How Do Lipoprotein(a) Concentrations Affect Clinical Outcomes for Patients With Stable Coronary Artery Disease Who Underwent Different Dual Antiplatelet Therapy After Percutaneous Coronary Intervention?

Background Lp(a) (lipoprotein[a]) plays an important role in predicting cardiovascular events in patients with coronary artery disease through its proatherogenic and prothrombotic effects. We hypothesized that prolonged dual antiplatelet therapy (DAPT) might be beneficial for patients undergoing percutaneous coronary intervention who had elevated Lp(a) levels. This study aimed to evaluate the effect of Lp(a) on the efficacy and safety of prolonged DAPT versus shortened DAPT in stable patients with coronary artery disease who were treated with a drug-eluting stent. Methods and Results We selected 3201 stable patients with CAD from the prospective Fuwai Percutaneous Coronary Intervention Registry, of which 2124 patients had Lp(a) ≤30 mg/dL, and 1077 patients had Lp(a) >30 mg/dL. Patients were divided into 4 groups according to Lp(a) levels and the duration of DAPT therapy (≤1 year versus >1 year). The primary end point was major adverse cardiovascular and cerebrovascular event, defined as a composite of all-cause death, myocardial infarction, or stroke. The median follow-up time was 2.5 years. Among patients with elevated Lp(a) levels, DAPT >1 year presented lower risk of major adverse cardiovascular and cerebrovascular event and definite/probable stent thrombosis compared with DAPT ≤1 year. In contrast, in patients with normal Lp(a) levels, the risks of major adverse cardiovascular and cerebrovascular event and definite/probable stent thrombosis were not significantly different between the DAPT >1 year and DAPT ≤1 year groups. Prolonged DAPT had 2.4-times higher risk of clinically relevant bleeding than shortened DAPT in patients with normal Lp(a) levels, although without statistical difference. Conclusions In stable patients with coronary artery disease, who underwent percutaneous coronary intervention with a drug-eluting stent, prolonged DAPT was associated with reduced risk of cardiovascular events among those with elevated Lp(a) levels, whereas it did not show statistically significant evidence of benefit for reducing ischemic events and tended to increase clinically relevant bleeding among those with normal Lp(a) levels.

dual antiplatelet therapy

drug‐eluting stent

inverse probability of treatment weighting

lipoprotein(a)

major adverse cardiovascular and cerebrovascular event

stent thrombosis

Clinical Perspective

What Is New?

The effect of prolonged dual antiplatelet therapy in patients who underwent percutaneous coronary intervention with a drug‐eluting stent has never been evaluated.

This cohort study first suggested that prolonged dual antiplatelet therapy was associated with reduced ischemic events in patients with elevated Lp(a) (lipoprotein[a]) levels but not in those with normal Lp(a) levels.

What Are the Clinical Implications?

This study provides convincing evidence for the role of prolonged dual antiplatelet therapy for stable patients with coronary artery disease with elevated Lp(a) levels who underwent percutaneous coronary intervention with a drug‐eluting stent.

Lp(a) levels might be an important consideration when deciding upon the duration of dual antiplatelet therapy for stable patients with coronary artery disease undergoing percutaneous coronary intervention with a drug‐eluting stent.

Elevated Lp(a) (lipoprotein[a]) is one of the most common genetic lipid disorders, affecting 20% to 30% of the population worldwide. Over the past decade, Lp(a) has been shown to be an independent and causal risk factor for cardiovascular disease. , , , , , , Moreover, increasing evidence supports that Lp(a) levels play an important role in predicting subsequent ischemic events in patients with coronary artery disease (CAD). , , , , In a prospective, multicenter study with 4078 stable patients with CAD undergoing percutaneous coronary intervention (PCI), Liu et al reported that high Lp(a) levels were associated with a poor prognosis at a mean follow‐up of 4.9 years. Nevertheless, there are no approved pharmacologic therapies that are specifically aimed at lowering Lp(a) levels. Although a novel therapeutic agent, hepatocyte‐directed antisense oligonucleotide apoA‐LRx (apolipoprotein A‐LRx), has showed an average of 80% reduction in Lp(a) levels, the impact of this Lp(a)‐lowering drug on major cardiovascular events in patients with CAD remains unknown.

Dual antiplatelet therapy (DAPT) is the cornerstone of pharmacological treatment for preventing thrombotic complications after PCI. Given that Lp(a) has a prothrombotic effect through its inactive, plasminogen‐like protease domain on apoA (apolipoprotein A), , prolonged DAPT may have a beneficial effect on reducing ischemic events in patients with CAD undergoing PCI who have elevated Lp(a) levels. However, the relative benefit of prolonged DAPT in this population has never been evaluated. Therefore, we conducted this study to assess the effect of Lp(a) levels on the efficacy and safety of prolonged DAPT (>1 year) versus shortened DAPT (≤1 year) in stable patients with CAD who underwent PCI with a drug‐eluting stent (DES) in a large and contemporary PCI registry.

Methods

We will make the data, methods used in the analysis, and materials used to conduct the research available to any researcher for purposes of reproducing the results or replicating the procedure. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Design and Population

This was an analysis of a single center, prospective study, and the study design has been previously described. , Patients with stable CAD who underwent PCI with DES implantation at Fuwai Hospital, National Center for Cardiovascular Diseases, between January 2013 and December 2013 were selected. Stable CAD refers to patients with CAD who are clinically stable (ie, who are not in an unstable phase such as an acute coronary syndrome [ACS]). This study was performed according to the principles of the Declaration of Helsinki, and ethics approval was obtained from the ethical committee of Fuwai Hospital. All patients provided written informed consent before enrollment. For the present analysis, patients with missing Lp(a) data, ACS, or infectious inflammatory disease or malignant tumor were not included. We excluded patients who did not receive DAPT, did not use a DES, or experienced major adverse events (death, myocardial infarction [MI], stent thrombosis [ST], stroke, repeat revascularization, or Bleeding Academic Research Consortium type 2, 3, or 5 bleeding) within the 1‐year follow‐up. There were 3201 patients selected for the final analysis.

Study Procedures and Biochemical Analysis

All procedures and medical therapies were performed according to guidelines’ recommendation and operators’ discretion. Detailed information on procedures has been previously described. After fasting for ≥12 hours before PCI, blood samples for measurement of Lp(a) and other biomarkers were obtained, and the test was conducted through the clinical chemistry department in our hospital. Lp(a) was measured by immunoturbidimetry method (LASAY Lp[a] auto; SHIMA Laboratories, Tokyo, Japan) with a normal range of <30 mg/dL. An Lp(a) protein‐validated standard was used to calibrate the examination, and the coefficient of variation for repetitive measurements was <10%. Low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and total cholesterol were analyzed using an automated biochemical analyzer (Hitachi 7150; Hitachi, Tokyo, Japan), and glycosylated hemoglobin was tested with the Tosoh Automated Glycohemoglobin Analyzer (HLC‐723G8; Tosoh, Tokyo, Japan).

Previous meta‐analyses and the current guidelines for the management of dyslipidemia from China and Canada suggested that the relationship between Lp(a) and cardiovascular risk inflects at a concentration of 30 mg/dL. , , , Therefore, we used a cutoff of >30 mg/dL to assign abnormal Lp(a) levels. Patients were divided into 4 groups according to Lp(a) levels (≤30 mg/dL versus >30 mg/dL) and the duration of DAPT therapy of DAPT ≤1 year versus DAPT >1 year.

Follow‑Up and End Points

Demographics, cardiovascular risk factors, clinical parameters, laboratory data, and angiographic and procedural details were extracted from our dedicated PCI registry by independent research personnel. After the index PCI, patients were followed up at 1, 6, and 12 months and annually thereafter. Data for end points were collected from medical records, clinical visits, and telephone interviews by trained investigators who were blind to the clinical data. To record ≥2‐year follow‐up information for each patient, we extended the follow‐up period to January 31, 2016. Adherence to antiplatelet medication was routinely assessed at each time of follow‐up, and the status of antiplatelet therapy (ie, aspirin and clopidogrel) was collected by dedicated questionnaires and the electronic prescribing system.

The primary end point was major adverse cardiovascular and cerebrovascular event (MACCE), defined as a composite of death, nonfatal MI, or stroke. Secondary end points consisted of the individual components of the primary end point, cardiac death, definite or probable ST, and Bleeding Academic Research Consortium type 2, ,3 or 5 bleeding. All deaths were considered to be cardiac‐related unless a noncardiac origin was documented. MI was defined in compliance with the third universal definition of MI, with periprocedural MI not included. Stroke was defined as new focal neurological deficit lasting >24 hours based on imaging evidence. Definite or probable ST was adjudicated on the basis of the Academic Research Consortium criteria. Bleeding events were categorized on the basis of the Bleeding Academic Research Consortium classifications. All events were carefully verified and adjudicated by independent clinicians.

Statistical Analysis

Continuous variables were expressed as mean±standard deviation or median (interquartile range), and categorical variables were expressed as frequency (percentage). Differences in various characteristics were compared using the Student t test, Wilcoxon rank sum test, Pearson χ2 test, or Fisher exact test, as appropriate. Cumulative incidence of clinical events was estimated using Kaplan‐Meier curves, and differences were assessed with log‐rank tests. Single‐variable and multivariable Cox regression analyses, as well as inverse probability of treatment weighting (IPTW) analysis, were performed to calculate hazard ratios (HRs) and 95% CIs.

An IPTW analysis was also conducted to adjust for differences in baseline characteristics for drawing inferences about the relative efficacy and safety of DAPT >1 year versus DAPT ≤1 year in each subgroup of patients (ie, patients with elevated Lp[a] levels [>30 mg/dL] and those with normal Lp[a] levels [≤30 mg/dL]. A propensity score was developed using a nonparsimonious multivariable logistic regression model and considering DAPT time (DAPT >1 year versus DAPT ≤1 year) as the dependent variable. Covariates used for the propensity score model were age, sex, body mass index, current smoker, diabetes, hypertension, dyslipidemia, previous MI, previous PCI, previous stroke, peripheral vascular disease, chronic obstructive pulmonary disease, total cholesterol, low‐density lipoprotein cholesterol, total lesion length, type B2 or C lesion, chronic total occlusion, bifurcation lesion, number of lesions treated, stent number, use of everolimus‐ or zotarolimus‐eluting stent, and use of a β‐blocker and statin at discharge. The detailed methods of IPTW analysis were previously described. All statistical analyses were conducted with SPSS version 23.0 (IBM, Armonk, NY) and R version 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria). A 2‐sided P value of <0.05 was considered statistically significant.

Results

Baseline Characteristics

Among the 3201 stable patients with CAD who underwent PCI, 2124 had normal Lp(a) concentrations, of which 608 received DAPT ≤1 year and 1516 received DAPT >1 year. Among the 1077 patients who had elevated Lp(a) levels, 292 received DAPT ≤1 year and 785 received DAPT >1 year (Figure 1). The median follow‐up period was 2.5 years (2.2–2.6 years). Compared with patients who received ≤1 year DAPT, patients who received >1 year DAPT had longer lesion length and more bifurcation lesions, and they received more 2‐stent techniques and more stent implantations with longer length during the intervention (Table 1). As shown in Table S1, compared with patients who had normal Lp(a) levels, those with elevated Lp(a) levels were older, less likely to be men or a current smoker, and had longer lesion length and more type B2 or C lesions. Subsequently, these patients used more stents with smaller diameter and longer total length during PCI. In patients with normal Lp(a) levels, those who received DAPT >1 year had longer lesion length, more bifurcation lesion, and received more 2‐stent techniques, and more stents implantations with longer total lesion length than those who received DAPT ≤1 year. In patients with elevated Lp(a) concentrations, more everolimus‐ or zotarolimus‐eluting stents were used in those who received DAPT >1 year than those who received DAPT ≤1 year (Table 2).

Figure 1

Flowchart of the study.

CAD indicates coronary artery disease; DAPT, dual antiplatelet therapy; DES, drug‐eluting stent; Lp(a), lipoprotein(a); and PCI, percutaneous coronary intervention.

Table 1

Baseline Patient, Angiographic, and Procedural Characteristics According to DAPT Duration

Variable	DAPT ≤1 y, n=900	DAPT >1 y, n=2301	P value
Age, y	58 (50–64)	58 (50–65)	0.433
Men, n (%)	723 (80.3)	1860 (80.8)	0.747
Body mass index, kg/m2	26.0 (24.1–28.0)	26.0 (24.0–27.8)	0.357
Current smoker, n (%)	520 (57.8)	1288 (56.0)	0.355
Diabetes, n (%)	282 (31.3)	701 (30.5)	0.632
Hypertension, n (%)	567 (63.0)	1493 (64.9)	0.317
Dyslipidemia, n (%)	613 (68.1)	1605 (69.8)	0.365
Previous myocardial infarction, n (%)	238 (26.4)	674 (29.3)	0.109
Previous PCI, n (%)	264 (29.3)	656 (28.5)	0.643
Previous CABG, n (%)	29 (3.2)	108 (4.7)	0.064
Previous stroke, n (%)	98 (10.9)	228 (9.9)	0.410
Peripheral vascular disease, n (%)	23 (2.6)	83 (3.6)	0.135
Chronic kidney disease, n (%)	74 (8.2)	227 (9.9)	0.152
COPD, n (%)	14 (1.6)	53 (2.3)	0.184
LVEF, %	65 (60–68)	64 (60–68)	0.094
LVEF <50%, n (%)	28 (3.2)	96 (4.3)	0.162
Systolic blood pressure, mm Hg	125 (120–140)	126 (120–140)	0.832
Laboratory data
WBC, 103/µL	6.50 (5.43–7.50)	6.33 (5.40–7.45)	0.138
Hemoglobin, g/L	146 (136–155)	145 (135–155)	0.801
Total cholesterol, mmol/L	3.97 (3.46–4.82)	4.00 (3.35–4.76)	0.432
LDL‐C, mmol/L	2.28 (1.88–3.0)	2.31 (1.80–2.94)	0.265
HDL‐C, mmol/L	1.02 (0.87–1.17)	1.01 (0.86–1.18)	0.347
HbA1c, %	6.2 (5.8–6.9)	6.2 (5.9–6.9)	0.261
Lp(a), mg/dL	17.1 (7.0–38.0)	16.8 (7.2–40.0)	0.592
Radial artery access, n (%)	758 (91.8)	1935 (91.3)	0.667
Multivessel disease, n (%)	673 (74.8)	1772 (77.0)	0.181
SYNTAX score	10 (6–16)	10 (7–17)	0.110
SYNTAX score >22, n (%)	93 (10.7)	260 (11.7)	0.407
Total lesion length, mm	32 (20–50)	34 (20–55)	0.032
Target lesion morphology
Bifurcation lesion, n (%)	167 (18.6)	528 (22.9)	0.007
2‐stent technique, n (%)	26 (2.9)	126 (5.5)	0.002
Chronic total occlusion, n (%)	164 (18.2)	428 (18.6)	0.804
In‐stent restenosis, n (%)	43 (4.8)	110 (4.8)	0.997
Severe calcification, n (%)	34 (3.8)	82 (3.6)	0.771
Angulation >45°, n (%)	94 (10.4)	276 (12.0)	0.217
Type B2 or C lesion, n (%)	685 (76.1)	1818 (79.0)	0.074
No. vessels treated	1 (1–2)	1 (1–1)	0.796
No. lesions treated	1 (1–2)	1 (1–2)	0.590
No. lesions treated ≥3, n (%)	64 (7.1)	168 (7.3)	0.852
Drug‐eluting stent number	2 (1–2)	2 (1–3)	0.002
Drug‐eluting stent number ≥3, n (%)	203 (22.6)	614 (26.7)	0.016
Type of drug‐eluting stent			0.038
PES/SES, n (%)	426 (47.3)	996 (43.3)
EES/ZES, n (%)	474 (52.7)	1305 (56.7)
Minimum stent diameter, mm	2.75 (2.50–3.00)	2.75 (2.50–3.00)	0.808
Total stent length, mm	34 (23–54)	38 (24–58)	0.016
DAPT score	2 (1–2)	2 (1–2)	0.667
DAPT score≥2, n (%)	500 (55.6)	1260 (54.8)	0.684
Medications at discharge
Aspirin, n (%)	900 (100)	2301 (100)	NA
P2Y12 receptor inhibitor, n (%)	900 (100)	2301 (100)	NA
Oral anticoagulant, n (%)	2 (0.3)	4 (0.3)	1.000
β‐Blockers, n (%)	823 (91.4)	2116 (92.0)	0.632
Statins, n (%)	862 (95.8)	2220 (96.5)	0.345
Calcium channel blockers, n (%)	405 (45.0)	1088 (47.3)	0.244
Antiplatelet drugs at 6 mo	n=900	n=2301
Aspirin, n (%)	891 (99.0)	2301 (100)	<0.001
P2Y12 receptor inhibitor, n (%)	888 (98.7)	2301 (100)	<0.001
Antiplatelet drugs at 12 mo	n=900	n=2301
Aspirin, n (%)	868 (96.4)	2301 (100)	<0.001
P2Y12 receptor inhibitor, n (%)	827 (91.9)	2301 (100)	<0.001
Antiplatelet drugs at 18 mo	n=899	n=2297
Aspirin, n (%)	833 (92.7)	2293 (99.8)	<0.001
P2Y12 receptor inhibitor, n (%)	24 (2.7)	2120 (92.3)	<0.001
Antiplatelet drugs at 24 mo	n=899	n=2287
Aspirin, n (%)	830 (92.3)	2248 (98.3)	<0.001
P2Y12 receptor inhibitor, n (%)	22 (2.4)	966 (42.2)	<0.001
Antiplatelet drugs at 30 mo	n=259	n=1009
Aspirin, n (%)	228 (88.0)	985 (97.6)	<0.001
P2Y12 receptor inhibitor, n (%)	12 (4.6)	306 (30.3)	<0.001
Mean DAPT time, d	350±56	667±166	<0.001
Median DAPT time, d	365 (365–365)	548 (548–810)	<0.001

CABG indicates coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; DAPT, dual antiplatelet therapy; EES, everolimus‐eluting stent; HbA1c, hemoglobin A1c; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a); LVEF, left ventricular ejection fraction; NA, not appliable. PCI, percutaneous coronary intervention; PES, paclitaxel‐eluting stent; SES, sirolimus‐eluting stent; SYNTAX, synergy between percutaneous coronary intervention with taxus and cardiac surgery; WBC, white blood cell; and ZES, zotarolimus‐eluting stent.

Table 2

Baseline Patient, Angiographic, and Procedural Characteristics According to Lp(a) Levels and DAPT Duration

	Lp(a) ≤30 mg/dL, n=2124			Lp(a) >30 mg/dL, n=1077
Variable	DAPT ≤1 y, n=608	DAPT >1 y, n=1516	P value	DAPT≤1 y, n=292	DAPT >1 y, n=785	P value
Age, y	58 (50–64)	58 (50–64)	0.839	59 (50–65)	59 (52–65)	0.303
Men, n (%)	492 (80.9)	1243 (82.0)	0.564	231 (79.1)	617 (78.6)	0.855
Body mass index, kg/m2	26.0 (24.2–28.3)	26.0 (24.2–27.8)	0.474	25.9 (24.0–27.7)	25.8 (23.9–27.7)	0.558
Current smoker, n (%)	359 (59.0)	869 (57.3)	0.467	161 (55.1)	419 (53.4)	0.606
Diabetes, n (%)	195 (32.1)	472 (31.1)	0.674	87 (29.8)	229 (29.2)	0.842
Hypertension, n (%)	384 (63.2)	983 (64.8)	0.464	183 (62.7)	510 (65.0)	0.484
Dyslipidemia, n (%)	414 (68.1)	1060 (69.9)	0.408	199 (68.2)	545 (69.4)	0.687
Previous myocardial infarction, n (%)	155 (25.5)	434 (28.6)	0.145	83 (28.4)	240 (30.6)	0.494
Previous PCI, n (%)	172 (28.3)	433 (28.6)	0.900	92 (31.5)	223 (28.4)	0.320
Previous CABG, n (%)	18 (3.0)	62 (4.1)	0.217	11 (3.8)	46 (5.9)	0.173
Previous stroke, n (%)	64 (10.5)	138 (9.1)	0.312	34 (11.6)	90 (11.5)	0.935
Peripheral vascular disease, n (%)	16 (2.6)	53 (3.5)	0.310	7 (2.4)	30 (3.8)	0.254
Chronic kidney disease, n (%)	52 (8.6)	144 (9.5)	0.496	22 (7.5)	83 (10.6)	0.135
COPD, n (%)	9 (1.5)	30 (2.0)	0.439	5 (1.7)	23 (2.9)	0.264
LVEF, %	65 (60–68)	64 (60–68)	0.338	65 (60–69)	64 (60–68)	0.131
LVEF <50%, n (%)	19 (3.2)	56 (3.8)	0.502	9 (3.2)	40 (5.2)	0.172
Systolic blood pressure, mm Hg	122 (120–140)	126 (120–140)	0.220	130 (120–140)	125 (120–140)	0.172
Laboratory data
WBC, 103/µL	6.45 (5.34–7.52)	6.40 (5.41–7.44)	0.534	6.58 (5.55–7.41)	6.25 (5.38–7.45)	0.082
Hemoglobin, g/L	146 (136–155)	146 (136–155)	0.873	145 (135–153)	144 (134–154)	0.885
Total cholesterol, mmol/L	3.88 (3.42–4.68)	3.93 (3.30–4.72)	0.691	4.12 (3.54–4.96)	4.12 (3.45–4.86)	0.340
LDL‐C, mmol/L	2.23 (1.84–2.91)	2.26 (1.75–2.90)	0.459	2.44 (1.97–3.16)	2.39 (1.90–3.08)	0.270
HDL‐C, mmol/L	1.01 (0.86–1.16)	1.00 (0.85–1.17)	0.286	1.04 (0.91–1.20)	1.04 (0.89–1.21)	0.832
HbA1c, %	6.2 (5.9–6.9)	6.2 (5.9–6.9)	0.330	6.2 (5.8–7.0)	6.2 (5.9–6.9)	0.569
Lp(a), mg/dL	9.9 (4.7–17.4)	9.7 (5.1–16.6)	0.789	51.5 (39.2–73.8)	52.4 (39.3–73.9)	0.777
Radial artery access, n (%)	519 (91.9)	1292 (92.3)	0.750	239 (91.6)	643 (89.3)	0.298
SYNTAX score	9 (6–16)	10 (7–17)	0.024	11 (7–17)	10 (6–18)	0.669
SYNTAX score >22, n (%)	60 (10.1)	167 (11.3)	0.427	33 (11.8)	93 (12.5)	0.771
Total lesion length, mm	31 (18–49)	33 (20–55)	0.035	33 (20–56)	34 (21–55)	0.497
Target lesion morphology
Bifurcation lesion, n (%)	106 (17.4)	355 (23.4)	0.003	61 (20.9)	173 (22.0)	0.685
Two‐stent technique, n (%)	14 (2.3)	84 (5.5)	0.001	12 (4.1)	42 (5.4)	0.407
Chronic total occlusion, n (%)	108 (17.8)	267 (17.6)	0.934	56 (19.2)	161 (20.5)	0.628
In‐stent restenosis, n (%)	29 (4.8)	72 (4.7)	0.984	14 (4.8)	38 (4.8)	0.975
Severe calcification, n (%)	21 (3.5)	59 (3.9)	0.632	13 (4.5)	23 (2.9)	0.217
Angulation >45 degrees, n (%)	60 (9.9)	176 (11.6)	0.248	34 (11.6)	100 (12.7)	0.628
Type B2 or C lesion, n (%)	456 (75.0)	1180 (77.8)	0.160	229 (78.4)	638 (81.3)	0.294
No. vessels treated	1 (1–1)	1 (1–1)	0.825	1 (1–2)	1 (1–2)	0.431
No. lesions treated	1 (1–2)	1 (1–2)	0.481	1 (1–2)	1 (1–2)	0.898
No. lesions treated ≥3, n (%)	41 (6.7)	113 (7.5)	0.568	23 (7.9)	55 (7.0)	0.624
Drug‐eluting stent number	2 (1–2)	2 (1–3)	0.001	2 (1–3)	2 (1–3)	0.595
Drug‐eluting stent number ≥ 3, n (%)	123 (20.2)	407 (26.8)	0.001	80 (27.4)	207 (26.4)	0.734
Type of drug‐eluting stent			0.311			0.031
PES/SES, n (%)	281 (46.2)	664 (43.8)		145 (49.7)	332 (42.3)
EES/ZES, n (%)	327 (53.8)	852 (56.2)		147 (50.3)	453 (57.7)
Minimum stent diameter, mm	2.75 (2.50–3.00)	2.75 (2.50–3.00)	0.958	2.75 (2.50–3.00)	2.75 (2.50–3.00)	0.544
Total stent length, mm	33 (23–53)	37 (23–58)	0.013	36 (23–59)	38 (24–60)	0.547
DAPT score	2 (1–2)	2 (1–2)	0.730	2 (1–3)	2 (1–2)	0.406
DAPT score≥2, n (%)	333 (54.8)	842 (55.5)	0.747	167 (57.2)	418 (53.2)	0.248
Medications at discharge
Aspirin, n (%)	600 (98.7)	1500 (98.9)	0.608	289 (99.0)	776 (98.9)	1.000
P2Y12 receptor inhibitor, n (%)	599 (98.5)	1498 (98.8)	0.586	287 (98.3)	776 (98.9)	0.466
Oral anticoagulant, n (%)	1 (0.2)	3 (0.3)	1.000	1 (0.5)	1 (0.2)	0.485
β‐Blockers, n (%)	558 (91.8)	1386 (91.4)	0.793	265 (90.8)	730 (93.0)	0.218
Statins, n (%)	581 (95.6)	1459 (96.2)	0.467	281 (96.2)	761 (96.9)	0.559
Calcium channel blockers, n (%)	271 (44.6)	713 (47.0)	0.304	134 (45.9)	375 (47.8)	0.583
Antiplatelet drugs at 6 mo	n=608	n=1516		n=292	n=785
Aspirin, n (%)	601 (98.8)	1516 (100)	<0.001	290 (99.3)	785 (100)	0.073
P2Y12 receptor inhibitor, n (%)	600 (98.7)	1516 (100)	<0.001	278 (95.2)	785 (100)	<0.001
Antiplatelet drugs at 12 mo	n=608	n=1516		n=292	n=785
Aspirin, n (%)	590 (97.0)	1516 (100)	<0.001	278 (95.2)	785 (100)	<0.001
P2Y12 receptor inhibitor, n (%)	561 (92.3)	1516 (100)	<0.001	266 (91.1)	785 (100)	<0.001
Antiplatelet drugs at 18 mo	n=607	n=1512		n=292	n=785
Aspirin, n (%)	563 (92.8)	1509 (99.8)	<0.001	270 (92.5)	784 (99.9)	<0.001
P2Y12 receptor inhibitor, n (%)	16 (2.6)	1393 (92.1)	<0.001	8 (2.7)	727 (92.6)	<0.001
Antiplatelet drugs at 24 mo	n=607	n=1504		n=292	n=783
Aspirin, n (%)	560 (92.3)	1475 (98.1)	<0.001	270 (92.5)	773 (98.7)	<0.001
P2Y12 receptor inhibitor, n (%)	16 (2.6)	626 (41.6)	<0.001	6 (2.1)	340 (43.4)	<0.001
Antiplatelet drugs at 30 mo	n=165	n=668		n=94	n=341
Aspirin, n (%)	145 (87.9)	649 (97.2)	0.003	83 (88.3)	336 (97.6)	<0.001
P2Y12 receptor inhibitor, n (%)	8 (4.8)	180 (26.9)	<0.001	4 (4.3)	126 (37.0)	<0.001
Mean DAPT time, d	349±59	662±163	<0.001	353±50	677±172	<0.001
Median DAPT time, d	365 (365–365)	548 (548–803)	<0.001	365 (365–365)	548 (54–834)	<0.001

CABG indicates coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; DAPT, dual antiplatelet therapy; EES, everolimus‐eluting stent; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a); LVEF, left ventricular ejection fraction; PES, paclitaxel‐eluting stent; PCI, percutaneous coronary intervention; SES, sirolimus‐eluting stent; WBC, white blood cell; and ZES, zotarolimus‐eluting stent.

DAPT Duration and 2.5‐Year Clinical Outcomes

As shown in Table 3 and Figure 2, patients who received DAPT >1 year had lower risks of MACCE (1.5% versus 2.6%; adjusted HR, 0.536 [95% CI, 0.313–0.915]), all‐cause death (0.1% versus 1.8%; adjusted HR, 0.045 [95% CI, 0.010–0.198]), and definite/probable ST (0.2% versus 1.0%; adjusted HR, 0.150 [95% CI, 0.046–0.498]) than those who received DAPT ≤1 year. All the candidate variables were well balanced between the DAPT ≤1 year and DAPT >1 year groups after IPTW analysis (Figure S1 and Figure S2), and it obtained consistent results that the risks of MACCE, all‐cause death, and definite/probable ST were significantly decreased in the prolonged DAPT group. However, the risk of clinically relevant bleeding in the prolonged DAPT group was almost twice that of the shortened DAPT group, although no statistical difference was found (1.3% versus 0.7%; adjusted HR, 1.733 [95% CI, 0.716–4.196]; IPTW HR, 1.851 [95% CI, 0.766–4.473]).

Table 3

Two‐Year Clinical Outcomes According to DAPT Duration

	No. patients with event, n (%)		Crude HR (95% CI)	Multivariable adjusted HR (95% CI)	IPTW adjusted HR (95% CI)
Clinical end point	DAPT ≤1 y	DAPT >1 y
All‐cause death/MI/stroke	23 (2.6)	35 (1.5)	0.566 (0.334–0.958)	0.536 (0.313–0.915)	0.514 (0.303–0.874)
All‐cause death	16 (1.8)	2 (0.1)	0.049 (0.011–0.212)	0.045 (0.010–0.198)	0.040 (0.009–0.175)
Cardiac death	10 (1.1)	0 (0)	NA	NA	NA
Nonfatal MI	5 (0.6)	13 (0.6)	0.981 (0.349–2.754)	1.043 (0.367–2.964)	0.827 (0.282–2.426)
Stroke	7 (0.8)	22 (1.0)	1.152 (0.491–2.701)	1.077 (0.452–2.567)	1.033 (0.440–2.423)
Definite/probable ST	9 (1.0)	4 (0.2)	0.168 (0.052–0.546)	0.150 (0.046–0.498)	0.142 (0.043–0.470)
BARC type 2, 3, or 5 bleeding	6 (0.7)	30 (1.3)	1.829 (0.760–4.399)	1.733 (0.716–4.196)	1.851 (0.766–4.473)

Variables included in Cox multivariable model were age, sex, body mass index, current smoker, diabetes, hypertension, dyslipidemia, previous MI, previous stroke, peripheral vascular disease, low‐density lipoprotein cholesterol, SYNTAX score, total lesion length, bifurcation lesion, minimum stent diameter, total stent length, and use of statin at discharge. Variables included in IPTW model were age, sex, body mass index, current smoker, diabetes, hypertension, dyslipidemia, previous MI, previous percutaneous coronary intervention, previous stroke, peripheral vascular disease, chronic obstructive pulmonary disease, total cholesterol, low‐density lipoprotein cholesterol, total lesion length, type B2 or C lesion, chronic total occlusion, bifurcation lesion, number of lesions treated, stent number, use of everolimus‐ or zotarolimus‐eluting stent, and use of β‐blocker and statin at discharge. BARC indicates Bleeding Academic Research Consortium; DAPT, dual antiplatelet therapy; HR, hazard ratio; IPTW, inverse probability of treatment weighting; MI, myocardial infarction; NA, not appliable; ST, stent thrombosis; and SYNTAX, synergy between percutaneous coronary intervention with taxus and cardiac surgery.

Figure 2

Kaplan–Meier curves for 2.5‐year clinical outcomes according to DAPT duration (>1 year vs ≤1 year) in overall population.

BARC indicates Bleeding Academic Research Consortium; DAPT, dual antiplatelet therapy; MI, myocardial infarction; and ST, stent thrombosis.

Lp(a) Levels and 2.5‐Year Clinical Outcomes

Clinical outcomes according to Lp(a) levels are shown in Table S2 and Figure S3. The risks of MACCE (2.6% versus 1.4%; adjusted HR, 1.733 [95% CI, 1.023–2.934]) and definite/probable ST (0.7% versus 0.2%; adjusted HR, 3.297 [95% CI, 1.060–10.251]) were higher in patients with elevated Lp(a) levels than those with normal Lp(a) levels. After IPTW adjustment, all the candidate variables were well balanced between the 2 groups with absolute standardized differences <10% (Figure S4 and Figure S5), and it showed that patients with elevated Lp(a) levels were significantly associated with increased risk of MACCE (HR, 1.695 [95% CI, 1.005–2.860]) and definite/probable ST (HR, 3.157 [95% CI, 1.015–9.822]) than those with normal Lp(a) concentrations.

DAPT ≤1 Year Versus DAPT >1 Year in Patients With Elevated and Normal Lp(a) Levels

Among patients with elevated Lp(a) levels, DAPT >1 year presented lower risk of MACCE (1.9% versus 4.5%; adjusted HR, 0.344 [95% CI, 0.159–0.744]) compared with DAPT ≤1 year. The risks of all‐cause death (0% versus 3.1%), cardiac death (0% versus 2.1%), and definite/probable ST (0.3% versus 2.1%; adjusted HR, 0.099 [95% CI, 0.019–0.512]) were also significantly lower in the DAPT >1 year group than that in the DAPT ≤1 year group. Moreover, the risk of clinically relevant bleeding was not statistical different between the prolonged and shortened DAPT groups (1.5% versus 1.0%; adjusted HR, 1.172 [95% CI, 0.318–4.321]) (Table S3, Figure 3A and Figure 4A). In contrast, no statistically significant difference was found between the DAPT >1 year and DAPT ≤1 year groups with respect to MACCE (1.3% versus 1.6%; adjusted HR, 0.775 [95% CI, 0.356–1.687]) and definite/probable ST (0.1% versus 0.5%; adjusted HR, 0.142 [95% CI, 0.017–1.165]) in patients with normal Lp(a) levels. Patients who received DAPT >1 year had lower risks of all‐cause mortality (0.1% versus 1.2%; adjusted HR, 0.092 [95% CI, 0.017–0.485]) and cardiac mortality (0% versus 0.7%) compared with those with DAPT ≤1 year. Notably, prolonged DAPT had 2.4‐times higher risk of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding than shortened DAPT, though without statistical difference (1.2% versus 0.5%; adjusted HR, 2.249 [95% CI, 0.658–7.689]) (Table S3, Figure 3B and Figure 4B).

Figure 3

Kaplan‐Meier curves for 2.5‐year clinical outcomes according to DAPT duration (>1 year vs ≤1 year) in patients with (A) Lp(a) levels >30 mg/dL and (B) Lp(a) levels ≤30 mg/dL, respectively.

BARC indicates Bleeding Academic Research Consortium; DAPT, dual antiplatelet therapy; Lp(a), lipoprotein(a); MI, myocardial infarction; and ST, stent thrombosis.

Figure 4

Unadjusted and adjusted association between DAPT duration and main clinical outcomes in patients with (A) Lp(a) levels >30 mg/dL and (B) Lp(a) levels ≤30 mg/dL, respectively.

BARC indicates Bleeding Academic Research Consortium; DAPT, dual antiplatelet therapy; HR, hazard ratio; Lp(a), lipoprotein(a); MI, myocardial infarction; and ST, stent thrombosis.

After IPTW adjustment, all the candidate variables were well balanced between the DAPT ≤1 year and DAPT >1 year groups for both patients with normal and elevated Lp(a) levels (Figure 5, Figure S6 and Figure S7). Similar to the results of multivariable‐adjusted analysis, the IPTW analysis demonstrated that patients who received DAPT >1 year had lower risks of MACCE (HR, 0.351 [95% CI, 0.164–0.751]) and definite/probable ST (HR, 0.092 [95% CI, 0.018–0.469]) than those who received DAPT ≤1 year in patients with elevated Lp(a) levels (Figure 4A), whereas prolonged DAPT was not associated with reduced risk of MACCE and definite/probable ST in patients with normal Lp(a) levels (Figure 4B).

Figure 5

Absolute standard difference before and after inverse probability of treatment weighting analysis between the DAPT >1 year and DAPT ≤1 year groups in patients with (A) Lp(a) levels >30 mg/dL and (B) Lp(a) levels ≤30 mg/dL, respectively.

COPD indicates chronic obstructive pulmonary disease; EES, everolimus‐eluting stent; LDL‐C, low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a); PCI, percutaneous coronary intervention; and ZES, zotarolimus‐eluting stent.

Discussion

To our knowledge, this is the first study to evaluate the effect of Lp(a) concentrations on the efficacy and safety of prolonged DAPT for stable patients with CAD who underwent PCI. The principal findings are: (1) Elevated Lp(a) levels were significantly associated with increased MACCE (death, MI, or stroke) and definite or probable ST in stable patients with CAD after PCI with a DES in the era of statin therapy. (2) Among patients with elevated Lp(a) levels, prolonged DAPT was associated with lower risks of MACCE and definite or probable ST without statistically increasing the clinically relevant bleeding, whereas in patients with normal Lp(a) levels, prolonged DAPT did not show statistically significant evidence of benefit for reducing MACCE and definite/probable ST, and it tended to increase the risk of clinically relevant bleeding after 2.5 years.

Lp(a) has been recognized as a risk factor for cardiovascular disease in recent years. In 2008, Kamstrup et al reported that extreme Lp(a) levels (≥120 mg/dL) predict a 3‐ to 4‐fold increase in risk of MI in 9330 general participants from the Copenhagen City Heart Study. Since then, a growing body of evidence from meta‐analyses, , Mendelian randomization studies, , and genome‐wide association studies , has demonstrated that Lp(a) is an independent, genetic, and causal risk factor for CAD. Recently, Liu et al reported that high Lp(a) levels are associated with higher incidence of a composite of cardiac death, MI, or stroke in stable patients with CAD treated with statins after PCI at a 4.9‐year follow‐up. A study with 1768 patients who received statin therapy after PCI also found that elevated Lp(a) levels were associated with increased cardiac death or ACS during a median follow‐up of 4.4 years (adjusted HR, 1.28 [95% CI, 1.04–1.58]). Similarly, we found a positive association between Lp(a) levels and subsequent composite ischemic events as well as definite or probable ST during a median follow‐up of 2.5 years. This finding was confirmed by Cox regression analysis and IPTW analysis.

However, there are currently no approved pharmacologic therapies that specifically target high Lp(a) levels. The commonly used statins have no Lp(a) lowering effect, and a close assessment of published studies has even indicated a slight Lp(a) increasing effect. Though having a 20% to 30% Lp(a)‐lowering effects, both niacin and mipomersen are associated with side effects, and mipomersen is only approved in homozygous familial hypercholesterolemia caused by hepatotoxicity. A post hoc analysis of the evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab trial indicated that Lp(a) lowering by proprotein convertase subtilisin/kexin type 9 inhibitor contributed independently to cardiovascular event reduction in patients with ACS, yet each 5‐mg/dL reduction in Lp(a) only predicted a 2.5% relative reduction in cardiovascular events. However, several Mendelian randomization analyses speculated that ≈66 to 100 mg/dL reduction of Lp(a) may be required to achieve equivalent protective effects yielded from a 39‐mg/dL (or 1 mmol/L) reduction of low‐density lipoprotein cholesterol. , Although Tsimikas et al found that a novel therapeutic agent, apoA‐LRx, provides potent reductions in levels of Lp(a) in patients with cardiovascular disease by reducing the production of apoA, which offers greater specificity than proprotein convertase subtilisin/kexin type 9 inhibitor. Further trials are needed to assess the impact of Lp(a) lowering with apoA‐LRx on ischemic events in patients with established CAD.

Lp(a) is composed of a low‐density lipoprotein cholesterol–like particle and an apoA, the pathognomonic component of Lp(a) that binds to apolipoprotein B100 via a disulfide bond. Because of the similarity between apoA and plasminogen, Lp(a) promotes thrombotic and fibrinolytic events through several mechanisms, including inflammation through its content of oxidized phospholipids, the presence of lysine binding sites that allow accumulation in the arterial wall, and potential antifibrinolytic roles by inhibiting plasminogen activation. , DAPT, consisting of aspirin and a P2Y12 inhibitor, represents the cornerstone of treatment to preventing thrombotic complications in patients with CAD undergoing PCI. Current guidelines on DAPT from Europe and the United States recommend aspirin indefinitely and clopidogrel for 6 months after implantation of a DES in stable patients with CAD, and DAPT prolongation beyond 6 months and up to 30 months may be considered in stable patients with CAD who are at low bleeding risk but high thrombotic risk. In real‐world clinical practice, almost all stable patients with CAD received DAPT for 6 to 12 months or >12 months after PCI with a DES in our center in 2013. In this setting, we compared the relative efficacy and safety of prolonged DAPT (>1 year) versus shortened DAPT (≤1 year) in patients with elevated Lp(a) levels and normal Lp(a) levels, respectively, and we hypothesized that patients with stable CAD and elevated Lp(a) levels would derive benefit from continuing DAPT beyond 12 months.

Potentially, the important finding of our study is that prolonged DAPT could reduce the risks of 2.5‐year MACCE and definite or probable ST, without statistically increasing clinically relevant bleeding for stable patients with CAD with elevated Lp(a) levels after PCI with a DES. In contrast, prolonged DAPT was not significantly associated with reduced incidence of the composite ischemic events in patients with normal Lp(a) levels. Furthermore, though without statistical difference, prolonged DAPT tended to increase the clinically relevant bleeding risk in this cohort of patients. The multicenter, randomized Ticagrelor in Patients with Diabetes and Stable Coronary Artery Disease with a History of Previous Percutaneous Coronary Intervention trial reported that the addition of ticagrelor to aspirin significantly reduced 3.3‐year cardiovascular death, MI, or stroke, and provided a favorable net clinical benefit in patients with diabetes and stable CAD who had a history of PCI. Stable patients with CAD with elevated Lp(a) levels were at heightened risk for ischemic events, and our study demonstrated that these patients can also benefit from prolonging DAPT duration after PCI with a DES. In this setting, Lp(a) levels might be an important consideration when deciding upon the duration of DAPT for stable patients with CAD in the future.

Our study presented several limitations. First, this is a single‐center, nonrandomized study; thus, it is limited by unbalanced baseline characteristics and selection bias. Actually, the duration of DAPT was not predefined but was individualized by physician discretion and patient preference. Although multivariable‐adjusted analysis and IPTW analysis were performed, it was hard to control all the confounding factors and eliminate the selection bias. Second, our findings were mainly derived from subgroup analysis of the cohort study; thus, we might have inadequate statistical power to provide a definitive answer on the relative efficacy and safety of prolonged DAPT in patients with elevated Lp(a) and normal Lp(a) levels, respectively. In this setting, the results should be interpreted as hypothesis generating. Third, the DAPT regimen in our study was based on the use of clopidogrel and aspirin; the clinical impact of DAPT >1 year with using a potent P2Y12 inhibitor plus aspirin according to Lp(a) concentrations in this population is unclear. Moreover, the results cannot be extrapolated to other patient populations, such as the ACS population. Fourth, Lp(a) was measured as mass concentration but not particle concentration; thus, variations of apoA size between assay calibrators and patients’ samples might overestimate or underestimate the real level of Lp(a).

Conclusions

In stable patients with CAD who underwent PCI, elevated Lp(a) levels were positively related to ischemic events at a 2.5‐year follow‐up. Prolonged DAPT (>1 year) was associated with reduced risk of cardiovascular events among patients with elevated Lp(a) levels, whereas it did not show statistically significant evidence of benefit for reducing ischemic events and tended to increase clinically relevant bleeding in patients with normal Lp(a) levels. Further well‐designed randomized trials are needed to confirm these findings.

Sources of Funding

The current study was funded by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021‐I2 M‐1‐008) and Beijing Municipal Health Commission‐Capital Health Development Research Project (2020‐1‐4032).

Disclosures

None.

Tables S1–S3

Figures S1–S7

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