50 20 mg 15 to mg* <15 Avoid use XARELTO should be taken once daily with the evening meal Coadministration of XARELTO 15 mg and 20 mg with food increases its bioavailability to approximately 100% If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as possible on the same day *Patients with CrCl 15 to 30 ml/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of XARELTO similar to those in patients with normal renal function. Please see the full Prescribing Information, including Boxed WARNINGS, available at this event. 3333

34 XARELTO (rivaroxaban): Drug-Drug Interaction Profile Drugs (examples) PK/PD Effects Recommendation Combined P-gp and strong CYP3A4 inhibitors Ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan Concomitant use increases XARELTO exposure and PD effects; significant increases in rivaroxaban exposure may increase bleeding risk Avoid concomitant use Combined P-gp and strong CYP3A4 inducers Carbamazepine, phenytoin, rifampin, St. John s wort Concomitant use decreases XARELTO exposure and PD effects, which may decrease efficacy of XARELTO Avoid concomitant use if these drugs must be coadministered Combined P-gp and weak or moderate CYP3A4 inhibitors in the presence of renal impairment (CrCl 15 to 50 ml/min) Amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, azithromycin, cimetidine, chloramphenicol Based on simulated PK data, patients with renal impairment receiving XARELTO concomitantly with combined P-gp and weak or moderate CYP3A4 inhibitors may have significant increases in exposure compared with patients with normal renal function. Although increases in exposure can be expected, results from ROCKET AF, which allowed concomitant use of combined P-gp and weak or moderate CYP3A4 inhibitors, did not show an increase in bleeding in patients with CrCl 30 to <50 ml/min Abbreviations: CYP = cytochrome P450; PK/PD = pharmacokinetic/pharmacodynamic. Please see the full Prescribing Information, including Boxed WARNINGS, available at this event. Use only if potential benefit justifies risk 34

35 Interrupting rivaroxaban Prior to Surgery or Intervention If anticoagulation must be discontinued to reduce the risk of bleeding with surgery, then XARELTO should be stopped at least 24 hours before the procedure In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established If oral medication cannot be taken after surgical intervention, consider a parenteral anticoagulant Wait at least 18 hours after last dose before removal of epidural catheter, and do not restart until at least 6 hours after removal. Please see the full Prescribing Information, including Boxed WARNINGS, available at this event. 35

36 Considerations for Managing Bleeding in Patients Receiving XARELTO (rivaroxaban) A specific antidote for XARELTO is not available XARELTO is not expected to be dialyzable due to high plasma-protein binding Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of XARELTO Use of procoagulant reversal agents, eg, PCC, APCC, or rfviia may be considered, but has not been evaluated in clinical trials There is no experience with antifibrinolytic agents in individuals receiving XARELTO There is neither scientific rationale for benefit nor experience with systemic hemostatics in individuals receiving XARELTO Abbreviations: APCC = activated prothrombin complex concentrate; PCC = prothrombin complex concentrate; rfviia = recombinant factor VIIa. Please see the full Prescribing Information, including Boxed WARNINGS, available at this event. 36

37 Apixaban (ELIQUIS) Direct, specific, competitive factor Xa inhibitor X TF/VIIa IX Half-life 12 hours Clearance : VIIIa IXa Apixaban 27% direct renal excretion Va Biliary and direct intestinal excretion Xa P-gp transport Oral, twice daily dosing without need for coagulation monitoring: 5mg bid. 2.5mg bid with at least 2 of: 80 or older, weight <60kg, creatinine >1.5 Fibrinogen II IIa Fibrin

38 Kaplan Meier Curves for the Primary Efficacy and Safety Outcomes. Granger CB et al. N Engl J Med 2011;365:

39 Bleeding Outcomes and Net Clinical Outcomes. Granger CB et al. N Engl J Med 2011;365:

40 APIXABAN DRUG INTERACTIONS Strong Dual Inhibitors of CYP3A4 and P-gp: Increase exposure to apixaban and increase the risk of bleeding. Decrease the dose of ELIQUIS to 2.5 mg twice daily (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin). In patients already taking ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp. Strong Dual Inducers of CYP3A4 and P-gp: Decrease exposure to apixaban and increase the risk of stroke. Avoid concomitant use of ELIQUIS e.g., rifampin, carbamazepine, phenytoin, St. John's wort.

41 APIXABAN ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled.

42 FDA POSITION FROM TRIALS Dabigatran significantly reduced stroke or systemic embolism, and ischemic stroke alone, with similar major bleeding versus warfarin. Rivaroxaban similar rates of stroke or embolism and major bleeding versus warfarin. Apixaban: significant reductions in stroke or systemic embolism, major bleeding and mortality compared to warfarin.

43 Pradaxa Xarelto Eliquis 150mg bid Cr.Cl >30 75mg bid Cr.Cl Avoid Cr.Cl <15 20mg Cr.Cl >50 15mg Cr.Cl Avoid Cr.Cl <15 5mg bid 2.5mg bid if 2 or more: >80, <60kg, >creat 1.5 With or without food Largest meal With or without food Avoid with rifampin, quinidine If Cr.Cl 30-50, reduce dose to 75mg bid with Multaq and ketoconazole. If Cr.Cl <30, avoid Multaq and ketoconazole. Verapamil may increase levels Avoid rifampin, carbamazepine, phenytoin, St. John s wart. Avoid ketoconazole, traconazole, lopinavir/ritonavir, itonavir, indinavir/ritonavir, conivaptan. Avoid amiodarone,diltiazem, verapamil, Multaq, erythromycin, Ranexa, azithromycin, cimetidine if Cr.Cl Avoid rifampin, carbamazepine, phenytoin, St. John s wart. Reduce to 2.5mg bid with ketoconazole, itraconazole, Biaxan. If on 2.5mg bid, stop Eliquis.

44 PRADAXA XARELTO ELIQUIS Converting from warfarin: start when INR<2 Rapid onset No monitoring (PTT) Converting from warfarin: start when INR<3 Rapid onset No monitoring (INR, PTT, anti-factor Xa activity) Converting from warfarin: start when INR<2 Rapid onset No monitoring (INR, PTT, anti-factor Xa activity) 1-2 day hold if Cr.Cl > if Cr.Cl <50 Baseline Cr.Cl, at least 6 monthly Extreme caution with epidural catheters At least 24 hours Baseline Cr.Cl, at least 6 monthly Extreme caution with epidural catheters At least 24 hours low risk At least 48 hours high risk Baseline Cr.Cl, at least 6 monthly Extreme caution with epidural catheters Cannot crush Can crush (apple sauce) Cannot crush

45 PRADAXA XARELTO ELIQUIS DVT, PE, extended DVT, PE, extended DVT, PE, extended Hip and knee prophylaxis Hip and knee prophylaxis

46 LAA Occluding Device

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49 PROTECT AF is a multicenter, prospective randomized clinical trial comparing the WATCHMAN LAAC device to long-term warfarin therapy, designed to demonstrate that WATCHMAN is non-inferior to warfarin for the combined endpoint of stroke, systemic embolism and cardiovascular or unexplained death. In the PROTECT AF 4-Year follow-up, the WATCHMAN Device showed a 40% relative risk reduction in composite endpoint of all stroke, cardiovascular or unexplained death and systemic embolization compared to warfarin in patients with non-valvular atrial fibrillation (AF), achieving statistical superiority