The Age of the Novel Anticoagulants. Peter Netzler, MD April 21, 2017 Carolina Cardiology Electrophysiology

Transcription

1 The Age of the Novel Anticoagulants Peter Netzler, MD April 21, 2017 Carolina Cardiology Electrophysiology

2 Disclosures Speaker bureau for the Bristol-Myers Squibb and Pfizer alliance for Eliquis

3 Direct Oral Anticoagulants or DOACS Not to bore you, but why we anticoagulate How we risk stratify The progression of evidence for antithrombotics and risk reduction Not so novel anymore- how we use on a daily basis Special populations

4 Atrial Fibrillation: Epidemiology Most common sustained arrhythmia Lifetime risk of developing AF: 1 in 4 adults > 40 years old fold increase in mortality fold increase in risk of stroke 2 1.NEJM 1982;306: Lancet 1987;1: Circulation 2004;110:

5 Atrial Fibrillation: Stroke

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7 CHADS 2 SCORING INDEX CHADS2 Risk Score CHF 1 Hypertension 1 Age > 75 1 Diabetes 1 Stroke or TIA 2 Moderate Risk > 2 Low Risk 0-1 From ESC AF Guidelines: CHADS2 score Patients (n = 1733) Adjusted stroke rate %/year

8 CHADS 2 -> CHA 2 DS 2 VASc CHADS2 Risk Score CHA2DS2-VASc Risk Score CHF 1 Hypertension 1 Age > 75 1 CHF or LVEF < 40% Hypertension 1 Age > 75 2 Diabetes 1 1 Diabetes 1 Stroke/TIA/ Thromboembolism 2 Stroke or TIA 2 Moderate-high Risk > 2 Intermediate Risk 1 Low Risk 0 From ESC AF Guidelines: Vascular Disease (MI,PVD,Aortic Plaque) Age Female 1 1

9 CHADS 2 -> CHA 2 DS 2 VASc CHADS2 score Patients (n = 1733) Adjusted stroke rate %/year CHA2DS2- VASc score Patients (n = 7329) Adjusted stroke rate (%/year) From ESC AF Guidelines:

10 Denmark National Hospital registry of AF patients 73,000 patients CHADS2 defined 32% as intermediate risk, whereas CHADS2Vasc found 91% of these were moderate to high risk Similarly CHADS2 defined 22% as low risk CHADS2Vasc classified these as 38% intermediate and 21% as high risk and only 8% were low risk BMJ 2011;342: d124

11 Bleeding Risk Scores in AF ATRIA HAS-BLED HEMORR 2 HAGES Anemia 1 3 Hypertension 4 1 Hepatic 10 or 1 Renal disease 2 1 Severe renal disease 2 3 Abnormal Renal 5 or 1 Liver function 6 1 Ethanol abuse 1 Age 75 yrs 2 Stroke 1 Malignancy 1 Any prior hemorrhage 1 Bleeding 1 Older Age (>75 yrs) 1 Hypertension 3 1 Labile INR 8 1 Reduced platelet number or function 11 1 Elderly (>65 yrs) 1 Rebleeding 12 2 Drugs 9 or Alcohol 1. Hemoglobin <13 g/dl men; <12 g/dl women 2. Estimated glomerular filtration rate <30 ml/min or dialysis-dependent 3. Diagnosed hypertension 4. Systolic blood pressure >160 mmhg 5. Presence of chronic dialysis or renal transplantation or serum creatinine 200 mmol/l 6. Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.) 8. Unstable/high INRs or poor time in therapeutic range (eg <60%) 9. Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc. 10. Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl 11. Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia 12. Prior hospitalization for bleeding 13. Most recent hematocrit <30 or hemoglobin <10 g/dl 14. CYP2C9*2 and/or CYP2C9*3 15. Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls 1 1 Hypertension 4 1 Anemia 13 1 Genetic factors 14 1 Excessive fall risk 15 1 Stroke 1 Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60: Jul 24. [Epub ahead of print] Online Appendix. PMID:

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13 How well are we doing? Canadian registry of patients with known AF admitted for stroke 597 patients were admitted with their first stroke (60% Disabling, 20% Fatal) 40% on Warfarin 75% having an INR < 2 on admission 30% on Antiplatelet therapy 29% on no Antithrombotics Stroke. 2009; 40:

14 STROKE PREVENTION IN AF 33% 19% (Fuster et al. Circulation 2011; 123: e269-e367)

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16 No. of Events Patient- Years AFASAK Warfarin versus Placebo BAATAF CAFA SPAF % SPINAF Combined Atrial Fibrillation Investigators. Arch Intern Med. 1994;154: Warfarin Better Risk Reduction, % Warfarin Worse

17 Warfarin Safety Bleeding risk 1.3% compared to 1% of patients treated with ASA or Placebo

18 ACTIVE W Warfarin superior to ASA/Plavix at reducing stroke/systemic embolism (SSE), MI or death (3.6% vs 5.4%) Warfarin with less bleeding (13.2% vs 15.4%) However, low quality anticoagulation with INR in TTR of < 58% showed no benefit

19 ACTIVE A ,554 pts deemed unsuitable for VKA therapy were given ASA/Plavix or ASA alone ASA/Plavix with 11% RRR in SSE, MI, or death But increase in major bleeds 2% vs 1.3% NO DIFFERENCE in combined outcome of vascular events plus major bleeding ASA vs. ASA/Plavix in patients who were felt to be non-candidates for warfarin showed a slight benefit (ARR of < 1%), but increased bleeding rates

20 1. For patients with ischemic stroke or TIA with paroxysmal (intermittent) or permanent AF, anticoagulation with a vitamin K antagonist (target INR, 2.5; range, ) is recommended (Class I; Level of Evidence A). 2. For patients unable to take oral anticoagulants, aspirin alone (Class I; Level of Evidence A) is recommended. The combination of clopidogrel plus aspirin carries a risk of bleeding similar to that of warfarin and therefore is not recommended for patients with a hemorrhagic contraindication to warfarin (Class III;

21 Stroke reductions from randomized trials Circulation. 2012;125:

22 DOACS Directly inhibit coagulation factors Thrombin Factor Xa No routine monitoring No dose adjustments Short half lives No food interactions Few drug interactions No reversal for factor Xa inhibitors Praxbind (idarucizumab) available for Pradaxa Approved for NVAF

23 DOACS-how did we get here 4 large randomized controlled trials Similar or lower strokes or systemic embolism (SSE) Similar or lower rates of bleeding Design of RCT s based on historical RCTs of warfarin for stroke prevention in AF patients Generally excluded pts with severe or moderate mitral stenosis and prosthetic heart valves

24 DOACs vs Warfarin Pradaxa Xarelto Eliquis Savaysa Stroke or Systemic Embolism Superior Non- Inferior Superior Non- Inferior Major Bleeding Non- Inferior Non- Inferior Superior Superior

25 NOACs-How we use daily Valvular heart disease Perioperative management Bleeding management Cardioversion Triple therapy Around time of a TIA/CVA

26 Evolving definitions of NVAF ACC/AHA/ESC 2001 Rhythm disturbance in absence of rheumatic mitral valve disease or prosthetic heart valve ACC/AHA/ESC 2006 update Now includes AF in the absence of mitral valve repair ACC/AHA/HRS 2014 AF in absence of rheumatic MS, a mechanical or bioprosthetic heart valve, or mitral valve repair ACCP 2012 non-rheumatic AF is synonymous with NVAF EHRA 2016 update AF in absence of prosthetic mechanical heart valves or moderate to severe mitral stenosis (usually from rheumatic disease). Other valvular disorders were commonly included in the NOAC trials and can be appropriately treated with these medications

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35 Agent Dosing Schedules Dabigatran 150mg, 75mg Apixaban 5mg, 2.5mg Rivaroxaban 20mg, 15mg Atrial Fibrillation Dosing Recommendations CrCl > 30 cc/min: 150 mg, BID CrCl 15 to 30 cc/min: 75 mg, BID Avoid < 15 cc/min CrCl > 15 cc/min: 5 mg, BID Any 2 ( > 80 yrs, < 60 kg, SCr > 1.5mg/dL: 2.5 mg, BID) Avoid < 15 cc/min CrCl > 50 cc/min: 20 mg, QD CrCl cc/min: 15 mg, QD Avoid CrCl < 15 cc/min Edoxoban 60mg, 30mg CrCl > 95 cc/min: avoid use CrCl cc/min: 60 mg, QD CrCl cc/min: 30mg QD

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37 Special Populations ESRD on dialysis FDA approved recomendations Obesity Eliquis at 5mg BID unless meets age >80 or weight <60kg Xarelto at 15mg Qday Data from the major trials lacking

38 ESRD: 2014 AHA/ACC/HRS For patients with nonvalvular AF with a CHADS2-VASC score of >=2 and who have ESRD (CrCl<15 ml/min) or are on hemodialysis, it is reasonable to prescribe warfarin (INR 2.0 to 3.0) for oral OAC (Class of recommendation: IIa; level of evidence: B) KDOQI Modification Dialysis patients are at increased risk for bleeding and careful monitoring should accompany intervention

39 ESRD Dialysis patients have a high baseline bleeding risk. It remains unclear to what extent VKAs affect the overall bleeding propensity, but they may significantly increase the risk of intracerebral hemorrhage. Vascular calcifications are extremely prevalent in dialysis patients and independently associated with an adverse outcome. Vitamin K antagonists inhibit the activity of key anticalcifying proteins and may thus compound the risk of vascular calcification progression in dialysis

40 Eliquis and HD FDA- approved prescribing recommendations for apixaban were revised in early 2014 for use in patients with end-stage CKD who Wang and colleagues investigated the pharmacokinetics, pharmacodynamics, and safety of apixaban in EIGHT patients with ESRD receiving HD after administration of a single 5-mg dose. A 4-hour HD session was associated with a 14% decrease in apixaban exposure in patients with ESRD and a 17% increase in apparent oral clearance. The authors concluded that due to the limited removal of apixaban by a 4-hour HD session, timing of the dose relative to HD is likely not important and that apixaban may be used without dose modification in patients with ESRD maintained on HD due to limited removal of apixaban during HD in this study. This study provides no insight or evidence regarding the effect of cumulative drug dosing and the extent of drug accumulation as well as the clinical impact or safety of continued apixaban use in this particular patient population.

41 Xarelto and HD Rivaroxaban is the other direct-acting oral anticoagulant that has dosing recommendations in patients receiving HD. In patients maintained on intermittent HD, administration of rivaroxaban 15 mg once daily for nonvalvular AF has been shown to provide similar concentrations and pharmacodynamic activity to those observed in clinical trials. These rivaroxaban dosing recommendations were based on a single-dose, pharmacokinetic study of EIGHT patients receiving HD, which is similar to the study design that brought the dosing recommendations to apixaban labeling.

42 ESRD Obvious concern nationwide about the use of cumulative DOACs dosing in this patient population. Monitoring may be desirable

43 Obesity Evidence that standard dosing with a BMI <=to 40 kg/m2 and weight <=120 kg for VTE treatment, VTE prevention, and prevention of SSE in NVAF. Limited clinical data with a BMI >40kgm 2 or a weight >120kg: PK/PD evidence Suggests decreased drug exposures, reduced peak concentrations and shorter half-lives raises concerns about under-dosing

44 Monitoring Dabigatran: Normal thrombin time excludes clinically relevant drug concentrations Activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive may be normal at trough levels Dilute thrombin time (R(2) = 0.92 to 0.99) and ecarin-based assays (R(2) = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification Rivaroxaban and Apixaban: anti-xa activity is linear (R(2) = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification and plasma concentrations Undetectable anti-xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification. To date, Apixaban and Xarelto calibrators and controls are available for research use only and have not been approved for use in the patient care setting.

45 Monitoring Anti-Xa levels might be useful to assess the pharmacodynamics of high-risk patients, such as high age, low body weight, and/or low renal function, and to assess the intensity of anticoagulation by using different methods of administration, such as crushed tablet via the nasogastric tube. The therapeutic range of anti-factor Xa activity must be established in patients receiving rivaroxaban and apixaban. Our results coincide well with the results of the recent sys- tematical review by Cuker et al. [17]. They reviewed studies that assessed relationships of drug levels of dabigatran, rivaroxaban, and apixaban to coagulation assay results. They concluded that for rivaroxaban and apixaban, anti-xa activity was linear over a wide range of drug levels and may be used for drug quantification. However, PT was less sensitive, especially for apixaban. A normal PT may not exclude clinically relevant levels. APTT demonstrated insufficient sensitivity and linearity for quantification [17].

46 uptodate For most NVAF pts on dialysis, we suggest no antiocoagulant therapy (Grade 2C). However for very high risk patients such as known atrial thrombus, valvular/rheumatic valve disease, and previous TIA or CVA, we suggest OAC with warfarin rather than no OAC (Grade 2C)

47 Monitoring Some suggest checking a drug-specific peak and trough levels in these and other special populations and circumstances No trial demonstrating what a therapeutic level is If the level falls within the expected range, continuation of the DOAC seems reasonable But questions remain what to do if below or above the normal levels Randomized Controlled Trials are needed Currently dosing needs to be individualized or avoided

48 Summary New tools create new responsibilities NOACS offer net clinical benefits in a wide breadth of patients Much experience and knowledge out so physicians should feel confident in use of NOACS We should recognize limitations in current knowledge

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