NOAC Update 2023
THE PERFECT CLOT
and how to block it!
The perfect clot requires adequate COAGULATION FACTORS
1. Coagulation cascade concept consists of intrinsic and extrinsic pathway.
2. One molecule of Factor X produces 1000 molecules of Thrombin (Factor II), so called "Thrombin Burst".
3. Vitamin K antagonist inhibits production of multiple coagulation factors.
Can NOAC be resumed early after acute ischemic stroke with AF?
Problems with Vitamin K Antagonist (VKA)
- 10% of intracranial bleeding is VKA related.
- Brain is the only organ with high expression of tissue factor
but low expression of tissue factor pathyway inhibitor.
-
In a patient with AF with acute ischemic stroke,
OAC is recommended to resume at least 1wk and 2wks after moderate and major stroke respectively.
-
Recent RCTs suggest that earlier resumption of NOAC was not inferior to delayed start.
Early initiation was noninferior to delayed start of NOAC after
acute ischemic stroke in patients with AF.
| Trials |
Composite Endpoints (early vs. delayed) |
Intracranial Hemorrhage (early vs. delayed) |
| at 30d |
at 90d |
| ELAN |
2.9% vs. 4.1%
RD = -1.18% (-2.84 to 0.47)
|
3.7% vs. 5.6%
RD = -1.92% (-3.82 to -0.02)
|
0.2% vs 0.2% at 30d
|
| TIMING |
NA |
6.89% vs. 8.68%
RD = −1.79% (−5.31% to 1.74%)
|
0 vs. 0 at 90d
|
RD = Risk Difference
In a patient with AF with acute ischemic stroke who has no contraindication to NOAC,
NOAC may be initiated or resumed within one week.
Cell-based Model of Hemostasis
1. Coagulation occurs on specific cell surfaces of tissue-factor (TF) bearing cells and platelets.
2. Thrombin activated platelets to recruit more platelet and enhance platelets aggregation.
3. Platelets then set the stage for a large scale of thrombin generation.
4. Factor X also directly activates protease-activated receptiors (PARs) on platelets.
Thrombin Generation in Mechanical Heart Valve
NOACs in Mechanical Heart Valve: Results from RCTs
| Trials |
Valve |
Timing after Surgery |
NOAC |
Results |
| NOAC | VKA |
RE-ALIGN
N = 252, f/u 150d
|
Bileaflet, Mitral and/or Aortic position |
Group A: within 7d
Group B: >3mos
|
Dabigatran 150-300 mg BID |
Stroke: 5%
Major Bleeding: 4%
|
Stroke: 0
Major Bleeding: 2%
|
RIWA
N = 44; f/u 90d |
Bileaflet, Mitral and/or Aortic position
|
> 3mos |
Rivaroxaban 15 mg BID |
Stroke: 0
Major Bleeding: 0
|
Stroke: 2.95%
Major Bleeding: 0
|
PROACT Xa
N = 863; f/u 13 mos
|
On-X, Aortic position |
> 3mos |
Apixaban 5 mg BID
+ ASA 81 mg in both arms
|
Valve thrombosis: 4.2%/pt-yr
Stroke: 2.9%/pt-yr
Major Bleeding: 3.6%/pt-yr
|
Valve thrombosis: 1.3%/pt-yr
Stroke: 0
Major Bleeding: 4.5%/pt-yr
|
1. The rate and amount of thrombin generation is the major determinant of clot structure.
2. Mechanical heart valve generates thrombin via intrinsic pathway.
3. In patients with mechanical heart valve(s), NOACs are not recommended.
Coagulation System in Advanced Chronic Kidney Disease
Guidelines Recommendation for use of OAC in AF with GFR<15ml/min or on dialysis.
| Guideline |
VKA | Rivaroxaban |
Apixaban | Dabigatran | Edoxaban |
| KDIGO 2018 |
Equipoise |
Unknown | Unknown |
Not recommended | Not recommended |
| ACC 2019 |
IIb |
Not recommended |
IIb |
Not recommended | Not recommended |
| CCS 2020 |
Should not routinely receive antithromotic therapy.
|
| ESC 2020 |
No solid evidence. Not recommended.
|
| Expert Opinions 2023 |
1. Bleeding > Stroke in AF on dialysis. Should OAC be given at all?
2. Should VKA be avoided after VALKYRIE and AXADIA?
3. In selected patients, Rivaroxaban and Apixaban may be used.
|
Roles of OAC in AF on dialysis remain unresolved.
Modern Concept of Coagulation Pathway
1. Modern concept of coagulation pathway suggest that pathologic thrombosis and physiologic hemostasis pathways are separated.
2. Factor XI inhibitors may serve as hemostasis-sparing anticoagulants.
3. In a phase 2 study, Asundexian, an oral factor XI inhibitor, was associated with lower rate of bleeding than Apixaban in patients with AF.
Conclusions
Perfect Clot requires:
- Right amount of coagulation factors
- Right steps of platelet activation
- Right amount and pattern of thrombin generation
NOAC 2023 Update
-
NOAC may be resumed within 4-7d after acute ischemic stroke with AF.
-
Role of OAC in AF on dialysis remains unsettled.
-
FXI inhibitor may serve as a hemostasis-sparing anticoagulant.
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