Medical topic

1. CLOPIDOGREL RESISTANCE
Dr.Sarwat Paiker Malik
Resident Cardiology
AFIC & NIHD

2. Introduction
 Clopidogrel is a pro-drug to an active metabolite in the liver by
cytochrome P450 enzymes, in which CYP2C19 plays an important
role.
 The active metabolite binds irreversibly to the P2Y12 receptor and
consequently inhibits the binding of ADP. This leads to a decrease in
platelet activation, platelet aggregation, and clot formation
 only a small proportion of administered clopidogrel is metabolised by
CYP. The majority of clopidogrel is hydrolysed by esterases to an
inactive carboxylic acid derivative that accounts for 85% of the
clopidogrel-related compounds circulating in plasma.
Oqueli E, Hiscock M, Dick R. Clopidogrel resistance. Heart Lung Circ [Internet]. 2007;16 Suppl 3:S17-28.
Available from: https://www.sciencedirect.com/science/article/pii/S1443950607001850

4. Definition
• Clopidogrel Resistance is defined as the failure of
the molecule to inhibit the target of its action.
mostly caused by a CYP2C19 polymorphism  a
relevant change in platelet function is absent
despite adequate clopidogrel dosage.
• Clopidogrel resistance is best demonstrated by the
evidence of residual post treatment P2Y12
activity by measuring ADP induced platelet
aggregation before and after treatment.

5. DEFINITION
• Clopidogrel resistance (defined as From a
pharmacological point of view, can be
delineated with a P2Y12 reaction units (PRU)
value ≥235 or percentage platelet inhibition
≤20%, determined using VerifyNow®)
• A subgroup of patients had more platelet
aggregation post Percutaneous Intervention
(PCI) than before they were defined as
“Heightened Platelet Reactivity to ADP.
. Gurbel et al. Change in inhibition of platelet aggregation
(IPA) of <10% using light transmittance aggregometry. Circulation 107:2908–2913. http://dx.doi.org/10.1161/01.CIR.0000072771.11429.83. [Ref list]

6. MECHANISMS OF CLOPIDOGREL RESISTANCE
There are several mechanisms of clopidogrel resistance, including:
 Differences in intestinal absorption, hepatic conversion of active
metabolite through cytochrome CYP2C19, ABC1 activity and platelet
receptor polymorphisms have been suggested.
 Genetic polymorphisms: genetic variations in the CYP2C19 gene
 Drug-drug interactions: Clopidogrel is metabolized by several enzymes
in the liver, including CYP2C19. proton pump inhibitors and certain
antidepressants interact with cytochrome.
 Non-compliance: Some patients may not take their medication as
prescribed, which can lead to suboptimal antiplatelet effects.
Mechanism of clopidogrel resistance:Sibbing, D., et al. (2010). Clopidogrel response and the influence of genetic polymorphisms and drug–drug interactions.
Journal of the American College of Cardiology, 55(10), 1001-1013.Angiolillo, D. J., & Fernandez-Ortiz, A. (2010).
Clopidogrel response variability: insights into the influence of clinical, genetic, and drug interactions. Clinical Pharmacology & Therapeutics, 88(6), 716-725.

7. MECHANISMS OF CLOPIDOGREL RESISTANCE
 Genetic polymorphism of ABC1-The ABCB1 gene, which is also
called MDR1 or TAP1, encodes the intestinal efflux transporter
pump P-glycoprotein and modulates the absorption of
clopidogreL
 GpIIb-IIIa, GPIa-IIa and P2Y12 receptors also causes clopidogrel
resistance.
 Patients with Diabetes exhibit heightened platelet reactivity
and this may further aggravate non responsiveness to
clopidogrel
 Insufficient metabolite generation secondary to limitations in
intestinal absorption.
Angiolillo D.J., Fernandez-Ortiz A., Bernardo E.
Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.
J Am Coll Cardiol. 2007 Apr 10;49:1505–1516. [PubMed] [Google Scholar] [Ref list]

8. International prevalence
• Clopidogrel resistance has been reported in various
populations around the world, ranging from 4% to 67%.
• A meta-analysis of 31 studies involving over 7,000 patients
found that the overall prevalence of clopidogrel resistance was
approximately 29%.
• Some factors that may contribute to the international variation
in clopidogrel resistance include:
Ethnicity:Asians and Pacific Islanders
Genetic polymorphisms: CYP2C19 gene
Comorbidities-diabetes and CKD, may have a higher
prevalence
Cuisset, T., et al. (2006). Prevalence of acetylsalicylic acid and clopidogrel resistance among patients with stable coronary artery disease: the RESIST study.
Journal of the American College of Cardiology, 47(10), 1985-1994.Wang, X., et al. (2011).
Clopidogrel resistance: prevalence, mechanisms, and clinical implications. Cardiovascular Diagnosis and Therapy, 1(2), 120-126.

9. Local prevalence
 The prevalence of clopidogrel resistance can also vary
within a given population. For example, a study conducted
in a hospital in Iran found that the prevalence of
clopidogrel resistance was 24.4% among patients with
acute coronary syndrome.
 However, the prevalence varied widely depending on the
type of acute coronary syndrome, ranging from 40.7% for
ST-segment elevation myocardial infarction.
 Similarly, a study conducted in a hospital in Pakistan found
that the prevalence of clopidogrel resistance was 34.4%-
51.4 % among patients undergoing percutaneous coronary
intervention.
Davoodi, G., et al. (2017).
Prevalence and predictors of clopidogrel resistance in patients with acute coronary syndrome.
Journal of Cardiovascular and Thoracic Research, 9(1), 15-20

10. “VerifyNow “Platelet Reactivity
Profile
• is a very practical bedside tool
• measures platelet aggregation to fibrinogen-coated beads in
whole blood in response to an ADP induced stimulus.
• Reported as values of P2Y12 reaction units (PRU),
• a higher PRU value reflects a higher P2Y12 mediated platelet
reactivity.
• Lower PRU levels are associated with expected antiplatelet
effect.
• <180 PRU – suggests P2Y12 inhibitor effect
• 180-376 PRU – suggests lack of P2Y12 inhibitor effect

11. Plavix VerifyNow Platelet Reactivity (PRU):
• Patients who have been treated with Glycoprotein IIb/IIIa
inhibitor drugs should not be tested until platelet function has
recovered. This time period is approximately 14 days after
discontinuation of drug adminstration for abciximab (ReoPro)
and up to 48 hours for eptifibatide (Integrilin) and tirofiban
(Aggrastat).
• Test Limitations:
• The Plavix VerifyNow Platelet Reactivity test performance has
been validated for hematocrit values between 33-52% and
platelet counts between 119-502 K/µL. Results outside of these
parameters have not been studied and results may be affected.
University of Wisconsin Hospitals. Coagulation [Internet].
UW Health. [cited 2023 Feb 21]. Available from:
https://www.uwhealth.org/lab-test-directory/coagulation/name-71825-en.html

12. Laboratory evaluation of clopidogrel
responsiveness
• Clopidogrel inhibits one of the two ADP receptors; ex-vivo
measurement of ADP induced platelet aggregation by light
transmittance aggregometry is the most commonly used “Gold
standard” method to evaluate clopidogrel responsiveness.
• Flow cytometric measurements of expression of GpIIb/IIIa
receptor and p selectin expression after ADP stimulation can
also identify clopidogrel nonresponsiveness.
• measurements of ADP induced fibrin clot strength is measured
by whole blood throomboelastography and the verify Now
P2Y12 receptor assay using ADP as agonist

13. STRATEGIES TO OVERCOME CLOPIDOGREL RESISTANCE
• Increasing the dose of clopidogrel: Higher doses of clopidogrel various
studies have shown that 600 mg dose was associated with higher level of
platelet inhibition, lower mean post treatment reactivity of ADP than the
300 mg loading dose
 Switching to a different antiplatelet agent: such as prasugrel or ticagrelor.
 Genetic testing
 Lifestyle modifications---Encouraging these patients to make lifestyle
modifications, such as quitting smoking, losing weight, or increasing
physical activity, may help improve their response to clopidogrel.
 Medication adherence
1. Breet, N. J., et al. (2013). Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent
implantation. Journal of the American College of Cardiology, 61(10), 1068-1074.2. Gurbel, P. A., & Tantry, U. S. (2008).
2. Clopidogrel resistance? Thrombosis Research, 123(1), 23-28.3. James, S. K., et al. (2008).
3. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from
prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ, 340, c2605.4. Sibbing, D., et al. (2010).
4. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thrombosis and Haemostasis, 103(4), 714-722.5. Wallentin, L.,
et al. (2009 ).
5. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 361(11), 1045-1057.

14. Trials on Management of clopidogrel
resistance
 The CURRENT OASIS-7
 most influencial trial related to clopidogrel resistance because it was a large-
scale study that included a broad range of patients.
 Double-dose versus standard-dose clopidogrel and high dose versus low-dose
aspirin in individuals undergoing percutaneous coronary intervention for acute
coronary syndromes
 trial randomized 25,087 patients with unstable angina or acute MI to a high
dose regimen
 (600 mg loading dose of clopidogrel, followed by 150 mg per day for 1 week) or
the standard regimen (300 mg on the first day followed by 75 mg/day) showed
benefit of 600 mg clopidogrel in ACS + PCI population but the primary end
point was mainly driven by MI alone. The Current OASIS trial however showed a
significant reduction in Definite Stent Thrombosis
 The trial found that ticagrelor reduced the rate of the primary endpoint (a
composite of cardiovascular death, myocardial infarction, or stroke) compared
to clopidogrel in patients with acute coronary syndrome

15. Trials on Management of clopidogrel
resistance
GRAVITAS (Gauging Responsiveness with A Verify Now
assay—Impact on Thrombosis And Safety trial-- found
that high-dose 150mg clopidogrel did not reduce the
rate of the primary endpoint compared to standard-dose
75mg clopidogrel in patients with HPR.
In the CLEAR PLATELETS (Clopidogrel Loading with
Eptifibatide to Arrest the Reactivity of Platelets) study;
600 mg loading dose was associated with a superior
pharmacodynamic antiplatelet profile compared to a
300 mg clopidogrel loading dose, in the absence of a
GPIIb/IIIa (Glycoprotein IIb/IIIa) inhibitor.

16. Trials on Clopidogrel resistance

17. Trials on Clopidogrel resistance
 ARCTIC trial: evaluated the clinical outcomes of patients with
high on-treatment platelet reactivity (HPR) who were treated
with either intensified antiplatelet therapy or standard
therapy. The trial found that intensified antiplatelet therapy
did not reduce the rate of the primary endpoint compared to
standard therapy in patients with HPR.
 POPular Genetics trial: evaluated the effectiveness of genetic
testing to guide antiplatelet therapy in patients undergoing
percutaneous coronary intervention. The genetic testing
assessed the presence of genetic polymorphisms associated
with clopidogrel resistance. The trial found that genetic
testing did not improve clinical outcomes compared to
standard therapy.

18. Newer P2Y12 receptor antagonists: Ticagrelor
& cangrelor
• Ticagrelor an oral, direct-acting, reversible, P2Y12 receptor antagonist, was
associated with less ischemic event occurrence than clopidogrel in patients with
acute coronary syndromes in the Platelet Inhibition and Patient Outcomes (PLATO)
trial.
• In RESPOND study the response to ticagrelor in clopidogrel non-responders in
stable CAD patients was studied in detail.In ticagrelor treated patients, platelet
reactivity was below the cut-off points previously associated with ischemic risk—
measured by LTA (Light Transmittance Aggregometry), Verify Now P2Y12 assay,
and VASP-P (Vasodilator Stimulated Phosphoprotein phosphorylation)—in 98%–
100% of patients versus 44%–76% of patients after clopidogrel Therapy
• Ticagrelor has a faster onset of action and a shorter half-life compared to
clopidogrel,
• However, ticagrelor is more expensive than clopidogrel and may cause more
dyspnea as a side effect.

19. New P2Y12 receptor antagonists:
Prasugrel
 Prasugrel is a novel thienopyridine introduced for the treatment of acute coronary
syndromes.
 Jernberg & Wallentine et al published that Prasugrel demonstrated higher and more rapid
inhibition of platelet aggregation and a greater reduction of pharmacodynamic non-
responders, compared with the standard clopidogrel dose of 75 mg.
 In another study Alexopoulos et al demonstrated in their trial that in ACS patients who are
on HTPR (high on treatment platelet reactivity) after PCI (Percutaneous Intervention)
Prasugrel is more effective compared to high dose clopidogrel in reducing platelet reactivity,
particularly in CYP2C19*2 carriers.
 In recent ACAPULCO (Prasugrel Compared with High Dose Clopidogrel in ACS) study by
Montalescot et al reinforced this observation by proving prasugrel's superiority in platelet
inhibition compared to high dose clopidogrel MD 150 mg or 900 mg LD.
 more expensive than clopidogrel and may increase the risk of bleeding as a side effect

20. Conclusion
 Clopidogrel was a gold standard drug and has been used in combination with
aspirin in patients with acute coronary syndrome.
 In recent studies it has been shown that high on platelet reactivity due to
clopidogrel resistance was associated with adverse thrombotic events
including stent thrombosis. The primary reason is suboptimal generation of
the active metabolite due to individual variability in intestinal absorption,
drug-drug interaction and polymorphism in the CYP isoenzymes.
 clopidogrel resistance is a complex issue that can be caused by genetic
polymorphisms, drug-drug interactions, and non-compliance.
 Clopidogrel resistance has been documented in the range of 5–44% across
the world.
 Methods to identify clopidogrel resistance are not standardized and not
freely available in Pakistan.
 One needs to confirm clopidogrel resistance especially in high risk ACS
patients (e.g. Diabetic patients, Renal Compromised patients, Patients with
prior h/o Stroke, TIA etc).
 Use of higher loading doses of clopidogrel (600 mg) or more potent P2Y12
receptor agents (e.g. prasugrel, ticagrelor, cangrelor) are the strategies to
overcome clopidogrel resistance.