Aspirin, dipyridamole, cilostazol, clopidogrel, ticlopidine

1. ANTI- THROMBOTIC THERAPY IN
DIFFICULT CLINICAL CONDITIONS

2. ▪ Anti – thrombotic therapy is a double edged sword
especially in certain critical situation .
▪ Attempts to reduce ischemic events is associated with
an increased risk of bleeding.
▪ Conversely, reducing bleeding complications may
increase coronary thrombotic ( ischemic ) events.
▪ Balancing both ends of the spectrum is essential.

3. ●Antiplatelet/Anti Coagulant drugs currently
available and their mechanism of action :
➢ASPIRIN : Irreversibly acetylates enzyme
cyclooxygenase . Selectively inhibits COX 1.
Thus prevents the synthesis of thromboxane
A2.This inhibits platelet aggregation.

4. ➢DIPYRIDAMOLE & CILOSTAZOL: Increases the
levels of c AMP in the platelets by blocking the
reuptake of adenosine and preventing c AMP
degradation( phosphodiesterase inhibition ). Thus
reducing the intracellular calcium levels which inturn
inhibits platelet activation and aggregation.

5. ➢CLOPIDOGREL, TICLOPIDINE & PRASUGREL:
Inhibit ADP activity by preventing its binding to
platelet receptor P2Y12. ADP stimulates expression of
GPIIb/IIIa receptor and mediate release of other
aggregation agonists .
Prasugrel is a pro drug( new thienopyridine ) and its
active form binds irreversibly to ADP P2Y12 receptor
on platelets.

6. ➢ABCIXIMAB , EPTIFIBATIDE & TIROFIBAN :
GPIIb/IIIa receptor antagonists block the final
common pathway in platelet activation. Due to high
affinity binding of abciximab to target receptor the
anti platelet effect of the drug persists for 24-48 hrs .
Residual platelet inhibition remains as high as 50-60%
for 24 hrs after the infusion ended.

7. ➢HEPARIN
Acts by activating plasma antithrombin.
Prevents conversion of fibrinogen to fibrin
Prevents conversion of prothrombin to thrombin.
➢WARFARIN
Indirectly interfere with the synthesis of vit k mediated
clotting factors in the liver.

8. DIFFICULT SITUATIONS FOR GIVING ANTI-THROMBOTIC
THERAPY :
● High ischemic burden
● High bleeding risk
● Non- cardiac surgery , post angioplasty, stenting
● Poor drug compliance
● Presence of anti-platelet therapy
● Renal dysfunction
● Pregnancy with prosthetic heart valve
● High INR levels
● Embolic stroke on anti- coagulant therapy

9. ASSESSMENT OF ISCHEMIC AND BLEEDING RISK :
ISCHEMIC RISK SHARED RISK FACTOR BLEEDING RISK
Recent ACS , PCI Elderly h/o bleeding
ACS with dual antiplatelet
therapy
Female Recurrent h’agic peptic
ulcer
LVEF<30% Obesity Intracranial surgery
TVD , DM Heart failure Transurethral
prostatectomy
Stent length >25mm Renal failure Surgery with extensive
detachment
Vessel diameter < 2.5mm Co- morbidites
Stent thrombosis

10. :CRITICAL CLINICAL CONDITIONS :
1. HIGH ISCHEMIC BURDEN :
▪ Rapid and greater inhibition of platelets to reduce
ischemic burden
▪ Diabetics, post PCI , small vessel disease, recent ACS
come in this category
▪ CLOPIDOGREL : slow onset of action , inhibits 50%
platelets , 25 % incidence of resistance
▪ PRASUGREL : inhibits ADP induced platelet
aggregation more rapidly and to a greater extent than
CLOPDOGREL .

11. ● In the Trial to Assess Improvement in Therapeutic
Outcomes by Optimising Platelet Inhibiton with
Prasugrel –Thrombolysis in Myocardial Infarction
(TRITON –TIMI 38 ) -
● Patients who underwent PCI had 19% risk reduction in
cardiovascular death, non-fatal MI, non-fatal stroke when
treated with PRASUGREL compared to CLOPIDOGREL .
● 52% risk reduction in stent thrombosis .
● But, 39% incresed risk of major bleeding with PRASUGREL
compared to CLOPIDOGREL

12. ● TICAGRELOR : Reversible ADP receptor inhibitor , more
rapid onset and more platelet inhibition than clopidogrel .
● The Platelet Inhibition and Patient Outcomes (PLATO)
trial : At ONE year , cardiovascular death, MI, stroke
occurred in 9.8 % patients receiving TICAGRELOR as
compared to 11.7% of those receiving CLOPIDOGREL , with
a significant 16% relative risk reduction .
● Patients who underwent PCI, rate of stent thrombosis was
lower with TICAGRELOR than CLOPIDOGREL (1.3% Vs
1.9% )

13. ● TICAGRELOR was associated with higher rates of fatal ICH
& major bleeding unrelated to CABG.
● Thus, patients with high ischemic risk , PRASUGREL or
TICAGRELOR is preferred over CLOPIDOGREL .
● But, their use should be discouraged in patients with high
bleeding risk .

14. 2. HIGH BLEEDING RISK :
▪ Patients whose bleeding risks out – weighs the potential
rewards of an aggressive anti-thrombotic strategy .
▪ They require a conservative approach to anti-thrombotic
therapy .
▪ Prasugrel should be avoided .
▪ Aspirin should be given in low doses .
▪ Loading dose of Clopidogrel should be 300mg .
▪ Bivalirudin ( synthetic short acting direct anti-thrombin
agent that binds specifically to thrombin ) is becoming an
alternative to UFH in ACS undergoing PCI .

15. ● Fondaparinux ( synthetic pure factor Xa inhibitor that
selectively binds to anti-thrombin causing rapid inhibition
of Xa ) has lower bleeding complications like Bivalirudin .
It has become an alternative to Heparin in ACS .
● It should always be used with Heparin as it may lead to
catheter thrombosis during PCI.

16. THERAPEUTIC STRATEGIES IN PCI THAT MAY INCREASE ANTI-
THROMBOTIC EFFICACY IN PATIENTS AT HIGH RISK OF
ISCHEMIC EVENTS :
● Use high-dose aspirin (e.g., 325 mg daily) for the
longest recommended duration after PCI (1 month for
BMS, 3 months for DES)
● Use higher-dose maintenance aspirin (e.g., 150 mg
daily) after PCI
● Use higher loading doses of clopidogrel (e.g., 600 mg;
consider 900 mg) during PCI
● Extend duration of post-PCI maintenance clopidogrel
therapy to at least 15 months after stenting.

17. ● Do not use fondaparinux as the sole anticoagulant during PCI.
● If LMWH is used, given higher periprocedural bolus dose (e.g.
enoxaparin 0.75 mg/kg).
● Therapeutic Strategies That May Reduce Hemorrhagic
Complications Of PCI In Patients At Higher Risk Of Bleeding
Events.
● Consider low-dose aspirin (e.g., 75mg daily) during the immediate
post-PCI period .

18. ● Use a lower leading dose of clopidogrel (300 mg
instead of 600 mg) during PCI
● Shorten the duration of post-PCI therapy to the
minimum recommended length (2 weeks for
angioplasty, 4 weeks for BMS, 12 months for DES);
discontinue at any time if bleeding events occur.
● Avoid prasugrel; if used, however, use lower
maintenance dose (5 mg daily)

19. ● If LMWH is used, give lower periprocedural bolus dose
(e.g. enoxaparin 0.5 mg/kg); if pre-PCI LMWH was
previously administered, give periprocedural
intravenous bolus dose (e.g., enoxaparin 0.3 mg/kg)
only if 8-12 hours have elapsed since the last
subcutaneous dose; avoid crossover from pre-PCI
heparin to procedural LMWH, and vice-versa.

20. ANTI-THROMBOTIC THERAPY IN PATIENTS UNDERGOING
NON-CARDIAC SURGERY POST ANGIOPLASTY AND STENTING :
● Cessation of antiplatelet therapy in the peri-operative
period can lead to rebound thrombotic phenomenon
which can result in stent thrombosis that can be fatal.
● At the same time continuing anti platelet therapy in
the peri-operative period may pose a threat of
increased risk of bleeding.
● American College of Cardiology recommends that you
delay any NCS for at least 12 months in case of DES
and 1 month in case of a bare metal stent .

21. ● Surgery with low bleeding risk e.g. cataract surgery,
oral dental surgery : Interruption of oral anti platelet
therapy is not necessary, irrespective of the ischemic
risk profile. Continue both aspirin and clopidogrel .
● Surgery with Intermediate bleeding risk e.g. GI
surgeries, cholecystectomy, appendicectomy etc :
Continue aspirin during peri-operative period. Stop
clopidogrel 5 days prior to surgery with
reintroduction as soon as possible.

22. ● Surgeries with high bleeding risk e.g. intracranial
surgeries, prostate surgery, aortic surgery, ENT
surgeries, and surgery in posterior segment of
eye: Stop Aspirin and Clopidogrel 5 days before
planned surgery,and substitute with alternative
antithrombotic therapies which may include low-
weight heparin (s.c. dose of 85– 100 iu per kg for 12
h). Regular treatment should be resumed as soon
as possible after surgery.

23. ANTI-THROMBOTIC THERAPY IN PATIENTS WITH POOR
DRUG COMPLIANCE :
WARFARIN :
● Cumbersome to use
● Multiple interactions to food and drugs.
● Regular INR monitoring required .
● Deviation from narrow therapeutic level can lead
to a fatal thrombotic episode or a bleeding
incident.

24. NEWER ORAL ANTI-COAGULANTS
(DABIGATRAN,RIVAROXABAN , APIXABAN ) :
● Directly inhibit thrombin or factor Xa.
● Predictable pharmacokinetic profile.

25. ● Lesser interactions with food and drugs .
● Various studies ( RELY , ROCKET-AF ,
ARISTOTLE ) have shown that these drugs have
an edge over Warfarin in terms of reduced
thrombotic events and bleeding events .
● When regular INR monitoring is a problem then
any of these 3 new oral anti-coagulants can be
used.

26. ANTI-COAGULANT THERAPY IN THE PRESENCE OF ANTI-
PLATELET THERAPY :
● Patients who undergo PTCA with a DES require a
long term dual antiplatelet drugs. If these patients
develop either an atrial fibrillation or left atrial
thrombus then they require an additional
Warfarin therapy .

27. ● When the triple therapy is needed : Dose of ASPRIN
should be kept as low as possible (i.e.75 mg). Clopidogrel
should be given at its standard dose of 75 mg/day.
Warfarin be administered under tight control to achieve a
slightly lower target INR of 1.5 to 2.0.
● PPIs should be administered prophylactically .

28. ● In patients who require long-term oral
anticoagulation: BMS prosthesis should be
considered for which dual antiplatelet treatment
is recommended for a shorter time .
● Newer anticoagulants ( Dabigatran, Rivaroxaban,
and Apixaban) have better predictable
pharmacodynamics and pharmacokinetics.

29. ANTI-COAGULANT THERAPY IN THE PRESENCE OF
RENAL DYSFUNCTION :
● Patients with renal failure have an increased risk of both
thrombotic and bleeding complications.
● A number of antithrombotic drugs undergo renal
clearance.
● In patients with severe renal insufficiency (creatinine
clearance [CrCl] < 30 mL/min) who require therapeutic
anticoagulation, the use of unfractionated heparin
(UFH) instead of LMWH is suggested.
● If LMWH is used, a 50% reduction of the total dose is
suggested.

30. ● Both tirofiban (PRISM-PLUS trial) and eptifibatide
(ESPRIT trial) have shown increased bleeding rates
in moderate to severe renal dysfunction.
● Although the manufacturer recommends reducing
both the bolus and infusion doses of tirofiban by
50% in CrCl < 30mL/min, the proper dose of
tirofiban and eptifibatide in such patients is
uncertain.

31. RENAL CLEARANCE OF ANTI-COAGULANTS :
HEPARIN LMWH FONDAPARIN
UX
BIVALIRUDIN
RENAL
CLEARANCE
MINIMAL 100% 100% 20%

32. ANTI-COAGULANT THERAPY IN PREGNANCY WITH
PROSTHETIC HEART VALVE :
● The anticoagulant approach for a pregnant woman
with mechanical valve needs to be individualized.
● Women with mechanical valves who become pregnant
- it is suggested to use either adjusted dose LMWH or
UFH throughout pregnancy, or adjusted-dose LMWH
or UFH (doses adjusted to keep APTT at least twice
control) until the thirteenth week with substitution by
VKAs until LMWH or UFH are resumed close to
delivery.

33. ● The use of warfarin throughout pregnancy until the 36
weeks has also been recommended when warfarin
dose is below 5 mg per day during the first trimester.

34. ● For a woman with older generation or tilting disc
mitral prosthesis ( which has a higher chance of
thrombosis) the safer approach : Warfarin for the first
34 weeks of pregnancy particularly if her dose is less than
5 mg/day.
● For a woman at lesser risk (aortic prosthesis or
bileaflet valves) : Heparin therapy may be selected as
soon as pregnancy is diagnosed, Warfarin substituted at
13 to 14 weeks and Heparin restarted at approximately 34
weeks in anticipation of delivery

35. ● For women with antiphospholipid antibodies and
recurrent (three or more) pregnancy loss or late
pregnancy loss and no history of venous or arterial
thrombosis - recommended actions include,
antepartum administration of prophylactic or
intermediate-dose UFH or prophylactic LMWH
combined with aspirin.

36. ● Lactating woman on antithrombotics - For lactating
women using warfarin or UFH, it is recommended to
continue these medications.

37. (CVA) in a patient on antithrombotics :
Initial response - It is recommended that both Warfarin
and heparin be stopped immediately when CVA occurs
(heparin shown to have a 15-25% chance of converting a
non hemorrhagic into a hemorrhagic stroke).
CT scan reveals no hemorrhage - Heparin should be
administered to maintain an aPTT at the lower end of
therapeutic level until Warfarin started.

38. CT scan reveals hemorrhage – antithrombotic
therapy should be withheld until the bleed is
stabilized (7 to 14 days)

39. ANTI-COAGULANT THERAPY IN PATIENTS WITH HIGH
INR LEVELS :
● For patients with INRs of > 9.0 and no significant
bleeding recommended actions include, holding
warfarin therapy and administering a higher dose
of vitamin K (2.5 to 5 mg) orally.
● Serious bleeding and elevated INR - regardless of
the magnitude of the elevation,hold warfarin
therapy and giving vitamin K (10 mg) by slow IV
infusion supplemented with fresh frozen plasma

40. ● For patients with INRs > 5.0 but < 9.0 and no
significant bleeding - omitting the next one or two
doses, and monitoring.

41. ● If bleeding occurs when INR is normal then occult
malignant disease should be ruled out.
● If INR varying then ensure : Lab value is real ,
drug compliance is adequate, drug and food
interactions .
● If still INR varying : Newer anti-coagulants should
be started .

42. ANTI-COAGULANT THERAPY IN PATIENTS WITH
EMBOLIC STROKE WHILE ON ANTI-COAGULANT :
● The anti-coagulant intensity should be increased
to a maximum target INR of 3-3.5 instead of
adding anti-platelet agents .
● Newer anti-coagulants ( Dabigatran, Rivaroxaban ,
Apixaban ) should be considered .

43. RISK OF DVT IN HOSPITALISED PATIENTS
PATIENT GROUPS DVT PREVALENCE %
MEDICAL 10-20
SURGICAL 15-40
GYNAECOLOGIC SURG 15-40
HIP OR KNEE
ARTHROPLASTY/HIP
FRACTURE SURG
40-60
MAJOR TRAUMA 40-60
SPINAL CORD INJURY 60-80
CRITICAL CARE 10-80

45. ● Balancing both ends of the spectrum with the proper
antithrombotic strategy is essential.
● An individualized approach to therapy is essential.