Presentation on theme: "Harry Potter and the new oral anticoagulants"— Presentation transcript:
1Harry Potter and the new oral anticoagulants V. MalavasiG. Biondi Zoccai
2BackgroundLast 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
3BackgroundWarfarin 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;63:630–41Baker WL J Manag Care Pharm 2009;15:
7BackgroundIt 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.
8Endpoints Efficacy: Safety Tolerability Stroke or SE Death Major bleedingTolerabilityDrug discontinuation
10Systematic 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 problemWhat 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
11Methods for pair-wise meta-analysis OR (A vs C)TREATMENT ATREATMENT CTREATMENT ATREATMENT CTREATMENT ATREATMENT CTREATMENT ATREATMENT CTREATMENT ATREATMENT CTREATMENT ATREATMENT CDifference in effect beween treatment A vs C is computed by means of a weighted average of differences stemming from individual studies
12Methods for indirect meta-analysis OR (A vs C)TREATMENT ATREATMENT CLn ORA-B = Ln ORA-C – Ln ORB-COR(A vs B)Var (Ln ORA-B) = Var (Ln ORA-C) – Var (Ln ORB-C)TREATMENT BTREATMENT COR (B vs C)
13Methods for network meta-analysis TREATMENT ATREATMENT COR (A vs C)OR(A vs B)TREATMENT BTREATMENT DOR (B vs D)OR(B vs A)TREATMENT ATREATMENT DOR (A vs D)
14Assumption behind indirect and network meta-analyses
177114 citations screened at the title/abstract level: 124 from CENTRAL6528 from Google Scholar100 from MEDLINE/PubMed362 from Scopus7103 citations excluded because patently not pertinent13 citations retrieved in full and appraised according to the selection criteria6 studies excluded because not fulfilling inclusion/exclusion criteria7 randomized trials finally included in the systematic review and meta-analysis
18Warfarin Apixaban Rivaroxaban HD dabigatran HD edoxaban LD dabigatran ARISTOTLEARISTOTLE-JROCKET AFApixabanRivaroxabanPetroRELYChung 2011Weitz 2010PetroRELYChung 2011Weitz 2010HD dabigatranHD edoxabanLD dabigatranLD edoxaban
21Main features of included studies Acronym, yearRegionDrugs testedDoses of new anticoagulant (mg)Other antiaggregant drugs and doses (mg)Petro, 2007Europe,NorthAmericaDabigatran vs warfarin50, 150, 300; all twice dailyNo aspirin, or 81 or 325 mgRe-LY LD, 2009Worldwide110 mg twicedailyConcomitant use of aspirin (at a dose of <100 mg per day) or other antiplatelet agents was permittedRe-LY HW, 2009150 mg twiceDailyWeitz,2010Edoxaban vswarfarin30, 60, 120No restriction about aspirinARISTOTLE J, 2011AsiaApixaban vs warfarin2.5; 5; all twice dailyARISTOTLE, 20115 twice dailyNo restriction about aspirin lower than 165 mg. Aspirin and clopidogrel together use were exclusion criteriaRocket AF,2011Rivaroxaban vs warfarin20Aspirin ≤100 mg monotherapy and thienopyridine monotherapy allowed.Chung,30, 60
22Main features of included studies Acronym, yearInclusion criteriaExclusion criteriaPetro, 2007AF with CHADS>=1mitral 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 studyRe-LY LD, 2009severe 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, 2009Weitz,2010AF with CHADS>=2Women 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 functionARISTOTLE J, 2011recent 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 hereditarybleeding tendencies; and scheduled electrical, pharmacological, or surgical cardioversion during the treatment period
23Main features of included studies Acronym, yearInclusion criteriaExclusion criteriaARISTOTLE, 2011AF with CHADS>=1AF due to a reversible cause, moderate or severe mitral stenosis, conditionsother 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 minuteRocket AF,2011AF with CHADS>=2Hemodynamically 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 diseaseChung,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.
24Main features of patients Acronym, yearN. of ptsParoxysmal AF (%)HF (%)HypertensionDiagnosis (%)Age (yrs)*DiabetesPrevious Stroke/TIAASA(%)Petro, 200750222.929.37170±8.32517.3-Re-LY LD, 20091203732.132.278.771.4±8.623.419.921.1Re-LY HW, 20091209832.631.878.971.5±8.823.120.319.6Weitz,2010114664.9±6.849.5ARISTOTLE J, 20112221.383.37027.924.3ARISTOTLE, 20111811315.135.587.370 (63-76)19.231Rocket AF,20111426417.562.690.373 (65-78)40.454.936.3Chung,2532865±93024
25Risk of stroke or systemic embolism Risk of death Risk of major bleedingRisk of drug discontinuation
38stroke or sistemic embolism NNT (or NNH) vs warfarindrugstroke or sistemic embolismdeathmajor bleedingdrug discontinuationRivaroxaban232100-73666Low-dose edoxaban773312High-dose edoxaban3724-783Low-dose dabigatran3351907217High-dose dabigatran8814220915Apixaban13715545-57
39DiscussionNovel 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 papersConnolly SJ N Engl J Med 2011
40LimitationsTo 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
41ConclusionsNovel 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.
42ConclusionsGiven 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.
43ConclusionsGiven 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.
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