Highlights
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Despite the large body of evidence confirming the role of residual platelet reactivity after PCI, less is known in the setting con combined antiplatelet and anticoagulant therapy.
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In a real-world unselected population of patients with AF undergoing PCI mainly after acute coronary syndrome (ACS), discharged in dual or triple antithrombotic therapy, P2Y12 dependent HPR assessed by VerifyNow and the carriage of CYP2C19*2 loss-of-function polymorphism independently predict the incidence of MACCE at 1-year follow-up.
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In the setting of combined antithrombotic therapy, both functional and genetic platelet function test have a pivotal role in guiding antithrombotic strategy, since we are often dealing with ACS patients receiving mostly clopidogrel alone or double antiplatelet therapy for a brief amount of time.
Introduction
Methods
Study population
Laboratory analyses
Follow-up and endpoints
Statistical analysis
Results
Total (n = 147) | TAT (n = 91) | DAT (n = 56) | P value | |
---|---|---|---|---|
Age [yrs], (mean ± SD) | 78 ± 8 | 77 ± 8 | 79 ± 8 | 0.093 |
Male sex, n (%) | 99 (67.3) | 62 (68.1) | 37 (66.1) | 0.796 |
Hypertension, n (%) | 122 (83.0) | 74 (81.3) | 48 (85.7) | 0.491 |
Dyslipidemia, n (%) | 86 (58.5) | 58 (63.7) | 28 (50.0) | 0.101 |
Smokers, n (%) | 16 (10.9) | 11 (12.1) | 5 (8.9) | 0.361 |
Former Smokers, n (%) | 58 (39.4) | 39 (42.9) | 19 (33.9) | |
Diabetes mellitus, n (%) | 50 (34.0) | 34 (37.4) | 16 (28.6) | 0.275 |
Family history of CVD, n (%) | 22 (15.0) | 15 (16.5) | 7 (12.5) | 0.511 |
BMI [kg/m2] (mean ± SD) | 27.0 ± 4.0 | 26.3 ± 3.5 | 28.0 ± 4.5 | 0.014 |
Prior MI, n (%) | 53 (36.0) | 33 (36.3) | 20 (35.7) | 0.946 |
Prior PCI, n (%) | 64 (43.5) | 41 (45.1) | 23 (41.1) | 0.636 |
Prior CABG, n (%) | 12 (8.2) | 8 (8.8) | 4 (7.1) | 0.723 |
Prior TIA/stroke, n (%) | 18 (12.2) | 11 (12.1) | 7 (12.5) | 0.941 |
PAD, n (%) | 48 (32.7) | 28 (30.8) | 20 (35.7) | 0.589 |
Prior bleeding, n (%) | 12 (8.2) | 5 (5.5) | 7 (12.5) | 0.212 |
ACS, n (%) | 103 (70.1) | 68 (74.7) | 35 (62.5) | 0.116 |
UA, n (%) | 27 (18.4) | 22 (24.2) | 5 (8.9) | 0.141 |
NSTEMI, n (%) | 55 (37.4) | 33 (36.3) | 22 (39.3) | |
STEMI, n (%) | 21 (14.3) | 13 (14.3) | 8 (14.3) | |
MI, n (%) | 66 (44.9) | 46 (50.1) | 20 (53.5) | 0.048 (vs UA) |
LVEF [%], (mean ± SD) | 46 ± 11 | 45 ± 11 | 48 ± 11 | 0.087 |
Number of diseased vessels | 2 (1–3) | 2 (1–3) | 1.5 (1–2) | < 0.001 |
1 n (%) | 45 (30.6) | 17 (18.9) | 28 (50.0) | |
2 n (%) | 55 (37.4) | 38 (42.2) | 17 (30.4) | |
3 n (%) | 46 (31.3) | 35 (38.9) | 11 (19.6) | |
LM disease, n (%) | 41 (27.9) | 32 (35.6) | 9 (16.1) | 0.011 |
Number of treated vessels, median (IQR) | 1 (1–2) | 1 (1–2) | 1 (1–2) | 0.020 |
Number of stent, median (IQR) | 2 (1–3) | 2 (1–3) | 1 (1–2) | 0.016 |
Total stent length, mm (mean ± SD) | 49.2 ± 34.1 | 53.4 ± 3.7 | 41.4 ± 32.1 | 0.054 |
CHA2DS2-VASc score (mean ± SD) | 4.7 ± 1.2 | 4.8 ± 1.4 | 4.7 ± 11.2 | 0.924 |
HAS-BLED score (mean ± SD) | 2.4 ± 0.7 | 2.5 ± 0.7 | 2.3 ± 0.6 | 0.695 |
Statin, n (%) | 128 (87.0) | 82 (90.1) | 46 (82.1) | 0.207 |
Atorvastatin, n (%) | 54 (69.4) | 70 (76.9) | 32 (57.1) | |
Rosuvastatin, n (%) | 16 (10.9) | 9 (9.9) | 7 (12.5) | |
Pravastatin, n (%) | 1 (0.7) | 0 (0) | 1 (1.8) | |
Simvastatin, n (%) | 9 (6.1) | 3 (3.3) | 6 (10.7) | |
PPI, n (%) | 136 (92.5) | 85 (93.4) | 51 (91.1) | 0.749 |
Lansoprazol, n (%) | 25 (17.0) | 14 (15.4) | 11 (19.6) | |
Omeprazol, n (%) | 3 (2.0) | 2 (2.2) | 1 (1.8) | |
Pantoprazol, n (%) | 108 (73.5) | 69 (75.8) | 39 (69.6) | |
WBC [× 103/uL] (mean ± SD) | 7.91 ± 2.99 | 7.99 ± 3.30 | 7.80 ± 2.43 | 0.712 |
Hb [g/dL], (mean ± SD) | 12.0 ± 2.5 | 11.8 ± 1.9 | 12.3 ± 3.3 | 0.224 |
Platelets [103/uL], (mean ± SD) | 221 ± 85 | 221 ± 87 | 222 ± 82 | 0.921 |
MCV [fL] (mean ± SD) | 89.3 ± 8.1 | 89.1 ± 9.0 | 89.8 ± 6.3 | 0.597 |
Creatinin [mg/dL], (mean ± SD) | 1.4 ± 0.9 | 1.6 ± 1.2 | 1.1 ± 0.3 | 0.001 |
eGFR [mL/min/1.73m2], (mean ± SD) | 52 ± 23 | 48 ± 24 | 57 ± 22 | 0.023 |
Dialysis, n (%) | 7 (4.7) | 7 (10.6) | 0 | 0.035 |
Follow-up
MACCE
MACCE | Major and non-major clinically relevant hemorrhagic events | All-cause mortality | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Univariate | Multivariable | Univariate | Multivariable | Univariate | Multivariable | |||||||
Variable | HR (95% C.I.) | P value | HR (95% C.I.) | P value | HR (95% C.I.) | P value | HR (95% C.I.) | P value | HR (95% C.I.) | P value | HR (95% C.I.) | P value |
Age* | 1.29 (0.73–2.30) | 0.373 | 1.27 (0.68–2.36) | 0.452 | 1.93 (0.98–3.82) | 0.058 | ||||||
Male gender | 0.34 (0.12–0.97) | 0.043 | 0.09 (0.15–0.53)a 0.07 (0.01–0.53)b | 0.008 0.010 | 0.41 (0.13–1.28) | 0.127 | 0.20 (0.06–0.63) | 0.007 | 0.15 (0.04–0.53) | 0.003 | ||
Diabetes | 1.15 (0.38–3.42) | 0.807 | 2.17 (0.70–6.73) | 0.181 | 2.48 (0.83–7.38) | 0.103 | ||||||
Hypertension | 0.74 (0.21–2.67) | 0.654 | 0.60 (0.16–2.21) | 0.442 | 2.37 (0.31–18.30) | 0.405 | ||||||
Dyslipidemia | 0.94 (0.33–2.70) | 0.907 | 0.72 (2.31–2.22) | 0.563 | 2.42 (0.67–8.80) | 0.179 | ||||||
Active smoke | 1.40 (0.31–6.26) | 0.658 | 3.10 (0.84–11.47) | 0.089 | 1.50 (0.33–6.77) | 0.598 | ||||||
Previous PCI | 0.68 (0.23–2.02) | 0.485 | 0.61 (0.18–2.03) | 0.442 | 0.56 (0.17–1.82) | 0.336 | ||||||
Previous CABG | 0.04 (0.00–171.60) | 0.458 | 0.04 (0.01–334.25) | 0.492 | 0.93 (0.12–7.13) | 0.942 | ||||||
Previous MI | 0.93 (0.31–2.78) | 0.898 | 0.33 (0.07–1.49) | 0.149 | 0.51 (0.14–1.87) | 0.313 | ||||||
PAD | 1.67 (0.51–5.48) | 0.396 | 0.44 (0.10–2.03) | 0.291 | 11. 28 (2.50–50.92) | 0.002 | 19.23 (3.85–96.02) | < 0.001 | ||||
Previous stroke/TIA | 2.27 (0.83–6.16) | 0.107 | 0.67 (0.86–5.17) | 0.697 | 1.43 (0.32–6.43) | 0.645 | ||||||
Previous bleeding | 0.43 (0.00–151.80) | 0.451 | 0.04 (0.01–284.75) | 0.484 | 0.90 (0.12–6.92) | 0.920 | ||||||
ACS | 5.95 (0.78–45.46) | 0.086 | 36.39 (0.21–6186.33) | 0.170 | 0.53 (0.69–40.69) | 0.109 | ||||||
Multivessel disease | 1.17 (0.37–3.72) | 0.795 | 5.38 (0.69–41.70) | 0.107 | 0.54 (0.18–1.61) | 0.269 | ||||||
LM disease | 1.03 (0.32–3.28) | 0.960 | 3.16 0.96–10.34) | 0.058 | 3.90 (1.14–13.34) | 0.030 | 1.60 (0.52–4.90) | 0.408 | ||||
N° of stents | 0.66 (0.39–1.13) | 0.130 | 1.05 (0.67–1.65) | 0.832 | 1.04 (0.69–1.57) | 0.870 | ||||||
Total stent length | 0.99 (0.97–1.01) | 0.173 | 0.99 (0.98–1.02) | 0.940 | 1.01 (0.98–1.2) | 0.901 | ||||||
CHA2DS2VASc score | 1.23 (0.87–1.95) | 0.206 | 0.97 (0.61–1.55) | 0.907 | 1.83 (1.05–3.19) | 0.034 | ||||||
HASBLED score | 0.74 (0.33–1.67) | 0.473 | 0.99 (0.42–2.32) | 0.976 | 1.42 (0.88–2.30) | 0.155 | ||||||
White blood cell count* | 1.66 (1.01–2.75) | 0.047 | 2.66 (1.07–6.63)b | 0.026 | 1.31 (0.70–2.46) | 0.392 | 2.12 (1.28–3.50) | 0.004 | 2.48 (1.37–4.48) | 0.003 | ||
Hb | 0.85 (0.64–1.46) | 0.290 | 1.11 (0.94–1.31) | 0.234 | 1.06 (0.86–1.32) | 0.591 | ||||||
Platelet* | 1.22 (0.78–1.87) | 0.361 | 1.52 (1.10–2.11) | 0.011 | 1.66 (1.16–2.37) | 0.005 | 1.11 (0.68–1.80) | 0.675 | ||||
eGFR* | 0.79 (0.45–1.36) | 0.392 | 0.92 (0.52–1.64) | 0.787 | 0.44 (0.23–0.82) | 0.011 | ||||||
INR | 0.25 (0.03–2.29) | 0.221 | 2.13 (1.08–4.20) | 0.030 | 1.13 (0.43–2.95) | 0.808 | ||||||
P2Y12 dependent platelet reactivity [PRU] * | 1.74 (1.19–2.55) | 0.004 | 2.93 (1.03–7.56)a | 0.027 | 1.18 (0.69–2.00) | 0.562 | 0.84 (0.46–1.53) | 0.574 | ||||
TXA2 dependent platelet reactivity [ARU]* | 0.70 (0.47–1.04) | 0.080 | 0.92 (0.54–1.56) | 0.756 | 1.36 (0.71–2.59) | 0.350 | ||||||
Combined TXA2 and P2Y12 dependent HPR | 3.99 (1.25–12.72) | 0.019 | 19.32 (2.83–131.95)b | 0.003 | ||||||||
CYP2C19 *2 genotype | 4.03 (0.90–18.00) | 0.068 | 5.21 (1.03–26.28)a 6.16 (1.09–34.78)b | 0.045 0.039 | 0.29 (0.04–2.27) | 0.238 | 0.77 (0.16–3.64) | 0.745 | ||||
DOAC vs. VKA | 2.60 (0.58–11.61) | 0.211 | 1.35 (0.37–4.99) | 0.652 | 0.36 (0.12–1.09) | 0.070 | 0.22 (0.07–0.74) | 0.014 | ||||
TAT vs. DAT | 1.14 (0.38–3.40) | 0.813 | 1.33 (0.40–4.42) | 0.640 | 1.02 (0.33–3.13) | 0.967 |
MACCE | Major and non-major clinically relevant hemorrhagic events | All-cause mortality | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Univariate | Multivariable | Univariate | Multivariable | Univariate | Multivariable | |||||||
Variable | HR (95% C.I.) | P value | HR (95% C.I.) | P value | HR (95% C.I.) | P value | HR (95% C.I.) | P value | HR (95% C.I.) | P value | HR (95% C.I.) | P value |
Age* | 0.95 (0.63–1.43) | 0.800 | 1.39 (0.83–2.31) | 0.208 | 2.31 (1.23–4.32) | 0.009 | 1.98 (1.10–3.55) | 0.022 | ||||
Male gender | 0.77 (0.32–1.83) | 0.768 | 0.47 (0.19–1.16) | 0.103 | 0.24 (0.09–0.66) | 0.005 | 0.27 (0.09–0.78) | 0.016 | ||||
Diabetes | 1.12 (0.50–2.82) | 0.704 | 1.57 (0.63–3.90) | 0.334 | 1.89 (0.73–4.90) | 0.191 | ||||||
Hypertension | 0.55 (0.22–1.42) | 0.221 | 0.57 (0.21–1.60) | 0.289 | 3.39 (0.45–25.58) | 0.236 | ||||||
Dyslipidemia | 1.00 (0.42–2.34) | 0.997 | 0.61 (0.25–1.50) | 0.280 | 2.27 (0.74–6.97) | 0.151 | ||||||
Active smoke | 0.83 (0.19–3.55) | 0.800 | 3.48 (1.25–9.67) | 0.017 | 1.10 (2.52.4.82) | 0.898 | ||||||
Previous PCI | 1.02 (0.44–2.36) | 0.967 | 0.54 (0.21–1.44) | 0.224 | 0.52 (0.18–1.48) | 0.221 | ||||||
Previous CABG | 1.07 (0.25–4.57) | 0.930 | 0.56 (0.76–4.24) | 0.580 | 0.67 (0.09–5.06) | 0.672 | ||||||
Previous MI | 0.96 (0.40–2.29) | 0.930 | 0.30 (0.09–1.03) | 0.057 | 0.27 (0.08–0.94) | 0.040 | 0.52 (0.17–1.60) | 0.254 | ||||
PAD | 1.53 (0.61–3.80) | 0.360 | 0.56 (0.18–1.69) | 0.302 | 3.87 (1.43–10.49) | 0.008 | 4.37 (1.55–12.34) | 0.005 | ||||
Previous stroke/TIA | 2.27 (0.83–6.16) | 0.107 | 0.84 (0.19–3.64) | 0.816 | 1.66 (0.455.78) | 0.425 | ||||||
Previous bleeding | 0.04 (0.01–29.40) | 0.345 | 0.58 (0.08–4.20) | 0.570 | 1.41 (0.32–6.19) | 0.644 | ||||||
ACS | 10.0 (1.35–74.24) | 0.024 | 9.91 (1.33–73.80) | 0.025 | 1.84 (0.61–5.57) | 0.276 | 2.11 (0.60–7.35) | 0.240 | ||||
Multivessel disease | 2.16 (0.73–6.38) | 0.164 | 4.16 (0.96–18.01) | 0.057 | 0.66 (0.25–1.74) | 0.402 | ||||||
LM disease | 0.98 (0.38–2.51) | 0.996 | 2.70 (1.07–6.80) | 0.035 | 2.92 (1.14–7.49) | 0.026 | 1.80 (0.69–4.75) | 0.231 | ||||
N° of stents | 0.82 (0.56–1.20) | 0.304 | 1.08 (0.75–1.53) | 0.681 | 0.88 (0.58–1.32) | 0.539 | ||||||
Total stent length | 0.99 (0.98–1.01) | 0.266 | 1.00 (0.99–1.02 | 0.728 | 0.99 (0.98–1.01) | 0.753 | ||||||
CHA2DS2VASc score | 1.24 (0.90–1.72) | 0.192 | 1.05 (0.73–1.05) | 0.786 | 1.67 (1.14–2.43) | 0.008 | ||||||
HASBLED score | 1.20 (0.68–2.15) | 0.530 | 1.18 (0.60–2.31) | 0.635 | 1.71 (0.94–3.10) | 0.078 | ||||||
White blood cell count* | 1.36 (0.89–2.09) | 0.154 | 1.22 (0.74–2.02) | 0.442 | 1.67 (1.05–2.67) | 0.031 | 1.84 (1.10–3.08) | 0.020 | ||||
Hb | 0.67 (0.37–1.22) | 0.193 | 1.08 (0.91–1.28) | 0.401 | 0.99 (0.79–1.25) | 0.984 | ||||||
PLT* | 1.07 (0.71–1.60) | 0.760 | 1.40 (1.04–1.87) | 0.027 | 1.06 (0.68–1.67) | 0.792 | ||||||
eGFR* | 0.71 (0.45–1.11) | 0.131 | 0.99 (0.63–1.55) | 0.953 | 0.45 (0.26–0.78) | 0.005 | ||||||
INR | 0.41 (0.10–1.79) | 0.238 | 2.26 (1.29–3.97) | 0.005 | 1.38 (0.70–2.75) | 0.347 | ||||||
P2Y12 dependent platelet reactivity [PRU] * | 1.73 (1.26–2.46) | 0.002 | 1.67 (1.20–2.34) | 0.003 | 0.87 (0.54–1.39) | 0.558 | 0.75 (0.44–1.28) | 0.300 | ||||
TXA2 dependent platelet reactivity [ARU]* | 0.91 (0.60–1.37) | 0.649 | 0.82 (5.57–1.20) | 0.309 | 1.23 (0.72–2.11) | 0.448 | ||||||
CYP2C19 *2 genotype | 1.67 (0.56–4.98) | 0.359 | 0.98 (0.32–3.03) | 0.968 | 0.94 (0.26–3.41) | 0.923 | ||||||
DOAC vs VKA | 0.91 (0.37–2.23) | 0.840 | 1.68 (0.55–5.07) | 0.355 | 0.38 (0.15–0.98) | 0.046 | 0.27 (0.10–0.72) | 0.009 |