Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Laboratory Measurements
2.2.1. Multiple Electrode Impedance Aggregometry by Multiplate
2.2.2. VerifyNow
2.2.3. Light Transmission Aggregometry (LTA)
2.2.4. CYP2C19 Analysis
2.3. Statistical Analysis
3. Results
3.1. Baseline Characteristics
3.2. Agreement between Platelet Function Tests
3.3. Residual Platelet Reactivity per Group of CYP2C19 Metabolism
3.4. Effect of Metabolizer Status on Platelet Reactivity
3.5. Relative Importance of Metabolizer Status on Platelet Reactivity
4. Discussion
5. Conclusions and Future Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Inclusion Criteria | Definition |
PCI 30–90 days before study inclusion | Elective or emergency procedure |
Dual/triple antithrombotic therapy | Including clopidogrel as P2Y12 inhibitor |
Classified as ‘vulnerable’ by ≥ 3 predefined risk factors: | Age ≥ 75 years Female gender Renal dysfunction (MDRD-eGFR ≤ 60 mL/min) Body weight ≤ 60 kg Hypertension (previously diagnosed, or on medication) Diabetes mellitus Anemia (Hb < 8.2 mmol/L for men, <7.3 mmol/L for women) Previous stroke Previous major bleeding Liver dysfunction (known hepatitis or transplant) History of gastric/duodenal ulcers Daily use of NSAIDs or SSRIs Triple antithrombotic therapy (DAPT + oral anticoagulants) Previous in-stent thrombosis or high-risk coronary stent (e.g., last remaining vessel or left main coronary artery) |
CYP2C19 polymorphism available | Analysis of CYP2C19 polymorphism performed by June 2018 |
Exclusion criteria | Definition |
Known platelet function disorders | Previously diagnosed platelet function disorders |
Recent coronary intervention | PCI or CABG ≤ 7 days |
Recent new ischemic event | ACS or stroke ≤ 7 days |
Signs of active infection | Fever, antibiotic treatment or hospital admission during laboratory assessment of platelet function |
Medication noncompliance | Confirmed noncompliance in antithrombotic medication by patient interview or pharmacy dispensing |
Variables | LTA ADP20 (n = 300) | VerifyNow P2Y12 (n = 304) | Multiplate (n = 305) | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Univariate | Multivariate * | Univariate | Multivariate * | Univariate | Multivariate * | |||||||||||||
B | 95% CI | p | B | 95% CI | p | B | p | B | 95% CI | p | B | 95% CI | p | B | 95% CI | p | ||
Age ≥ 75 years | 3.456 | −0.072–6.983 | 0.055 | 3.746 | 0.27–7.23 | 0.035 | 28.013 | 11.050–44.976 | 0.001 | 11.381 | −3.88–26.64 | 0.143 | 3.121 | −2.373–8.615 | 0.264 | 3.493 | −1.99–8.97 | 0.211 |
Gender, female | −1.292 | −4.793–2.209 | 0.468 | 3.973 | −12.950–20.986 | 0.644 | 2.306 | −3.097–7.709 | 0.402 | |||||||||
Weight < 60 kg | −10.356 | −16.454–−4.259 | 0.001 | −5.386 | −11.64–0.87 | 0.091 | −51.291 | −79.540–−23.042 | 0.000 | −30.905 | −56.79–−5.02 | 0.019 | −3.585 | −13.115–5.944 | 0.460 | −6.025 | −15.64–3.59 | 0.218 |
Diabetes Mellitus | 0.033 | −3.537–3.602 | 0.986 | −0.028 | −3.45–3.40 | 0.987 | 13.874 | −3.480–31.229 | 0.117 | 7.221 | −7.83–22.27 | 0.346 | 4.480 | −1.044–10.003 | 0.112 | 2.753 | −2.64–8.15 | 0.316 |
Hypertension | −1.171 | −5.851–3.510 | 0.623 | 4.893 | −17.597–27.383 | 0.669 | −1.923 | −9.114–5.268 | 0.599 | |||||||||
Renal dysfunction | −1.263 | −4.734–2.209 | 0.475 | −0.878 | −4.31–2.56 | 0.615 | 25.743 | 9.140–42.346 | 0.002 | 8.096 | −7.01–23.20 | 0.292 | 4.920 | −0.449–10.288 | 0.072 | 4.474 | −0.96–9.91 | 0.106 |
History of bleeding | −0.288 | −5.095–4.520 | 0.906 | 8.777 | −14.269–31.824 | 0.454 | 4.724 | −2.634–12.082 | 0.207 | |||||||||
Stroke in history # | 4.733 | 1.013–8.453 | 0.013 | 3.699 | 0.11– 7.29 | 0.043 | 17.203 | −0.919–35.325 | 0.063 | 17.793 | 2.02–33.57 | 0.027 | 8.439 | 2.641–14.236 | 0.004 | 8.390 | 2.70–14.08 | 0.004 |
Current smoking # | −3.147 | −8.176–1.883 | 0.219 | −2.370 | −7.23–2.49 | 0.338 | −33.738 | −58.169–−9.308 | 0.007 | −15.310 | −36.84–6.22 | 0.163 | −0.760 | −8.635–7.116 | 0.850 | −0.019 | −7.65–7.62 | 0.996 |
(Es-) omeprazole | 1.490 | −3.505–6.484 | 0.558 | 1.644 | −3.97 –7.26 | 0.565 | 24.248 | 0.236–48.259 | 0.048 | 39.726 | 14.96–64.49 | 0.002 | 8.702 | 1.036–16.369 | 0.026 | 13.40 | 4.49–22.32 | 0.003 |
Aspirin | −6.837 | −10.478–−3.197 | 0.000 | −4.471 | −11.64–2.70 | 0.220 | 6.074 | −12.011–24.160 | 0.509 | −0.286 | −31.20–30.63 | 0.986 | −2.491 | −8.305–3.324 | 0.400 | −0.979 | −12.12–10.17 | 0.863 |
Anticoagulant | 6.134 | 2.587–9.681 | 0.001 | 2.343 | −4.61–9.30 | 0.508 | −3.139 | −20.674–14.396 | 0.725 | −4.957 | −34.91–24.99 | 0.745 | 2.204 | −3.422–7.831 | 0.441 | 2.064 | −8.70–12.83 | 0.706 |
Hemoglobin (mmol/L) | 2.347 | 0.774–3.920 | 0.004 | 2.145 | 0.50–3.79 | 0.011 | −20.674 | −28.101–−13.248 | 0.000 | −22.703 | −30.01–−15.40 | 0.000 | −3.396 | −5.864–−0.928 | 0.007 | −1.021 | −3.64–1.60 | 0.444 |
Platelets (1×109/L) | −0.035 | −0.056–−0.014 | 0.001 | −0.013 | −0.04–0.01 | 0.246 | −0.223 | −0.324–−0.122 | 0.000 | −0.243 | −0.34–−0.15 | 0.000 | 0.070 | 0.038–0.103 | 0.000 | 0.076 | 0.04–0.11 | 0.000 |
Metabolizer status PM IM EM RM | 6.895 | −3.222–17.012 | 0.181 | 8.644 | −1.16–18.44 | 0.084 | 79.859 | 28.945–130.773 | 0.002 | 47.029 | 1.49–92.56 | 0.043 | 3.859 | −12.154–19.872 | 0.636 | 6.243 | −9.30–21.78 | 0.430 |
3.173 | −1.147–7.492 | 0.149 | 2.958 | −1.23–7.14 | 0.165 | 30.234 | 9.804–50.664 | 0.004 | 23.981 | 5.64–42.32 | 0.011 | 8.264 | 1.488–15.040 | 0.017 | 8.792 | 2.21–15.37 | 0.009 | |
ref | ref | - | ref | ref | - | ref | - | ref | ref | - | ref | - | ref | ref | - | |||
−4.153 | −8.154–−0.151 | 0.042 | −4.648 | −8.49–−0.81 | 0.018 | −17.381 | −36.306–1.543 | 0.072 | −12.047 | −28.87–4.77 | 0.160 | 1.757 | −4.533–8.047 | 0.583 | 1.516 | −4.55–7.58 | 0.623 |
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All Patients (n = 308) |
RM (n = 107) |
EM (n = 112) |
IM (n = 80) |
PM (n = 9) | p ^ | |
---|---|---|---|---|---|---|
Age, years | 75.2 (8.5) | 74.9 (9.6) | 74.7 (7.9) | 76.5 (7.4) | 74.3 (9.4) | 0.478 |
Female | 127 (41.2) | 47 (43.9) | 43 (38.4) | 34 (42.5) | 3 (33.3) | 0.807 |
BMI, kg/m2 | 27.4 (4.5) | 27.8 (4.5) | 27.2 (4.6) | 27.3 (4.6) | 25.6 (3.9) | 0.477 |
Current smoking | 41 (13.3) | 12 (11.2) | 18 (16.5) | 11 (14.5) | 0 (0.0) | 0.429 |
Index PCI–ACS | 172 (55.8) | 59 55.1 | 60 (53.6) | 47 (58.8) | 6 (66.7) | 0.809 |
Index PCI–Elective | 136 (44.2) | 48 (44.9) | 52 (46.4) | 33 (41.2) | 3 (33.3) | |
Medication | ||||||
Clopidogrel | 308 (100.0) | 107 (100.0) | 112(100.0) | 80(100.0) | 9 (100.0) | 1.000 |
Aspirin | 214 (69.5) | 71 (66.4) | 77 (68.8) | 57 (71.3) | 9 (100.0) | 0.204 |
VKA | 72 (23.4) | 28 (26.2) | 27 (24.1) | 17 (21.3) | 0 (0.0) | 0.328 |
DOAC | 32 (10.4) | 10 (9.3) | 12 (10.7) | 10 (12.5) | 0 (0.0) | 0.668 |
(es-)omeprazole use | 28 (9.1) | 9 (8.4) | 13 (11.6) | 5 (6.3%) | 1 (11.1) | 0.646 |
Risk factors | ||||||
Age ≥ 75 years | 193 (62.7) | 65 (60.7) | 67 (59.8) | 56 (70.0) | 5 (55.6) | 0.459 |
Women | 127 (41.2) | 47 (43.9) | 43 (38.3) | 34 (43.) | 3 (33.3) | 0.807 |
Weight < 60 kg | 28 (9.1) | 11 (10.3) | 10 (8.9) | 7 (8.8) | 0 (0.0) | 0.778 |
Diabetes mellitus | 110 (35.7) | 35 (32.7) | 39 (34.8) | 29 (36.3) | 7 (77.8) | 0.060 |
Hypertension | 258 (83.8) | 94 (87.9) | 92 (82.1) | 66 (82.5) | 6 (66.7) | 0.313 |
Anemia | 107 (34.7) | 37 (34.6) | 39 (34.8) | 27 (33.8) | 4 (44.4) | 0.938 |
Renal dysfunction | 178 (57.8) | 52 (48.6) | 67 (59.8) | 53 (66.3) | 6 (66.7) | 0.088 |
Liver failure | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | - |
Peptic ulcer disease | 42 (13.6) | 12 (11.2) | 15 (13.4) | 13 (16.3) | 2 (22.2) | 0.667 |
Prior major bleeding | 47 (15.3) | 21 (19.6) | 13 (11.6) | 11 (13.8) | 2 (22.2) | 0.360 |
Previous stroke | 89 (28.9) | 31 (29.0) | 32 (28.8) | 24 (30.0) | 2 (22.2) | 0.971 |
Use of NSAIDs | 14 (4.5) | 4 (3.7) | 6 (5.4) | 4 (5.0) | 0 (0.0) | 0.850 |
Use of SSRIs | 15 (4.9) | 4 (3.7) | 7 (6.3) | 4 (5.0) | 0 (0.0) | 0.748 |
Triple therapy | 34 (11.0) | 11 (10.3) | 15 (13.4) | 7 (8.8) | 1 (11.1) | 0.772 |
High-risk PCI | 17 (5.5) | 9 (8.4) | 5 (4.5) | 3 (3.8) | 0 (0.0) | 0.398 |
Previous history | ||||||
Prior PCI | 113 (36.7) | 31 (29.0) | 42 (37.5) | 35 (43.8) | 5 (55.6) | 0.118 |
Prior CABG | 69 (22.4) | 22 (20.6) | 30 (26.8) | 16 (20.0) | 1 (11.1) | 0.520 |
Atrial fibrillation | 90 (29.2) | 33 (30.8) | 30 (26.8) | 27 (33.8) | 0 (0.0) | 0.174 |
Active malignancy | 16 (5.2) | 4 (3.7) | 6 f(5.4) | 5 (6.3) | 1 (11.1) | 0.732 |
Laboratory test | ||||||
Hemoglobin, mmol/L | 8.2 (1.1) | 8.3 (1.1) | 8.2 (1.0) | 8.1 (1.1) | 7.9 (1.0) | 0.582 |
Platelet count, 1×109/L | 257 (76) | 269 (85) | 256 (73) | 246 (66) | 218 (45) | 0.080 |
Creatinine, µmol/L | 117 (67) | 104 (48) | 126 (85) | 120 (55) | 131 (85) | 0.102 |
MDRD-eGFR, mL/min/1.73 m2 | 56.1 (20.1) | 59.9 (18.6) | 54.9 (21.6) | 52 (19.1) | 55.4 (23.1) | 0.082 |
Metabolism | CYP2C19 Alleles | Frequency n (%), n = 308 | Group Total n (%) |
---|---|---|---|
Rapid metabolizer (RM) | *1/*17 | 91 (29.5) | 107 (34.7) |
*17/*17 | 16 (5.2) | ||
Extensive metabolizer (EM) | *1/*1 | 112 (36.4) | 112 (36.4) |
Intermediate metabolizer (IM) | *1/*2 | 67 (21.8) | 80 (26.0) |
*2/*17 | 12 (3.9) | ||
*1/*3 | 1 (0.3) | ||
Poor metabolizer (PM) | *2/*2 | 9 (2.9) | 9 (2.9) |
Platelet Function Test | CYP2C19 Metabolism * | Patients, n(%) Total n = 308 | Median [IQR] | Jonckheere -Terpstra Test ^ |
---|---|---|---|---|
LTA (n = 300), % max aggr | Metabolizer status | <0.0001 | ||
Rapid metabolizer | 103 (34.3%) | 41.0 (30.0–51.0) | 0.02 | |
Extensive metabolizer | 110 (36.7%) | 46.0 (36.0–54.0) | Ref. | |
Intermediate metabolizer | 78 (26.0%) | 49.0 (39.8–57.0) | 0.03 | |
Poor metabolizer | 9 (3.0%) | 48.0 (43.0–66.5) | 0.08 | |
VerifyNow (n = 304), PRU | Metabolizer status | <0.0001 | ||
Rapid metabolizer | 106 (34.9%) | 150.0 (89.3–195.0] | 0.06 | |
Extensive metabolizer | 110 (36.2%) | 152.0 (112.0–217.5] | Ref. | |
Intermediate metabolizer | 80 (26.3%) | 193.5 (144.0–236.5] | <0.01 | |
Poor metabolizer | 8 (2.6%) | 247.0 (144.0–236.5] | <0.01 | |
Multiplate (n = 305), AU | Metabolizer status | 0.10 | ||
Rapid metabolizer | 105 (34.4%) | 49.0 (37.5–64.0) | n/a | |
Extensive metabolizer | 111 (36.3%) | 47.0 (33.0–64.0) | ||
Intermediate metabolizer | 80 (26.3%) | 55.5 (41.0–72.8) | ||
Poor metabolizer | 9 (3.0%) | 54.0 (38.5–68.5) |
Variables | LTA | VerifyNow | Multiplate |
---|---|---|---|
Beta Weight | Beta Weight | Beta Weight | |
Age > 75 years | 0.119 | 0.077 | 0.079 |
Body weight < 60 kg | −0.099 | −0.119 | −0.068 |
Diabetes | 0.003 | 0.049 | 0.054 |
Renal dysfunction | −0.029 | 0.053 | 0.090 |
Previous stroke | 0.112 | 0.111 | 0.163 * |
Current smoking | −0.054 | −0.073 | −0.002 |
(es-) omeprazole use | 0.035 | 0.156 | 0.156 * |
Aspirin use | −0.139 * | 0.005 | −0.013 |
Anticoagulant use | 0.073 | −0.033 | 0.049 |
Hemoglobin | 0.155 * | −0.337 * | −0.046 |
Platelet count | −0.072 | −0.268 * | 0.265 * |
Metabolizer group | 0.227 * | 0.212 * | 0.110 |
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Olie, R.H.; Hensgens, R.R.K.; Wijnen, P.A.H.M.; Veenstra, L.F.; de Greef, B.T.A.; Vries, M.J.A.; van der Meijden, P.E.J.; ten Berg, J.M.; ten Cate, H.; Bekers, O.; et al. Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients. J. Clin. Med. 2021, 10, 3992. https://doi.org/10.3390/jcm10173992
Olie RH, Hensgens RRK, Wijnen PAHM, Veenstra LF, de Greef BTA, Vries MJA, van der Meijden PEJ, ten Berg JM, ten Cate H, Bekers O, et al. Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients. Journal of Clinical Medicine. 2021; 10(17):3992. https://doi.org/10.3390/jcm10173992
Chicago/Turabian StyleOlie, Renske H., Rachelle R. K. Hensgens, Petal A. H. M. Wijnen, Leo F. Veenstra, Bianca T. A. de Greef, Minka J. A. Vries, Paola E. J. van der Meijden, Jurriën M. ten Berg, Hugo ten Cate, Otto Bekers, and et al. 2021. "Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients" Journal of Clinical Medicine 10, no. 17: 3992. https://doi.org/10.3390/jcm10173992