ORAL ANTICOAGULANTS IN
CEREBROVASCULAR ACCIDENT
DR.B.PRAKASH.
NEUROLOGY
PSG IMS&R / KASTURI NEURO CENTRE
Physicians Meet,
...
DISCUSSION
• ORAL ANTICOAGULANTS
• OAC IN PREVENTION OF STROKE
• OAC IN ATRIAL FIBRILLATION
• ASPIRIN VS OAC IN STROKE
• O...
DISCUSSION
• ORAL ANTICOAGULANTS
• OAC IN PREVENTION OF STROKE
• OAC IN ATRIAL FIBRILLATION
• ASPIRIN VS OAC IN STROKE
• O...
ORAL ANTICOAGULANTS
• Agent that prevents formation of blood clot at the site of
injury.
• Coagulation mechanism comprises...
ORAL ANTICOAGULANTS IN STROKE
• Antiplatelet drugs are used to prevent arterial stroke
• Oral Anticoagulants (OAC) and Hep...
BASICS ORAL ANTICOAGULANTS
• Hemostasis and Anticlotting mechanisms prevents bleeding
and progression of clot
• Heparin an...
HISTORY OF ANTICOAGULANTS
1909: leech were used as hirudin extract for anticoagulation
1915: Jay McLean discovered heparin...
ORAL ANTICOAGULANTS
NATURAL ANTICOAGULANTS
– PG 1,2 / Anti Thrombin
– Protein C / Heparin
– Tis. factor path inhibitor
1ST...
ORAL ANTICOAGULANTS (OAC/VKA)
• Coumarin derivatives
– First available
– 1-2% of population are using Warfarin/ Acenocouma...
CLASSIFICATION OF ANTI COAG
Mechanism of Action OF OAC
• Derived from 4 hydroxy Coumarin
• Vitamin K Antagonist
• > 90% bound to protein
• Inhibit Vit...
Glutamate
Residues
Amino
Terrminal
LIVER
CLOTTING
FACTORS II,VII,IX,X
THROMBIN
Vitamin K
Ca , PL
γ Carboxyl
group
VKA
DOSE TITRATION FOR ACENOCOUMAROL
INTERACTIONS
WARFARIN Vs ACENOCOUMAROL
FAVORABLE FOR ACENOCOUMAROL:
Rapid onset of action
Longer duration of action (15-20hrs)
1st dose...
DISCUSSION
• ORAL ANTICOAGULANTS
• OAC IN PREVENTION OF STROKE
• OAC IN ATRIAL FIBRILLATION
• ASPIRIN VS OAC IN STROKE
• O...
• OAC ( Coumarin Derivatives )
– Induces Vit K Deficiency
– Prevents Vit K Epoxide metabolism
•  ↓Thrombin Generation  ↓...
INDICATIONS FOR OAC
AF
IHD
VHD
DVT
PE
PVD
• OAC therapy is essential in Valv / NV AF
• INR to be maintained 2-3 in high ri...
SPAF III (1996)
• Fixed dose VKA (INR 1.2-1.5) + Aspirin (325mg/d) Vs Adjusted dose VKA (INR 2-3)
• 1044 AF patients with ...
RECOMMENDED THERAPEUTIC RANGE FOR
ORAL ANTICOAGULANT THERAPY (2001)
Indications International Normalized Ratio
(INR)
Proph...
SPORTIF-III (Lengyl M. 2004 Dec 26)
• To compare acenocoumarol with warfarin
• Same group of 74 patients, with chronic atr...
ACENOCOUMAROL
SUPERIOR ANTICOAGULANT STABILITY THAN WARFARIN (2004)
1. Orv Hetil. 2004 ; 26 ; 145(52) : 2619-2621.
Percent...
META ANALYSIS (2006)
• Stroke prevention with Asprin, Warfarin and Ximelagatran in patients with NVAF
• No significant inc...
ANTI THROMBOTIC DRUGS IN TIA (2007)
• TIA and Stroke has same Pathophysiology.
Hence Aspirin should be superior
• EXPRESS ...
LONG TERM STUDY WITH ACENOCOUMAROL (2009)
• Ten years experience with acenocoumarol treatment
• Ambulatory cohort of rural...
POOLED ANALYSIS OF LARGE RANDOMIZED TRIALS
• OAC had reduced the stroke rate in pts with variety of risk factors by 3-fold
DISCUSSION
• ORAL ANTICOAGULANTS
• OAC IN PREVENTION OF STROKE
• OAC IN ATRIAL FIBRILLATION
• ASPIRIN VS OAC IN STROKE
• O...
ORAL ANTICOAGULANTS ARE NOT NEEDED
• Sinus rhythm
• No evidence of Cardiogenic Embolism
WHY ATRIAL FIBRILALITON IS IMPORTANT ?
• Hemodynamic instability
• Chronic tachy-arrhythmias (68)
• The risk of stroke is ...
STROKE PREVENTON IN
ATRIAL FIBRILLATION
• AF is the most common sustained cardiac
arrhythmias (66)
• AF affects 2.5 millio...
RATE Vs RHYTHM
• Rate control
– Control of ventricular rate
• Rhythms control
– Cardio version to normal sinus rhythm
• St...
TYPES OF ATRIAL FIBRILLATION
• First AF
– First documented AF
• Recurrent AF (65)
– Second and additional AF
• Paroxysmal ...
STROKE PREVENTION IN AF
• 12 RCT (28 publications were analyzed)
• For stroke and systemic embolism (SSE)
• There is no di...
ANTI THROMBOTIC DRUGS IN ATRIAL FIBRILLATION
• Atrial Fibrillation increases first stroke and recurrent stroke
• CHADS2 he...
STROKE PREVENTION IN AF
• OAC are recommended if CHA2DS2-VASc score ≥2
• Several trials in AF for prevention of stroke
– A...
EUROPEAN SOCIETY OF CARDIOLOGY (ESC) PROTOCOL
FOR STROKE PREVENTION IN AF WITH OAC
OAC induced Bleeding Risk Score in AF
• If ≥ 3 Caution to be exercised / Regular review
TREATMENT : ACCP 2012 guidelines
• RHD + AF / Previous Embolism / LA thrombus
– Anticoagulation in native valve disease (V...
STROKE PREVENTION IN VHD
• Rheumatic valve disease has more risk than MVP / Calcific VHD
– Risk of stroke is for ⅕ of all ...
TREATMENT : ACCP 2012 guidelines
• Mechanical Prosthetic valve
– Always require OAC
– LMWH after surgery
• Aortic valve (V...
DISCUSSION
• ORAL ANTICOAGULANTS
• OAC IN PREVENTION OF STROKE
• OAC IN ATRIAL FIBRILLATION
• ASPIRIN VS OAC IN STROKE
• O...
PRIMARY PREVENTION OF STROKE
• Healthy diet and life style
• Exercise
• Low cholesterol
• Treatment of Blood pressure
• Tr...
PRIMARY PREVENTION OF STROKE
• Ischemic stroke
– Antiplatelet therapy
– Lipid lowering therapy
• Cardio Embolic stroke
– O...
ASPIRIN IN PRIMARY PREVENTION OF STROKE
• Used for several years
• Reduces MI by 30%, but increases
– ICH by 40% and
– GI ...
OAC VS ANTIPLATELETS AGAINST TIA - 1980
• OAC is being used as Prophylaxis since 1950
• OAC Vs ASA+DP in patients with TIA...
OAC Vs CLOPIDOGREL-ASPIRIN IN AF 2006
OAC better than aspirin
• Improved outcomes by 40% in patients with AF (29 trials wi...
ORAL ANTICOAGULANT VS. ANTIPLATELET ON ALL STROKES
(ISCHEMIC AND HAEMORRHAGIC)
• 8 Randmz’d Trials / 9598 pts / NVAF / No ...
TREATMENT OF ACUTE STROKE
• The proven effective interventions are
– Stroke unit care
– Aspirin
– Thrombolytic therapy
ASC...
EXCEPT FOR PREVENTION OF CARDIO EMBOLIC STROKE,
THERE IS NO EVIDENCE TO SUPPORT THE USE OF EARLY
ANTICOAGULATION
ANTIPLATE...
DISCUSSION
• ORAL ANTICOAGULANTS
• OAC IN PREVENTION OF STROKE
• OAC IN ATRIAL FIBRILLATION
• ASPIRIN VS OAC IN STROKE
• O...
RECOMMENDATIONS FOR
OAC THERAPY IN DVT AND PE
For patients with a first episode of DVT secondary to a reversible risk fact...
OAC DURING PREGNANCY
In Valvular atrial fibrillation
Use anticoagulation throughout pregnancy
Use UFH  LMWH in the first ...
ANTICOAGULATION IN SURGERIES
• Minor procedures (with mild bld’g risk) may induce significant bleeding.
– Need adjustments...
RENAL IMPAIRMENT
• Renal function decreases with age
• Heparin congeners are eliminated largely through urine
• Renal func...
VKA IN THE ELDERLY
VKA are the first choice for long-term anticoagulation
therapy.1
VKA do not require dosage adjustments ...
MANAGEMENT OF BLEEDING WITH VKA
For moderate bleeding
Vitamin K1 : 2–5 mg orally.1
For severe bleeding
Vitamin K1 : 5–10 m...
INDIAN CHALLENGES WITH VKA’S
• Monitoring of vitamin K antagonist therapy
• Food and drug interactions.
– Inconsistent con...
GUIDELINES FOR Mx OF STROKE - 2013
• Antiplts / OAC are C/I ed during first 24 hrs after IV-rTPA
• Early use of LMWH / OAC...
THANK YOU
Oac in cva
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  • The above slide depicts the recommendations of the Committee on Antithrombotic Therapy of the American College of Chest Physicians and the National Heart, Lung, and Blood Institute for the optimal therapeutic range for the various indications . The target international normalized ratio remains between 2 and 3 for different conditions such as prophylaxis and treatment of venous thrombosis, treatment of pulmonary embolism, acute myocardial infarction. More intense therapy is needed for mechanical prosthetic valve surgery as the recommended INR value is between 2.5 and 3.5.1

    Reference

    Hirsh J, Dalen JE, Anderson DR, et al. Oral Anticoagulants: Mechanism of action, clinical effectiveness and optimal therapeutic range. Chest 2001;119;8S21S.


  • Acenocoumarol a coumarin oral anticoagulant with a shorter half-life. In patients with chronic atrial fibrillation, a superior anticoagulant effect was noted with acenocoumarol than warfarin. Further, it causes less frequent supratherapeutic values (p<0.001)1

    Reference

    Lengyel M. Warfarin or acenocoumarol is better in the anticoagulant treatment of chronic atrial fibrillation? Orv Hetil.2004;145(52):26192621.
  • A large scale which included 29 trials and 28,044 patients found warfarin to be better than aspirin in patients with atrial fibrillation as it improved outcomes by 40%. Other studies have shown that the protective effect of warfarin evident even in patients older than 75 years.1

    Recently, after the widespread use of clopidogrel, it has been postulated that combination of clopidogrel with aspirin could replace warfarin . The ACTIVE W study compared the vascular and bleeding outcomes with warfarin vs. clopidogrel-aspirin combination. The results of the study showed warfarin to be superior to clopidogrel-aspirin combination in the prevention of vascular events (p=0.0002) with no increased bleeding incidences.2

    References

    Altman R, Vidal HO. Battle of oral anticoagulants in the field of atrial fibrillation scrutinized from a clinical practice (the real world) perspective. Thrombosis J. 2011;9:12.
    ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S: Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): A randomised controlled trial. Lancet 2006, 367:1903-1912.
  • A recent Cochrane review included 8 randomized trials and 9598 patients, compared oral anticoagulants to antiplatelet therapy for the prevention of stroke in patients with non-valvular atrial fibrillation and who had no history of stroke or transient ischemic attacks. Treatment with oral anticoagulants was found to be associated with lower risk of all stroke (odds ratio (OR) 0.68, 95% confidence interval (CI) 0.54 to 0.85), ischemic stroke (OR 0.53, 95% CI 0.41 to 0.68) and systemic emboli (OR 0.48, 95% CI 0.25 to 0.90). The results showed a 1/3 rd reduction in stroke, disabling stroke and other major vascular events with oral anticoagulants when compared with antiplatelet therapy.

    Reference
    Aguilar MI, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks (Review) Cochrane Database of Systematic Reviews 2007;3. Art. No.: CD006186.


  • The recommendations for oral anticoagulation therapy in DVT and PE are summarized here.

    Reference:
    1. Lemos Silva R, Carvalho de Sousa J, Calisto C, et al. Oral anticoagulant therapy. Fundamentals, clinical practice and recommendations. Rev Port Cardiol. 2007;26(7–8):769–788.
  • Hemostatic changes during pregnancy, along with the increased concentration of coagulation factors, coupled with decreased fibrinolysis, result in hypercoagulability, and hence increased risk of thromboembolic disorders.1
    Anticoagulation is recommended in patients with paroxysmal, or permanent atrial fibrillation. 1
    Patients with valvular atrial fibrillation are at high thromboembolic disease. Use of oral anticoagulation throughout pregnancy is reported to be beneficial.2 Immediate anticoagulation with UFH, followed by LMWH in the first and last trimester, and oral anticoagulants or LMWH during second trimester is recommended. 1
    Though teratogenic, the risk of embryopathy is probably lower with VKAs when used at a dose <5 mg (for warfarin) daily. However, no definite conclusions can be drawn. Similarly, acenocoumarol at a dose <2.0 mg may be considered as safe in such population.3 The risk of embryopathy with coumarin derivatives can be eliminated by substituting coumarin derivatives with UFH or LMWH from the 6th to the 12th week of pregnancy.4

    References:
    1. Regitz-Zagrosek V, Lundqvist CB, Borghi C, et al. ESC guidelines on the management of cardiovascular diseases during pregnancy. European Heart Journal. 2011;32:3147-3197.
    2. Management of pregnant women with artificial heart valves: Inconsistency in ESC publications. Available at: http://eurheartj.oxfordjournals.org/content/28/19/2419.1.full.pdf. Assessed on: 5 October 2012.
    3. Vasu S, Stergiopoulos K. Valvular heart disease in pregnancy. Hellenic J Cardiol. 2009;50:498–510.
    4. Pieper PG, Balci A, Van Dijk AP. Pregnancy in women with prosthetic heart valves. Neth Heart J. 2008;16(12):406–411.
  • 1. Robert-Ebadi H, Gal GL, Righini M. Use of anticoagulants in elderly patients: practical recommendations. Clinical Interventions in Aging. 2009;4:165-177.
    2. Grand’Maison A, Charest AF, Geerts WH. Anticoagulant use in patients with chronic renal impairment. Am J Cardiovasc Drugs. 2005;5:291-305.
  • The bleeding complicattions with anticoagulants usually manifests as nasal bleeds, hematemesis, hemoptysis, gastro-intestinal bleeding, vaginal bleeding, hematuria, cutaneous hemorrhages, gingival bleeding, hematomata, bleeding into joints or menorrhagia.1
    In case of bleeding with VKAs, following precautions should be taken:1
    Reduce INR to a safe level (<5) if excessive increase in PT and/or INR occur without bleeding or prospective surgery.
    In case of serious bleeding, reduce INR to 1 as soon as possible.
    In case of elective or urgent surgery, reduce INR to 1–1.5 at the time of surgery.
    Temporary reduction in INR can be done by withdrawing anticoagulant therapy, and oral or parentral vitamin K administration.
    Vitamin K can antagonize the effect of VKAs in 3–5 hours.2

    References:
    http://www.drugs.com/mmx/acenocoumarol.html
    Acitrom PI
  • Oac in cva

    1. 1. ORAL ANTICOAGULANTS IN CEREBROVASCULAR ACCIDENT DR.B.PRAKASH. NEUROLOGY PSG IMS&R / KASTURI NEURO CENTRE Physicians Meet, Grand Regent, Coimbatore 12th JULY, 2014 8:30 TO 10:00 PM
    2. 2. DISCUSSION • ORAL ANTICOAGULANTS • OAC IN PREVENTION OF STROKE • OAC IN ATRIAL FIBRILLATION • ASPIRIN VS OAC IN STROKE • OAC IN OTHER CONDITIONS
    3. 3. DISCUSSION • ORAL ANTICOAGULANTS • OAC IN PREVENTION OF STROKE • OAC IN ATRIAL FIBRILLATION • ASPIRIN VS OAC IN STROKE • OAC IN OTHER CONDITIONS
    4. 4. ORAL ANTICOAGULANTS • Agent that prevents formation of blood clot at the site of injury. • Coagulation mechanism comprises of 3 pathways (Intrinsic, Extrinsic & common )
    5. 5. ORAL ANTICOAGULANTS IN STROKE • Antiplatelet drugs are used to prevent arterial stroke • Oral Anticoagulants (OAC) and Heparin are used to prevent recurrence of venous stroke • There are special situations where OAC are used in arterial strokes – Cardiogenic / Embolic stroke – Valvular / Non-valvular Atrial Fibrillation associated stroke
    6. 6. BASICS ORAL ANTICOAGULANTS • Hemostasis and Anticlotting mechanisms prevents bleeding and progression of clot • Heparin and Vit.K Antagonists (VKA) are main OAC • History of Anticoagulants are marked by their Perseverance and Surprise
    7. 7. HISTORY OF ANTICOAGULANTS 1909: leech were used as hirudin extract for anticoagulation 1915: Jay McLean discovered heparin (in dog liver) 1935: Purified heparin was developed (sulfated Glycosaminoglycan). Henrik Dam postulated vitamin K, a sterol prevents bleeding Prothrombin time or Quick test was developed 1939: Dicumarol (VKA) was identified by Link in sweet clover hay. 1950: Link developed warfarin, as rodenticide Dicumarol was used for myocardial infarction. 1980: LMWH developed 2000: factor Xa inhibitors were developed. 2004: Direct thrombin inhibitors were introduced. 2008: Oral direct factor Xa inhibitors were introduced
    8. 8. ORAL ANTICOAGULANTS NATURAL ANTICOAGULANTS – PG 1,2 / Anti Thrombin – Protein C / Heparin – Tis. factor path inhibitor 1ST PARENTAL ANTI COAG’NT – Heparin MODIFIED HEPARIN – LMWH – Fondaparinaux DIRECT THRMBIN INHIBIT’RS – Argatroban – Bivalirudin – Lepirudin – Recombinant Hirudin VIT K ANTOGONIST – Coumarin • Warfarin • Acenocoumarol • Phenprocouman ORAL DTI – Dabigatron ORAL Xa INHIBITOR – Rivroxaban – Apixaban
    9. 9. ORAL ANTICOAGULANTS (OAC/VKA) • Coumarin derivatives – First available – 1-2% of population are using Warfarin/ Acenocoumarol • Used for – prevention of embolism in AF / DVT – mechanical heart valves – 2° prevention : Stroke, IHD • Challenges in VKA : – Narrow therapeutic window – Variability of dose response (due to genetic factor) – Interaction with drug / diet – Difficulty in lab standardization – Poor patient understanding
    10. 10. CLASSIFICATION OF ANTI COAG
    11. 11. Mechanism of Action OF OAC • Derived from 4 hydroxy Coumarin • Vitamin K Antagonist • > 90% bound to protein • Inhibit Vit. K dependent clotting factors: – Fact II (Prothrombin) / Fact VII / Fact IX / Fact X – Factors are synthesized by liver • Require Vit.K for post synthetic addition of γ Carboxy group to Glutamate residues at amino terminal • γ Carboxy glutamate enable clotting factors to bind to Ca + + and PL • Prothrombin + PL with CaThrombin (20,000 times faster than PL alone) • VKA Prevents γ Carboxylation
    12. 12. Glutamate Residues Amino Terrminal LIVER CLOTTING FACTORS II,VII,IX,X THROMBIN Vitamin K Ca , PL γ Carboxyl group VKA
    13. 13. DOSE TITRATION FOR ACENOCOUMAROL
    14. 14. INTERACTIONS
    15. 15. WARFARIN Vs ACENOCOUMAROL FAVORABLE FOR ACENOCOUMAROL: Rapid onset of action Longer duration of action (15-20hrs) 1st dose Prothrmbin induction <36hr Easy to maintain INR Dose titration protocol is easy Effect can be stopped quickly Needs smaller dose of Vit.K Shorter half life Less CYPZ C9 enz dep’t metabolism Earlier approved British Approved Name is Nicoumalone, while the now approved by rINN (recommended International Non-Proprietary Name) is Acenocoumarol
    16. 16. DISCUSSION • ORAL ANTICOAGULANTS • OAC IN PREVENTION OF STROKE • OAC IN ATRIAL FIBRILLATION • ASPIRIN VS OAC IN STROKE • OAC IN OTHER CONDITIONS
    17. 17. • OAC ( Coumarin Derivatives ) – Induces Vit K Deficiency – Prevents Vit K Epoxide metabolism •  ↓Thrombin Generation  ↓Clot formation • The effects are gradual (days) and reversible • OAC ↓es risk of isch stroke (68%) and H’gic stroke (62%) in AF • Significant 1⁰ & 2⁰ Stroke reductions are observed • Adjusted dose Warfarin (INR 2-3) is highly efficacious OAC IN THE PREVENTION OF STROKE
    18. 18. INDICATIONS FOR OAC AF IHD VHD DVT PE PVD • OAC therapy is essential in Valv / NV AF • INR to be maintained 2-3 in high risk pts • VKA are superior to Aspirin as per SPAF II – 1.8% ICH occurred with INR > 3 / Age > 75
    19. 19. SPAF III (1996) • Fixed dose VKA (INR 1.2-1.5) + Aspirin (325mg/d) Vs Adjusted dose VKA (INR 2-3) • 1044 AF patients with at least 1 thrombotic risk factor • Trial stopped prematurely within 1 yr due to higher rate of ischemic stroke / systemic embolism with combination therapy (7.9% per year Vs 1.9% per year) • This study unequivocally demonstrated that VKA with INR 2-3 reduced stroke in high risk patients with NVAF LANCET 1996 ; 348 : 633 - 8
    20. 20. RECOMMENDED THERAPEUTIC RANGE FOR ORAL ANTICOAGULANT THERAPY (2001) Indications International Normalized Ratio (INR) Prophylaxis of venous thrombosis (high-risk surgery) Treatment of venous thrombosis Treatment of pulmonary embolism Prevention of systemic embolism Tissue heart valves Acute myocardial infarction (to prevent systemic embolism)* Valvular heart disease Atrial fibrillation 2.0–3.0 Mechanical prosthetic valves (high risk) 2.5–3.5 Bileaflet mechanical valve in aortic position 2.0–3.0 *If oral anticoagulant therapy is elected to prevent recurrent myocardial, an INR of 2.5 to 3.5 is recommended consistent with US Food and Drug Administration recommendations. 1. Chest. 2001;119;8S21S.
    21. 21. SPORTIF-III (Lengyl M. 2004 Dec 26) • To compare acenocoumarol with warfarin • Same group of 74 patients, with chronic atrial fibrillation • Started to with warfarin, changed to acenocoumarol. • Prospective study • 3 months treatment each with warfarin and acenocoumarol Results: • The % of sub therapeutic values were not different between the treatments • The supra therapeutic values occurred more frequently on warfarin than on acenocoumarol • The anti coagulation effect stability was superior for acenocoumarol compared to warfarin Orv Hetil. 2004 Dec 26;145(52):2619-21
    22. 22. ACENOCOUMAROL SUPERIOR ANTICOAGULANT STABILITY THAN WARFARIN (2004) 1. Orv Hetil. 2004 ; 26 ; 145(52) : 2619-2621. Percentage of INR in therapeutic and supra therapeutic range with acenocoumarol and warfarin in chronic AF patients1 49 28 56 19 0 10 20 30 40 50 60 Therapeutic INR Supra-therapeutic INR PercentageofINRvalues Warfarin Acenocoumarol
    23. 23. META ANALYSIS (2006) • Stroke prevention with Asprin, Warfarin and Ximelagatran in patients with NVAF • No significant increase in bleeding risk with adjusted dose OAC • The higher rate of ICH in SPAF II study is due to inclusion of elderly (> 75yrs) • ACTIVE -W : – Compared bleeding outcome with VKA (INR 2-3) Vs Clop (75) + Asp(75/100) – 670 patients – Study stopped prematurely due to superiority of OAC Thrombosis Res 2006 ; 321 - 33
    24. 24. ANTI THROMBOTIC DRUGS IN TIA (2007) • TIA and Stroke has same Pathophysiology. Hence Aspirin should be superior • EXPRESS study (2007) – Early initiation of treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke.
    25. 25. LONG TERM STUDY WITH ACENOCOUMAROL (2009) • Ten years experience with acenocoumarol treatment • Ambulatory cohort of rural Spanish patients • Objective: – To analyze incidence of hemorrhagic and thrombotic events (1997-2007) • Out of 1544 patients, 1086 were on acenocoumarol • AF was the most frequent indication. • The total follow up was 5,462 patient years. • Median Age: 74 years • INR therapeutic range was 2-3 in 82.5% • Observations: – Incidence of hemorrhagic events were 2.27/100 patient years – Incidence of thrombotic events was 0.2/100 patient years – Age & therapeutic ranges of INR were not ass’d with ↑ed risk of bleeding Trullas-Viola JC et al. , J Thhromb Thrombolysis 2009 nov; 28(4):436-43
    26. 26. POOLED ANALYSIS OF LARGE RANDOMIZED TRIALS • OAC had reduced the stroke rate in pts with variety of risk factors by 3-fold
    27. 27. DISCUSSION • ORAL ANTICOAGULANTS • OAC IN PREVENTION OF STROKE • OAC IN ATRIAL FIBRILLATION • ASPIRIN VS OAC IN STROKE • OAC IN OTHER CONDITIONS
    28. 28. ORAL ANTICOAGULANTS ARE NOT NEEDED • Sinus rhythm • No evidence of Cardiogenic Embolism
    29. 29. WHY ATRIAL FIBRILALITON IS IMPORTANT ? • Hemodynamic instability • Chronic tachy-arrhythmias (68) • The risk of stroke is increased by 5 fold with NVAF ; more with valvular heart disease • AF related stroke has higher mortality and greater disability (69) • AF  Stasis of blood  Clot formation in left atrial appendage Embolize to cerebral and systemic circulation • All patients with high risk AF should be anticoagulated (67)
    30. 30. STROKE PREVENTON IN ATRIAL FIBRILLATION • AF is the most common sustained cardiac arrhythmias (66) • AF affects 2.5 million people in US (67) • More common in men (67) • Prevalence of AF is directly related to age • The average age of AF is 72
    31. 31. RATE Vs RHYTHM • Rate control – Control of ventricular rate • Rhythms control – Cardio version to normal sinus rhythm • Studies (AFFIRM, RACE etc.,) – Rhythm control does not have any reduction in risk of stroke / death
    32. 32. TYPES OF ATRIAL FIBRILLATION • First AF – First documented AF • Recurrent AF (65) – Second and additional AF • Paroxysmal AF AF that terminates spontaneously • Persistent AF – Sustained AF more than 7 days • Permanent AF – Long standing AF • Lone AF – AF in age less than 60 with no HT or Cardio Pulmonary disease
    33. 33. STROKE PREVENTION IN AF • 12 RCT (28 publications were analyzed) • For stroke and systemic embolism (SSE) • There is no difference among antiplatelets of either type or dose • Low dose antiplatelets are significantly less effective than any OAC • OAC are favorable in preventing SSE, however the bleeding risk is more. • No benefit of adding Clopidogrel with Aspirin in prevention of SSE • Higher doses of ASA does not offer any protection against SSE – But has increase risk of bleeding
    34. 34. ANTI THROMBOTIC DRUGS IN ATRIAL FIBRILLATION • Atrial Fibrillation increases first stroke and recurrent stroke • CHADS2 helps to identify pts who benefit from OAC • It has a disadvantage: Underestimates stroke risk in young. – Hence CHAD2DS2VASc score is preferred • OAC are much beneficial in preventing stroke with AF • Reduction of stroke rate from 4.5 to 1.4% following OAC (INR 2-3) • Aspirin has similar risk of major bleeding • Dual Antiplatelet is inferior to OAC, but superior to Aspirin – OAC > DUAL ANTIPLT > ASA
    35. 35. STROKE PREVENTION IN AF • OAC are recommended if CHA2DS2-VASc score ≥2 • Several trials in AF for prevention of stroke – AFASAK I,II (AF, Aspirin, Anticoagulation) – SPAF II,III (Stroke prevention in AF) – EAFT ( European AF trial) • All revealed greater stroke risk reduction with VKA compared to Aspirin Ann Int Med 2007 ; 146 : 857 - 67
    36. 36. EUROPEAN SOCIETY OF CARDIOLOGY (ESC) PROTOCOL FOR STROKE PREVENTION IN AF WITH OAC
    37. 37. OAC induced Bleeding Risk Score in AF • If ≥ 3 Caution to be exercised / Regular review
    38. 38. TREATMENT : ACCP 2012 guidelines • RHD + AF / Previous Embolism / LA thrombus – Anticoagulation in native valve disease (VKA with INR 2-3) • RHD WITH NSR (Normal Sinus Rhythm) – LA Dia > 55mm • VKA (INR : 2-3) – LA Dia < 55mm • No Antithrombotics • Mitral annular calcification (MAC) – Similar treatment options • Calcific Aortic Valve – No role for antithrombotic treatment • Newer OAC are not studied in Prosthetic heart valves
    39. 39. STROKE PREVENTION IN VHD • Rheumatic valve disease has more risk than MVP / Calcific VHD – Risk of stroke is for ⅕ of all patients – Further increase in risk if associated illness like AF • Mechanical prosthetic valve – Greatest valvular stroke risk – Mitral position - further increase in risk – Bioprosthetic valve : usually within first 3 months – Associated AF: Further increase in stroke
    40. 40. TREATMENT : ACCP 2012 guidelines • Mechanical Prosthetic valve – Always require OAC – LMWH after surgery • Aortic valve (VKA 2-3) • Additional risk (VKA 2.5-3.5) – Mitral valve / AF / Double valve • All should receive additional low dose Aspirin • Bioprosthetic valve – Aortic valve • Low dose Aspirin - first 3 months after surgery – Trascatheter aortic Bioprosthetic • Aspirin + Clopidogrel - first 3 months – Mitral valve • VKA (2-3) first 3 months long term Aspirin
    41. 41. DISCUSSION • ORAL ANTICOAGULANTS • OAC IN PREVENTION OF STROKE • OAC IN ATRIAL FIBRILLATION • ASPIRIN VS OAC IN STROKE • OAC IN OTHER CONDITIONS
    42. 42. PRIMARY PREVENTION OF STROKE • Healthy diet and life style • Exercise • Low cholesterol • Treatment of Blood pressure • Treatment of dyslipidemia • Avoid Diabetes
    43. 43. PRIMARY PREVENTION OF STROKE • Ischemic stroke – Antiplatelet therapy – Lipid lowering therapy • Cardio Embolic stroke – Oral Anticoagulants • All strokes – Blood Pressure reduction – Diabetes control – Life style modification – Smoking cessation
    44. 44. ASPIRIN IN PRIMARY PREVENTION OF STROKE • Used for several years • Reduces MI by 30%, but increases – ICH by 40% and – GI bleed by 70% • The risks and benefits should be balanced • If allergic Aspirin –  Clopidogrel • If the calculated 10 yrs stroke risk is more than 20%  – Consider 75mg Aspirin per day
    45. 45. OAC VS ANTIPLATELETS AGAINST TIA - 1980 • OAC is being used as Prophylaxis since 1950 • OAC Vs ASA+DP in patients with TIA and RIND • All patients received OAC x 2m, then randomized • 156 patients / 9 months / during 1977 / 5 hospitals / Sweden • 21 patients were excluded – 135 patients randomized • LP done to rule out hemorrhage • CT done only in 13% to rule out tumor or bleed COMPARED TO UNTREATED TIA / RIND, BOTH TREATMENTS WERE FOUND TO HAVE PROPHYLACTIC EFFECT AGAINST CEREBRAL INFARCTION
    46. 46. OAC Vs CLOPIDOGREL-ASPIRIN IN AF 2006 OAC better than aspirin • Improved outcomes by 40% in patients with AF (29 trials with 28,044 participants) • Protective even in patients older than 75 years1 ACTIVE - W Study Outcomes2 Outcomes Clopidogrel + Aspirin OAC p Vascular events (%/year) 5.64 3.63 0.0002 Major bleeding (%/year) 2.42 2.21 0.67 NNT or NNH 50 476 NNH=number needed to harm; NNT=number needed to treat 1. Thrombosis J. 2011,9:12. 2. Lancet. 2006;367:1903 1912 .
    47. 47. ORAL ANTICOAGULANT VS. ANTIPLATELET ON ALL STROKES (ISCHEMIC AND HAEMORRHAGIC) • 8 Randmz’d Trials / 9598 pts / NVAF / No H/O CVA TIA / OAC Vs Anti Plt • OAC lowers risk of all strokes 1. Cochrane Database of Systematic Reviews 2007;3.:Art.No.: CD006186.
    48. 48. TREATMENT OF ACUTE STROKE • The proven effective interventions are – Stroke unit care – Aspirin – Thrombolytic therapy ASCEND TRIAL (2018) http://ctsu.ox.ac.uk/ascend/ • Shows little evidence of benefit from Aspirin in Diabetes ??? • Patients with uncontrolled blood pressure, (>150/90) should not be given antiplatelets
    49. 49. EXCEPT FOR PREVENTION OF CARDIO EMBOLIC STROKE, THERE IS NO EVIDENCE TO SUPPORT THE USE OF EARLY ANTICOAGULATION ANTIPLATELET AND ANTICOAGUALANT DRUGS • Antiplatelet therapy reduces the rate of death if given early • 300mg daily for 2 weeks followed by secondary prevention • Clopidogrel is an alternative
    50. 50. DISCUSSION • ORAL ANTICOAGULANTS • OAC IN PREVENTION OF STROKE • OAC IN ATRIAL FIBRILLATION • ASPIRIN VS OAC IN STROKE • OAC IN OTHER CONDITIONS
    51. 51. RECOMMENDATIONS FOR OAC THERAPY IN DVT AND PE For patients with a first episode of DVT secondary to a reversible risk factor, long-term treatment with VKAs for 3 months is recommended. For patients with a first episode of idiopathic DVT, treatment with VKAs for at least 6 to 12 months is recommended. For patients with DVT and cancer, LMWH is recommended for the first 3 to 6 months of long-term anticoagulant therapy. For these patients, anticoagulation is recommended indefinitely or until the cancer is resolved. For patients with a first episode of DVT and documented antiphospholipid syndrome or who have two or more thrombophilic risk factors (e.g. combined factor V Leiden and prothrombin 20210 gene mutations), treatment for 12 months is recommended. Indefinite anticoagulant therapy is also recommended in these patients. For patients with a first episode of DVT who have documented deficiency of antithrombin, protein C or protein S, or the factor V Leiden or prothrombin 20210 gene mutation, homocysteinemia, or high factor VIII levels (>90th percentile), treatment for 6 to 12 months is recommended. Indefinite therapy is recommended, as for patients with idiopathic thrombosis. For patients with two or more episodes of objectively documented DVT, indefinite treatment is suggested. It is recommended that the VKA dose be adjusted to maintain a target INR of 2.5 (2.0–3.0) for all treatment durations. The guidelines recommend against high- intensity VKA therapy (3.1–4.0) and against low-intensity therapy (INR range, 1.5–1.9) compared to INR range of 2.0 to 3.0. In patients who receive indefinite anticoagulant treatment, the risk-benefit of continuing such treatment should be reassessed at periodic intervals. Repeat testing with Doppler ultrasound is suggested to exclude residual thrombosis or measurement of plasma D-dimers, to help determine the duration of the treatment. Rev Port Cardiol. 2007;26(7–8):769–788.
    52. 52. OAC DURING PREGNANCY In Valvular atrial fibrillation Use anticoagulation throughout pregnancy Use UFH  LMWH in the first and last trimesters OAC or LMWH during second trimester In paroxysmal / permanent atrial fibrillation during pregnancy Anticoagulation is recommended 1. http://eurheartj.oxfordjournals.org/content/28/19/2419.1.full.pdf 2. European Heart Journal. 2011;32:3147–3197.
    53. 53. ANTICOAGULATION IN SURGERIES • Minor procedures (with mild bld’g risk) may induce significant bleeding. – Need adjustments in OAC regimens, according to the risk of thromboembolism and the risk of bleeding – Can be performed with INR < 2 – OAC can be resumed on the day of surgery • Cataract extractions and other oculoplastic surgical procedures – Discontinuing OAC before is not necessary • Major surgical procedures require lowering of the INR to <1.5. – Anticoagulation needs to be maintained with heparin. – Heparin to be continued until 6 hrs before surgery & resumed 6–12 hrs after surgery – Oral anticoagulation can be resumed 1–2 days after surgery • Dental surgery is one of the safe procedure – Do not require major changes in OAC. – Maintain INR in the range of 2.0–2.5 • For left heart catheterization – Brachial route : INR <2.5 – Radial route : INR < 2.0 – Femoral route : INR < 1.8
    54. 54. RENAL IMPAIRMENT • Renal function decreases with age • Heparin congeners are eliminated largely through urine • Renal function before prescribing anticoagulants is suggested • Anti-factor Xa monitoring should be conducted periodically • Dosing and monitoring of anticoagulants are important • Anti-Xa activity is prolonged in severe renal impairment • Drug clearance is reduced by 40% in sev renal impairment • Concerns about bleeding complications
    55. 55. VKA IN THE ELDERLY VKA are the first choice for long-term anticoagulation therapy.1 VKA do not require dosage adjustments in renal impairment,2 which is quite common in the elderly.1 Most of the other anticoagulants require dosage adjustments in renal impairment.2 1. Clinical Interventions in Aging. 2009;4:165–177. 2. Am J Cardiovasc Drugs. 2005;5:291–305.
    56. 56. MANAGEMENT OF BLEEDING WITH VKA For moderate bleeding Vitamin K1 : 2–5 mg orally.1 For severe bleeding Vitamin K1 : 5–10 mg injected i.v. very slowly (at a rate <1 mg/min). Additional doses (up to 40mg daily) at 4-hour intervals.1 Serious overdose/life-threatening bleeding Immediate restoration of clotting factors by transfusion of fresh frozen plasma or whole blood or prothrombin (factor IX) complex concentrate, along with vitamin K.2 1. Acitrom PI 2. http://www.drugs.com/mmx/acenocoumarol.html
    57. 57. INDIAN CHALLENGES WITH VKA’S • Monitoring of vitamin K antagonist therapy • Food and drug interactions. – Inconsistent consumption of green leafy vegetables – Cabbage, cauliflower, spinach and other foods rich with vitamin K – Would prevent the achievement of target INR & cause lability in INR values. • Poor Patient compliance • VKA’s are the drug of choice in India – Due to a comfort level developed – Years of usage – Lot of relevant data available
    58. 58. GUIDELINES FOR Mx OF STROKE - 2013 • Antiplts / OAC are C/I ed during first 24 hrs after IV-rTPA • Early use of LMWH / OAC  – Increased risk of bleeding complications – No ↓ in the risk of Neurological worsening (including cardio embolic stroke) • The effectiveness of urgent anticoagulation is not established – Severe stroke / Art diss’n / IA or Cardiac thrombi / VBI • The role of adjunct OAC with fibrinolysis : not been established – The newer OAC  in the settings of clinical trials • Urgent OAC in severe ICA stenosis is not established – class-II b, evidence B
    59. 59. THANK YOU

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