Second-Generation vs. First-Generation Drug-Eluting Stents in Patients With Calcified Coronary Lesions　― Pooled Analysis From the RESET and NEXT Trials ―

Abstract

Background: The comparative efficacy of second-generation (G2) vs. first-generation (G1) drug-eluting stents (DES) for calcified coronary lesions is unknown.

Methods and Results: We compared the 3-year clinical outcomes of patients with G1- or G2-DES according to the presence or absence of calcified coronary lesions as assessed in an angiographic core laboratory using data from 2 large-scale prospective multicenter randomized trials, RESET and NEXT. G1-DES and G2-DES were implanted in 299 and 1,033 patients, respectively, in the Calc stratum (≥1 lesion with moderate/severe calcification), and 1,208 and 3,550 patients, respectively, in the Non-calc stratum (no/mild calcification). The patients in the Calc stratum had a significantly higher adjusted risk for the primary outcome measure (any target-lesion revascularization (TLR)) than those in the Non-calc stratum (HR: 1.38, 95% CI: 1.11–1.71, P=0.004). The cumulative 3-year incidence of any TLR was not significantly different between the G1-DES and G2-DES groups in both the Calc and Non-calc strata (12.1% vs. 9.7%, P=0.22, and 6.8% vs. 6.1%, P=0.44, respectively). After adjusting for confounders, the effect of G2DES relative to G1-DES for any TLR remained insignificant in both the Calc and Non-calc strata (HR: 0.78, 95% CI: 0.48–1.25, P=0.3, and HR: 0.84, 95% CI: 0.61–1.17, P=0.31, respectively, P interaction=0.55).

Conclusions: The effect of G2-DES relative to G1-DES for TLR was not significantly different regardless of the presence or absence of lesion calcification.

Calcified coronary lesions are the one of the most common complex lesions in patients treated with percutaneous coronary intervention (PCI) and are reported to be related to the increased risk for ischemic outcomes such as target-lesion revascularization (TLR), and stent thrombosis (ST).^1–4 Severe lesion calcification often damages the polymer coating on the metallic stent platform, because of difficulties with stent delivery, and prevents adequate stent expansion, both of which might lead to higher risk for in-stent restenosis.^5–8 Several previous studies have suggested that calcified lesions as compared with non-calcified lesions incur a higher risk of TLR even when treated with first-generation drug-eluting stents (G1-DES), although G1-DES as compared with bare-metal stents improved the outcomes of ischemic patients with calcified lesions.^9–14 Moreover, worse clinical outcomes have been suggested for calcified lesions than for non-calcified lesions even after treatment with second-generation drug-eluting stents (G2-DES) despite their improved delivery, flexibility, and more biocompatible polymer composition.^15–18 Several previous randomized controlled trials suggested non-inferiority of G2-DES to G1-DES for TLR, and a meta-analysis demonstrated superiority of G2-DES for TLR in patient populations including both calcified and non-calcified lesions.^19–22 However, there has not been a study comparing G2-DES with G1-DES in patients with lesion calcification. Therefore, the aim of the present study was to compare the clinical outcomes between G2-DES and G1-DES according to the presence or absence of lesion calcification in a pooled database of 2 large DES-vs.-DES trials conducted in Japan.

Methods

This pooled analysis compared 3-year clinical outcomes between G1-DES and G2DES according to the presence or absence of coronary lesion calcification, using individual patient-level data from RESET (Randomized Evaluation of Sirolimus-Eluting Versus EverolimusEluting Stent Trial) and NEXT (NOBORI Biolimus-Eluting Versus XIENCE/PROMUS EverolimusEluting Stent Trial).^20,23 The protocol, patient enrollment, and 3-year clinical outcomes of the RESET and NEXT studies have been previously described in detail.^20,23–25 In brief, RESET and NEXT were prospective, multicenter, randomized, open-label trials comparing an everolimus-eluting stent (EES: a G2-DES using a durable polymer) with a sirolimus-eluting stent (SES: most widely used G1-DES), and an EES with a biolimus-eluting stent (BES: a G2-DES using a biodegradable polymer), in daily clinical practice in Japan without any exclusion criteria.

The statistician, members of the independent clinical events committee, steering committee, clinical research organization (Research Institute for Production Development, Kyoto, Japan), angiographic core laboratory (Cardiocore, Tokyo, Japan), and sponsors (Abbot Vascular and Terumo Japan) were blinded to the study group assignments (Appendix S1). The protocol of each trial was approved by the institutional review boards of the participating centers (Appendix S2). Written, informed consent was given by all patients.

Qualitative and quantitative angiographic analyses pre- and post-PCI were conducted in an angiography core laboratory. Coronary artery calcification was defined as obvious density within the arterial wall and at lesion sites that appeared as an X-ray-absorbing mass. The severity of the calcification was classified as severe (density noted without cardiac motion before contrast injection and generally involving both sides of the arterial wall), moderate (density noted only during the cardiac cycle before contrast injection), mild (lesions other than severe and moderate lesion calcification), or absent.²⁶

Recommended antiplatelet regimen was aspirin (≥81 mg daily) indefinitely and a thienopyridine (75 mg clopidogrel daily or 200 mg ticlopidine) for at least 3 months. Duration of dual antiplatelet therapy was left to the discretion of each attending physician. Persistent discontinuation of thienopyridine was defined as cessation of at least 2 months.

RESET enrolled 3,196 patients (EES: 1,596 patients; SES: 1,600 patients), and NEXT enrolled 3,235 patients (EES: 1,618 patients; BES: 1,617 patients). From among the 6,431 patients enrolled in the 2 trials, the current study population consisted of 6,090 patients, after excluding 341 patients with missing data regarding lesion calcification. The Calc stratum (≥1 target lesion with moderate to severe calcification) included 1,332 patients (G1-DES: 299 patients; G2-DES: 1,033 patients) and the Non-calc stratum (no or only mild calcification in all target lesions) included 4,758 patients (G1-DES: 1,208 patients; G2-DES: 3,550 patients) (Figure 1).

Figure 1.

Study flow chart. BES, biolimus-eluting stent; Calc, calcification; DES, drug-eluting stent; EES, everolimus-eluting stent; ITT, intention-to-treat; G1, 1st-generation; G2, 2nd-generation; NEXT, NOBORI biolimus-eluting stent Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial; RESET, Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial; SES, sirolimus-eluting stent.

The primary endpoint was any TLR at 3 years, which was prespecified in both RESET and NEXT. TLR was defined as either PCI or coronary artery bypass grafting for restenosis or thrombosis of the target lesion, which included the proximal and distal edge segments, as well as the ostium of the side branches. Only those lesions treated at the time of the index randomized PCI procedure were regarded as target lesions; lesions treated at the time of scheduled staged PCI procedures were not regarded as target lesions.

The primary endpoint events were adjudicated by the independent clinical event committee. In patients with target-vessel revascularization (TVR), the angiography core laboratory analyzed the angiograms in order to distinguish TLR from TVR other than TLR. The secondary outcomes evaluated at 3-year follow-up included all-cause death, cardiac death, myocardial infarction (MI), ST, any TLR, clinically-driven TLR, TVR, hospitalization for heart failure, stroke, bleeding, a composite of death or MI, a device-oriented composite, a patient-oriented composite, target-lesion failure (TLF: cardiac death, target-vessel MI, or clinically-driven TLR), target-vessel failure (TVF: cardiac death, target-vessel MI, or clinically-driven TVR), and major adverse cardiac events (MACE: cardiac death, MI, or clinically-driven TLR). Definitions for each endpoints have been described in detail (Appendix S3).^20,23

Statistical Analysis

Categorical variables are presented as counts and percentages and were compared using chi-squared or Fisher’s exact tests. Continuous variables are expressed as mean±SD or median with interquartile range. Continuous variables were compared using Student’s t-test or the Wilcoxon rank-sum test based on their distributions.

Clinical outcomes were analyzed according to the intention-to-treat principle. Clinical outcomes at 3 years were compared between G1-DES and G2-DES groups stratified by the presence or absence of lesion calcification. The cumulative incidence of each endpoint was estimated using the Kaplan-Meier method, and the curves of the 2 groups were compared by log-rank test.

Multivariable Cox proportional hazards models were used to adjust for the baseline differences between groups. The following variables were carefully selected to avoid over-fitting and were included into the multivariable Cox proportional hazards models for each clinical outcome: stent type (G1-/G2-DES), study (RESET/NEXT), age ≥75 years, diabetes mellitus, insulin-treated diabetes, dialysis, heart failure, multivessel treatment, and culprit vessel for ST-segment elevation MI. The effect of G2-DES relative to G1-DES was expressed as a hazard ratio (HR) with a 95% confidence interval (CI). We conducted the formal interaction test between the presence of lesion calcification and the effects of G2-DES relative to G1-DES on the primary and secondary endpoints.

Two physicians (K. Nishida and K. Nakastuma) and a statistician (T. Morimoto) analyzed all data using SPSS version 20 (SPSS Inc., Chicago, IL, USA), JMP version 10.0 (SAS Institute, Cary, NC, USA), and SAS version 9.2 (SAS Institute). All reported P values were 2-sided and P<0.05 was considered statistically significant.

Results

Baseline Characteristics: G1-DES vs. G2-DES

Baseline patient characteristics were almost similar between the G1-DES and G2-DES groups for the entire study population and in both the Non-calc and Calc strata. However, the G2-DES group compared with the G1-DES group included more patients with high SYNTAX scores in the Calc stratum (Table 1).

Table 1. Baseline Patients’ Characteristics

	Entire study population			Non-Calc stratum			Calc stratum
	G1-DES (n=1,507)	G2-DES (n=4,583)	P value	G1-DES (n=1,208)	G2-DES (n=3,550)	P value	G1-DES (n=299)	G2-DES (n=1,033)	P value
Clinical characteristics
Age, years	69.3±9.6	69.1±9.8	0.46	68.8±9.6	68.5±10	0.48	71.5±9.2	71±8.9	0.43
≥75 years	484 (32)	1,462 (32)	0.88	365 (30)	1,071 (30)	0.98	119 (40)	391 (38)	0.54
Male	1,142 (76)	3,549 (77)	0.18	933 (77)	2,783 (78)	0.4	209 (70)	766 (74)	0.14
Body mass index	24.3±3.5 (1,494)	24.2±3.6 (4,553)	0.17	24.4±3.5 (1,196)	24.3±3.6 (3,526)	0.44	23.8±3.7 (298)	23.6±3.4 (1,027)	0.27
Hypertension	1,214 (81)	3,704 (81)	0.82	966 (80)	2,846 (80)	0.88	248 (83)	858 (83)	0.96
Diabetes mellitus	665 (44)	2,077 (45)	0.42	521 (43)	1,559 (44)	0.63	144 (48)	518 (50)	0.55
Insulin-treated diabetes	150 (10)	484 (11)	0.5	114 (9.4)	339 (9.6)	0.91	36 (12)	145 (14)	0.37
Treated with oral medication only	359 (24)	1,115 (24)	0.69	284 (24)	855 (24)	0.69	75 (25)	260 (25)	0.98
Treated with diet therapy only	97 (6.4)	293 (6.4)	0.95	75 (6.2)	216 (6.1)	0.88	22 (7.4)	77 (7.5)	0.96
Dyslipidemia	1,139 (76)	3,523 (77)	0.31	928 (77)	2,780 (78)	0.28	211 (71)	743 (72)	0.65
ESRD (eGFR <30 mL/ min/1.73 m2) not dialysis	38 (2.5)	108 (2.4)	0.73	30 (2.5)	77 (2.2)	0.53	8 (2.7)	31 (3.0)	0.76
Dialysis	72 (4.8)	266 (5.8)	0.13	36 (3.0)	132 (3.7)	0.23	36 (12)	134 (13)	0.67
Atrial fibrillation	116 (7.7)	300 (6.5)	0.12	90 (7.5)	223 (6.3)	0.16	26 (8.7)	77 (7.5)	0.48
Anemia (hemoglobin <11.0 g/dL)	194 (12.9)	564 (12.3)	0.57	139 (12)	361 (10)	0.20	55 (19)	203 (20)	0.64
Chronic obstructive pulmonary disease	28 (1.9)	111 (2.4)	0.2	21 (1.7)	86 (2.4)	0.17	7 (2.3)	25 (2.4)	0.94
Malignancy	104 (6.9)	321 (7.0)	0.89	88 (7.3)	242 (6.8)	0.58	16 (5.4)	79 (7.7)	0.17
Current smoker	797 (53)	2,560 (56)	0.04	651 (54)	2,031 (57)	0.04	146 (49)	529 (51)	0.47
Family history of CAD	257 (20)	693 (16)	0.002	207 (20)	564 (17)	0.03	50 (20)	129 (13)	0.009
Previous MI	467 (31)	1,311 (29)	0.08	383 (32)	1,038 (29)	0.11	84 (28)	273 (26)	0.57
Previous stroke	149 (9.9)	496 (11)	0.31	111 (9.2)	360 (10)	0.34	38 (13)	136 (13)	0.84
Heart failure	188 (13)	555 (12)	0.71	138 (11)	398 (11)	0.84	50 (17)	157 (15)	0.52
Peripheral vascular disease	131 (8.7)	460 (10)	0.13	101 (8.4)	321 (9.0)	0.47	30 (10)	139 (13)	0.12
Previous PCI	766 (51)	2,265 (49)	0.34	622 (52)	1,797 (51)	0.6	144 (48)	468 (45)	0.38
Previous CABG	98 (6.5)	213 (4.6)	0.005	68 (5.6)	140 (3.9)	0.01	30 (10)	73 (7.1)	0.09
Clinical presentation			0.04			0.26			0.04
Stable CAD	1,222 (81)	3,824 (83)		978 (81)	2,942 (83)		244 (82)	882 (85)
Unstable angina	204 (14)	511 (11)		159 (13)	407 (12)		45 (15)	104 (10)
Acute MI	81 (5.4)	248 (5.4)		71 (5.9)	201 (5.7)		10 (3.3)	47 (4.5)
LVEF <30%	29 (2.2)	75 (1.9)	0.48	19 (1.8)	56 (1.8)	0.95	10 (3.8)	19 (2.1)	0.11
Angiographic characteristics
Multivessel disease	741 (49)	2,282 (50)	0.68	555 (46)	1,645 (46)	0.81	186 (62)	637 (62)	0.87
Target-vessel location
Left main coronary artery	34 (2.3)	129 (2.8)	0.24	20 (1.7)	68 (1.9)	0.56	14 (4.7)	61 (5.9)	0.42
LAD	739 (49)	2,212 (48)	0.6	571 (47)	1,611 (45)	0.26	168 (56)	601 (58)	0.54
Left circumflex coronary artery	388 (26)	1,155 (25)	0.67	322 (27)	954 (27)	0.88	66 (22)	201 (20)	0.32
Right coronary artery	468 (31)	1,498 (34)	0.24	375 (31)	1,196 (34)	0.09	93 (31)	302 (29)	0.53
Bypass graft	8 (0.7)	32 (0.9)	0.43	8 (0.7)	32 (0.9)	0.43	0	0	0
No. of treated lesions per patient	1.23±0.49	1.22±0.49	0.49	1.21±0.46	1.21±0.48	0.82	1.31±0.58	1.26±0.54	0.24
SYNTAX score
No. of patients analyzed	1,306	4,223		1,060	3,306		246	917
Median (interquartile range)	9 (6–15)	10 (6–16)	0.13	9 (5–14)	9 (5–15)	0.32	14 (9–20)	14 (9–21)	0.68
Tertiles			0.01			0.63			0.01
Low (<23)	1,203 (92)	3,797 (90)		993 (94)	3,074 (93)		210 (85)	723 (79)
Intermediate (≥23 to <33)	90 (6.9)	336 (8.0)		58 (5.5)	194 (5.9)		32 (13)	142 (15)
High (≥33)	13 (1.0)	90 (2.1)		9 (0.9)	38 (1.2)		4 (1.6)	52 (5.7)
Medications
Aspirin	1,499 (99.5)	4,569 (99.7)	0.21	1,201 (99.4)	3,541 (99.8)	0.09	298 (99.7)	1,028 (99.5)	0.73
Thienopyridines	1,493 (99.1)	4,559 (99.5)	0.08	1,197 (99.1)	3,532 (99.5)	0.12	296 (99.0)	1,027 (99.4)	0.43
Clopidogrel	1,289 (87)	3,911 (86)	0.97	1,034 (86)	3,018 (86)	0.78	255 (86)	893 (87)	0.67
Ticlopidine	202 (14)	615 (14)	0.97	162 (14)	486 (14)	0.78	40 (14)	129 (13)	0.67
Statins	1,172 (78)	3,512 (77)	0.36	956 (79)	2,774 (78)	0.47	216 (72)	738 (71)	0.84
β-blockers	574 (38)	1,710 (37)	0.59	460 (38)	1,296 (37)	0.33	144 (38)	414 (40)	0.61
ACEI/ARB	916 (61)	2,818 (62)	0.61	735 (61)	2,204 (62)	0.44	181 (61)	614 (60)	0.76
Calcium-channel blockers	690 (46)	2035 (44)	0.35	542 (45)	1,558 (44)	0.55	148 (50)	477 (46)	0.46
Nitrates	442 (29)	1,167 (26)	0.003	346 (29)	894 (25)	0.02	96 (32)	273 (26)	0.12
Coumadin	128 (8.5)	343 (7.5)	0.2	105 (8.7)	258 (7.3)	0.11	23 (7.7)	85 (8.2)	0.71

Data are presented as number (%) or mean±SD, unless otherwise specified. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blockers; CABG, coronary artery bypass grafting; CAD, coronary artery disease; Calc, calcification; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; G1-DES, 1 st-generation drug-eluting stent; G2-DES, 2nd-generation drug-eluting stent; LAD, left anterior descending coronary artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; SYNTAX, Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery.

In terms of lesion and procedural characteristics, the G2-DES group more frequently had long lesions, direct stenting, and lower maximum inflation pressure in both the Non-calc and Calc strata. The prevalence of rotational atherectomy use was similar between G1-DES and G2-DES in the Calc stratum. In the Calc stratum, the G2-DES group had a shorter procedure time and higher lesion success rate than the G1-DES group (Table 2). The 3-year cumulative incidence of persistent discontinuation of dual antiplatelet therapy was significantly different between the G1- and G-2 DES groups in the Non-calc stratum (Calc stratum: 35.2% vs. 34.8%, P=0.65; Non-calc stratum: 34.9% vs. 38.4%; P=0.049; Figure S1).

Table 2. Lesion and Procedural Characteristics

	Entire study population			Non-Calc stratum			Calc stratum
	G1-DES (n=1,507)	G2-DES (n=4,583)	P value	G1-DES (n=1,208)	G2-DES (n=3,550)	P value	G1-DES (n=299)	G2-DES (n=1,033)	P value
No. of lesions treated before index procedure	1,853	5,589		1,462	4,284		391	1,305
Lesion length, mm	16.8±10.7 (1,688)	18.5±12.4 (5,194)	<0.0001	16.2±10.2 (1,342)	17.6±11.7 (3,981)	<0.0001	19.3±12.4 (346)	21.6±14.1 (1,213)	0.003
RVD, mm	2.57±0.63 (1,779)	2.61±0.6 (5,472)	0.02	2.58±0.63 (1,410)	2.60±0.60 (4,199)	0.18	2.53±0.65 (369)	2.62±0.58 (1,273)	0.02
Minimum lumen diameter, mm	0.81±0.46 (1,783)	0.78±0.44 (5,485)	0.01	0.81±0.45 (1,412)	0.78±0.45 (4,207)	0.02	0.81±0.50 (371)	0.79±0.44 (1,278)	0.33
Diameter stenosis, %	68±8 (1,783)	70±15 (5,484)	<0.0001	68.8±15.6 (1,412)	70.5±15.2 (4,206)	0.0003	68.7±17.2 (371)	70.4±15.1 (1,278)	0.09
Thrombus	64/1,783 (3.6)	156/5,485 (2.8)	0.11	56/1,412 (4.0)	137/4,207 (3.3)	0.21	8/371 (2.2)	19/1,278 (1.5)	0.37
Chronic total occlusion	140/1,853 (7.6)	418/5,589 (7.5)	0.91	103/1,462 (7.1)	309/4,284 (7.2)	0.83	37/391 (9.5)	109/1,305 (8.4)	0.49
In-stent restenosis	204/1,853 (11)	621/5,589 (11)	0.9	185/1,462 (13)	538/4,284 (13)	0.92	19/391 (4.9)	83/1,305 (6.4)	0.27
Culprit for STEMI	55/1,853 (3)	186/6,689 (3.3)	0.45	49/1,462 (3.4)	154/4,284 (3.6)	0.66	6/391 (1.5)	32/1,305 (2.5)	0.28
Bifurcation	707/1,783 (40)	2,316/5,486 (42)	0.06	528/1,412 (37)	1,673/4,208 (40)	0.11	179/371 (48)	643/1,278 (50)	0.48
Small vessel (RVD ≤2.75 mm)	1,166/1,779 (66)	3,389/5,472 (62)	0.006	921/1,410 (65)	2,601/4,199 (62)	0.02	245/369 (66)	788/1,273 (62)	0.12
Long lesion (lesion length >18 mm)	566/1,688 (34)	2,059/5,194 (40)	<0.0001	418/1,342 (31)	1,459/37 (37)	0.0002	148/346 (43)	600/1,213 (49)	0.03
Procedural factors
No. of stents used
Per patient	1.49±0.74 (1,495)	1.56±0.81 (4,573)	0.004	1.43±0.67 (1,205)	1.49±0.77 (3,546)	0.004	1.77±0.91 (290)	1.78±0.9 (1,031)	0.92
Per lesion	1.25±0.53 (1,793)	1.29±0.58 (5,513)	0.001	1.21±0.49 (1,426)	1.25±0.55 (4,230)	0.003	1.4±0.64 (397)	1.43±0.66 (1,283)	0.45
Total stent length, mm
Per patient	31.7±19.0 (1,495)	32.2±19.7 (4,572)	0.41	29.8±17.3 (1,205)	30.4±18.9 (3,544)	0.25	39.7±23.1 (290)	38.1±21.6 (1,028)	0.29
Per lesion	26.4±15.4 (1,793)	26.7±15.6 (5,512)	0.55	25.1±13.9 (1,426)	25.5±14.8 (4,229)	0.40	31.4±19.2 (367)	30.5±17.5 (1,283)	0.44
Stent diameter, mm	2.96±0.37 (1,793)	2.97±0.41 (5,530)	0.46	2.97±0.37 (1,426)	2.98±0.4 (4,237)	0.61	2.92±0.35 (367)	2.94±0.45 (1,293)	0.39
Multivessel treatment	150/1,507 (10.0)	511/4,583 (11.1)	0.2	104/1,208 (8.6)	346/3,550 (9.8)	0.24	46/299 (15)	165/1,033 (16)	0.81
Direct stenting	417/1,793 (23)	1,337/5,513 (24)	0.39	373/1,462 (26)	1,148/4,230 (27)	0.47	44/367 (12)	189/1,283 (15)	0.18
Maximum stent inflation pressure, atmospheres	18.0±4.0 (1,793)	16.9±4.4 (5,513)	<0.0001	17.9±4.0 (1,426)	16.8±4.4 (4,230)	<0.0001	18.4±4.0 (367)	17.5±4.6 (1,283)	<0.0001
Postdilatation	1,280/1,790 (72)	4,082/5,528 (74)	0.052	1,011/1,424 (71)	3,084/4,236 (73)	0.19	269/366 (74)	998/1,292 (77)	0.14
Bifurcation 2-stent approach	22/1,853 (1.2)	58/2,600 (2.2)	0.01	14/1,462 (1.0)	39/1,966 (2.0)	0.02	8/391 (2.1)	19/634 (3.0)	0.36
Intravascular ultrasound use	1,253/1,507 (83)	3,934/4,583 (86)	0.01	1,002/1,208 (83)	3,012/3,550 (85)	0.07	251/299 (84)	913/1,033 (88)	0.04
Rotational atherectomy	76/1,853 (4.1)	197/5,589 (3.5)	0.25	8/1,462 (0.6)	13/4,284 (0.3)	0.21	68/391 (17)	184/1,305 (14)	0.11
Stent fracture	4/283 (1.4)	8/831 (1.0)	0.51	2/233 (0.9)	7/660 (1.1)	1.00	2/50 (4.0)	1/171 (0.6)	0.13
Received study stent only	1,747/1,853 (94.8)	5,458/5,589 (97.7)	<0.0001	1,401/1,462 (95.8)	4,194/4,284 (97.9)	<0.0001	356/391 (91)	1,264/1,305 (96.9)	<0.0001
Duration of procedure, min	70.4±45.5 (1,507)	70.1±42.1 (4,583)	0.87	65.5±43.0 (1,208)	66.6±39.2 (3,550)	0.41	90.1±49.8 (299)	82.3±48.9 (1,033)	0.02
After index procedure
Minimum lumen diameter, mm
In-stent	2.46±0.46 (1,768)	2.48±0.47 (5,456)	0.07	2.48±0.47 (1,406)	2.50±0.48 (4,190)	0.27	2.38±0.45 (362)	2.44±0.46 (1,266)	0.03
In-segment	2.04±0.54 (1,768)	2.07±0.55 (5,467)	0.06	2.06±0.54 (1,406)	2.08±0.55 (4,194)	0.29	1.96±0.52 (362)	2.04±0.54 (1,273)	0.02
Diameter stenosis, %
In-stent	10.5±8.2 (1,767)	10.1±8.2 (5,454)	0.16	10.1±8.0 (1,405)	9.7±7.9 (4,188)	0.11	11.8±9.1 (362)	11.5±8.8 (1,266)	0.58
In-segment	23.1±11.8 (1,405)	21.9±11.8 (5,456)	<0.0001	22.9±11.8 (1,405)	21.7±11.6 (4,192)	0.001	23.8±11.7 (362)	22.3±12.4 (1,273)	0.03
Acute gain, mm
In-stent	1.64±0.52 (1,768)	1.70±0.52 (5,455)	<0.0001	1.67±0.52 (1,406)	1.71±0.52 (4,189)	0.003	1.56±0.52 (362)	1.65±0.49 (1,266)	0.005
In-segment	1.23±0.56 (1,768)	1.29±0.55 (5,466)	<0.0001	1.25±0.56 (1,406)	1.30±0.55 (4,193)	0.003	1.15±0.54 (362)	1.25±0.53 (1,273)	0.001
Successful outcome
Lesion success by any treatment modality	1,835/1,853 (99.0)	5,575/5,589 (99.7)	<0.0001	1,455/1,462 (99.5)	4,276/4,284 (99.8)	0.06	380/391 (97.2)	1,299/1,305 (99.5)	<0.0001
Lesion success by study stents (acute device success)	1,766/1,853 (95.3)	5,468/5,546 (98.6)	<0.0001	1,408/1,462 (96.3)	4,199/4,258 (98.6)	<0.0001	358/391 (91.6)	1,269/1,288 (98.5)	<0.0001
Procedural success (patient level)	1,454/1,507 (96.5)	4,455/4,583 (97.2)	0.15	1,176/1,208 (97.4)	3,470/3,550 (97.8)	0.43	278/299 (93)	985/1,033 (95.4)	0.10
Staged PCI procedures	371/1,507 (25)	1,167/4,583 (26)	0.51	282/1,208 (23)	861/3,550 (24)	0.52	89/299 (30)	306/1,033 (30)	0.96

Data are presented as number (%) or mean±SD. Stent implantation was not attempted in 17 patients (G1-DES: 9 patients; G2-DES: 8 patients) because of guidewire failure, undilatable lesion, or complications. Non-study stents were attempted without an attempt of implanting a study stent in 19 patients (G1-DES: 7 patients; G2-DES: 12 patients; protocol violation). RVD, reference vessel diameter; STEMI, ST-segment elevation myocardial infarction. Other abbreviations as in Table 1.

Clinical Outcomes: G1-DES vs. G2-DES

The cumulative 3-year incidence of the primary endpoint (any TLR) was not significantly different between the G1-DES and G2-DES groups of the entire study population or in both the Calc and Non-calc strata (Figure 2, Table 3). After adjusting for confounders, the effect of G2DES relative to G1-DES for any TLR remained insignificant in the entire study population and in both the Calc and Non-calc strata without any significant interaction between lesion calcification and the effect of G2-DES relative to G1-DES (Figure 3).

Figure 2.

Cumulative 3-year incidence of any TLR: G1-DES vs. G2-DES. (A) Entire study population, (B) Calc stratum, (C) Non-calc stratum. Calc, calcification; CI, confidence interval; G1-DES, 1st-generation drug-eluting stent; G2-DES, 2nd-generation drug-eluting stent; HR, hazard ratio; PCI, percutaneous coronary intervention; TLR, target-lesion revascularization.

Table 3. Clinical Outcomes at 3 Years: G1-DES vs. G2-DES

	Entire study population			Non-Calc stratum			Calc stratum
	No. of patients with event (cumulative incidence, %)			No. of patients with event (cumulative incidence, %)			No. of patients with event (cumulative incidence, %)
	G1-DES (n=1,507)	G2-DES (n=4,583)	P value	G1-DES (n=1,280)	G2-DES (n=3,550)	P value	G1-DES (n=299)	G2-DES (n=1,033)	P value
TLR
Any	114 (7.8)	308 (6.9)	0.24	79 (6.8)	212 (6.1)	0.44	35 (12.1)	96 (9.7)	0.22
Clinically-driven	88 (6.1)	223 (5.0)	0.11	59 (5.1)	159 (4.6)	0.50	29 (10.1)	64 (6.5)	0.03
TVR	159 (10.9)	459 (10.3)	0.52	117 (10.0)	324 (9.4)	0.51	42 (14.6)	135 (13.7)	0.69
Coronary revascularization
Any	291 (20.0)	893 (20.1)	0.98	220 (18.8)	655 (18.9)	0.96	71 (24.8)	238 (24.2)	0.78
CABG	20 (1.4)	52 (1.2)	0.54	14 (1.2)	33 (1.0)	0.47	6 (2.2)	19 (2.0)	0.85
Death
All-cause	108 (7.3)	314 (6.9)	0.66	70 (5.9)	198 (5.6)	0.74	38 (13.0)	116 (11.4)	0.51
Cardiac causes	41 (2.8)	114 (2.5)	0.61	22 (1.9)	56 (1.6)	0.55	19 (6.6)	58 (5.8)	0.65
MI
Any	68 (4.6)	176 (3.9)	0.24	43 (3.6)	109 (3.1)	0.39	25 (8.5)	67 (6.6)	0.26
Q wave	20 (1.4)	43 (1.0)	0.19	11 (0.9)	25 (0.7)	0.47	9 (3.1)	18 (1.8)	0.18
Target vessel	57 (3.8)	143 (3.2)	0.21	36 (3.0)	86 (2.4)	0.28	21 (7.2)	57 (5.4)	0.33
Hospitalization for heart failure	68 (4.7)	180 (4.1)	0.3	48 (4.1)	123 (3.6)	0.38	20 (7.0)	57 (5.8)	0.45
Stroke
Any	34 (2.3)	143 (3.2)	0.09	25 (2.1)	101 (2.9)	0.16	9 (3.1)	42 (4.3)	0.41
Ischemic	24 (1.6)	93 (2.1)	0.3	17 (1.5)	65 (1.9)	0.34	7 (2.4)	28 (2.9)	0.73
Hemorrhagic	11 (0.8)	53 (1.2)	0.16	9 (0.8)	39 (1.1)	0.3	2 (0.7)	14 (1.4)	0.34
Bleeding
TIMI major	57 (3.9)	136 (3.1)	0.11	45 (3.8)	102 (3.0)	0.13	12 (4.2)	34 (3.5)	0.54
TIMI minor/major	82 (5.6)	196 (4.4)	0.06	61 (5.2)	141 (4.1)	0.10	21 (7.5)	55 (5.6)	0.28
TIMI minimal/minor/major	105 (7.3)	328 (7.4)	0.88	80 (6.8)	233 (6.7)	0.91	26 (9.2)	95 (9.5)	0.76
GUSTO severe	53 (3.6)	135 (3.0)	0.26	41 (3.5)	96 (2.8)	0.21	12 (4.2)	39 (3.9)	0.85
GUSTO moderate/severe	79 (5.4)	195 (4.4)	0.11	59 (5.0)	135 (3.9)	0.09	20 (7.1)	60 (6.0)	0.59
Death or MI	166 (11.1)	455 (10.0)	0.21	110 (9.2)	293 (8.3)	0.33	56 (19.0)	162 (15.8)	0.22
Device-oriented composite endpoint	192 (13.0)	509 (11.3)	0.07	129 (10.9)	327 (9.4)	0.12	63 (21.4)	182 (17.9)	0.17
Patient-oriented composite endpoint	418 (28.0)	1,227 (27.0)	0.4	309 (25.8)	871 (24.7)	0.39	109 (36.9)	356 (34.7)	0.51
TLF	168 (11.4)	429 (9.5)	0.04	110 (9.3)	277 (7.9)	0.14	58 (19.8)	152 (15.0)	0.051
TVF	203 (13.8)	545 (12.1)	0.1	139 (11.8)	359 (10.3)	0.16	64 (21.9)	186 (18.3)	0.19
MACE	178 (12.1)	454 (10.1)	0.03	117 (9.9)	296 (8.5)	0.14	61 (20.8)	158 (15.6)	0.04
ST
Definite ST	7 (0.5)	16 (0.4)	0.52	3 (0.3)	9 (0.3)	0.98	4 (1.4)	7 (0.7)	0.27
Possible	20 (1.4)	70 (1.6)	0.59	11 (1.0)	39 (1.1)	0.60	9 (3.2)	31 (3.2)	1.0
Definite or probable	10 (0.7)	18 (0.4)	0.18	5 (0.4)	9 (0.3)	0.37	5 (1.8)	9 (0.9)	0.24
Definite, probable, or possible	30 (2.1)	86 (1.9)	0.76	16 (1.4)	47 (1.4)	0.98	14 (4.9)	39 (4.0)	0.49

Cumulative incidences were estimated by the Kaplan-Meier method. GUSTO, Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries; MACE, major adverse cardiac event; ST, stent thrombosis; TIMI, Thrombolysis in Myocardial Infarction; TLF, target-lesion failure; TLR, target-lesion revascularization; TVF, target-vessel failure; TVR, target-vessel revascularization. Other abbreviations as in Table 1.

Figure 3.

Forest plot for the adjusted HRs of G2-DES relative to G1-DES for clinical outcomes in the entire study population, and in the Calc and Non-calc strata. Other covariates included in the models were study type, age ≥75 years, diabetes mellitus, insulin-treated diabetes, dialysis, heart failure, multivessel treatment, and culprit vessel for STEMI. MACE, major adverse cardiac events; MI, myocardial infarction; STEMI, ST-segment elevation MI; TLR, target-lesion revascularization. Other abbreviations as in Figure 2.

Regarding the secondary endpoints in the entire study population, the cumulative 3-year incidences of MACE and TLF were significantly lower in G2DES than in G1-DES (Table 3). After adjusting for confounders, the lower risk of G2DES relative to G1-DES for MACE, TLF, and TVF was significant (Figure 3). In the Calc stratum, the cumulative 3-year incidences of clinically-driven TLR and MACE were significantly lower with G2DES than with G1-DES (Table 3). After adjusting for confounders, the lower risk of G2DES relative to G1-DES for MACE was significant. The cumulative incidence of definite ST was extremely low and not significantly different between the G1-DES and G2-DES groups in the entire study population or in both the Calc and Non-calc strata (Table 3). There was no significant interaction between lesion calcification and the effect of G2-DES relative to G1-DES for all the endpoints evaluated (Figure 3).

Baseline Characteristics: Non-Calc vs. Calc

Of the total of 6,090 patients, the Calc stratum included 1,332 patients (21.9%). Patients in the Calc stratum were older and more often had complex lesions as represented by a higher prevalence of previous coronary artery bypass grafting, and multivessel disease, and higher SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) scores and comorbidities such as heart failure, dialysis, and anemia than patients in the Non-calc stratum in both the entire study population and for each generation of DES. Rotational atherectomy was almost exclusively used in the Calc stratum (15% in the entire Calc stratum) (Tables S1,S2).

Clinical Outcomes: Non-Calc vs. Calc

In the entire study population and in each generation of DES, the cumulative 3-year incidences of adverse outcomes such as any TLR, death or MI, TLF, TVF, MACE, and definite ST were significantly higher in the Calc stratum than in the Non-calc stratum. After adjusting for confounders, the higher risk of the Calc stratum relative to the Non-calc stratum in the entire study population remained significant for any TLR, death or MI, TLF, TLF, and MACE (Figure 4, Table 4).

Figure 4.

Clinical outcomes at 3 years in the entire study population and in each DES generation: Non-calc stratum vs. Calc stratum. (A) Any TLR, (B) Death or MI, (C) MACE, (D) Definite ST. ST, stent thrombosis. Other abbreviations as in Figures 1,3.

Table 4. Clinical Outcomes at 3 Years in the Entire Study Population and in Each Generation of DES: Non-Calc vs. Calc Strata

	No. of patients with event (cumulative incidence, %)		P value	Unadjusted HR (95% CI)	P value	Adjusted HR (95% CI)	P value	Interaction P value
	Non-Calc	Calc
Any TLR
Total	291 (6.3)	131 (10.3)	<0.0001	1.7 (1.38–2.1)	<0.0001	1.38 (1.11–1.71)	0.004	0.55
G1-DES	79 (6.8)	35 (12.1)	0.001	1.89 (1.27–2.81)	0.002	1.52 (0.98–2.25)	0.06
G2-DES	212 (6.1)	96 (9.7)	<0.0001	1.64 (1.29–2.09)	<0.0001	1.35 (1.05–1.73)	0.02
Death or MI
Total	403 (8.5)	218 (16.5)	<0.0001	2.03 (1.72–2.4)	<0.0001	1.58 (1.33–1.88)	<0.001	0.67
G1-DES	110 (9.2)	56 (19)	<0.0001	2.17 (1.57–2.99)	<0.0001	1.60 (1.14–2.23)	0.007
G2-DES	293 (8.3)	162 (15.8)	<0.0001	2 (1.65–2.42)	<0.0001	1.58 (1.29–1.92)	<0.001
MACE
Total	413 (8.8)	219 (16.7)	<0.0001	2 (1.7–2.36)	<0.0001	1.64 (1.38–1.95)	<0.001	0.41
G1-DES	117 (9.9)	61 (20.8)	<0.0001	2.26 (1.65–3.07)	<0.0001	1.83 (1.32–2.51)	<0.001
G2-DES	296 (8.5)	158 (15.6)	<0.0001	1.93 (1.59–2.34)	<0.0001	1.58 (1.29–1.93)	<0.001
Definite ST
Total	12 (0.3)	11 (0.9)	0.002	3.36 (1.48–7.62)	0.004	NA	NA	NA
G1-DES	3 (0.3)	4 (1.4)	0.01	5.49 (1.23–24.5)	0.03	NA	NA
G2-DES	9 (0.3)	7 (0.7)	0.04	2.76 (1.03–7.4)	0.04	NA	NA
TLF
Total	387 (8.3)	210 (16.1)	<0.0001	2.04 (1.73–2.42)	<0.0001	1.67 (1.40–1.98)	<0.001	0.48
G1-DES	110 (9.3)	58 (19.8)	<0.0001	2.27 (1.65–3.11)	<0.0001	1.82 (1.30–2.53)	<0.001
G2-DES	277 (7.9)	152 (15)	<0.0001	1.98 (1.63–2.42)	<0.0001	1.62 (1.31–1.98)	<0.001
TVF
Total	498 (10.7)	250 (19.1)	<0.0001	1.91 (1.64–2.22)	<0.0001	1.59 (1.36–1.86)	<0.001	0.78
G1-DES	139 (11.8)	64 (21.9)	<0.0001	1.99 (1.48–2.68)	<0.0001	1.64 (1.20–2.22)	0.002
G2-DES	359 (10.3)	186 (18.3)	<0.0001	1.89 (1.58–2.26)	<0.0001	1.58 (1.31–1.89)	<0.001

Cumulative incidences were estimated by the Kaplan-Meier method. Effect of treatment is expressed as HR with 95% CI by Cox proportional hazard models. CI, confidence interval; HR, hazard ratio; NA, not assessed. Other abbreviations as in Table 3.

Discussion

The 2 main findings of the present study were as follows. (1) The effect of G2-DES relative to G1-DES for TLR was not significantly different, regardless of the presence or absence of lesion calcification, although the rate of TLR in patients with lesion calcification was numerically lower with G2-DES than with G1-DES. (2) Patients with moderately to severely calcified lesions treated with G1- or G2-DES as assessed by the independent angiography core laboratory had worse clinical outcomes during 3-year follow-up than those with no or mild calcified lesions.

Patients with moderately or severely calcified lesions have been excluded from enrollment in most pivotal DES trials.^27–29 Moreover, most all-comer randomized trials have not analyzed coronary calcification at an angiography core laboratory. Therefore, there have been only a few previous observational studies that have investigated the efficacy of DES in calcified lesions,^14,16–18 and these have suggested that lesion calcification is associated with worse clinical outcome. The prevalence of lesion calcification was reported to be 19–32% in recent pooled analyses and meta-analyses of studies in patients with different clinical presentations.^14–18 Calcified lesions were slightly low, at 21.9%, in the present study, suggesting that the population of this study might have had a lower risk profile than previous studies, although both the RESET and NEXT had an all-comer study design. Nevertheless, worse clinical outcomes in patients with calcified lesions were observed in the present study, in which a large number of patients with moderate to severe calcification in real-world clinical practice were treated with G1-DES and G2-DES.

CAC is known to be associated with advanced age, male sex, diabetes mellitus, hypertension, smoking, STEMI, and renal dysfunction.^14,30 It is also considered to be a marker of advanced atherosclerosis; thus, there was a large difference in the comorbidities and lesion complexity between patients with and without CAC in the present study. Therefore, the worse clinical outcomes in patients with lesion calcification may indicate that CAC is associated with a more extensive coronary, as well as systemic, atherosclerotic burden. Furthermore, a possible explanation for the worse stent-related outcomes is that inadequate stent expansion, stent mal-apposition, and polymer damage, which occur frequently in calcified lesions, may lead to less acute gain and more late loss because of excessive neointimal proliferation.

Several previous meta-analyses have clearly demonstrated the markedly lower ST risk with G2-DES, EES in particular, as compared with G1-DES as well as bare-metal stents (odds ratio: 0.26–0.48).^31,32 A previous meta-analysis comparing a G2-DES (EES) with a G1-DES (SES) also demonstrated a significantly lower TLR risk with the EES (odds ratio: 0.83, P=0.03); however, the magnitude of risk reduction for TLR was much smaller than for ST.²² In the present study, we could not demonstrate the superiority of G2-DES over G1-DES for the prevention of TLR in the entire study population; however, the magnitude of risk reduction for TLR in the present study (HR: 0.78) was not different from that in the previous meta-analysis. Therefore, the negative TLR result in the present study may be a type II error caused by a lack of adequate statistical power, but G2-DES were associated with a significantly lower risk for the secondary composite endpoints than G1-DES.

This is the first report comparing the mid-term clinical outcomes of a large number of patients treated with G1-DES or G2-DES according to the presence or absence of CAC. G2-DES have improved safety through the use of a polymer with improved biocompatibility and improved stent performance, such as deliverability, flexibility, and stent strut thickness.^22,31,32 We hypothesized that the improved deliverability of G2-DES as compared with G1-DES might lead to less damage to the polymer, particularly in calcified lesions, and, therefore, the efficacy of G2-DES relative to G1-DES for preventing restenosis might be more prominent in calcified lesions than in non-calcified lesions. Also, optimal apposition often cannot be achieved in calcified lesions, which might lead to diminished tissue concentration of the antiproliferative drugs.^33–35 A current meta-analysis showed that the frequency of stent mal-apposition detected by optical coherence tomography may be lower in patients implanted with G2-DES³⁵ because these stents are thinner and more flexible than G1-DES. However, the magnitude of the effect of G2-DES relative to G1-DES for TLR and the secondary composite endpoints was not different between calcified and non-calcified lesions. Polymer damage caused by calcified lesions treated with G1-DES might not be a clinically relevant cause of DES restenosis. Alternatively, a calcified lesion might damage the polymer, and G2-DES may also suffer from polymer damage despite their improved deliverability.^7,8 Also, the extent of mal-apposition may not be related to DES restenosis, because a previous report suggested that the incidence of clinical events was low and similar regardless of stent mal-apposition detected by optimal coherence tomography and/or intravascular ultrasound.^33,34 Alternatively, the extent of mal-apposition may be different between G1-DES and G2-DES in non-calcified lesions, but not in calcified lesions.

Study Limitations

There are several to note. First, the timing, treatment strategy, case selection, lesion morphology, and treatment in the 2 randomized trials from which the data were pooled for analysis were different. However, both trials were performed with the same protocols in the same Japanese centers during almost the same time period. Therefore, heterogeneity is likely minimal. Second, despite being a pooled analysis of 2 large DES-vs.-DES trials, the current analysis did not have adequate power to compare TLR risk between G1-DES and G2-DES. In particular, the number of cases of G1-DES with calcified lesions was small in the subgroup. Third, despite the all-comers design of RESET and NEXT, the study population analyzed mainly comprised patients with low SYNTAX scores and stable angina; thus, patient with intermediate to high SYNTAX scores with calcified lesions were not adequately analyzed. Finally, lesion calcification was classified using coronary angiography, which is less sensitive than gray-scale intravascular ultrasound or optimal coherence tomography. Moreover, the distribution or extent of either intimal or medial lesion calcification was not evaluated.

Conclusions

The effect of G2-DES relative to G1-DES for TLR was not significantly different regardless of the presence or absence of lesion calcification, although the rate of TLR in patients with lesion calcification was numerically lower with G2-DES than with G1-DES.

Acknowledgments

The authors appreciate the efforts of the members of the cardiac catheterization laboratory and clinical research coordinators in the participating centers.

Disclosures

K. Kozuma has served on the advisory boards of Abbott Vascular and Terumo and has received lecture fees from Abbott Vascular and Terumo. K. Kadota has received honoraria from Abbott Vascular and Terumo and has served on the advisory boards of Abbott Vascular. K. Tanabe has served on the advisory board of Terumo Japan and Abbott Vascular. Y. Morino has served on the advisory board of Abbott Vascular and Terumo. T. Kimura has served on the advisory board of Terumo and Abbott Vascular. The other authors report no conflicts of interest.

Names of Grants

This work was supported by Abbott Vascular Japan and Terumo.

Supplementary Files

Supplementary File 1

Appendix S1. Study Organization

Appendix S2. List of Participating Centers and the Investigators in RESET and NEXT

Appendix S3. Definitions of Endpoints

Figure S1. Persistent discontinuation of dual antiplatelet therapy in (A) the entire study population, (B) Calc stratum and (C) non-Calc stratum.

Table S1. Patient characteristics in the entire study population and in each DES generation: non-Calc vs. Calc

Table S2. Lesion and procedural characteristics in the entire study population and in each generation of DES: non-Calc vs. Calc

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-0746

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