1. Antiplatelet agents and
anticoagulants
Associate professor of the Department of Clinical
Pharmacology and Propaedeutic of Internal Diseases
of I.M. Sechenov First Moscow State Medical
University
George S. Anikin
2. What we must understand?
Effects localization
Anticoagulants –
coagulations factors in
veins (venous and
cordial thrombosis)
Antiplatelet agents –
platelets (mainly in arterial
flow).
6. Benefit and harm of low-dose aspirin in well-treated hypertensives:
sub-analisis of HOT trial
(18 790 hypertensive patients within 3,8 years of treatment)
In moderate and high risk hypertensive patients use of ASA low
dose от (75 mg per day) significantly overweight risk of
complications:
-3.2
1.3
-4
-3
-2
-1
0
1
2
Zanchetti A., Hansson L., Dahlöf B. et al. Benefit and harm of low-dose aspirin in well-treated hypertensives at different
baseline cardiovascular risk. J Hypertens 2002; 20(11): 2301-7.
The absolute risk per 1000 patients per year while taking ASA compared with placebo
MI, stroke, cardiac death
Large bleeding: fatal, life-
threatening, requiring
hospitalization
7. • Prevention of cardiovascular events
such as stroke, MI
• Acute treatment of cerebral infarction,
myocardial infarction
• Thromboprophylaxis due to atrial
fibrillation
ASA- indication
8. • Allergy to ibuprofen or naproxen or who have salicylate intolerance or a
more generalized drug intolerance to NSAIDs
• Asthma or NSAID-precipitated bronchospasm
• Active stomach bleeding
• Hemophilia or other bleeding tendencies
• glucose-6-phosphate dehydrogenase deficiency,
• hyperuricemia, or gout
• Age < 12 years, as this has been linked with Reye's syndrome.
• Pregnancy
• Lactation
ASA- contraindication
9. Different form of ASA tablets – different
pharmacokinetics
Sagar K., Smyth M. A comparative bioavailability study of different aspirin formulations using on-line multidimensional chromatography. J
Pharm Biomed Anal. 1999 Nov; 21(2): 383-92.
Plasma ASA
concetration,
Mkg/ml
100 200 300 400 500 600 700
0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
Кишечнорастворимая АСК
Enteric tablet
Tablet
Time
11. Dual effects of clopidogrel and ASA on
platelets aggregation
• Irreversible inhibition of ADF-receptors
by clopidogrel
• ASA irreversibly inhibit Cox-1
COX
ASA
16. Clopidogrel: indication
1. Acute Coronary Syndrome (ACS)
• Clopidogrel tablet is indicated to reduce the rate of myocardial infarction
and stroke (MI) in patients with non-ST-segment elevation ACS [unstable
angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including
patients who are to be managed medically and those who are to be
managed with coronary revascularization. Clopidogrel tablets should be
administered in conjunction with aspirin.
• Clopidogrel tablet is indicated to reduce the rate of myocardial infarction
and stroke in patients with acute ST-elevation myocardial infarction
(STEMI) who are to be managed medically. Clopidogrel tablets should be
administered in conjunction with aspirin.
2. Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
In patients with established peripheral arterial disease or with a history of recent
myocardial infarction (MI) or recent stroke Clopidogrel tablet is indicated to
reduce the rate of MI and stroke.
17. • Allergy to any ingredient in clopidogrel.
• Active bleeding problem (eg, bleeding stomach
ulcer, bleeding in the brain)
• Use of dabigatran or certain proton pump
inhibitors (PPIs) (eg, omeprazole, esomeprazole)*
*Dexlansoprazole, lansoprazole and pantoprazole had less effect on the
antiplatelet activity of Clopidogrel than did omeprazole or esomeprazole
Clopidogrel: contraindication
26. Risk of stroke in AF
1
2.97
5.28
0
1
2
3
4
5
6
<65 65-74 ≥75
Age
1.14 1.17
1.09
1.19
1
1.19 1.17
0
0.2
0.4
0.6
0.8
1
1.2
1.4
CVD AG MI PCI without RF DM Female sex
1
5
0
1
2
3
4
5
6
without AF AF
European Heart Journal (2012) 33, 2719–2747
Rate,%
27. AF and the risk of embolism
Thomas Vanassche et al. Eur Heart J 2015;36:281-288
ACTIVE-A and AVERROES studies
28. AF and the risk of embolism ROCKET-AF
Benjamin A. Steinberg et al. Eur Heart J 2014;eurheartj.ehu359
29. C (congestive heart failure) 1 point
H (hypertension) 1 point
A (age) 2 points
D (diabetes mellitus) 1 point
S2 (stoke) 2 points
V (Vascular disease) 1 point
A (Age 65–74 years) 1 point
Sc Female sex 1 point
H Hypertension 1 point
A Abnormal renal/liver function
1 or 2
points
S Stroke 1 point
B
Bleeding history or
predisposition
1 point
L Labile INR - 1 point
E Elderly - >65 лет 1 point
D Drugs/alcohol concomitantly -
1 or 2
points
2 points is enough to prescribe
anticoagulants in case of AF
31. What will be our tactic? 1
Man, 41 y.o.
2 episodes of AF in 2 years
DM 2,
Without LV hypertrophy
• Nothing?
• ASA?
• Warfarin or NOAC?
32. Man 63 y.o.
Persistent AF for 5 y
Mitral valve bioprosthesis.
LV EF - 51%
LA – 5,6 sm
• Nothing?
• ASA?
• Warfarin or NOAC?
What will be our tactic? 2
33. What will be our tactic? 3
Woman 66 y.o.
Paroxysmal AF,
AG 1 degree.
• Nothing?
• ASA?
• Warfarin or NOAC?
34. 0
1
0
0
0
0
0
1+1
1
1 point
0 point
3 points
Not predictable score for
stroke
C (congestive heart failure) 1 point
H (hypertension) 1 point
A (age) 2 points
D (diabetes mellitus) 1 point
S2 (stoke) 2 points
V (Vascular disease) 1 point
A (Age 65–74 years) 1 point
Sc Female 1 point
36. Baber, U. et al. (2014) Balancing ischaemia and bleeding risks with novel oral anticoagulants
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2014.170
Death from bleeding and stroke
22%
48,6%
5,1%
0.49% vs. 0.74%, p=0.019 – ривароксабан
0.33% vs. 0.80%, p<0.001 – апиксабан
37. %
of
bleeding
Time from prescription (days)
0
0
1
2
3
4
5
30 60 90 120 150 180 210 240 270 300 330 360 390
warfarin
Apixaban
Dabigatran Rivaroxaban
Dabigatran (N=4,173)
150 мг NR
N=3 768 N=405
Rivaroxaban (N=10 050)
20 мг NR
N=8 066 N=1 984
Apixaban (N=2 402)
5 мг NR
N=2 057 N=345
Warfarin (N=12 713)
Lip et al. Poster presentation at ESC Aug/Sept 2015; London, UK Poster/oral poster no.P6217
Comparison of bleeding rate in US from different WARF and
NOAC
38. Warfarin: more the 60 years in
medicine
1948 г. Warfarin synthesis
1956 г. US president Dwight D. Eisenhower took warfarin after MI.
39. INR and risk of stroke and bleeding
5.0 6.0 8.0
1.0 2.0 3.0 4.0 7.0
5
15
10
Ischemic stroke Intracranial bleeding
1
20
OR
INR
Fang MC, et al. Ann Intern Med 2004; 141:745.
Hylek EM, et al. N Engl J Med 1996; 335:540.
40. What’s
wrong with
warfarin?
Difficult to
manage for
invasive
procedures
Multiple drug
and dietary
interactions
Slow offset of
action (long
duration of action,
long elimination
half life)
Slow onset
of action
Narrow
therapeutic
range
Efficacy is
dependent upon
infrastructure
Time in therapeutic range
(TTR) is associated with
improved safety and
efficacy
TTR is greater in countries
with more sophisticated
health care infrastructure.
Monitoring required to
maintain in therapeutic
range
Under-use of therapy due
to fear of adverse events
and complexity of
management
41. TTR in clinical practise
J Am Heart Assoc. 2015;4:e001921 doi: 10.1161/JAHA.115.001921
45. Features Warfarin NOAC
Onset Slow Rapid
Dosing Variable Fixed
Food effect Yes No
Drug interactions Many Few
Monitoring Yes No
Half-life Long Short
Antidote Yes No
Comparison between NOAC and Warfarin
50. A 65 years old woman was admitted in clinic, with the diagnosis of coronary heart
disease, permanent atrial fibrillation, arterial hypertension stage 2 with very high risk
of CVC, congestive cardiac failure.
She has also stomach ulcer 12 duodenal ulcer.
She felt tachycardia, weakness, dyspnea with exertion.
Physical examination revealed the state of moderate severity, mild peripheral edema,
BP - 160/80 mm Hg, pulse - 105 per minute, heart rate - 95 per minute, arrhythmic
heart sounds. Echo-CG is showed LVEF -50%, ECG - atrial fibrillation, left ventricular
hypertrophy.
Drug history:
• warfarin 1.5 Tb per day (1Tb - 2.5 mg),
• digoxin (0.25 mg) half Tb once daily,
• metoprolol 25 mg once daily,
• enalapril 10 mg once daily.
After admission to the hospital digoxin was canceled and metoprolol dose was
increased up to 50 mg (daily), as well as enalapril dose up to 20 mg, spironolactone
was prescribed in 25 mg daily dose, and warfarin dose was corrected because of INR
(1.79).
1. Evaluate the treatment in clinic in this case.
2. Was it essential to cancelled digoxin? Why?
3. In what way was warfarin dose corrected? What drugs may you offer as an
alternative to warfarin?
Task 1
51. A 58 years old man with the history of myocardial infarction, angina, paroxysmal atrial fibrillation.
He has been taking
amiodarone 200 mg over a year,
spironolactone 25 mg,
warfarin 5 mg,
torasemide 10 mg.
The last analysis revealed high cholesterol level up to 7,2 mmol/l and high level of LDL-
cholesterol. For this reason, the patient was prescribed simvastatin 40 mg. After 7 days he have
noted muscle pain.
1. What doctor have to do for estimating effectiveness and safety of amiodarone and warfarin
treatment?
2. What is the main cause of muscle pain?
3. If amiodarone is a drug of choice in this case?
Task 2
52. A 52 years old man suffers from exertional angina, stage 2 Hypertension, very high risk of CVC.
His normal BP level is up to 130/80 mm Hg.
He takes antihypertensive treatment:
Noliprel A forte (perindopril arginine 5 mg plus indapamide 1.25 mg) in combination with 2.5 mg of
bisoprolol.
Doctor measured the BP up to 170/100 mm Hg for several days, frequent angina attacks, non-
productive cough.
He cancelled Noliprel A forte and prescribed
valsartan (diovan) 80 mg daily,
acetylsalicylic acid 75 mg daily,
torasemide 5 mg daily,
bisoprolol 2.5 mg daily.
A week later, the BP is 130/80 mm Hg, heart rate - 68 per minute.
1. Comment the treatment. What was the main reason of cough?
2. Is beta-blockers + Sartan a rational combination in this case?
3. How we can estimate effectiveness and safety of therapy?
Task 3
53. A 63 year old woman with 2nd stage hypertension, an average risk of CVC.
Concomitant diseases: knee’s osteoarthritis, cholelithiasis. She takes elanapril 10 mg BID,
amlodipine 5 mg once daily. Her BP is stable - 130/80 mm Hg.
After hypothermia she felt pain in both knee during walking, "starting pain ', swelling of the right
knee joint. She was diagnosed osteoarthritis exacerbation. T
he doctor prescribed
lornoxicam 10 mg BID,
1500 mg glucosamine per day.
On this treatment, she felt well but daily monitoring of blood pressure revealed an increase up to
160/90 mm. Hg.
1. What drug may lead to increasing of BP level?
2. What is the mechanism of increasing of blood pressure while taking this drug?
3. What other cardiovascular complications may develop when using this drug?
4. What tactic of treatment you suggest in this case?
Task 4
54. A 56 years old man has been suffering from stage 2 hypertension for 5 years.
On examination, BP 160/95 mm Hg, HR 76 bpm, rhythmic cardiac tones,
atherosclerosis of the lower limbs max 50% (for 10 years).
Suggest an antihypertensive therapy.
1. Should we prefer a mono- or combined antihypertensive therapy? Explain
your opinion.
2. What kind of antihypertensive drug or drugs will you prescribe as the first
line therapy?
3. Doctor prescribed enalapril 10 mg 2 times a day. Is it correct to use this
drug?
4. Are antiplatelet agents indicated for this patient? If yes, name the drug and
dose.
5. Are anticoagulants indicated for this patient? If yes, name the drug and
dose.
Task 5
55. A 64-year-old man is a smoker suffered from arterial hypertension stage 3, very high
risk of CVC.
He discharged from a hospital 3 weeks ago after myocardial infarction (stenting of the
right coronary artery).
Now he suffers from weakness and headache. There is not any pain in the chest.
According to recommendations he takes
bisoprolol 5 mg per day,
perindopril 10 mg per day,
atorvastatin 20 mg per day,
acetylsalicylic acid 50 mg a day and clopidogrel 75 mg.
PE: RS – Normal, CVS: BP 160/100 mm Hg, HR - 62 bpm. ECG –1st degree AV-block,
that was not present on the ECG from the hospital.
1. Can you explain what drug may cause ECG abnormalities? Why?
2. How must we change antihypertensive medication in our patient?
3. Is it dose of statin right? If no, how we should change it?
4. Is it possible to cancel one of the antiplatelet?
5. What additional drug could you prescribe?
Task 6
