Tối Ưu Điều Trị Thuyên Tắc Phổi Cấp Trên Bệnh Nhân Có Tiền Sử Nhồi Máu Cơ Tim

Tối ưu điều trị thuyên tắc phổi cấp
trên bệnh nhân có tiền sử
nhồi máu cơ tim
Bs. Nguyễn Ngô Thanh Phương
BS. Đinh Đức Huy
Bv Tim Tâm Đức


Trường hợp lâm sàng
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Bệnh nhân C. J, 50 tuổi
BMI 28 (CC 183cm, CN 96kg)
Hút thuốc lá(+)
Rối loạn mỡ máu (+)
THA (-), ĐTĐ (-)
Tiền căn NMCT ST chênh lên (2011)  can thiệp
1 stent không phủ thuốc vào đoạn đầu LAD
• Điều trị : Aspirin, Bisoprolol, Losartan,
Rosuvastatin
• BN không triệu chứng


Trường hợp lâm sàng
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1 tháng trước, bệnh nhân bay từ HCM-London
Khó thở khi gắng sức ngày càng tăng
Đau chân bên phải
Nhập viện vì khó thở
Tỉnh táo, không dấu thần kinh khu trú, không sốt
TST 88 bpm
HA 135/80 mmHg
TS thở 16 bpm SpO2 96% (room air)
Tim đều, không âm thổi
Phổi trong
Chân bên phải hơi lớn hơn chân bên trái


Xét nghiệm
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BC 9.7k/uL, HGB 15 g/dL, TC 200K/uL

Creatinin 101 mmol/L, eGFR:78ml/ph/1.73m2
Hs-CRP 70mg/L
AST 26 U/L
ALT 28 U/L
Cholesterol 2.1
HDL-C 0.5
LDL-C 1.5
TG: 1.2
mmol/L
• NT proBNP 1692pg/ml
• Hs-TnT 21-22 pg/ml
• D-Dimer 5990 ng/mL


ECG

Sinus rythm, 85 bpm, normal QRS axis and PR interval


Cận lâm sàng
Siêu âm tim
• EF 62%, không RLVĐ vùng
• Không bệnh lý van tim
• Không tăng áp phổi (PAPs
=20mmHg)
• Không huyết khối
• Lớn thất phải, TAPSE 19

Siêu âm mạch máu
• Tắc hoàn toàn tĩnh mạch

đùi nông bên phải
• Huyết khối lan tỏa đến
tĩnh mạch khoeo bên phải

CTR: 0.55
Tuần hoàn phổi bên phải giảm


Chẩn đoán
Thuyên tắc phổi/ Nhồi máu cơ tim đã đặt 1 stent
Xác định bằng MSCT phổi


Xử trí
Ngày 1-2:
Enoxaparin 0.9ml TDD /12 giờ
Acenocoumarol 1mg / ngày
ASA 81mg /ngày
Bisoprolol 2.5mg /ngày
Losartan 25mg /ngày
Rosuvastatin 10mg /ngày
Ngày 3: Bệnh nhân từ chối kiểm tra INR hằng
ngày


VTE treatment with VKAs
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VKAs = standard treatment for VTE (PE & DVT)
Highly prevent recurrent VTE (RRR 85% vs placebo)
Recurrence risk of 3% with patient on treatment
Limitations of VKA treatment






need frequent INR monitoring
major bleeding of 2.1% during the first 6 months of treatment
case-fatality rate 11%
intracranial bleeding 8.7% of major bleeds with mortality risk of 46%
most major bleeds occur during the first weeks of VKA treatment


N Engl J Med 2012;366:1287-97


EINSTEIN PE: study design
Randomized, open-label, event-driven, non-inferiority study
• Up to 48 hours’ heparins/fondaparinux treatment permitted before study entry
• 88 primary efficacy outcomes needed
• Non-inferiority margin: 2.0
Predefined treatment period of 3, 6, or 12 months
Day 1

Objectively

confirmed PE ±
DVT

N=4833

Day 21
Rivaroxaban

Rivaroxaban

15 mg bid

20 mg od

R
Enoxaparin bid for at least 5 days,
plus VKA INR 2.5 (range 2.0–3.0)



Primary efficacy outcome: first recurrent VTE



Principal safety outcome: first major or nonmajor clinically relevant bleeding

30-day poststudy
treatment
period

Patient flow
Rivaroxaban

*As treated

Enoxaparin/VKA

2420

Randomized
(N=4833)

2413

2419

ITT population

2413

2412

Safety population*

2405

2224

Per-protocol population

2238

66

Withdrawal of consent

118

8

Lost to follow-up

10


EINSTEIN PE: primary efficacy
outcome analysis
Rivaroxaban
(N=2419)
First symptomatic recurrent VTE
Recurrent DVT
Recurrent DVT + PE
Non-fatal PE
Fatal PE/unexplained death where
PE cannot be ruled out

Enoxaparin/VKA
(N=2413)

n

(%)

n

(%)

50

(2.1)

44

(1.8)

18
0
22

(0.7)
(0.9)

17
2
19

(0.7)
(<0.1)
(0.8)

10

(0.4)

6

(0.2)

HR
1.12

0.75
0

1.68*

1.00

2.00

Rivaroxaban
superior

Rivaroxaban
non-inferior

p=0.57 for superiority
(two-sided)

P=0.0026 for non-inferiority
(one-sided)

Rivaroxaban
inferior

*Potential relative risk increase <68.4%; absolute risk difference 0.24% (–0.5 to 1.02)


Cumulative event rate (%)

EINSTEIN PE: principal safety outcome –
major or non-major clinically relevant bleeding
Enoxaparin/VKA
N=2405

15
14
13
12
11
10
9
8
7
6
5
4
3
2

1
0

Rivaroxaban
N=2412

0

30

60

90

120

150

Rivaroxaban
n/N (%)

Enoxaparin/VKA
n/N (%)

HR (95% CI)
p-value

249/2412
(10.3)

274/2405
(11.4)

0.90 (0.76–1.07)
p=0.23

180

210

240

270

300

330

360

Time to event (days)
Number of patients at risk
Rivaroxaban

2412 2183

2133

2024

1953

1913

1211

696

671

632

600

588

313

Enoxaparin/VKA

2405 2184

2115

1990

1923

1887

1092

687

660

620

589

574

251

Safety population


Cumulative event rate (%)

EINSTEIN PE: major bleeding
3.0

Rivaroxaban
n/N (%)

Enoxaparin/VKA
n/N (%)

HR (95% CI)
p-value

2.5

26/2412
(1.1)

52/2405
(2.2)

0.49 (0.31–0.79)
p=0.0032

Enoxaparin/VKA
N=2405

2.0

1.5
1.0

Rivaroxaban
N=2412

0.5
0.0
0

30

60

90

120

150

180

210

240

270

300

330

360

Time to event (days)
Number of patients at risk
Rivaroxaban

2412 2281

2248

2156

2091

2063

1317

761

735

700

669

659

350

Enoxaparin/VKA

2405 2270

2224

2116

2063

2036

1176

746

719

680

658

642

278

Safety population


EINSTEIN PE: conclusions
In patients with acute symptomatic PE with or without DVT,
rivaroxaban showed:
Non-inferiority to LMWH/VKA for efficacy
HR=1.12 (0.75–1.69); pnon-inferiority =0.0026
for non-inferiority margin of 2.0

Similar findings for principal safety outcome
HR=0.90 (0.76–1.07); p=0.23

Superiority for major bleeding
HR=0.49 (0.31–0.79) p=0.0032

Consistent efficacy and safety results irrespective of age,
body weight, gender, kidney function and cancer
No evidence for liver toxicity


Clinical trials of NOACs for PE acute phase



Systemic review and meta-analysis
Introduction:
Meta-analysis to determine the efficacy and safety of NOACs as
compared with those of VKAs in patients with acute VTE
Methods:
MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews
and the Clinical Trials Registry up to October 2013. Eligible studies
included phase 3 trials comparing NOACs with VKAs in patients with
acute VTE. RRs, absolute risk differences and NNTs to prevent one
event were calculated for recurrent VTE, fatal PE, overall mortality,
major bleeding, and other bleeding complications, with randomeffects models.


Study outcomes & Definitions
1. Efficacy outcomes
Recurrent VTE, fatal PE, and overall mortality
2. Safety outcomes
Major bleeding, non-fatal major bleeding at a critical site,
clinically relevant non-major bleeding, non-fatal intracranial
bleeding, major gastrointestinal bleeding, and fatal bleeding

during anticoagulant treatment
3. Definition of major bleeding
Overt and associated with a decrease in the Hb level of
≥2g/dL, requiring transfusion of at least 2 units of blood,
occurring in a critical site (intracranial, intraspinal, intraocular,
pericardial, intra-articular intramuscular with compartment
syndrome, retroperitoneal), or contributing to death


Study selection


Study characteristics


Main findings
1. Five studies were included, 4 NOACs (rivaroxaban, dabigatran,
apixaban, edoxaban) in 24 455 patients with acute VTE
2. RR for
recurrent VTE
0.88 (95% CI 0.74–1.05)
fatal PE
1.02 (95% CI 0.39–5.96)
overall mortality
0.97 (95% CI 0.83–1.14)
major bleeding
0.60 (95% CI 0.41–0.88)
fatal bleeding
0.36 (95% CI 0.15–0.87)
3. NNT to prevent

one major bleed
149
one fatal bleed
1111
4. No significant differences between individual NOACs and
rivaroxaban (Fixed-effect network analysis )


Efficacy outcomes

Recurrent VTE
Fatal PE
Mortality

241/12 151 patients (2.0%) vs
9/12 151 patients (0.07%) vs
290 /12 197 patients (2.4%) vs

273 /12 153 patients (2.2%)
9/12 153 patients (0.07%)
298 /12 193 patients (2.4%)


Safety outcomes