Patient Characteristics
Between October 2015 and January 2017, a total of 1502 genotyped patients were recruited after successful deployment of at least one drug-eluting stent (Fig. 1). Of these, four patients experienced outcome events during the first 24 hours after the index PCI, 11 participants switched to ticagrelor from clopidogrel under the guidance of physicians during the first year after PCI, and 146 subjects were lost to follow-up, resulting in 1341 patients being included in the primary analysis. Among 1341 patients in the final study cohort, the mean age was 58.69 ± 9.786 years and 75.2% were male. A total of 1256 patients (93.7%) presented with ACS (including 128 [9.5%] with STEMI, 138 [10.3%] with NSTEMI and 990 [73.8%] with unstable angina).
The overall baseline characteristics of the patients are listed in Table 1 according to CYP2C19 metabolic phenotypes. Based on the platelet function test results, the mean maximum amplitude of ADP-induced platelet-fibrin clot strength (MA-ADP) was highest in the PM group (36.25 [25.4–47.3] mm), intermediate (38.05 [25.8–49.7] mm) in the IM group and lowest (43.0 [28.5–54.4] mm) in the NLOFMs (p = 0.004). Patients in the NLOFM group had the highest rates of low responsiveness to clopidogrel (LRC) (n = 135, 24.2%); LRC rates were intermediate (n = 199, 32.0%) in the IM group and lowest (n = 62, 38.5%) in PMs (p < 0.001). Compared with the other two groups, the PM group had the highest proportion of LAD lesions and the lowest proportion of LCX lesions.
Table 1
Baseline Characteristics Among Patients According to CYP2C19 Phenotype
Covariates
|
Non-LOF Metabolizer
(n = 559)
|
Intermediate Metabolizer
(n = 621)
|
Poor Metabolizer
(n = 161)
|
p Value
|
Demographics
|
Age, yrs
|
58.8 ± 10.0
|
58.5 ± 9.9
|
58.9 ± 8.6
|
0.866
|
Female
|
139 (24.9)
|
151 (24.3)
|
43 (26.7)
|
0.822
|
Body mass index, kg/m2
|
26.0 ± 3.10
|
26.0 ± 3.4
|
25.8 ± 3.2
|
0.842
|
Cardiovascular risk factors
|
Current or previous smoker
|
193 (34.5)
|
214 (34.5)
|
58 (36.0)
|
0.929
|
Family history of CAD
|
70 (12.5)
|
88 (14.2)
|
23 (14.3)
|
0.679
|
Previous PCI
|
127 (22.7)
|
124 (20.0)
|
36 (22.4)
|
0.491
|
Previous CABG
|
15 (2.7)
|
21 (3.4)
|
2 (1.2)
|
0.332
|
Previous myocardial infarction
|
68 (12.2)
|
66 (10.6)
|
26 (16.1)
|
0.153
|
Comorbidities
|
Diabetes mellitus
|
187 (33.5)
|
210 (33.8)
|
60 (37.3)
|
0.655
|
Hypertension
|
357 (63.9)
|
395 (63.6)
|
104 (64.6)
|
0.973
|
Hyperlipidemia
|
255 (45.6)
|
285 (45.9)
|
66 (41.0)
|
0.519
|
Cerebrovascular disease
|
44 (7.9)
|
43 (6.9)
|
18 (11.2)
|
0.201
|
Peripheral arterial disease
|
13 (2.3)
|
17 (2.7)
|
5 (3.1)
|
0.830
|
Chronic kidney disease
|
73 (13.1)
|
73 (11.8)
|
16 (9.9)
|
0.532
|
Coronary artery disease presentation
|
0.006
|
Stable coronary disease
|
40 (7.2)
|
36 (5.8)
|
9 (5.6)
|
|
Acute coronary syndrome
|
519 (92.8)
|
585 (94.2)
|
152 (94.4)
|
|
Unstable angina
|
435 (77.8)
|
445 (71.7)
|
110 (68.3)
|
|
Non-STEMI
|
40 (7.2)
|
72 (11.6)
|
26 (16.1)
|
|
STEMI
|
44 (7.9)
|
68 (11.0)
|
16 (9.9)
|
|
Coronary angiography
|
Left main artery
|
19 (3.4)
|
27 (4.3)
|
6 (3.7)
|
0.697
|
Left anterior descending artery
|
410 (73.3)
|
421 (67.8)
|
129 (80.1)
|
0.004
|
Circumflex artery
|
197 (34.9)
|
255 (41.1)
|
50 (31.1)
|
0.020
|
Right coronary artery
|
215 (38.5)
|
244 (39.3)
|
52 (32.3)
|
0.259
|
Multiple-vessel disease
|
199 (35.6)
|
220 (35.4)
|
55 (34.2)
|
0.944
|
Number of stents implanted per patient
|
2.0 (1.0–2.0)
|
2.0 (1.0–2.0)
|
2.0 (1.0–2.0)
|
0.747
|
Baseline laboratory evaluation
|
PLT, × 109/L
|
213.4 ± 50.6
|
213.8 ± 47.6
|
216.6 ± 52.7
|
0.775
|
ADP-induced platelet inhibition rate
|
51.3 (32.7–72.8)
|
49.7 (27.0-72.6)
|
37.5 (17.7–61.7)
|
< 0.001
|
MAADP, mm
|
36.3 (25.4–47.3)
|
38.05 (25.8–49.7)
|
43.0 (28.5–54.4)
|
0.004
|
Number of low responsiveness to clopidogrel a
|
135 (24.2)
|
199 (32.0)
|
62 (38.5)
|
< 0.001
|
Concomitant medication
|
Statin
|
497 (88.9)
|
560 (90.2)
|
142 (88.2)
|
0.676
|
Beta-blocker
|
400 (71.6)
|
456 (73.4)
|
124 (77.0)
|
0.374
|
ACE inhibitor or ARB
|
339 (60.6)
|
384 (61.8)
|
82(50.9)
|
0.039
|
Proton pump inhibitor
|
141 (25.2)
|
150 (24.2)
|
41 (25.5)
|
0.891
|
Values were mean ± SD, No. (%) or median (IQR). |
non-LOF metabolizer non-loss-of-function metabolizer, CAD coronary artery disease, PCI percutaneous coronary intervention, CABG coronaryartery bypass grafting, non-STEMI non-ST-segment elevation myocardial infarction, STEMI ST-elevation myocardial infarction, PLT platelet count, IQR interquartile range, ADP adenosine diphosphate, MAADP the maximum amplitude of ADP-induced platelet-fibrin clot strength, ACE angiotensin-converting enzyme, ARB angiotensin receptor blocker. |
a Low responsiveness to clopidogrel was defined as the ADP-induced platelet-fibrin clot strength (MAADP) > 47 mm plus an ADP-induced platelet inhibition rate < 50%. |
Genotypes And Phenotypes
The distribution of genotypes and associated phenotypes is shown in Table 2. The frequencies of the CYP2C19*1, *2, *3, and *17 alleles were 63.4%, 29.8%, 5.4% and 1.4%, respectively. Among all recruited patients, 621 subjects (46.3%) who carried 1 copy of the LOF CYP2C19 allele were defined as IMs, 161 participants (12.0%) who had 2 copies of the LOF CYP2C19 alleles were regarded as PMs, and 559 patients (41.7%) without any LOF CYP2C19 allele were considered NLOFMs.
Table 2
Distribution of CYP2C19 Alleles and Genotypes Among Patients
Allele
|
Frequency No. (%)
|
Genotype
|
Frequency No. (%)
|
Phenotype
|
Frequency No. (%)
|
*1
|
1701 (63.4)
|
*1/*1
|
535 (39.9)
|
NLOFM
|
559 (41.7)
|
*2
|
799 (29.8)
|
*1/*2
|
510 (38.0)
|
IM
|
621 (46.3)
|
*3
|
144 (5.4)
|
*1/*3
|
98 (7.3)
|
PM
|
161 (12.0)
|
*17
|
38 (1.4)
|
*1/*17
|
23 (1.7)
|
|
|
|
|
*2/*2
|
121 (9.0)
|
|
|
|
|
*2/*3
|
36 (2.7)
|
|
|
|
|
*2/*17
|
11 (0.8)
|
|
|
|
|
*3/*3
|
4 (0.3)
|
|
|
|
|
*3/*17
|
2 (0.2)
|
|
|
|
|
*17/*17
|
1 (0.1)
|
|
|
NLOFM non-loss-of-function metabolizer, was the composite of ultrarapid metabolizer (*17/*17), rapid metabolizer (*1/*17) and normal metabolizer (*1/*1); IM intermediate metabolizer (*1/*2, *1/*3, *2/*17, or *3/*17); PM poor metabolizer (*2/*2, *2/*3, or *3/*3). |
Clinical Outcomes
The median time from indexed procedure to clinical outcome events or censoring was 392 days (interquartile range: 379 to 405 days). Over the follow-up period, death from any cause, the first occurrence of nonfatal myocardial infarction, nonfatal ischemic stroke or stent thrombosis (the primary outcome) occurred in 76 cases (5.67%), the secondary outcome consisting of death from any cause, the first occurrence of nonfatal myocardial infarction, nonfatal ischemic stroke, stent thrombosis or urgent TVR occurred in 90 cases (6.71%), and the occurrence of clinically significant bleeding events was documented in 41 cases (3.06%).
The 12-month composite clinical outcomes and the landmark analysis of time-to-first event within and after 90 days are shown in Table 3. In the 1-year analysis, the rates of the primary outcome were not significantly different between groups (NLOFM 4.7%; IM 6.0%; PM 8.1%; log-rank p = 0.213). Similarly, the secondary outcome rates were not significantly different among groups (NLOFM 5.5%; IM 7.1%; PM 9.3%; log-rank p = 0.193) in the 365-day analysis. From the 12-month landmark analysis, there were significant differences in the primary outcome and secondary outcome between different metabolizer groups at the initially reported 90-day follow-up period (primary outcomes: NLOFM 1.8%, IM 2.3%, PM 5.6%, log-rank p = 0.019; secondary outcomes: NLOFM 6.2%, IM 2.3%, PM 1.8%, log-rank p = 0.005) (Fig. 2, Online Figure S1). However, those differences did not persist at 91–365 days of follow-up (primary outcomes: NLOFM 2.9%, IM 3.8%, PM 2.6%, log-rank p = 0.631; secondary outcomes: NLOFM 3.8%, IM 4.9%, PM 3.3%, log-rank p = 0.529). Furthermore, there was no in-group difference in bleeding outcome between the three groups in any time period (Table 3).
Table 3
Clinical Outcomes and Individual Components According to CYP2C19 Phenotype
Outcomes
|
0-365 Days
|
0–90 Days
|
91–365 Days
|
NLOFM
|
IM
|
PM
|
p Value a
|
NLOFM
|
IM
|
PM
|
p Value
|
NLOFM
|
IM
|
PM
|
p Value
|
Primary Outcome b
|
26 (4.7)
|
37 (6.0)
|
13 (8.1)
|
0.213
|
10 (1.8)
|
14 (2.3)
|
9 (5.6)
|
0.019
|
16 (2.9)
|
23 (3.8)
|
4 (2.6)
|
0.631
|
Death from Any Cause
|
7 (1.3)
|
11 (1.8)
|
8 (5.0)
|
0.009
|
3 (0.5)
|
7 (1.1)
|
6 (3.7)
|
0.004
|
4 (0.7)
|
4 (0.7)
|
2 (1.3)
|
0.708
|
Myocardial Infarction
|
13 (2.3)
|
15 (2.4)
|
4 (2.5)
|
0.990
|
5 (0.9)
|
6 (1.0)
|
2 (1.2)
|
0.922
|
8 (1.5)
|
9 (1.5)
|
2 (1.3)
|
0.99
|
Stent Thrombosis
|
5 (0.9)
|
8 (1.3)
|
1 (0.6)
|
0.688
|
2 (0.4)
|
1 (0.2)
|
1 (0.6)
|
0.599
|
3 (0.5)
|
7 (1.2)
|
0 (0.0)
|
0.254
|
Ischemic Stroke
|
1 (0.2)
|
3 (0.5)
|
0 (0.0)
|
0.482
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
—
|
1 (0.2)
|
3 (0.5)
|
0 (0.0)
|
0.482
|
Secondary Outcome c
|
31 (5.5)
|
44 (7.1)
|
15 (9.3)
|
0.193
|
10 (1.8)
|
14 (2.3)
|
10 (6.2)
|
0.005
|
21 (3.8)
|
30 (4.9)
|
5 (3.3)
|
0.529
|
Urgent TVR
|
5 (0.9)
|
7 (1.1)
|
2 (1.2)
|
0.893
|
0 (0.0)
|
0 (0.0)
|
1 (0.6)
|
0.026
|
5 (0.9)
|
7 (1.1)
|
1 (1.7)
|
0.821
|
Bleeding Outcome d, e
|
18 (3.2)
|
17 (2.7)
|
6 (3.7)
|
0.772
|
5 (0.9)
|
2 (0.3)
|
2 (1.2)
|
0.311
|
13 (2.3)
|
15 (2.4)
|
4 (2.5)
|
0.991
|
Values were No. (%). |
NLOFM non-loss-of-function metabolizer, IM intermediate metabolizer, PM poor metabolizer, TVR target‑vessel revascularization. |
a The p values were evaluated with log-rank test in Kaplan–Meier analysis. |
b Primary outcome was the composite of death from any cause, myocardial infarction, definite or probable stent thrombosis and ischemic stroke. |
c Secondary outcome was the composite of death from any cause, myocardial infarction, ischemic stroke, definite or probable stent thrombosis and urgent target‑vessel revascularization. |
d Bleeding outcome was clinically significant bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria (including BARC 2, BARC 3, BARC 4) |
e BARC was the criteria for grading and categorizing bleeding events, BARC 2 was defined as any overt, actionable sign of bleeding that requires medical intervention or evaluation, but not meet criteria for type 3 or higher BARC bleeding; BARC 3 indicated overt bleeding plus a decrease in hemoglobin of more than 3 g/dL, intracranial hemorrhage or intraocular hemorrhage compromising vision; BARC 4 was bleeding related to coronary‑artery bypass grafting. |
As presented in Table 4, a higher risk of primary outcomes was observed among PMs than among NLOFMs (adjusted HR 2.944, 95% CI 1.184–7.321, p = 0.020) during the first 90 days following the index PCI. Likewise, PMs had significantly higher rates of secondary outcomes than NLOFMs (adjusted HR 3.309, 95% CI 1.363–8.033, p = 0.008). According to the individual components of the clinical outcomes listed in Online Table S1, the between-group differences in clinical outcomes were driven by a higher incidence of all-cause mortality (adjusted HR 7.600, 95% CI 1.826–31.627 p = 0.005). In the analysis of subsequent time periods, HRs of primary outcome for PMs compared with NLOFMs were 1.192 (95% CI 0.231–6.152, p = 0.834) at 3–6 months of follow-up, 1.206 (95% CI 0.123–11.833, p = 0.872) at 6–9 months of follow-up and 0.432 (95% CI 0.052–3.610, p = 0.439) at 9–12 months of follow-up. Additionally, the incidences of all clinical outcomes were similar between IMs and NLOFMs throughout the follow-up period (Table 4).
Table 4
Primary Outcome, Secondary Outcome and Bleeding Outcome with CYP2C19 Phenotype
Outcomes
|
0-365 Days
|
0–90 Days
|
91–365 Days
|
Hazard Ratio (95% CI) a
|
p Value a
|
Hazard Ratio (95% CI)
|
p Value
|
Hazard Ratio (95% CI)
|
p Value
|
Primary Outcome b
|
NLOFM
|
Reference
|
—
|
Reference
|
—
|
Reference
|
—
|
IM
|
1.308 (0.788–2.170)
|
0.299
|
1.232 (0.544–2.790)
|
0.616
|
1.641 (0.560–4.808)
|
0.366
|
PM
|
1.698 (0.865–3.3315)
|
0.124
|
2.944 (1.184–7.321)
|
0.020
|
1.194 (0.393–3.630)
|
0.754
|
Secondary Outcome c
|
NLOFM
|
Reference
|
—
|
Reference
|
—
|
Reference
|
—
|
IM
|
1.310 (0.824–2.083)
|
0.253
|
1.234 (0.546–2.794)
|
0.613
|
1.372 (0.785-2.400)
|
0.267
|
PM
|
1.677 (0.898–3.131)
|
0.105
|
3.309 (1.363–8.033)
|
0.008
|
0.884 (0.332–2.353)
|
0.805
|
Bleeding Outcome d, e
|
NLOFM
|
Reference
|
—
|
Reference
|
—
|
Reference
|
—
|
IM
|
0.885 (0.455–1.721)
|
0.718
|
0.366 (0.069–1.951)
|
0.239
|
1.075 (0.510–2.266)
|
0.849
|
PM
|
1.152 (0.455–2.918)
|
0.766
|
1.172 (0.208–6.610)
|
0.857
|
1.086 (0.352–3.346)
|
0.886
|
CI confidence interval, NLOFM non-loss-of-function metabolizer, IM intermediate metabolizer, PM poor metabolizer. |
a Hazard Ratios, confidence intervals and p values were calculated by means of Cox proportional hazard regression models adjusting for age, sex, coronary artery disease presentation, diabetes mellitus, hypertension, multiple-vessel disease, cerebrovascular disease, chronic kidney disease and previous myocardial infarction. |
b Primary outcome was the composite of death from any cause, myocardial infarction, definite or probable stent thrombosis and ischemic stroke. |
c Secondary outcome was the composite of death from any cause, myocardial infarction, definite or probable stent thrombosis, ischemic stroke and urgent target‑vessel revascularization. |
d Bleeding outcome was clinically significant bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria (including BARC 2, BARC 3, BARC 4) |
e The BARC criteria were used for grading and categorizing bleeding events, BARC 2 referred to any overt, actionable sign of bleeding that requires medical intervention or evaluation, but not meet criteria for type 3 or higher BARC bleeding; BARC 3 indicated overt bleeding plus a decrease in hemoglobin of more than 3 g/dL, intracranial hemorrhage or intraocular hemorrhage compromising vision; BARC 4 was bleeding related to coronary‑artery bypass grafting. |
Patients who underwent PCI with the ACS indication accounted for the majority of events in the analysis, including 73 of 86 events in the composite MACCE outcome (84.9%) and 40 of 41 clinical bleeding events (97.6%). In line with the analysis of the overall study population, among subjects with ACS, an early MACCE occurred more often in PMs than in NLOFMs (adjusted HR 3.046, 95% CI 1.237–7.501, p = 0.015) (Online Table S2). A higher early risk of a component of MACCE plus urgent TVR was also been found among PMs (adjusted HR 3.309, 95% CI 1.363–8.033, p = 0.008). Nevertheless, after the first 90 days, nevertheless, the differences in clinical outcome event risk among the groups were attenuated in the ACS subset (Online Table S2).