Oral Anticoagulation: 65 Years of Achievement Freek W.A. Verheugt - - PowerPoint PPT Presentation
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
Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG) Amsterdam, The Netherlands
Research support/ principal investigator Bayer HealthCare, Boehringer Ingelheim, Eli Lilly and Roche Consultant Bayer Healthcare, Eli Lilly, Daiichi-Sankyo, and Merck Speakers’ bureau none Honoraria Bayer Healthcare, Eli Lilly, Daiichi-Sankyo and Merck Scientific advisory board AstraZeneca and Cardialysis B.V.
Virchow R .Zur pathologischen Physiologie des Blutes. Virch Arch 1847; I::546
Rudolf Virchow – Charité Berlin (1821-1902)
“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
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
n = 3,404
ASPECT-2. Lancet 2002:360:109-113
WARIS-2. N Engl J Med 2002; 347:969-974
n = 3,630
2 4 6 8 10 12 14 30 60 90 120 150 180 Days after randomization 7.4 11.1 ximelagatran (alle doses) vs placebo: HR=0.66 (0.48; 0.90), p=0.0105
placebo (n = 638) alle doses ximelagatran (n = 1.245)
Lancet 2003;362:789-797
ASA dose: 75–100 mg, prior stroke excluded
Event-driven study – 983 events
Physician's decision whether or not to add thienopyridine
N=15,526*
Rivaroxaban 2.5 mg bid (n=349) Stratum 1: ASA alone (7%) Stratum 2: ASA + thienopyridine (93%) Placebo (n=355) Rivaroxaban 5 mg bid (n=349) Rivaroxaban 2.5 mg bid (n=4825) Rivaroxaban 5 mg bid (n=4827) Placebo (n=4821) YES NO
N Engl J Med 2012;366:9–19
Months after randomization HR=0.84 (95% CI 0.74–0.96) ARR=1.8% mITT p=0.008 ITT p=0.002 NNT=56 10.7% 8.9% 2-year Kaplan–Meier estimate Estimated cumulative rate (%) Rivaroxaban Placebo 12 15 10 8 6 4 2 21 12 9 3 24 Primary efficacy endpoint (CV death/MI/stroke) Combined rivaroxaban doses, both strata 6 18 N Engl J Med 2012;366:9–19
The primary efficacy endpoint reduction was driven by reduced mortality
Cardiovascular death All-cause death CV death/MI/stroke (primary efficacy endpoint)
5 13
Months NNT=71
24
4.1% 2.7% Placebo Rivaroxaban 2.5 mg bid HR=0.66 mITT p=0.002 ITT p=0.005
18 12 6 5
Months 4.5% 2.9%
24
Placebo Rivaroxaban 2.5 mg bid HR=0.68 mITT p=0.002 ITT p=0.004
18 12 6
NNT=63 Months Cumulative incidence (%) HR=0.84 mITT p=0.02 ITT p=0.007 10.7% 9.1% Rivaroxaban 2.5 mg bid Placebo
24 18 12 6
NNT=63 N Engl J Med 2012;366:9–19
*p=0.04 vs placebo; #p=0.005 vs placebo; ‡p<0.001 vs placebo.
Rivaroxaban vs placebo p=NS Rivaroxaban vs placebo p=NS
*
# ‡ ‡
(principal safety outcome)
NNH = 575
2-year Kaplan–Meier estimate HR=0.69 (95% CI 0.51–0.93) RRR=31% mITT p=0.02 ITT p=0.008 2.9% 2.3% Months after randomization Rivaroxaban Placebo Estimated cumulative incidence (%) 2 3 6 12 15 24 21 ARC definite/probable: HR=0.65, mITT p=0.02, ITT p=0.01 3 1 18 9 Combined rivaroxaban doses, both strata
Gibson CM . J Am Coll Cardiol 2013;62:286–290
trial f/u (m) NOAC placebo NNT APPRAISE-2 8 0.9 1.3 250 ATLAS-21 13 2.3 2.9 250 stent thrombosis (%) n 7,392 15,526 RR 95% CI) 0.73 (0.47 - 1.12)* 0.69 (0.51 - 0.93)**
reported
1 both doses *
p = 0.15
** p = 0.02
Verheugt FWA. Eur Heart J 2013;34:1618-1620
All comers ACS with ASA
(n = 3,000) primary safety endpoint: TIMI major, TIMI minor, CRNM bleeding in CCU discretion MD clopidogrel ticagrelor
day 1-4
R R
ASA 100mg riva 2.5 mg bid ticagrelor ticagrelor secondary efficacy endpoint: death, MI, stroke + + NCT02293395 follow-up: 6 months ASA 100mg riva 2.5 mg bid clopidogrel clopidogrel + +
Riva 5 mg bid Riva 2.5 mg bid + ASA 100 mg qd ASA 100 mg qd PPI no PPI PPI no PPI PPI no PPI
CAD without indication for DAPT*,or PAD after 3w ASA run-in
(n = 27,400) primary efficacy endpoint: CV death/MI/ischemic stroke safety endpoint: ISTH major bleeding *previous MI , or *CAG > 1vd, or *PCI > 1 vessel, or *CABG > 1 vessel > 4yr
30d washout 30d washout 30d washout
Substudies: COMPASS CABG (n = 2,000) and COMPASS MIND (n = 1,500)
SPINAF Relative risk reduction of stroke (95% CI) 100 50
warfarin worse warfarin better 62% (48% to 72%)
AFASAK I SPAF BAATAF CAFA EAFT All trials=6
Lip GY. BMJ 2002;325:1022-1025
Clot
Intrinsic pathway Extrinsic pathway
TF Ca2+
Xa X
II IX XI XII XIIa Fibrin Fibrinogen Xa Va PL Ca2+ IIa VII XIa VIIa VIIIa Ca2+ PL IXa
Adapted from Brouwer MA, Verheugt FWA. Circulation 2002;105:1270-1274
direct inhibition by NOACSs formation inhibited by VKA
ENGAGE AF-TIMI 48 ARISTOTLE ROCKET AF RE-LY Combined Favors NOAC Favors Warfarin 0.88 (0.75 - 1.02) 0.80 (0.67 - 0.95) 0.88 (0.75 - 1.03) 0.66 (0.53 - 0.82) 0.81 (0.73 - 0.91) Risk Ratio (95% CI)
p=<0.0001
0.5 1 2
[Random Effects Model]
N=58,541
Heterogeneity p=0.13 [60 mg] [150 mg] Ruff CT. Lancet 2014;383:955-962
All-Cause Mortality MI Hemorrhagic Stroke Ischemic Stroke 0.90 (0.85 - 0.95) 0.97 (0.78 - 1.20) 0.49 (0.38 - 0.64) 0.92 (0.83 - 1.02) Risk Ratio (95% CI)
p=0.0003 p=0.77 p<0.0001 p=0.10 Favors NOAC Favors Warfarin 0.2 0.5 1 2
Heterogeneity p=NS for all outcomes Ruff CT. Lancet 2014;383:955-962
ARISTOTLE ROCKET AF Combined Favors NOAC Favors Warfarin Risk Ratio (95% CI) 0.80 (0.71 - 0.90) 0.71 (0.61 - 0.81) 1.03 (0.90 - 1.18) 0.94 (0.82 - 1.07) 0.86 (0.73 - 1.00) 0.5 1 2
[Random Effects Model]
N=58,498
p=0.06
Heterogeneity p=0.001
RE-LY
[150 mg]
ENGAGE AF-TIMI 48
[60 mg] Ruff CT. Lancet 2014;383:955-962