Oral Anticoagulation: 65 Years of Achievement Freek W.A. Verheugt Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG) Amsterdam, The Netherlands
D ISCLOSURES FOR F REEK W. A. V ERHEUGT Research support/ Bayer HealthCare, Boehringer Ingelheim, principal investigator Eli Lilly and Roche Bayer Healthcare, Eli Lilly, Daiichi-Sankyo, Consultant and Merck Speakers’ bureau none Bayer Healthcare, Eli Lilly, Daiichi-Sankyo and Honoraria Merck Scientific advisory board AstraZeneca and Cardialysis B.V.
Virchow‘s Triad of Thrombogenesis Rudolf Virchow – Charité Berlin (1821-1902) Alterations of vessel wall Virchow R .Zur pathologischen Physiologie des Blutes. Virch Arch 1847; I::546
1933 - A dead Cow and Blood that would not Clot Wisconsin Alumni Research Foundation COUMARIN “In 1941, Karl Paul Link successfully isolated the anticoagulant factor, which initially found commercial application as a rodent-killer. Warfarin is now one of the most widely prescribed medicines in the world.”
Ann Intern Med 1949;30:80-91
Ann Intern Med 1949;30:80-91
BMJ 1959 (5125);ii:804-810
BMJ 1964;ii:837-843
Acta Med Scand 1967;182:549-566
Acta Med Scand 1967;182:549-566
Acta Med Scand 1967;182:549-566
Lancet 1980;ii:989-994
Lancet 1980;ii:989-994 n = 878
n = 1,214 WARIS. N Engl J Med 1990;323:147-152
n = 3,404 ASPECT. Lancet 1994;343:499-503
primary endpoint (death, reMI, stroke) mortality ASPECT-2. Lancet 2002:360:109-113
n = 3,630 WARIS-2. N Engl J Med 2002; 347:969-974
ESTEEM : death, MI or stroke 14 ximelagatran (alle doses) vs placebo: 12 HR=0.66 (0.48; 0.90), p =0.0105 11.1 10 8 7.4 6 4 placebo (n = 638) alle doses ximelagatran (n = 1.245) 2 0 0 30 60 90 120 150 180 Days after randomization Lancet 2003;362:789-797
ATLAS ACS 2 TIMI 51: A randomized, double-blind, event-driven phase III trial in patients hospitalized with ACS N=15,526* NO YES Physician's decision whether or not to add thienopyridine Stratum 1: ASA Stratum 2: ASA + alone (7%) thienopyridine (93%) Rivaroxaban Rivaroxaban Rivaroxaban Rivaroxaban Placebo Placebo 5 mg bid 2.5 mg bid 5 mg bid 2.5 mg bid (n=355) (n=4821) (n=349) (n=349) (n=4825) (n=4827) Event-driven study – 983 events ASA dose: 75 – 100 mg, prior stroke excluded N Engl J Med 2012;366:9 – 19
ATLAS ACS 2 TIMI 51: Rivaroxaban (combined doses) reduced the primary efficacy endpoint vs placebo Primary efficacy endpoint (CV death/MI/stroke) 12 Combined rivaroxaban doses, both strata 2-year Kaplan – Meier estimate 10.7% 10 Estimated cumulative rate (%) Placebo 8.9% 8 HR=0.84 Rivaroxaban (95% CI 0.74 – 0.96) 6 ARR=1.8% 4 mITT p =0.008 ITT p =0.002 2 NNT=56 0 6 9 15 18 24 0 3 12 21 Months after randomization N Engl J Med 2012;366:9 – 19
ATLAS ACS 2 TIMI 51: Rivaroxaban 2.5 mg bid significantly reduced CV events and death The primary efficacy endpoint reduction was driven by reduced mortality CV death/MI/stroke (primary efficacy endpoint) Cardiovascular death All-cause death 13 5 5 HR=0.68 Placebo HR=0.84 HR=0.66 4.5% Placebo Placebo mITT p =0.02 mITT p =0.002 mITT p =0.002 4.1% 10.7% Cumulative incidence (%) ITT p =0.007 ITT p =0.005 ITT p =0.004 9.1% 2.9% 2.7% Rivaroxaban 2.5 mg bid Rivaroxaban Rivaroxaban 2.5 mg bid 2.5 mg bid NNT=63 NNT=71 NNT=63 0 0 0 0 6 12 18 24 0 6 12 18 24 0 6 12 18 24 Months Months Months N Engl J Med 2012;366:9 – 19
ATLAS ACS 2 TIMI 51: Rivaroxaban did not increase fatal bleeding or fatal ICH versus placebo ‡ ‡ Rivaroxaban Rivaroxaban # vs placebo vs placebo p =NS p =NS * (principal safety outcome) NNH = 575 * p =0.04 vs placebo; # p =0.005 vs placebo; ‡ p <0.001 vs placebo. 1. Mega et al, N Engl J Med 2012;366:9 – 19; 2. Gibson et al, AHA 2011 (www.clinicaltrialresults.org)
ATLAS ACS 2 TIMI 51: Rivaroxaban significantly reduced stent thrombosis Combined rivaroxaban doses, both strata 2-year Kaplan – Meier estimate 3 2.9% Estimated cumulative incidence (%) Placebo 2.3% 2 HR=0.69 Rivaroxaban (95% CI 0.51 – 0.93) RRR=31% 1 mITT p =0.02 ITT p =0.008 ARC definite/probable: HR=0.65, mITT p =0.02, ITT p =0.01 0 0 3 6 9 12 15 18 21 24 Months after randomization Gibson CM . J Am Coll Cardiol 2013;62:286 – 290
S TENT T HROMBOSIS WITH NOAC S AFTER ACS reported stent thrombosis (%) trial f/u (m) n NOAC placebo RR 95% CI) NNT 0.73 (0.47 - 1.12) * APPRAISE-2 8 7,392 0.9 1.3 250 ATLAS-2 1 0.69 (0.51 - 0.93) ** 13 15,526 2.3 2.9 250 1 both doses * p = 0.15 ** p = 0.02 Verheugt FWA. Eur Heart J 2013;34:1618-1620
GEMINI ACS-1 NCT02293395 (n = 3,000) All comers ACS with ASA in CCU discretion MD ticagrelor clopidogrel R R day 1-4 ticagrelor ticagrelor clopidogrel clopidogrel + + + + riva 2.5 mg bid ASA 100mg riva 2.5 mg bid ASA 100mg follow-up: 6 months primary safety endpoint: TIMI major, TIMI minor, CRNM bleeding secondary efficacy endpoint: death, MI, stroke
COMPASS (n = 27,400) CAD without indication for DAPT*,or PAD after 3w ASA run-in Riva 2.5 mg bid Riva 5 mg bid ASA 100 mg qd + ASA 100 mg qd no PPI no PPI no PPI PPI PPI PPI 30d washout 30d washout 30d washout *previous MI , or primary efficacy endpoint: CV death/MI/ischemic stroke *CAG > 1vd, or safety endpoint: ISTH major bleeding *PCI > 1 vessel, or *CABG > 1 vessel > 4yr Substudies: COMPASS CABG (n = 2,000) and COMPASS MIND (n = 1,500)
Warfarin vs nil Relative risk reduction of stroke (95% CI) AFASAK I SPAF BAATAF CAFA SPINAF EAFT 62% (48% to 72%) All trials=6 0 100 50 -50 -100 warfarin better warfarin worse Lip GY. BMJ 2002;325:1022-1025
Intrinsic pathway Extrinsic pathway XII XIIa TF XI XIa VII VIIa IXa IX Ca 2+ VIIIa Ca 2+ X Xa PL Xa oral direct Xa blocker Va oral direct IIa blocker Ca 2+ IIa PL II formation inhibited by VKA Fibrinogen Fibrin direct inhibition by NOACSs Clot Adapted from Brouwer MA, Verheugt FWA. Circulation 2002;105:1270-1274
All NOACS: Stroke or SEE Risk Ratio (95% CI) 0.66 (0.53 - 0.82) RE-LY [150 mg] ROCKET AF 0.88 (0.75 - 1.03) 0.80 (0.67 - 0.95) ARISTOTLE ENGAGE AF-TIMI 48 0.88 (0.75 - 1.02) [60 mg] Combined 0.81 (0.73 - 0.91) [Random Effects Model] p=<0.0001 N=58,541 0.5 1 2 Favors NOAC Favors Warfarin Heterogeneity p=0.13 Ruff CT. Lancet 2014;383:955-962
Secondary Efficacy Outcomes Risk Ratio (95% CI) Ischemic Stroke 0.92 (0.83 - 1.02) p=0.10 Hemorrhagic Stroke 0.49 (0.38 - 0.64) p<0.0001 MI 0.97 (0.78 - 1.20) p=0.77 All-Cause Mortality 0.90 (0.85 - 0.95) p=0.0003 0.2 0.5 1 2 Favors Warfarin Favors NOAC Heterogeneity p=NS for all outcomes Ruff CT. Lancet 2014;383:955-962
All NOACS: Major Bleeding Risk Ratio (95% CI) RE-LY 0.94 (0.82 - 1.07) [150 mg] ROCKET AF 1.03 (0.90 - 1.18) ARISTOTLE 0.71 (0.61 - 0.81) ENGAGE AF-TIMI 48 0.80 (0.71 - 0.90) [60 mg] Combined 0.86 (0.73 - 1.00) [Random Effects Model] p=0.06 N=58,498 0.5 1 2 Favors NOAC Favors Warfarin Heterogeneity p=0.001 Ruff CT. Lancet 2014;383:955-962
Conclusions 1 In the past 65 years oral anticoagulation has made tremendous progress in fighting thrombosis in 1. secondary prevention after acute coronary syndromes 2. stroke prevention in atrial fibrillation
Conclusions 2 Given their complexity and risks vitamin K antagonists (VKA) are currently replaced by non- vitamin K oral anticoagulants (NOACs) for the indications usually covered by VKA
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