Rung nhĩ và hội chứng vành cấp - Nguyễn Thượng Nghĩa

egistry) 
• Một vài nghiên cứu ngẫu nhiên, có đối chứng (RCTs) 
•  Thay đổi khuyến cáo 
• 
heartj.ehu298.full?keytype=ref&ijkey=eAuRJ78zu3804sd 
Combination Better 
Trials 
Aspirin Better 
1 0.5 2 0.1 10 
Odds Ratio & 95% CI N 
All studies 
14 25,307 16.6 18.0 
Bleeding 14 25,307 10.1 10.9 
Extracranial 10 12,488 9.6 12.2 
Intracranial 10 12,488 16.7 16.5 
Death/MI/Stroke 10 7,836 9.4 12.3 
Bleeding 10 7,836 2.6 1.1 
Extracranial 7 3,820 2.3 0.9 
Intracranial 7 3,820 0.3 0.0005 
Combo Aspirin 
% 
Andreotti EHJ 2006;27:519-26 
Warfarin After Acute Coronary Syndrome 
* non-fatal thromboembolic 
5 0.2 
Death/MI/Stroke* 
Studies with INR 2-3 
Risk of Bleeding with Single, Dual, or Triple 
Therapy in Patients with Atrial Fibrillation 
Nghiên cứu đăng ký sổ bộ toàn Đan Mạch (Danish Registry) 
N= 118,606 BN rung nhĩ 
• Warfarin (n = 50,919) 
• Aspirin (n = 47,541) 
• Clopidogrel (n = 3,717) 
• ASA/Clop (n = 2,859) 
• Warfarin + aspirin (n = 18,345) 
• Warfarin + aspirin + clopidogrel (n = 1,261) 
• Tiêu chí chính: Biến chứng xuất huyết nặng nhập viện gây 
tử vong hoặc không tử vong (Tỉ lê ̣ % bn-năm). 
Arch Intern Med. 2010;170:1433-1441 
0.2 
0.4 
0.8 
0.6 
0.4 
0.6 
0.2 
3.6 
3.3 
4.8 
7 
6.4 
13.3 
15.4 
3.9 
3.7 
5.6 
7.4 
6.8 
13.9 
15.7 
0 2 4 6 8 10 12 14 16 18
War
ASA
Clop
ASA/Clop
War/ASA
War/Clop
War/ASA/Clop
XH nặng chung XH nặng không tử vong XH nặng tử vong 
Risk of Bleeding with Single, Dual, or Triple 
Therapy in Patients with Atrial Fibrillation 
Arch Intern Med. 2010;170:1433-1441 
J Am Coll Cardiol. 2013 Sep 10;:981-9 Ti ̉ lệ % BN-năm 
So sánh với War/ASA/Clop(MACE) 
War/Clop: HR 0.69 (95% CI: 0.48 -1.0) 
War/ASA: HR 0.96(95% CI: 0.77 -1.19) 
ASA/Clop: HR 1.17 (95% CI: 0.96 -1.42) 
Stroke HR 1.5 (95% CI:1.03 -2.20) 
So sánh với War/ASA/Clop (Tử vong): 
War/Clop: HR 0.69 (95% CI: 0.48 -1.0) 
War/ASA: HR 1.52(95% CI: 1.17 -1.99) 
ASA/Clop: HR 1.60 (95% CI: 1.25 -2.05) 
6.80% 
3.70% 
7.00% 
7.40% 
5.90% 
4.30% 
7.00% 
3.90% 
8.50% 
12.00% 
14.20% 
15.70% 
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
16.00%
18.00%
Buresly 21,443 Sorensen 40,812 Lamberts 11,480 Hansen 118,606
NC sô ̉ bô ̣: Tỉ lê ̣ xuất huyết % 
DAPT
OAC
 TOAT
Clin Cardiol 2013; July 
 | 
The WOEST Trial: First randomised trial comparing two 
regimens with and without aspirin in patients on oral 
anticoagulant therapy undergoing coronary stenting 
Willem Dewilde, Tom Oirbans, Freek Verheugt, Johannes Kelder, Bart 
De Smet, Jean-Paul Herrman, Tom Adriaenssens, Mathias Vrolix, 
Antonius Heestermans, Marije Vis, Saman Rasoul, Kaioum 
Sheikjoesoef, Tom Vandendriessche, Carlos Van Mieghem, Kristoff 
Cornelis, Jeroen Vos, Guus Brueren, Nicolien Breet and Jurriën ten Berg 
The WOEST Trial= What is the Optimal antiplatElet and anticoagulant 
therapy in patients with oral anticoagulation and coronary StenTing 
(clinicaltrials.gov NCT00769938) 
WOEST ESC, Hotline III, Munchen, August 28th, 2012 
 | 
Thiết kế nghiên cứu 
1:1 Randomisation: 
Double therapy group: 
 OAC + 75mg Clopidogrel qd 
1 month minimum after BMS 
1 year after DES 
Triple therapy group 
OAC + 75mg Clopidogrel qd + 80mg Aspirin qd 
1 month minimum after BMS 
1 year after DES 
Follow up: 1 year 
Primary Endpoint: The occurence of all bleeding events (TIMI criteria) 
Secondary Endpoints: 
- Combination of stroke, death, myocardial infarction, stent thrombosis and 
 target vessel revascularisation 
- All individual components of primary and secondary endpoints 
WOEST 
Willem Dewilde ,ESC, Hotline III, Munchen, August 28th, 2012 
N= 279 N=284 
 | 
Tiêu chí chính : TIMI bleeding events 
WOEST 
Days 
C
u
m
u
la
ti
ve
 i
n
c
id
e
n
c
e
 o
f 
b
le
e
d
in
g
0 30 60 90 120 180 270 365 
0 % 
10 % 
20 % 
30 % 
40 % 
50 % 
284 210 194 186 181 173 159 140 n at risk: 
279 253 244 241 241 236 226 208 
Triple therapy 
Double therapy 44.9% 
19.5% 
p<0.001 
HR=0.36 95%CI[0.26-0.50] 
Primary Endpoint: Bleeding events TIMI classification 
0
5
10
15
20
25
30
35
40
45
50
ICH TIMI Minor TIMI Major Any TIMI
bleeding
Double
therapy
Triple
therapy
1.0 1.0 
11.2 
27.2 
3.3 
5.8 
19.5 
44.9 
% 
p<0.001 p<0.001 
p=0.159 
WOEST 
Tiêu chí phụ: Death, MI,TVR, Stroke, ST 
WOEST 
Days 
C
u
m
u
la
ti
ve
 i
n
c
id
e
n
c
e
0 30 60 90 120 180 270 365 
0 % 
5 % 
10 % 
15 % 
20 % 
284 272 270 266 261 252 242 223 n at risk: 
279 276 273 270 266 263 258 234 
17.7% 
11.3% 
p=0.025 
HR=0.60 95%CI[0.38-0.94] 
Triple therapy 
Double therapy 
WOEST: Tiêu chí phụ 
0
1
2
3
4
5
6
7
8
9
Death MI TVR Stroke ST
Double therapy
Triple therapy
MI=any myocardial infarction; TVR= target vessel revascularisation (PCI + CABG); ST= stent thrombosis 
2.6 
6.4 
3.3 
4.7 
7.3 
6.8 
1.1 
2.9 
1.5 
3.2 
p=0.027 
p=0.382 
p=0.128 p=0.165 
WOEST 
p=0.876 
Duration of triple therapy in patients requiring oral 
anticoagulation after drug-eluting stent implantation 
(ISAR-TRIPLE Trial) 
Katrin A., Nicolaus S.: TCT 2014 
Duration of triple therapy in patients requiring oral 
anticoagulation after drug-eluting stent implantation 
(ISAR-TRIPLE Trial) 
Katrin A., Nicolaus S.: TCT 2014 
6 
2 
4 
3 
6-week group 6-month group Hazard ratio p value 
(n=307) (n=307) (95% CI) 
Death 12 (4.0) 16 (5.2) 0.75 (0.35 -1.59) 0.45 
Cardiac death 5 (1.7) 9 (3.0) 0.56 (0.19 - 1.66) 0.29 
Myocardial infarction (2.0) 0 - 0.03 
Definite stent thrombosis (0.7) 0 - 0.50 
Stroke (1.3) 6 (2.0) 0.67 (0.14 - 2.78) 0.75 
Ischemic stroke (1.0) 4 (1.3) 0.75 (0.11 - 4.40) 0.99 
Katrin A., Nicolaus S.: TCT 2014 
Biến cô ́ tim mạch – Xuất huyết: 
TOAT 6 tuần không hiệu quả 
hơn 6 tháng 
ISAR-TRIPLE Trial: Duration of triple therapy in patients requiring 
oral anticoagulation after drug-eluting stent implantation 
TOAT (OAC + DAPT) vs. OAC + Clopidogrel 
• Kháng đông phối hợp (OAC/Clopidogrel) làm 
giảm nguy cơ xuất huyết, bên cạnh khuynh 
hướng làm giảm các biến cô ́ tim mạch nặng 
• Cần nghiên cứu RCTs 
Chest. 2012;141:e531S-e575S 
What has changed since 2010, and why? 
What is the risk of TOAT when 
a novel anticoagulant is used 
in ACS? 
Apixaban 5 mg BID 
CrCl<40 ml/min 2.5 mg BID 
Primary Outcome: CV Death, MI, Ischemic Stroke 
Safety: TIMI Major Bleeding 
Randomize 1:1 
Double blind 
• Aspirin 
• Other antiplatelet therapy 
N=10,800 
Placebo 
Recent (≤7days) Acute Coronary Syndrome 
(STEMI (40%)or NSTE-ACS (60%) 
At Least 2 Additional Risk-Factors 
APPRAISE -2: Thiết kê ́ nghiên cứu 
Alexander ,NEJM 2011;365:699-708 www.escardio.org 
APPRAISE -2 
Tiêu chí hiệu quả: Tử vong tim mạch, NMCT, Đột quỵ 
Apixaban 279 (7.5%) 
Placebo 293 (7.9%) 
HR 0.95; 95% CI 0.80-1.11; p=0.509 
Alexander, NEJM 2011;365:699-708 www.escardio.org 
APPRAISE -2 
Tiêu chí an toàn: TIMI Major Bleeding 
Apixaban 48 (1.3%) 
Placebo 18 (0.5%) 
HR 2.59; 95% CI 1.50–4.46; p=0.001 
Alexander NEJM 2011;365:699-708 
Recent ACS: STEMI, NSTEMI, UA 
Stabilized 1-7 Days Post-Index Event 
Exclusions: increased bleeding risk, warfarin use, ICH, prior 
stroke if on ASA + thienopyridine 
Primary endpoints: 
Efficacy: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin) 
Safety: TIMI major bleeding not associated with CABG 
 Rivaroxaban 
5.0 mg BID 
n=5,176 
Stratified by Thienopyridine Use at MD Discretion 
ASA 75 to 100 mg/day 
Placebo 
n=5,176 
 Rivaroxaban 
2.5 mg BID 
n=5,174 
Event driven trial with 1,002 primary efficacy events 
Mega NEJM 2012;366:9-19 www.escardio.org 
05
10
1
Months 
E
s
ti
m
a
te
d
 C
u
m
u
la
ti
v
e
 I
n
c
id
e
n
c
e
 (
%
) 
Placebo 
Rivaroxaban 
5 mg BID 
0 
8.8% 
10.7% 
Rivaroxaban “liều thấp” 
5.0 mg BID 
24 
Cardiovascular Death CV Death / MI / Stroke 
HR 0.94 
mITT 
p=0.63 
ITT 
p=0.57 
Months 
0 24 
4.0% 
4.1% 
Placebo 
Rivaroxaban 
5 mg BID 
HR 0.85 
mITT 
p=0.028 
ITT 
p=0.010 
NNT=53 
Mega NEJM 2012;366:9-19 
Rivaroxaban“liều rất thấp” 
2.5 mg BID 
0 24 
Cardiovascular Death 
Months 
CV Death / MI / Stroke 
E
s
ti
m
a
te
d
 C
u
m
u
la
ti
v
e
 i
n
c
id
e
n
c
e
 (
%
) HR 0.84 
mITT 
p=0.020 
ITT 
p=0.007 
HR 0.66 
mITT 
p=0.002 
ITT 
p=0.005 
10.7% 
9.1% 
0 24 
Placebo 
Months 
4.1% 
2.7% 
Rivaroxaban 
2.5 mg BID 
Rivaroxaban 
2.5 mg BID 
Placebo 
NNT = 71 NNT = 63 
12 12 
12% 
5% 
Mega NEJM 2012;366:9-19 
TIMI Major Bleeding 
Overall 
HR=3.96 
(2.46-6.38) 
P<0.001 
Riva 5 BID 
HR=4.47 
(2.71-7.36) 
P<0.001 
Riva 2.5 BID 
HR=3.46 
(2.08-5.77) 
P<0.001 
www.escardio.org 
Mega NEJM 2012;366:9-19 
Intracranial Hemorrhage 
Riva 2.5 BID: HR 2.8 (1.0-7.9) 
Riva 5.0 BID: HR 3.7 (1.4-10.1) 
APPRAISE-2 & ATLAS ACS-2 TIMI- 51 
NOACS with Antiplatelet Therapy in ACS 
REDEEM trial: Dabigatran 
• The RE-DEEM trial randomized 1861 patients at a 
mean of 7.5 days after an ACS (60% STEMI) to either 
dabigatran (50 mg, 75 mg, 110 mg, 150 mg twice 
daily), or placebo. 
• Dabigatran increased major or clinically relevant 
minor bleeding in a dose-dependent fashion (1.8-fold 
to 4.3-fold), without reducing the risk of MI or stroke 
after 6 months. 
Kết luận 
• Rung nhĩ tăng nguy cơ Đột quy ̣ và biến cô ́ thuyên tắc 
• Rx Warfarin vẫn điều trị kinh điển và hiệu quả trên thực 
hành lâm sàng, nhưng kiểm soát TTR ly ́ tưởng hơi kho ́ 
khăn 
• Các thuốc NOACs  hiệu quả và an toàn trong một sô ́ 
NC RCTs gần đây 
• Rung nhĩ sau HCVC vẫn nhiều nguy cơ: 
– Biến cô ́ tim mạch nặng tái phát 
– Xuất huyết do kháng đông- kháng kết tập tiểu cầu 
• TOAT ( OAC + DAPT ) có nhiều triển vọng khi hạn chê ́ tối 
thiểu nguy cơ xuất huyết, cần RCTs