Ticagrelor in acute myocardial infarctionVasif Mayan
Potential benefits of dual antiplatelet therapy beyond 1 year after an MI has not been studied
Patients with MI are at increased risk of RECURRENT ISCHAEMIC EVENTS
Intensive secondary prevention is theoretically beneficial
Finding an ideal drug with best risk-benefit ratio is a challenge
TICAGRELOR
--- Direct acting
Not a pro-drug; does not require metabolic activation
Rapid onset of inhibitory effect on the P2Y12 receptor
Greater inhibition of platelet aggregation than clopidogrel
--- Reversibly bound
Degree of inhibition reflects plasma concentration
Faster offset of effect than clopidogrel
Functional recovery of circulating platelets within ~48 hours
PLATO trial
PEGASUS TIMI trial
SGLT2 inhibitors in Heart failure: A prized addition to HF treatment optionsahvc0858
Early Diabetes and Dyslipidaemia Treatment Optimisation.
Presentation by Dr Chan Wan Xian
Cardiologist, Echocardiologist
Heart Failure Intensivist
Asian Heart & Vascular Centre
www.ahvc.com.sg
Rivaroxaban is a Factor Xa inhibitor. This presentation covers in brief regarding need for NOACs, kinetics, effects, indications, dosage, toxity, and antidote of rivaroxaban. It also covers in brief all the published trials
Ticagrelor in acute myocardial infarctionVasif Mayan
Potential benefits of dual antiplatelet therapy beyond 1 year after an MI has not been studied
Patients with MI are at increased risk of RECURRENT ISCHAEMIC EVENTS
Intensive secondary prevention is theoretically beneficial
Finding an ideal drug with best risk-benefit ratio is a challenge
TICAGRELOR
--- Direct acting
Not a pro-drug; does not require metabolic activation
Rapid onset of inhibitory effect on the P2Y12 receptor
Greater inhibition of platelet aggregation than clopidogrel
--- Reversibly bound
Degree of inhibition reflects plasma concentration
Faster offset of effect than clopidogrel
Functional recovery of circulating platelets within ~48 hours
PLATO trial
PEGASUS TIMI trial
SGLT2 inhibitors in Heart failure: A prized addition to HF treatment optionsahvc0858
Early Diabetes and Dyslipidaemia Treatment Optimisation.
Presentation by Dr Chan Wan Xian
Cardiologist, Echocardiologist
Heart Failure Intensivist
Asian Heart & Vascular Centre
www.ahvc.com.sg
Rivaroxaban is a Factor Xa inhibitor. This presentation covers in brief regarding need for NOACs, kinetics, effects, indications, dosage, toxity, and antidote of rivaroxaban. It also covers in brief all the published trials
Diabetes and acute coronary syndrome
Diabetic patients as compared to non diabetics withacute cornary syndrome (ACS) at 2 years showed a
1.8 fold increase in cardiovascular deaths
1.4 fold increase in myocardial infarctions (MI)
www.srisriholistichospitals.com
PLATO (Platelet Inhibition and Patient Outcomes)theheart.org
- Background:
Ticagrelor, a new antiplatet agent and not a thienopyridine, has a unique mechanism of action in that it is reversible
- Population and treatment:
18 624 ACS patient, with or without ST-segment elevation, randomized in a double-blind, double-dummy fashion to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg thereafter) for one year
Patients also received aspirin 75 mg to 100 mg day, unless they could not tolerate the drug
- Primary outcome:
A composite of death from vascular causes, MI, or stroke
See the article at http://www.theheart.org/article/995621.do
Antiplatelet therapy there is a gap between guidelines and implementationA.Salam Sharif
platelets play an important role in cardiovascular diseases, the final event leading to ACS is a spontaneous atherosclerotic plaques which initiates a platelet response with platelet adhesion to vascular wall with activation and agregation and finally clot formation with clinical sequences od CV deaths, MI and myocardial ischemia and arrhythmias, so atiplatelet therapy is crucial in treatment of ACS, in the topic I review the traditional agents and new agents , focusing on guidelines and real world of their cinical uses .
Dabigatran for Atrial Fibrillation: Cardioversion and Ablationlarriva
The presentation covers background information regarding atrial fibrillation (A-fib) and the use of oral anticoagulant dabigatran surrounding cardioversion and ablation for A-fib. The information surrounds a patient case in which the patient prefers dabigatran over warfarin. Available literature on the topic is analyzed to make a patient specific recommendation.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
2. Past...
Clopidogrel remained the gold standard along with
aspirin for several years of DAPT
Participated in the wide expansion of percutaneous
coronary intervention(PCI).
4. Stent thrombosis continued to occur, leading investigators to
suspect clopidogrel "resistance."
Studies showed that clopidogrel,
• pro-drug
• short-lived active metabolite,
• mild potency,
• slow onset of action, and
• large inter-individual variability.
These limitations were associated with adverse ischemic events
including stent thrombosis
Why newer P2Y12 antagonist were
needed
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-9260
5. To present!
Since then, new P2Y12-ADP receptor
antagonists, have been developed
• Prasugrel
• Ticagrelor and
• Cangrelor
6. Ticagrelor (AZD 6140):
an oral reversible P2Y12 antagonist
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
OH
OH
O
O H
N
F
S
N
H
N
N
N
N
F
7. Metabolism of P2Y12 Receptor
Antagonists
Schomig A. NEJM. 2009;361(11):1108-1111.
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-9260
CYP3A4/5
Ketoconazole
Clarithromycin
Nefazadone
ritonavir and
atazanavir
-
P-glycoprotein
CYP2C19
8. Direct acting
• does not require metabolic activation
• Rapid onset of inhibitory effect (0.5 – 4 hrs) on the P2Y12 receptor than
clopidogrel (2 – 8 hrs)
• Greater inhibition of platelet aggregation (90%) than clopidogrel (60%)
Reversibly bound
• Degree of inhibition reflects plasma concentration
• Faster offset of effect than clopidogrel
• Functional recovery of all circulating platelets
Eliminated via hepatic metabolism T1/2 - 7.2 hrs, whereas active
metabolite via biliary excretion T1/2 8.5 hours.
Circulation. 2017;136:1955–1975. DOI: 10.1161/CIRCULATIONAHA.117.031164
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-9260
9. Unique characteristic
• ability to increase adenosine levels; it being a precursor of
adenosine
o anti-inflammatory,
o cardioprotective,
o cerebroprotective,
o antisclerotic, and
o antifibrotic properties.
o coronary vasodilator.
Postgraduate Medicine, Volume 125, Issue 4, July 2013:1941-9260
10. Properties of P2Y12 Receptor Antagonists
Clopidogrel Prasugrel Ticagrelor
Metabolic Activation
through CYP2C19
Yes
sensitive to polymorphisms
and drug interactions
Yes
less sensitive to polymorphisms
and drug interactions
No
Indications ACS, PCI, PAD, CVD PCI ACS, PCI
Loading/Maintenance
Dosing
300 mg /75 mg OD 60 mg/10 mg OD 180 mg/90 mg BID
Inhibition Irreversible Irreversible Reversible
Efficacy ++
• Further 2% ARR over ASA
monotherapy
+++
• Further 2% ARR over clopidogrel +
ASA
+++
• Further 2% ARR over
clopidogrel + ASA
Bleeding risk + ++ ++
Issues • Rash
4.2% observed in clinical trials
leading to 0.5% drug
discontinuation
• Further increased bleeding risk in:
Prior Stroke / TIA
< 60 Kg
>75 yrs
• Increased fatal bleeding
• Dyspnea (14%)
• Ventricular pause
• Hyperuricemia
• Slight increased Cr
12. Study design:
Patients with high risk ACS(NSTE/STEMI) within 24 hrs.
All patients received standard therapy, including ASA
Excluded patients receiving fibrinolytics
Randomized to ticagrelor 180 mg load followed by 90 mg
bid or clopidogrel 300 mg load followed by 75 mg daily
n=18,624 (43 countries including India and China)
Wallentin L, et al. N Engl J Med. 2009;361(11):1045-1057.
13. PLATO inclusion criteria
• Hospitalisation for STEMI or NSTEMI ACS, with onset during the
previous 24 hours
• With STEMI, the following two inclusion criteria were required
Persistent STEMI or new LBBB
Primary PCI planned
• With NSTEMI ACS, at least two of the following three were required
ST-segment changes on ECG indicating ischaemia
Positive biomarker indicating myocardial necrosis
One of the following risk indicators
• ≥60 years of age
• Previous MI or CABG
• CAD with ≥50% stenosis in ≥2 vessels
• Previous ischaemic stroke, TIA, carotid stenosis (≥50%)
• Diabetes mellitus
• Peripheral artery disease
• Chronic renal dysfunction (creatinine clearance <60 mL/min)
18. Other findings – laboratory parameters
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186) p value*
% increase in creatinine from baseline
At 1 month
At 12 months
Follow-up visit
10 22
11 22
10 22
8 21
9 22
10 22
<0.001
<0.001
0.59
% increase in uric acid from baseline
At 1 month
At 12 months
Follow-up visit
14 46
15 52
7 43
7 44
7 31
8 48
<0.001
<0.001
0.56
Values are mean % SD; *p values were calculated using Fisher’s exact test
19. Time to major bleeding – primary safety event
No. at risk
Clopidogrel
Ticagrelor
9,186
9,235
7,305
7,246
6,930
6,826
6,670
Days from first IP dose
5,209
5,129
3,841
3,783
3,479
3,433
0 60 120 180 240 300 360
10
5
0
15
Clopidogrel
Ticagrelor
11.20
11.58
6,545
HR 1.04 (95% CI 0.95–1.13), p=0.434
K-Mestimatedrate(%peryear)
20. Total major bleeding
NS
NS
NS
NS
NS
0
K-Mestimatedrate(%peryear)
PLATO major
bleeding
1
2
3
4
5
6
7
8
9
10
12
11
TIMI major
bleeding
Red cell
transfusion*
PLATO life-
threatening/
fatal bleeding
Fatal bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically
programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15;*Proportion of patients (%);
11.6
11.2
7.9
7.7
8.9 8.9
5.8 5.8
0.3 0.3
Ticagrelor
Clopidogrel
21. Conclusions (PLATO)
• Ticagrelor in comparison with clopidogrel in a
broad population with ST- and non-ST-elevation
ACS provides
Reduction in myocardial infarction and stent thrombosis
Reduction in cardiovascular and total mortality
No change in the overall risk of major bleeding
Ticagrelor is a more effective alternative than clopidogrel for the
continuous prevention of ischaemic events, stent thrombosis and death in
the acute and long-term treatment of patients with ACS
22. Prevention of Cardiovascular Events in Patients with Prior
Heart Attack Using Ticagrelor Compared to Placebo on a
Background of Aspirin–TIMI 54 (PEGASUS-TIMI 2015)
23. Design of PEGASUS-TIMI 54
Stable pts with history of MI 1-3 yrs prior
+ 1 additional atherothrombosis risk factor*
Ticagrelor
90 mg bid
Placebo
RANDOMIZED
DOUBLE BLIND
Follow-up Visits
Q4 mos for 1st yr, then Q6 mos
Planned treatment with ASA 75 – 150 mg &
Standard background care
* Age >65 yrs, diabetes, 2nd prior MI,
multivessel CAD, or chronic non-end stage
renal dysfunction (Crcl <60ml/min)
Minimum 1 year follow-up
Event-driven trial
Ticagrelor
60 mg bid
N=21,162 (33 countries)
Follow up – 33 months
24. Exclusion criteria
• Planned use of a P2Y12 receptor antagonist (dipyridamole,
cilostazol) or anticoagulant therapy
• bleeding disorder
• H/o ischemic stroke or intracranial bleeding,
• CNS tumor,
• intracranial vascular abnormality
• GI bleeding within 6 months or
• major surgery within 30 days.
27. Addition of ticagrelor, at a dose of 90 mg twice daily or 60
mg twice daily, to low-dose aspirin reduced the risk of
cardiovascular death, myocardial infarction, or stroke and
increased the risk of TIMI major bleeding among patients
who had MI 1 to 3 years earlier.
Conclusion
28. Examining Use of Ticagrelor in Peripheral
Artery Disease (EUCLID) - 2016
This article was published on November 13, 2016, at NEJM.org.
29. Basis
Clopidogrel monotherapy shown to be more effective
than aspirin monotherapy in reducing CV events in
patients with PAD.
Hypothesis
Monotherapy with ticagrelor would be superior to
clopidogrel in preventing CV events in patients with
symptomatic peripheral artery disease
30. EUCLID
• CV death, MI, or ischemic stroke:
10.8% - ticagrelor vs 10.6% - clopidogrel (p = 0.65)
• Acute limb ischemia:
1.7% - ticagrelor vs 1.7% with clopidogrel
• Major bleeding:
1.6% with ticagrelor vs. 1.6% with clopidogrel
• Dyspnea resulting in drug discontinuation:
4.8% - ticagrelor vs 0.8% - clopidogrel (p < 0.001)
Trial design: Patients with peripheral arterial disease (PAD) randomized to
ticagrelor 90 mg BID (n = 6,930) vs. clopidogrel 75 mg QD (n = 6,955). (28 countries)
Results
Conclusions
•In patients with symptomatic PAD, ticagrelor was
not superior to clopidogrel in preventing MACE
•Acute limb ischemia and major bleeding were also
similar between treatment groupsHiatt WR, et al. N Engl J Med 2017;376:32-40
Ticagrelor Clopidogrel
%
(p = 0.65)
10.8 10.6
32. Available at jama.com and on The JAMA Network Reader at
mobile.jamanetwork.com
The Writing Committee for the
TREAT Study Group
Ticagrelor vs Clopidogrel After
Fibrinolytic Therapy in Patients With
ST-Elevation Myocardial Infarction:
A Randomized Clinical Trial
Published online March 11, 2018
33. Patients (Age ≥ 18 years and ≤ 75 years) with STEMI with in 24h and treated with fibrinolytic
therapy (N=3,799) (10 countries including China)
Ticagrelor
180 mg as early as possible after the index event and
90 mg twice daily for 12 months
Clopidogrel
300 mg as early as possible after the index event and
75 mg/day for 12 months
Follow up visits at hospital discharge or 7th day, 30 days, 6 and 12 months
Primary safety outcome: TIMI Major Bleeding
Secondary safety outcomes: Other bleeding events (PLATO trial, BARC, TIMI)
Exploratory efficacy outcomes: CV death, MI, or stroke
CV = cardiovascular ; MI = Myocardial infarction; TIA = transient ischemic attack
TIMI = Thrombolysis in Myocardial Infarction; BARC = Bleeding Academic Research Consortium
Study Design
34. Contraindication to clopidogrel or ticagrelor
Need for oral anticoagulation therapy
Dialysis required
Clinically important thrombocytopenia
Clinically important anemia
Pregnancy or lactation
Key Exclusion Criteria
35. Outcomes at 30 days
Ticagrelor
(n=1,913)
Clopidogrel
(n=1,886)
Hazard Ratio
P Value
(95% CI)
Death from vascular causes, MI, or stroke 4.0 4.3 0.91 (0.67 to 1.25) 0.57
Death or MI 3.2 3.6 0.90 (0.63 to 1.27) 0.54
MI or stroke 2.0 2.3 0.85 (0.55 to 1.31) 0.47
Death (from vascular causes) 2.5 2.6 0.95 (0.63 to 1.41) 0.79
Total MI 1.0 1.3 0.79 (0.44 to 1.42) 0.43
Total stroke 0.9 1.1 0.89 (0.47 to 1.68) 0.71
Other arterial thrombotic events 0.1 0.2 0.33 (0.03 to 3.16) 0.34
Death (from any cause) 2.6 2.6 0.99 (0.66 to 1.47)
0.95
Exploratory Efficacy Outcomes
36. Patients aged ≤ 75 yrs with STEMI, administration of ticagrelor after
fibrinolytic therapy was noninferior to clopidogrel for TIMI major
bleeding at 30 days.
Total bleeding was increased with ticagrelor and there was no
benefit on exploratory efficacy outcomes.
Ticagrelor is a reasonable option for patients ≤ 75 years who have
received fibrinolytic therapy (and clopidogrel) within the past 24
hours, with comparable safety compared to clopidogrel.
Conclusions and Implications
37. SETFAST: The Safety and Efficacy of Ticagrelor
for Coronary Stenting Post Thrombolysis Trial.
Patients (Age ≥ 18 years and ≤ 75 years) with STEMI treated with fibrinolytic therapy and
planned for PCI
Ticagrelor
180 mg as early as possible after the index event and
90 mg twice daily for 12 months
Clopidogrel
300 mg as early as possible after the index event and
75 mg/day for 12 months
RESULTS AWAITED
38. Summary
Dual antiplatelet therapy improves outcomes for patients
with ACS
Strong evidence for replacing clopidogrel with ticagrelor in
patients with ACS undergiong PCI comes from PLATO
study.
The above statement also holds true for Indian population.
Replacing clopidogrel with either ticagrelor or prasugrel
improves outcomes to similar magnitude BUT at a cost of
increased bleeding
Patient characteristics and revascularization method affect
drug choice
Stent thrombosis continued to occur despite DAPT, leading investigators to suspect clopidogrel "resistance
, to overcome these limitations and further improve the clinical outcome of patients suffering from ACS.
Not a prodrug; does not require metabolic activation
absorption is limited by the drug efflux transporter P-glycoprotein (encoded by the ABCB1 gene)
It is important to note that ticagrelor is orally active without metabolic transformation whereas clopidogrel and prasugrel require metabolic activation to exert their pharmacologic effect on inhibition of platelet activation and aggregation. CYP3A4/5 is the major drug metabolizing enzyme(s) for ticagrelor; CYP enzymes 1A2, 2C19, and 2E1 do not contribute meaningfully to metabolism of ticagrelor in vitro. Therefore drug-drug interactions with drugs that either inhibit or induce CYP3A4/5 can be expected to have an effect on ticagrelor plasma concentrations and hence clinical effect. The concomitant use of ticagrelor with strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, nefazadone, ritonavir, and atazanavir is not recommended.
Absorption of ticagrelor is rapid with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with a median tmax of approximately 2.5 hours. The Cmax and AUC of ticagrelor and the active metabolite increased in an approximately proportional manner with dose over the dose range studied (30-1260 mg). The mean absolute bioavailability of ticagrelor was estimated to be 36%, (range 25.4%-64.0%). In a study of healthy subjects, ingestion of a high-fat meal had no effect on ticagrelor Cmax or the AUC of the active metabolite, but resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite Cmax. These changes are considered of minimal clinical significance. Ticagrelor was administered without regard to food in PLATO. Therefore, ticagrelor may be given with or without food.
The steady state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (> 99%).
The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor. CYP3A is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. Ticagrelor and the active metabolite are weak p-glycoprotein inhibitors.
The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in feces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the active metabolite is most likely via biliary secretion. The mean t1/2 was approximately 6.9 hours (range 4.5-12.8 hours) for ticagrelor and 8.6 hours (range 6.5-12.8 hours) for the active metabolite.
Clopidogrel, a thienopyridine, is a prodrug. After intestinal absorption, it undergoes two steps of cytochrome P450 (CYP)-dependent oxidation to generate its active drug. After absorption clopidogrel is rapidly metabolized by two metabolic pathways in the liver one of which is hydrolysis by esterases leading to inactive metabolites (approx 85% of circulating metabolite) and the other by multiple CYP450 enzymes leading to a two-step formulation of the active thiol metabolite.
Prasugrel is rapidly metabolized in the intestine to a thiolactone, which is then converted to its active metabolite by a single step of cytochrome P450 metabolism primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19.
Background
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate
receptor P2Y12 that has a more rapid onset and more pronounced platelet
inhibition than clopidogrel.
Methods
In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg
loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading
dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624
patients admitted to the hospital with an acute coronary syndrome, with or without
ST-segment elevation.
Results
At 12 months, the primary end point — a composite of death from vascular causes,
myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ticagrelor
as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84;
95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing
of secondary end points showed significant differences in the rates of other composite
end points, as well as myocardial infarction alone (5.8% in the ticagrelor
group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes
(4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of
death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel;
P<0.001). No significant difference in the rates of major bleeding was found
between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively;
P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related
to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more
instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.
Conclusions
In patients who have an acute coronary syndrome with or without ST-segment elevation,
treatment with ticagrelor as compared with clopidogrel significantly reduced
the rate of death from vascular causes, myocardial infarction, or stroke without an
increase in the rate of overall major bleeding but with an increase in the rate of non–
procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)