ANTITHROMBOTIC THERAPY IN DIFFICULT CLINICAL

CONDITIONS

CHAIR PERSON- DR. RAGHUVANSH KUMAR SPEAKER- DR.UMESH HANGE

INTRODUCTION• Among most extensively prescribed drugs in

the world.• Development of newer and potent agents

have dramatically reduced cardiovascular mortality and ischemic complications in dangerous cardiac events.

• Double edged sword.• Used to decrease cardiovascular mortality and

at the same time may lead to fatal bleeding .• Hence, balancing both ends of the spectrum is

essential.

DIFFICULT CLINICAL CONDITIONS• In high ischemic burden.• In high bleeding risk.• In patients undergoing non-cardiac surgery post angioplasty

and stenting.• In patients on antithrombotics with high INR level.• In pregnancy with prosthetic heart valve.• In presence of renal dysfunction.• In patients of atrial fibrillation.

HIGH ISCHEMIC BURDEN• Recent ACS.• Recent PCI.• Recurrent ACS with dual antiplatelet therapy.• LVEF < 30%.• Triple vessel disease.• Diabetes.• Stent length >25mm.• Vessel diameter <2.5mm.• Incomplete revascularization.• Stent thrombosis.

Shared risk factors for increased thrombotic and bleeding tendancy.

• Elderly.• Females.• Obesity.• Heart failure.• Renal failure.• Co-morbidities.

Therepeutic strategies in PCI that enhance antithrombotic efficacy in such patients.

• Use high dose aspirin (e.g. 325 mg daily) for longest recommended duration( 1 month for BMS, 3 month for SES, 6 month for PES).

• Use higher maintenance dose of aspirin (162 mg daily) after PCI.

• Use higher loading dose of clopidogrel( 600 to 900 mg) during PCI.

• Extend duration of post – PCI maintaince clopidogrel therapy to at least 15 months after stenting.

• Consider prasugrel instead of clopidogrel for both pre PCI loading and post PCI maintainance therapy.

• Consider upstream administration of GP IIb/IIIa inhibitor prior to PCI and may continue after PCI also.

• Use periprocedural heparin at higher target activated clotting time(>300 sec).

• Do not use fondaparinux as sole anticoagulant during PCI (Always use with heparin).

• PRASUGREL VS CLOPIDOGREL.

• 1. Acts more rapidly, more consistently and to greater extent than clopidogrel.

• 2. In TRITON-TIMI38 trial patients who underwent PCI had significant 19% reduction in cardiovascular death when treated with prasugrel(9.7% vs 11.9% respectively p=0.0001).

• 3.Prasugrel associated with 52% reduction in stent thrombosis(1.13%vs 2.23%respectively p=<0.0001).

• 4.however, 39% increased risk of bleeding with prasugrel(1.71%vs1.23% p=0.036) which is not significant.

• TICAGRELOR VS CLOPIDOGREL.

• 1.It is reversibe adenosin diphosphate receptor inhibitor having more rapid and more effective platelet inhibition than clopidogrel.

• 2. In PLATO trial ticagrelor leads to 16% relative risk reduction (p=<0.001) due to cardivascular death.

• 3.Rate of stent thrombosis was significantly lower with ticagrelor than clopidogrel (1.3% vs 1.9% p=0.009).

• 4.No significant diffrence in overall rate of major bleeding(0.1% vs 0.01% p=0.02).

• Hence, in patients with high ischemic risk prasugrel or ticagrelor should be preffered over clopidogrel. However they shuld not be used in patients with high bleeding risk.

HIGH BLEEDING RISK.• Prior history of bleeding.• Recurrent haemorrrhgic peptic ulcer.• Intracranial surgery.• Transurethral prostectomy.• Surgery with extensive detachment.

Hemorrhagic Transformation of Embolic Stroke

transplantedkidney

blood collection

Perinephric (Transplant) Hematoma

THERAPEUTIC STRATEGIES THAT REDUCE HAEMORRHAGIC COMPLICATIONS OF PCI IN SUCH

PATIENTS.• Consider low dose aspirin (75 to 81mg daily) during

immediate post PCI period.• Use lower maintenance dose of aspirin (75mg daily) after PCI.• Use lower loading dose of clopidogrel (300 mg instead of

600mg ) during PCI.• Shorten the post-PCI clopidogrel therapy to minimum

recommended length(2 weeks for angioplasty, 4 weeks for BMS,12 months for DES), discontinue at any time if bleeding occurs.

• Avoid prasugrel,if used, use lower maintainance dose(5mg daily).

• Avoid upstream administration of GP IIb/IIIa inhibitors, consider bolus only or abbreviated-infusion strategies of GP IIb/IIIa inhibitors during PCI.

• Consider lower dose periprocedural anticoagulant e.g. target activated clotting time <200sec, as long as triple antiplatelet therapy is given.

• Use periprocedural bivalirudin instead of heparin.

• FONDAPARINUX. 1. synthetic, pure factor Xa ihibitor having rapid and

predictable inhibition. 2.Has linear pharmacokinetics and less individiual variability

obviating need for lab monitoring. 3. Administered subcutaneously, in OD dosage. 4. Associated with lower bleeding complications made it

superior to heparin in ACS. 5.However, in PCI always use fondaparinux along with

heparin, because used alone lead to stent thrombosis.

IN PATIENTS UNDERGOING NON CARDIAC SURGERY POST ANGIOPLASTY AND STENTING

• Always a dilemma whether to stop antiplatelet or continue them in perioperative period.

• Cessation of antiplatelet therapy lead to rebound thrombotic phenomenon and continuing antiplatelet in perioperative period lead to increased risk of bleeding.

• American college of cardiology recommends to delay any NCS for at least 12 month in DES and for 1 month in BMS.

• However ,if you cannot postpone surgery then there are three possible scenarios of temporarily withdrawl of antiplatelet agent.

1.SURGERY WITH LOW BLEEDING RISK.

• Cataract surgery.• Oral dental surgery.

Recommendation- - No need of interruption of oral antiplatelet therapy

irrespective of ischemic profile. - Continue both aspirin and clopidogrel.

2.SURGERY WITH INTERMEDIATE BLEEDING RISK.

• GI surgeries.• Cholecystectomy.• Appendicectomy. Recommendation- - Continue aspirin during perioperative period. - Stop clopidogrel 5 days prior to surgery with reintroduction

as soon as possible.

3.SURGERY WITH HIGH BLEEDING RISK

• Intracranial surgery.• Prostate surgery.• ENT surgery.• Surgery in posterior segment of eye.

Recommendation. - Stop aspirin and clopidogrel 5 days before planned surgery. - Substitute them with alternative like LMWH. - Ticagrelor which is short acting can be used. - Regular treatment should be started as soon as possible

after surgery.

A 68-year-old woman receiving chronic warfarin for recurrent DVT (most recent was 1 year ago) will undergo two dental extractions that will include local anesthetic injections…

CASE NO. 1

…Patient has concerns about dental bleeding

1. Stop warfarin at day -5 before procedure, give therapeutic-dose bridging with LMWH (eg, enoxaparin, 1 mg/kg bid)

2. Continue warfarin without dose reduction and give prohemostatic mouthwash (cyclokapron) around procedure

3. Continue warfarin without dose reduction

4. Stop warfarin 2 days before procedure and resume after procedure

Case No. 1: Management Options

Patients Requiring Minor Procedures

• Recommendation: In patients who require minor dental surgery, minor skin procedures, cataract surgery who are receiving VKA (VITAMINE K ANTAGONIST) therapy, it is suggested to continue VKA with co-administration of an oral prohemostatic agent instead of alternative strategies .

1. Stop warfarin at day -5 before procedure, give therapeutic-dose bridging with LMWH (eg, enoxaparin, 1 mg/kg bid)

Continue warfarin without dose reduction and give prohemostatic mouthwash (cyclokapron) around procedure

3 Continue warfarin without dose reduction

4 Stop warfarin 2 days before procedure and resume after procedure

Case No. 1: Answer.

A 54-year-old man with a mechanical mitral valve replacement on long-term warfarin therapy is scheduled for total hip replacement…

CASE NO. 2

1. Stop warfarin 5 days preop, administer therapeutic-dose bridging with LMWH (eg, enoxaparin, 1 mg/kg bid) preop and postop

2. Continue warfarin but reduce dose by 50% starting 5 days preop

3. Stop warfarin 5 days preop and resume after procedure

Case No. 2: Management Options

Patients at High Risk for TE having Major Surgery

• Recommendation: In patients who require temporary interruption of a VKA (VITAMINE K ANTAGONIST) before surgery, it is recommended to stop VKAs approximately 5 days before surgery instead of stopping VKAs a shorter time before surgery and to resume VKAs approximately 12-24 hrs after surgery.

• Recommendation: In patients with a mechanical heart valve, atrial fibrillation or VTE at high risk for TE, bridging anticoagulation is suggested instead of no bridging during interruption of VKA therapy ..

Stop warfarin 5 days preop, administer therapeutic-dose bridging with LMWH (eg, enoxaparin, 1 mg/kg bid) preop and postop

2. Continue warfarin but reduce dose by 50% starting 5 days preop

3. Stop warfarin 5 days preop and resume after procedure

Case No. 2: Answer

Concerns About Post-Op Bleeding With Bridging…

Perioperative Administration of Bridging

• Recommendation: In patients who are receiving bridging anticoagulation with therapeutic-dose SC LMWH, administer the last preoperative dose of LMWH approximately 24 h before surgery instead of 12 h before surgery.

• Recommendation: In patients who are receiving bridging anticoagulation with SC LMWH and are undergoing high bleeding-risk surgery, resume LMWH 48-72 h after surgery instead of resuming LMWH within 24 h after surgery.

IN PATIENTS ON ANTITHROMBOTICS WITH HIGH INR LEVELS.

• Life threatening bleeding. - Stop warfarin - Immediate treatment with cryoprecipitate and FFP to

normalize INR and achieve haemostasis. - Recombinant factor VIIa concentrate provide safe and rapid

reversal of warfarin induced excessive anticoagulation. - Give injectable dose of vit K.• Minor bleeding with high INR level. - Stop warfarin . - No need of administration of FFP. - If INR > 9 without major bleeding then just oral dose of 2.5

mg of vit K is reliable and safe method for rapidly correcting INR.

- Avoid injectable vit K in such cases since it makes patient refractory to warfarin up to 2 weeks.

• If INR is varying too much then consider following points. 1. abnormal lab value is real and not artificial. 2. patients drug compliance is adequate or not. 3. common drug interaction. 4. take proper dietry history of the patient . - After doing all this excersise, if INR is varying too much then

consider new anticoagulants with predictable pharmacokinetics like dabigatran,rivaroxaban.

IN PRGNANCY WITH PROSTHETIC HEART VALVES.

• Treatment in such patients is particularly challenging because of risk to both mother and child and also there are no controlled trials to provide guidelines in these patients.

• Oral anticoagulant warfarin causes fetal embryopathy while replacing warfarin with heparin reported to be ineffective in preventing thromboembolic complications.

• Hence, individualised approach is necessary after counselling the patient about extent of risk and its consequnces.

• FOR WOMEN WITH OLDER GENERATION OR TILTING DISC MITRAL PROSTHESIS.

- Has very high chances of thrombosis. - Hence, safer approach is to treat with warfarin for first 34

weeks of pregnancy particularly if her dose is < 5 mg/ day.

• FOR WOMEN WITH PROSTHETIC AORTIC VALVES OR BILEAFLET VALVES.

- Lesser risk of thrombosis. - Use heparin as soon as pregnancy is diagnosed, warfarin

substituted at 13 to 14 weeks and heparin restarted at approximately 34 weeks in anticipation of delivery.

• FOR PROPHYLAXIS OF VTE AND THROMBOPHILIAS IN PREGNANCY.

- LMWH is preferred over UFH and warfarin. - But discontinue LMWH at least 24 hrs prior to induction of

labor or cesaren section. - They should be continued at least 6 weeks postpartum(for

min 3 months duration) with targeted INR between 2.0 to 3.0.

• ANTITHROMBOTICS PREFFERED IN LACTATING WOMEN.

1. Warfarin. 2. Acenocoumarol. 3. UFH. 4. LMWH. 5. Danaparoid. 6. r- hirudin.

• ANTITHROMBOTICS NOT PREFFERED IN LACTATING WOMEN. 1. Fondaparinux. 2. Debigatran. 3. Rivoraxaban. 4. Apixaban.

IN PATIENTS WITH CHRONIC KIDNEY DISEASE.• Patients with CKD may present with platelet dysfunction and

abnormalities in the enzymatic coagulation cascade. This may explain why patients with CKD may experience 2 opposite haemostatic complications: bleeding diathesis and thrombotic tendancies.

• Platelet dysfunction main factor responsible for hemorrhagic tendencies in advanced CKD and is likely to be multifactorial.

- defective platelet adehsion due to decreased GPIb receptor expression.

- aggregation defect due to decreased GPIIb/IIIa receptor. - several intrinsic abnormalities of platelets.

ASPIRIN IN CKD.• Eliminated mainly by hepatic metabolism but also excreted

unchanged in urine.• By inhibiting renal prostaglandin aspirin makes CKD patients

vulnerable to further deterioration of renal function.• Recommendation. - Avoid high dose aspirin in patients with severe renal

impairment. - Low dose aspirin (<100 mg) can be used in CAD patients with

severe renal impairment. - Avoid NSAIDS other than aspirin and paracetamol in CKD.

• P2Y RECEPTOR ANTAGONIST IN CKD. 1. CLOPIDOGREL. -Clopidogrel treatment significantly increases the

risk of minor bleeding in all forms of CKD. -In CREDO trial clopidogrel reduced the composite

end point of death, MI, and stroke in patients with normal renal function, but a trend in the opposite direction was noted in patients with stage 2 to 4 CKD.

-CHARISMA trial suggested that clopidogrel may even be harmful in patients with diabetic nephropathy because of higher clopidogrel resistance in stage 3 to 4 CKD.

• PRASUGREL IN CKD. -In patients with stage 3 to 4 CKD , the incidence of ischemic

events was not significantly different between those taking prasugrel and those taking clopidogrel (15.1% versus 17.5%).

- TRITON TIMI38 trial shown minor risk of increased bleeding with prasugrel hence it should be used cautiously in stage 4 and 5 CKD.

• INDIRECT THROMBIN INHIBITORS IN CKD. - Unfractionated heparin is metabolized primarily in

the liver and endothelium, thereby not requiring dose adjustment in stage 4 to 5 CKD.

-Low molecular-weight heparin, is eliminated predominantly via the renal pathway. Although monitoring and dose adjustment of LMWH are not required in stage 2 to 3 CKD ,those with stage 4 CKD experience decreased clearance of LMWH leading to increased half-life and bleeding risk.

• As a consequence,guidelines recommend extending the dosing interval of the maintenance dose of LMWX(1.0 mg/kg) from 12 to 24 hours in patients with stage 4 CKD presenting with ACS.

• FONDAPARINUX IN CKD. - Fondaparinux is eliminated mainly as unchanged

drug by the kidneys in subjects with normal kidney function.

- No dose reduction is required for patients with stage 2 to 3 CKD, whereas fondaparinux should be avoided in patients with stage 4 CKD.

• ORAL ANTICOAGULANTS IN CKD. -Warfarin and acenocoumarol elimination is not

governed primarily by the kidneys. -careful dosing and more frequent INR ratio

monitoring have been recommended in patients with stage 3 CKD because of the higher baseline risk of bleeding complications.

-They are contraindicated in patients with stages 4 to 5 CKD.

• DABIGATRAN IN CKD. - 80% Of dose excreted unchanged in urine. - FDA approved dose reduction to 75 mg BD in stage

4 CKD.

IN PATIENTS OF ATRIAL FIBRILLATION.

• AF is most common sustained cardiac arrythmia.• Overall, it confers 5 fold increase in stroke risk.• Antithrombotic therapy to prevent stroke associated

with increased risk of bleeding.

Stroke Risk Stratification in AF• CHADS2 score is has been extensively validated and is easy for clinicians

The to remember and use:

Risk factor PointsC Recent Congestive heart failure exacerbation 1

H Hypertension 1

A Age ≥ 75 years 1

D Diabetes mellitus 1

S Prior history of Stroke or transient ischemic attack 2

Other risk factors for stroke include age 65 to 74 years and female gender, which have been more consistently validated, and vascular disease, which has been less well validated.

IN PATIENTS WITH NON –RHEUMATIC AF.• 1. Patients who are at low risk of stroke. - CHADS2 score = 0. - No antithrombotic therapy recommended in such patients. - For patients who do choose antithrombotic therapy aspirin

(75 to 325 mg once daily) rather than oral anticoagulant can be used.

• In patients with intermediate to high risk of stroke. - CHADS2 score= 1 or 2. - Oral anticoagulant like warfarin preferred over aspirin and

clopidogrel in such patients. - Dabigatran 150 mg twice daily may be preferred over

adjusted dose of oral anticoagulant. But it is contraindicated if creatinine clearance is < 30 ml/min. There is NO ANTIDOTE for dabigatran.

PATIENTS OF AF AND MITRAL STENOSIS.

- Oral anticoagulant like warfarin preferred over aspirin and clopidogrel in such patients with targeted INR level between 2.0 – 3.0 .

• For patients with AF and stable coronary artery disease (eg, no acute coronary syndrome within the previous year) and who choose oral anticoagulation it is recommonded to take adjusted-dose VKA therapy alone ( target INR = 2.0-3.0) rather than the combination therapy with aspirin and clopidogrel.

PATIENTS WITH AF AND STABLE CORONARY ARTERY DISEASE

SUMMARY• Antithrombotic therapy can be tricky in certain clinical

situations hence weighing risk Vs benefits in an individualized approach to therapy is necessary.

• In clinical settings where there is scarcity of resources,lack of knowledge of patient,poor compliance and follow up step wise approach is necessary rather than aggressive treatment.

• The coumbersomeness of Coumadin therapy is overcomed by newer drugs because of better side effect profile, less monitoring and overall smoothness of management.

• Cost continues to be prohibitory especially in indian context but like many other molecules , wider applications and subsidiaries may help as time goes by.

• So , we hope conditions which seems difficult now might become simpler in due course of time……………