Harry Potter and the new oral anticoagulants V. Malavasi G. Biondi Zoccai

Background Last published atrial fibrillation (AF) guidelines show as crucial point oral anticoagulants (OAC) Rx before rhythm management Aspirin and other antiplatelet Rx are simple to take but have lower efficacy in preventing stroke or systemic embolism (SE) than vitamin K antagonists (VKA) 1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354

Background Warfarin is very effective at preventing stroke in patients with AF. Warfarin has several limitations, including drug and food interactions, a narrow therapeutic range, need for anticoagulation monitoring, and bleeding. Due to those caveats many pts remain untreated with VKA. Pts in VKA live about half of their time out of optimal INR range. Turpie AG. Eur Heart J 2008;29:155–65; Khoo CW et al. Int J Clin Pract 2009;63:630–41 Baker WL J Manag Care Pharm 2009;15:244-52.

Background

Background Baker WL J Manag Care Pharm 2009;15:244-52.

Background

Background It is unclear whether they do really represent a favorable breakthrough in the management of AF. In addition, the practicing physician remains uncertain about the relative strengths and weaknesses of each of these new treatment options as no direct comparison among them is available nor is foreseeable.

Endpoints Efficacy: Safety Tolerability Stroke or SE Death Major bleeding Tolerability Drug discontinuation

Methods =

Systematic reviews and pair-wise meta-analyses What is a systematic review? A systematic appraisal of the methodological quality, clinical relevance and consistency of published evidence on a specific clinical topic in order to provide clear suggestions for a specific healthcare problem What is a pair-wise meta-analysis? A quantitative synthesis that, preserving the identity of individual studies comparing two treatments, tries to provide an estimate of the overall effect of an intervention in comparison to the other

Methods for pair-wise meta-analysis OR (A vs C) TREATMENT A TREATMENT C TREATMENT A TREATMENT C TREATMENT A TREATMENT C TREATMENT A TREATMENT C TREATMENT A TREATMENT C TREATMENT A TREATMENT C Difference in effect beween treatment A vs C is computed by means of a weighted average of differences stemming from individual studies

Methods for indirect meta-analysis OR (A vs C) TREATMENT A TREATMENT C Ln ORA-B = Ln ORA-C – Ln ORB-C OR (A vs B) Var (Ln ORA-B) = Var (Ln ORA-C) – Var (Ln ORB-C) TREATMENT B TREATMENT C OR (B vs C)

Methods for network meta-analysis TREATMENT A TREATMENT C OR (A vs C) OR (A vs B) TREATMENT B TREATMENT D OR (B vs D) OR (B vs A) TREATMENT A TREATMENT D OR (A vs D)

Assumption behind indirect and network meta-analyses

A notable example Psaty BM. JAMA 2003;289:2534-2544.

A notable example Psaty BM. JAMA 2003;289:2534-2544.

7114 citations screened at the title/abstract level: 124 from CENTRAL 6528 from Google Scholar 100 from MEDLINE/PubMed 362 from Scopus 7103 citations excluded because patently not pertinent 13 citations retrieved in full and appraised according to the selection criteria 6 studies excluded because not fulfilling inclusion/exclusion criteria 7 randomized trials finally included in the systematic review and meta-analysis

Warfarin Apixaban Rivaroxaban HD dabigatran HD edoxaban LD dabigatran ARISTOTLE ARISTOTLE-J ROCKET AF Apixaban Rivaroxaban Petro RELY Chung 2011 Weitz 2010 Petro RELY Chung 2011 Weitz 2010 HD dabigatran HD edoxaban LD dabigatran LD edoxaban

Main features of included studies Acronym, year Region Drugs tested Doses of new anticoagulant (mg) Other antiaggregant drugs and doses (mg) Petro, 2007 Europe, North America Dabigatran vs warfarin 50, 150, 300; all twice daily No aspirin, or 81 or 325 mg Re-LY LD, 2009 Worldwide 110 mg twice daily Concomitant use of aspirin (at a dose of <100 mg per day) or other antiplatelet agents was permitted Re-LY HW, 2009 150 mg twice Daily Weitz, 2010 Edoxaban vs warfarin 30, 60, 120 No restriction about aspirin ARISTOTLE J, 2011 Asia Apixaban vs warfarin 2.5; 5; all twice daily ARISTOTLE, 2011 5 twice daily No restriction about aspirin lower than 165 mg. Aspirin and clopidogrel together use were exclusion criteria Rocket AF, 2011 Rivaroxaban vs warfarin 20 Aspirin ≤100 mg monotherapy and thienopyridine monotherapy allowed. Chung, 30, 60

Main features of included studies Acronym, year Inclusion criteria Exclusion criteria Petro, 2007 AF with CHADS>=1 mitral stenosis, prosthetic heart valves, planned cardioversion, recent (<1 month) myocardial infarction, recent stroke or transient ischemic attack, coronary stent placement within 6 months, any contraindication to or another indication for anticoagulant therapy, major hemorrhage in the past 6 months, glomerular filtration rate <30 ml/min, abnormal liver function, risk of pregnancy, investigational drug use within 30 days, or any other condition that would not allow participation in the study Re-LY LD, 2009 severe heart-valve disorder, stroke within 14 days or severe stroke within 6 months before screening, a condition that increased the risk of hemorrhage, a creatinine clearance <30 ml per minute, active liver disease, and pregnancy. Re-LY HW, 2009 Weitz, 2010 AF with CHADS>=2 Women must have been ≥2 years post-menopausal and/or have undergone bilateral oophorectomy. Patients were excluded if they had mitral valve disease, endocarditis, or a mechanical valve; contraindications to anticoagulation therapy, including a known bleeding disorder, recent major bleeding, uncontrolled hypertension, a haemoglobin less than 10.0 g/dl, a platelet count less than 100,000/μl or a white blood cell count less than 3,000/μl; a requirement for ongoing treatment with a thienopyridine; AF secondary to reversible disorders (e.g., thyrotoxicosis); left ventricular aneurysm or atrial myxoma; an estimated life expectancy < 12 months; planned surgery or intervention within the study period; a history of hepatitis B or C or HIV infection; creatinine clearance < 30 ml/minute (min); a cardiac pacemaker or implantable cardioverter-defibrillator; investigational drug treatment (including edoxaban) or device implantation in the last three months, or plan to receive such therapy dur- ing the study period. impaired hepatic function ARISTOTLE J, 2011 recent stroke or TIA, valvular heart disease; sick sinus syndrome or severe conduction disturbance; non-cardiogenic stroke requiring ASA >100 mg/day or concomitant ASA and antiplatelet agents; contraindications for warfarin use; severe or refractory hypertension; New York Heart Association class IV heart failure; current thrombocytopenia: alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal; creatinine clearance <25 ml/min by Cockcroft Gault calculation; known or suspected hereditary bleeding tendencies; and scheduled electrical, pharmacological, or surgical cardioversion during the treatment period

Main features of included studies Acronym, year Inclusion criteria Exclusion criteria ARISTOTLE, 2011 AF with CHADS>=1 AF due to a reversible cause, moderate or severe mitral stenosis, conditions other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve), stroke within the previous 7 days, a need for aspirin at a dose of >165 mg a day or for both aspirin and clopidogrel, calculated creatinine clearance of <25 ml per minute Rocket AF, 2011 AF with CHADS>=2 Hemodynamically significant mitral valve stenosis, Prosthetic heart valve; Planned cardioversion (electrical or pharmacological); AF due to a reversible cause, Active endocarditis; Active internal bleeding; Platelet count <90,000/μL at the screening visit; Sustained uncontrolled hypertension; Severe, disabling stroke within 3 months or any stroke within 14 days before the randomization visit; Transient ischemic attack within 3 days before the randomization visit; Indication for anticoagulant therapy for a condition other than atrial fibrillation; Aspirin >100 mg daily; Aspirin in combination with thienopyridines within 5 days before randomization; Intravenous antiplatelets within 5 days before randomization; Fibrinolytics within 10 days before randomization; Systemic treatment with a strong inhibitor or inducer of cytochrome P450 3A4, such as ketoconazole or protease; hemoglobin <10 g/dL at the screening visit; pregnancy or breast-feeding: any other contraindication to warfarin; known HIV infection at time of screening; renal clearance <30 mL/min at the screening visit; known significant liver disease Chung, previous valve surgery, contraindication to anticoagulants, known bleeding disorder, conditions associated with high risk of bleeding (e.g. past history of major bleeding; uncontrolled hypertension; uncontrolled diabetes; haemorrhagic disorder; significant thrombocytopenia), ongoing treatment with an antiplatelet agent, AF second ary to other reversible disorders, acute coronary syndrome or revascularisation procedures, stroke, transient ischaemic attack, any major surgery within the previous 30 days, left ventricular aneurysm or atrial myxoma, impaired hepatic function, serum creatinine ≥1.5 mg/dl, women of child-bearing potential without adequate contraception, pregnancy or lactation.

Main features of patients Acronym, year N. of pts Paroxysmal AF (%) HF (%) Hypertension Diagnosis (%) Age (yrs)* Diabetes Previous Stroke/TIA ASA(%) Petro, 2007 502 22.9 29.3 71 70±8.3 25 17.3 - Re-LY LD, 2009 12037 32.1 32.2 78.7 71.4±8.6 23.4 19.9 21.1 Re-LY HW, 2009 12098 32.6 31.8 78.9 71.5±8.8 23.1 20.3 19.6 Weitz, 2010 1146 64.9±6.8 49.5 ARISTOTLE J, 2011 222 1.3 83.3 70 27.9 24.3 ARISTOTLE, 2011 18113 15.1 35.5 87.3 70 (63-76) 19.2 31 Rocket AF, 2011 14264 17.5 62.6 90.3 73 (65-78) 40.4 54.9 36.3 Chung, 253 28 65±9 30 24

Risk of stroke or systemic embolism Risk of death Risk of major bleeding Risk of drug discontinuation

Risk of stroke or systemic embolism

Risk of death

Risk of major bleedings

Risk of drug discontinuation

Risk of stroke or systemic embolism

Risk of death

Risk of major bleeding

Risk of drug discontinuation

Stroke or sistemic embolism Rivaroxaban Low-dose edoxaban High-dose edoxaban Low-dose dabigatran High-dose dabigatran Apixaban Warfarin 1 2 3 4 5 6 7 8 9 10 2,99 1,91 0,74 3,12 2,28 2,69 3,42

Death % 1 2 3 4 5 6 7 8 9 10 Rivaroxaban Low-dose edoxaban High-dose edoxaban Low-dose dabigatran High-dose dabigatran Apixaban Warfarin 1 2 3 4 5 6 7 8 9 10 5,21 4,91 2,07 5,68 5,51 5,56 6,21 %

Major bleeding % 1 2 3 4 5 6 7 8 9 10 Rivaroxaban Low-dose edoxaban High-dose edoxaban Low-dose dabigatran High-dose dabigatran Apixaban Warfarin 1 2 3 4 5 6 7 8 9 10 7,48 4,32 8,61 5,96 6,86 5,11 7,34 %

Drug discontinuation % 10 20 30 40 50 60 Rivaroxaban Low-dose edoxaban High-dose edoxaban Low-dose dabigatran High-dose dabigatran Apixaban Warfarin 10 20 30 40 50 60 23,51 30,15 59,87 27,72 28,45 20,25 22 %

stroke or sistemic embolism NNT (or NNH) vs warfarin drug stroke or sistemic embolism death major bleeding drug discontinuation Rivaroxaban 232 100 -736 66 Low-dose edoxaban 77 33 12 High-dose edoxaban 37 24 -78 3 Low-dose dabigatran 335 190 72 17 High-dose dabigatran 88 142 209 15 Apixaban 137 155 45 -57

Discussion Novel OAC are effective as or more than VKA in preventing stroke or SE. Novel OAC share a strong evidence to decrease mortality: thus, is it still ethically sound to use VKA? Tolerability is a key point, due to significantly differentheterogeneity: apixaban appears to be the best drug, as confirmed in several papers Connolly SJ N Engl J Med 2011

Limitations To be(lieve) or not to be(lieve): this is the question Limited choice of endpoints: e.g. AMI, reasons for discontinuation, type of bleeding not considered

Conclusions Novel OAC are effective to prevent stroke or SE and death without serious concerns about safety when compared with warfarin. In a head-to-head comparison, apixaban and HD dabigatran are more effective than warfarin but apixaban is better tolerated. Rivaroxaban is a valid alternative to warfarin but appears less effective than HD dabigatran and apixaban.

Conclusions Given the superiority in one or more aspects (efficacy, safety, ease-of-use) of novel OAC, warfarin should not remain first choice therapy for anticoagulation in patients with non-valvular atrial fibrillation and at least moderate thromboembolic risk.

Conclusions Given the superiority in one or more aspects (efficacy, safety, ease-of-use) of novel OAC, warfarin should not remain first choice therapy for anticoagulation in patients with non-valvular atrial fibrillation and at least moderate thromboembolic risk.

Thank you for your attention For any correspondence: gbiondizoccai@gmail.com For these and further slides on these topics feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html