despite controversy the atorvastatin and clopiodgrel combination was found to be beneficial in reducing the MACE EVENTS on a large metanalysis

1. Role of Statin & Clopidogrel in
Atherothrombotic Events
Dr.Nagula Praveen, MD,DM
Assistant Professor of Cardiology,
Osmania General Hospital,
Hyderabad
drpraveennagula@gmail.com
Twitter: @kizashipraveen

4. Aspirin
• Various laboratory parameters assessing the efficacy of aspirin like
– Bleeding time,
– Platelet reactivity,
– Thromboxane-A2 (TX-A2) production, and
– Measurement of platelet aggregation,
• Confirmed the lack of its uniform effect on the platelets
Few studies have reported
Aspirin resistance to the tune of 5 - 45%
JIACM 2009; 10(3): 134-9

5. Clopidogrel
• It is Thienopyridine derivative
• The drug specifically and irreversibly inhibits the ADP receptor
• It is used to inhibit blood clots in coronary artery disease,
peripheral vascular disease, cerebrovascular disease, and to
prevent myocardial infarction

6. “The development of
Clopidogrel is from the
predecessor Ticlopidine
- out of the 4850
analogues found the S
enantiomer was not
having adverse effects
and that was the
revolutionary drug,
Clopdiogrel”.

7. Clopidogrel
Clopidogrel is a
relatively new
antiplatelet agent &
is currently the most
widely prescribed
drugs for the
treatment of
symptomatic
coronary artery
disease
Cardiovascular Drugs & Therapy 17, 467-477; 2003

10. CAPRIE- Study
• Multicenter, double-blind,
parallel-group, randomized
controlled trial
• N=19,185
• Clopidogrel 75 mg once
daily (n=9,599)
• Aspirin 325 mg once
daily (n=9,586)
• Mean follow-up: 1.9 years
5.32
5.83
5
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
Clopidogrel Aspirin
Risk of cardiac events %
Clopidogrel reduces CV outcomes more than aspirin when used as
secondary prevention among patients with prior stroke or MI.
Lancet 1996 Nov 16;348(9038):1329-39.

11. STATINS
Selective, Competitive Inhibitor Of HMG-CoA Reductase

18. WHY ATORVASTATIN AND CLOPIDOGREL
COMBINATION IS OF DOUBTFUL BENEFIT ???

20. Conclusion: Certain statins which are substrates of the CYP3A4 isoform competitively
inhibit the metabolic activation of clopidogrel. As a result the relative clopidogrel induced
platelet inhibition (P-selectin-expression) is diminished--but still there is a relative
clopidogrel effect of more than 80% in the maintenance phase. It may be reasonable to
test the therapeutic efficacy of clopidogrel in those patients who require long-term
treatment.

22. studies

23. Statins Significantly Reduce Mortality In
Patients Receiving Clopidogrel
• Combination of statins and clopidogrel is frequently administered in patients with
coronary artery disease (CAD)
• PubMed, Embase, the Cochrane Library, Web of Science and Clinical Trials. gov were
searched
• Randomized controlled trials (RCTs) and cohort studies were taken into quality evaluation
• Data were pooled using random effect models to estimate standard mean difference
(SMD) or risk ratio (RR) with 95% confidence interval (CI).
• In total, 28 studies representing 25,267 participants were included
• Statins reduce the mortality of patients administered clopidogrel (RR 0.54; 95% CI
0.40,0.74; p = 0.000), no differences were found in platelet aggregation (PA) (SMD
0.02; 95% CI -0.38,0.42; p = 0.920) and the expressions of P-selectin (SMD -0.04;
95% CI -0.14,0.05; p = 0.346), CD40L (SMD 0.09; 95% CI -0.29,0.48; p = 0.633),
CD63 (SMD 0.09; 95% CI -0.01,0.19; p = 0.079) and PAC-1 (SMD 0.03; 95% CI -
0.08,0.13; p = 0.633)
Meta-analysis confirmed that statins reduce mortality in patients undergoing
clopidogrel treatment without affecting platelet activation and aggregation.

24. Simultaneous administration of high dose
Atorvastatin and Clopidogrel during PCI
• Total 60 subjects undergoing
PCI randomized
• Group 1: Atorvastatin 80 mg
+ clopidogrel 600 mg
loading dose (n=28)
• Group 2: Clopidogrel 600
mg alone (n=32) at the time
of PCI.
57
37 35
61
39 37
0
10
20
30
40
50
60
70
Baseline Aft. 4 hrs Aft. 16-24 hrs.
Platelet aggregation %
Baseline Aft. 4 hrs Aft. 16-24 hrs.
No significant
difference
observed in
platelet
aggregation
between both
groups
Statin reloading with high doses of atorvastatin at the time of PCI appears
to be safe without adverse effects on platelet inhibition by clopidogrel
Clin Pharmacol 2016 Jun 3;8:45-50., PCI : percutaneous coronary interventions

25. Impact of atorvastatin or rosuvastatin co-administration on
platelet reactivity in patients treated with dual antiplatelet
therapy
• Total of 374 patients, 240
receiving atorvastatin, 134
rosuvastatin
• In the 163 patients treated
with clopidogrel, rosuvastatin
co-administration was
associated with a significantly
increased rate of HRPR (55.6%
vs 32%, p = 0.01)
55.6
32
0
10
20
30
40
50
60
Category 1
High-on treatment platelet reactivity
(HRPR) %
Rosu. Atorva.
Among patients receiving dual antiplatelet therapy, rosuvastatin but
not atorvastatin is associated with an increased rate of HRPR for clopidogrel
without any influence on the antiplatelet effect of ASA or ticagrelor
Atherosclerosis. 2015 Dec;243(2):389-94.

26. GRACE- Study
• By utilizing data from Global Registry of Acute Coronary Event (GRACE),
• 15,693 patients with non-ST-segment elevation myocardial infarction (MI) or
unstable angina were studied.
Group 2
Aspirin +
Clopidogrel
Group 4
Aspirin +
Clopidogrel +
Statin
Group 1
Aspirin
Group 3
Aspirin +
Statin
Atherosclerosis. 2015 Dec;243(2):389-94.

27. GRACE- Study
5.8
3.6
4.8
2.1
Gropu 1 Group 2 Group 3 Group 4
Death rate %
The combination of clopidogrel with a statin has synergistic effects on
the clinical outcomes of patients with non-ST-segment elevation ACS
Atherosclerosis. 2015 Dec;243(2):389-94.

28. A Subgroup Analysis of The CILON-T
Trial
• To compare responsiveness
to clopidogrel in patients
prescribed atorvastatin vs.
rosuvastatin, following
percutaneous coronary
intervention.
• 915 patients were randomized
• Atorvastatin(20 mg/day, n=295)
or
• Rosuvastatin(10 mg/day, n=261)
• Follow up : 6 months
217
221
241
226.4
Rosu. Group Atorva Group
Comparisons of PRU values
Baseline At 6 months
Atorvastatin offered better P2Y12 inhibition
Rosuvastatin is associated with high on-treatment platelet reactivity compared
with atorvastatin following the co-administration of clopidogrel
J Atheroscler Thromb. 2014;21(2):140-50

29. Insights from the TRITON-TIMI 38
• The TRITON-TIMI 38 enrolled 13,608 patients with an acute coronary syndrome (ACS)
and planned percutaneous coronary intervention (PCI), and randomized them to
clopidogrel or prasugrel
• Of the 6,795 subjects assigned to clopidogrel, 4794 (70.6%) were on a CYP3A4-
metabolized statin
• In patients with ACS undergoing PCI, the use of statins was not associated with an
increased risk of CV events in clopidogrel-treated patients.
Consistent results were observed when the drugs were administered
alone, together, or in combination with proton pump inhibitors.
TRITON-TIMI 38: Trial to Assess Improvement in Therapeutic Outcomes by
Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial
Infarction 38

30. Atorvastatin Reduces Total Events Overall
And Across Vascular Beds in The SPARCL Trial
Atorvastatin prevented more than twice the number of total events than first
events, with reductions in all vascular beds. Total event reduction is a useful
metric to gauge atorvastatin efficacy after recent stroke or TIA
Proceedings of the American College of Cardiology's 69th Annual Scientific Session & Expo; 2020 March 28-30; 2020 in Chicago, Illinois: 1074-03

31. Lipid Management in Acute Coronary Syndrome
Patients Among The Tier Three Hospitals
Proceedings of the American College of Cardiology's 69th Annual Scientific Session & Expo; 2020 March 28-30; 2020 in Chicago, Illinois: 1362143
Few of ACS patients among tier 3 hospitals in China achieved the LDL-C
goal, indicating huge potential for improving outcome by use of more
intensive LLT.

32. Differential Effects of Dual Antiplatelet Therapy In Patients
With Acute Coronary Syndrome Versus Stable Ischemic Heart
Disease After Coronary Artery Bypass Grafting
Proceedings of the American College of Cardiology's 69th Annual Scientific Session & Expo; 2020 March 28-30; 2020 in Chicago, Illinois: 1362143
• Optimal antiplatelet strategy following revascularization with coronary artery
bypass grafting (CABG) remains controversial
• The current study sought to evaluate whether long-term clinical outcomes
according to the use of dual antiplatelet therapy (DAPT) or single antiplatelet
therapy (SAPT) differed between acute coronary syndrome (ACS) and stable
ischemic heart disease (SIHD) patients who underwent CABG
• N= 3,260 patients with ACS (55.3%) and 2,633 with SIHD (44.7%) were enrolled
• The study population was stratified by the use of DAPT or SAPT in ACS patients
and SIHD patients and primary outcome was cardiac death at 5 years
Conclusion Among ACS patients who underwent CABG, the use of DAPT
was associated with lower cardiac mortality than the use of SAPT, but
this was not the case in SIHD patients.

33. RECENT DATA

34. Aim:
To investigate the effects of switching from ticagrelor to
clopidogrel in an Asian population, after accounting for various
switch points as in a real-world environment
Acta Cardiol Sin 2020; 36: 8-15

35. Outcomes
Acta Cardiol Sin 2020; 36: 8-15
Primary Outcome
• Composite of an efficacy endpoint
[major adverse cardiac and
cerebrovascular events (MACCEs)], and a
safety endpoint [clinically significant
bleeding (CSB)]
Secondary Outcome
• MACCEs and CSB as individual endpoint
• MACCEs: all-cause mortality, myocardial infarction, target vessel revascularization or ischemic
stroke
• CSB: type 2 bleeding and above according to the Bleeding Academic Research Consortium (BARC)
classification
• First study to examine and control for a variety of switch points as a primary objective

36. Primary Outcome (Composite:
bleeding + MACCE
Acta Cardiol Sin 2020; 36: 8-15
• Compared to the ticagrelor only group, the switched group was not
significantly associated with MACCE or CSB events (p = 0.114)
10
13.8
0
2
4
6
8
10
12
14
16
Switched to clopidogrel group Ticagrelor only group
%ofpatients
Composite – bleeding + MACCE

37. Secondary Outcome (MACCEs only)
Acta Cardiol Sin 2020; 36: 8-15
• There was also no significant difference when MACCEs were
analyzed alone (p = 0.332)
2.3
7.7
0
1
2
3
4
5
6
7
8
9
Switched to clopidogrel group Ticagrelor only group
%ofpatients
MACCE only

38. Secondary Outcome (CSB only)
Acta Cardiol Sin 2020; 36: 8-15
• For CSB, the switched group 70% less likely to have a CSB event
(p = 0.047)
7.8
8.5
7.4
7.6
7.8
8
8.2
8.4
8.6
Switched to clopidogrel
group
Ticagrelor only group
%ofpatients
CSB only

39. Why switching from Ticagrelor to
Clopidogrel?
Acta Cardiol Sin 2020; 36: 8-15
• Concerns over increased bleeding risks with the more potent
ticagrelor remain the most common reasons for switching to
clopidogrel
• Other side effects such as dyspnea are also a potential reason for
switching away from ticagrelor
• Reduced cost

40. Conclusions
Acta Cardiol Sin 2020; 36: 8-15
• No significant difference between staying on ticagrelor and
switching to clopidogrel was reported.
• Switching might decrease the incidence of CSB.
• De-escalation from ticagrelor to clopidogrel could translate to
cost savings for Asian patients without compromising safety and
efficacy.

41. Take Home Message
• Clopidogrel is more effective than aspirin in reducing CV outcomes more
• The combination of clopidogrel with a statin has synergistic effects on the
clinical outcomes of patients with non-ST-segment elevation ACS
• Aaddition of high-dose atorvastatin (80mg) for 30 days significantly
improves the pharmacodynamic effects of double-dose clopidogrel,
reducing platelet reactivity and improving optimal clopidogrel response in
statin naïve patients with high-on treatment platelet reactivity on standard-
dose clopidogrel.
• Among patients receiving dual antiplatelet therapy, rosuvastatin but
not atorvastatin is associated with an increased rate of HRPR for
clopidogrel
• Statin reloading with high doses of atorvastatin at the time of PCI appears
to be safe without adverse effects on platelet inhibition by clopidogrel

42. THANK YOU