Drug-Eluting or Bare-Metal Stents for Left Anterior Descending or Left Main Coronary Artery Revascularization.

Background New-generation drug-eluting stents (DES) reduce target-vessel revascularization compared with bare-metal stents (BMS), and recent data suggest that DES have the potential to decrease the risk of myocardial infarction and cardiovascular mortality. We evaluated the treatment effect of DES versus BMS according to the target artery (left anterior descending [LAD] and/or left main [LM] versus other territories [no-LAD/LM]). Methods and Results The Coronary Stent Trialist (CST) Collaboration gathered individual patient data of randomized trials of DES versus BMS for the treatment of coronary artery disease. The primary outcome was the composite of cardiac death or myocardial infarction. Hazard ratios (HRs) with 95% CIs were derived from a 1-stage individual patient data meta-analysis. We included 26 024 patients across 19 trials: 13 650 (52.4%) in the LAD/LM and 12 373 (47.6%) in the no-LAD/LM group. At 6-year follow-up, there was strong evidence that the treatment effect of DES versus BMS depended on the target vessel (P-interaction=0.024). Compared with BMS, DES reduced the risk of cardiac death or myocardial infarction to a greater extent in the LAD/LM (HR, 0.76; 95% CI, 0.68-0.85) than in the no-LAD/LM territories (HR, 0.93; 95% CI, 0.83-1.05). This benefit was driven by a lower risk of cardiac death (HR, 0.83; 95% CI, 0.70-0.98) and myocardial infarction (HR, 0.74; 95% CI, 0.65-0.85) in patients with LAD/LM disease randomized to DES. An interaction (P=0.004) was also found for all-cause mortality with patients with LAD/LM disease deriving benefit from DES (HR, 0.86; 95% CI, 0.76-0.97). Conclusions As compared with BMS, new-generation DES were associated with sustained reduction in the composite of cardiac death or myocardial infarction if used for the treatment of LAD or left main coronary stenoses. Registration URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42017060520.

bare‐metal stent

drug‐eluting stent

individual patient data

left main

target‐vessel revascularization

Clinical Perspective

What Is New?

Patients undergoing percutaneous coronary intervention in the territory of the left main or left anterior descending artery are at increased risk of cardiac death or myocardial infarction.

What Are the Clinical Implications?

In about 26 000 patients randomized to new‐generation drug‐eluting stents or bare‐metal stents, randomization to drug‐eluting stents was associated with a stronger reduction in the risk of cardiac death or myocardial infarction when stents were implanted in the territory of the left main or left anterior descending artery compared with other territories.

Myocardial revascularization by means of percutaneous coronary intervention (PCI) has a central role in the management of patients with coronary artery disease. Among patients undergoing PCI, lumen narrowing at the left anterior descending (LAD) coronary artery is reported to be as frequent as 40%, rendering the LAD artery the most common target vessel requiring coronary stenting. While left main (LM) coronary stenoses were traditionally regarded as an indication for surgical revascularization, more recent studies using first‐ or newer‐generation drug‐eluting stents (DES) showed similar outcomes on hard end points compared with coronary artery bypass grafting in patients with mild to moderate complexity/extension of coronary artery disease. ,

The extent of myocardium subtended to the LAD, and even more for LM systems, amounts to as much as 50% to 60% of the left ventricle and, as a result, significant LAD/LM disease is associated with impaired prognosis compared with coronary disease in other territories. , Contemporary, new‐generation DES are recommended over bare‐metal stents (BMS) in patients undergoing PCI for all lesions and patient subsets. In an individual patient data (IDP) analysis including all available randomized trials, we found that new‐generation DES reduced the risk of cardiac death or myocardial infarction (MI) compared with BMS mainly if used to treated the LAD territory. In the present analysis, we leveraged the data from the Coronary Stent Trialists (CST) Collaboration to thoroughly investigate the efficacy and safety of new‐generation DES in patients undergoing PCI in the LAD and/or LM artery compared with other territories.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Design and Patient Population

Methodological aspects of the present individual patient data (IPD) analysis were reported elsewhere, and the study was registered online in the PROSPERO (International Prospective Register of Systematic Reviews; http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017060520). Briefly, the CST Collaboration includes all randomized clinical trials comparing new‐generation DES versus BMS in patients undergoing PCI. The search algorithm of the study is provided in Data S1. All principal investigators provided IPD using an anonymized electronic data set (Data S1). Data were checked for completeness and consistency, and were compared with the results of original publications. New‐generation DES were identified as any DES subsequent to the Cypher sirolimus‐eluting stent (Cordis, Miami Lakes, FL) and the Taxus paclitaxel‐eluting stent (Boston Scientific, Natick, MA).

The present study was designed to evaluate the outcomes associated with DES versus BMS among patients undergoing PCI in the LAD/LM arteries compared with the target vessels. For the purpose of this analysis, we excluded patients with missing information on the intervened vessel as well as studies contributing only to 1 group (LAD/LM versus non‐LAD/LM) aiming to compare the risks of events within each trial and minimize the risk of heterogeneity across studies influencing the results (ecological bias).

All trials complied with the provisions of the Declaration of Helsinki, and the ethics committees at each study center approved the study protocols. All patients provided written informed consent for participation in the individual studies.

Outcomes

The prespecified primary outcome in this analysis was the time to first occurrence of composite of cardiac death or MI. Secondary outcomes included the time to first occurrence of all‐cause death, cardiac death, MI, target‐vessel revascularization (TVR), and definite stent thrombosis. Outcomes were analyzed at the longest available follow‐up in the primary analysis, as well as at 5‐ and 1‐year follow‐up and with a 30‐day and 1‐year landmark. End point definitions in each trial are reported in Data S1.

Statistical Analysis

Continuous variables were summarized by their means and SD across all included patients. Categorical variables were summarized by the corresponding counts and percentages.

The risk of adverse events among patients undergoing PCI in the LAD/LM versus no‐LAD/LM was evaluated by using a multivariable Cox regression model adjusted for clinically relevant variables, including age, sex, smoking, hypertension, hyperlipidemia, diabetes, previous MI, previous PCI, previous coronary artery bypass grafting, clinical presentation, and multivessel disease. All outcomes were analyzed using time‐to‐event analysis and according to the intention‐to‐treat principle (ie, patients were analyzed according to the allocated treatment to DES or BMS). We first summarized the data using unadjusted Kaplan‐Meier estimates at the longest available follow‐up. We then performed a series of IPD meta‐analyses. For all analyses, the pooled risk estimates were expressed as hazard ratios (HRs) with 95% CIs. We used a 1‐stage fixed‐effect model by using Cox regression analyses stratified by trial with robust estimator of variance. Heterogeneity was calculated with the I2 statistics from a 2‐stage meta‐analysis. As a guide, I2 values <25% indicated low, 25% to 50% indicated moderate, and >50% indicated high heterogeneity. Two landmark analyses were performed: (1) an analysis with 1 landmark time point, calculating HRs between 0 and 365 days versus HRs >365 days; and (2) an analysis with 2 landmark time points, calculating HRs between 0 and 30 days versus HRs between 31 and 365 days versus HRs >365 days. As sensitivity analysis, we evaluated the treatment effect of DES versus BMS in LAD and LM groups, separately, as well as in patients receiving a new‐generation DES (ie, after the exclusion of early‐generation DES). Finally, we performed a 2‐stage meta‐analysis using the DerSimonian‐Laird random‐effects model.

All P values we calculated were based on 2‐sided tests. We used Stata Statistical Software, release 14 (StataCorp LP, College Station, TX).

Results

From the initial 26 616 participants, we excluded 408 patients from one trial because PCI was exclusively performed in saphenous vein grafts and 185 patients across 12 trials because of missing information on the target vessel. Therefore, the final population consists of 26 023 patients enrolled across 19 trials, of whom 13 650 (52.4%) belonged to the LAD/LM group and 12 373 (47.6%) to the no‐LAD/LM group. , , , , , , , , , , , , , , , , , , In the LAD/LM group, 12 037 (46.3%) patients received stenting in the LAD, 1369 (5.3%) patients underwent stenting in the LM and 244 (0.9%) in both coronary territories. Data S1 describes study characteristics, patient populations, and the definitions used for outcomes (Tables S1 through S3). In the LAD/LM group, 7346 (53.8%) were randomized to DES and 6304 (46.2%) were randomized to BMS; in the no‐LAD/LM group, 6521 (52.7%) were randomized to DES and 5852 (47.3%) were randomized to BMS. Baseline clinical characteristics were largely balanced between the 2 study groups (Table 1). Mean age between groups varied between 64.9 and 66.6 years. About 74% of patients were men, and about 19% had diabetes. Approximately 50% of patients had MI with or without ST‐segment elevation at the time of the index PCI. Types of implanted devices are listed in Table S4. In both groups, patients randomized to BMS tended to receive stents with larger diameters and shorter lengths. The majority of patients received thin‐strut stents (<100 μm); yet DES‐treated patients more frequently received thick‐strut stents (≥100 μm) as compared with those allocated to BMS irrespective of lesion location. Duration of dual antiplatelet therapy was longer (on average 45–55 days) in patients randomized to DES in both LAD/LM and no‐LAD/LM groups. The mean (±SD) follow‐up time was 3.1±1.8 years (median, 2.1; interquartile range, 1.9–4.9). Table S5 provides details on the risk of bias assessment. Overall, trials were judged at low risk of bias, although blinding of patients and performing physicians was done only in 2 trials.

Table 1

Clinical and Procedural Characteristics Stratified by Type of Presentation and Randomization

	Patients with LAD/LM (n=13 650)		Patients without LAD/LM (n=12 373)
	DES (n=7346)	BMS (n=6304)	DES (n=6521)	BMS (n=5852)
Age, y	n=7344, 66.1±12.5	n=6302, 66.6±12.7	n=6521, 64.9±11.9	n=5852, 65.5±12.0
Male, n (%)	n=7346, 5481 (74.6)	n=6304, 4633 (73.5)	n=6521, 4897 (75.1)	n=5852, 4317 (73.8)
Smokers, n (%)	n=7154, 1939 (27.1)	n=6098, 1703 (27.9)	n=6298, 2315 (36.8)	n=5664, 2078 (36.7)
Hypertension, n (%)	n=7326, 4331 (59.1)	n=6285, 3681 (58.6)	n=6502, 3784 (58.2)	n=5828, 3362 (57.7)
Hyperlipidemi, n (%)a	n=7198, 4029 (56.0)	n=6167, 3436 (55.7)	n=6349, 3741 (58.9)	n=5676, 3236 (57.0)
Diabetes, n (%)	n=7332, 1401 (19.1)	n=6295, 1159 (18.4)	n=6512, 1265 (19.4)	n=5844, 1055 (18.1)
Insulin‐treated	n=1383, 226 (16.3)	n=1134, 191 (16.8)	n=1231, 198 (16.1)	n=1067, 151 (14.2)
Previous MI, n (%)	n=7324, 968 (13.2)	n=6289, 859 (13.7)	n=6500, 1077 (16.6)	n=5829, 954 (16.4)
Previous PCI, n (%)	n=5328, 849 (15.9)	n=4295, 738 (17.2)	n=4420, 954 (21.6)	n=3825, 867 (22.7)
Previous CABG, n (%)	n=7339, 247 (3.4)	n=6302, 221 (3.5)	n=6519, 514 (7.9)	n=5852, 446 (7.6)
Indication to PCI, n (%)
Stable CAD	n=7257, 2165 (29.8)	n=6235, 1857 (29.8)	n=6469, 1794 (27.7)	n=5786, 1586 (27.4)
Unstable angina	n=7320, 1068 (14.6)	n=6272, 995 (15.9)	n=6491, 849 (13.1)	n=5819, 782 (13.4)
Non–ST‐elevation MI	n=7277, 1858 (25.5)	n=6260, 1601 (25.6)	n=6495, 1566 (24.1)	n=5812, 1485 (25.6)
ST‐elevation MI	n=7255, 1994 (27.5)	n=6235, 1620 (26.0)	n=6466, 2095 (32.4)	n=5784, 1793 (31.0)
Glycoprotein IIb/IIIa receptor inhibitors, n (%)	n=6454, 1367 (21.2)	n=5530, 1132 (20.5)	n=5705, 1392 (24.4)	n=5118, 1189 (23.2)
Multivessel disease	n=7127, 3271 (45.9)	n=6091, 2633 (43.2)	n=6190, 2398 (38.7)	n=5517, 2003 (36.3)
Number of implanted stents	n=7341, 1.7±1.1	n=6295, 1.7±1.1	n=6512, 1.5±0.9	n=5842, 1.5±0.8
Total stent length, mm	n=7310, 29.8±21.5	n=6259, 27.7±19.3	n=6468, 26.9±17.1	n=5802, 25.9±16.8
Mean stent diameter, mm	n=7311, 3.2±0.5	n=6257, 3.2±0.5	n=6467, 3.3±0.6	n=5801, 3.3±0.7
Overlapping stent	n=6982, 1284 (18.4)	n=5963, 1109 (18.6)	n=6238, 1090 (17.5)	n=5542, 1010 (18.2)
Number of stented segments, n (%)	n=7345	n=6301	n=6518	n=5850
0	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.0)
1	4936 (67.2)	4271 (67.8)	5211 (79.9)	4661 (79.7)
2	1684 (22.9)	1432 (22.7)	1047 (16.1)	988 (16.9)
3	537 (7.3)	433 (6.9)	208 (3.2)	165 (2.8)
4	140 (1.9)	114 (1.8)	47 (0.7)	27 (0.5)
5	37 (0.5)	44 (0.7)	3 (0.0)	8 (0.1)
6	9 (0.1)	6 (0.1)	1 (0.0)	0 (0.0)
7	2 (0.0)	1 (0.0)	1 (0.0)	0 (0.0)
Target‐vessel location, n (%)
Left main artery	n=7346, 1022 (13.9)	n=6304, 591 (9.4)	n=6521, 0 (0.0)	n=5852, 0 (0.0)
Left anterior descending artery	n=7346, 6476 (88.2)	n=6304, 5805 (92.1)	n=6521, 0 (0.0)	n=5852, 0 (0.0)
Left circumflex artery	n=7346, 1117 (15.2)	n=6304, 907 (14.4)	n=6521, 2930 (44.9)	n=5852, 2526 (43.2)
Right coronary artery	n=7346, 1127 (15.3)	n=6303, 897 (14.2)	n=6521, 4133 (63.4)	n=5852, 3777 (64.5)
Type of DES, n (%)
Everolimus‐eluting stent	n=7335, 3925 (53.5)	…	n=6508, 3536 (54.4)	…
Biolimus‐eluting stent	n=7335, 1463 (20.0)	…	n=6508, 1178 (18.1)	…
Zotarolimus‐eluting stent	n=7335, 1207 (16.5)	…	n=6508, 1169 (17.9)	…
Sirolimus‐eluting stent	n=7335, 339 (4.6)	…	n=6508, 325 (5.0)	…
Other	n=7335, 394 (5.4)	…	n=6508, 305 (4.6)	…
Type of polymer, n (%)	n=7180	…	n=6375	…
Permanent‐polymer DES	5188 (72.3)	…	4765 (74.7)	…
Biodegradable‐polymer DES	1305 (18.2)	…	1076 (16.9)	…
Polymer‐free DES	687 (9.6)	…	534 (8.4)	…
Thin‐strut stent (<100 μm), n (%)	n=7335, 5772 (78.7)	n=6298, 5339 (84.8)	n=6508, 5223 (80.3)	n=5838, 4953 (84.8)
Type of P2Y12 receptor inhibitor, n (%)	n=6719	n=5750	n=5761	n=5247
None	0 (0.0)	2 (0.0)	1 (0.0)	1 (0.0)
Clopidogrel	5475 (81.5)	5060 (88.0)	5081 (88.2)	4804 (91.6)
Ticagrelor	53 (0.8)	32 (0.6)	36 (0.6)	30 (0.6)
Prasugrel	1191 (17.7)	656 (11.4)	643 (11.2)	412 (7.9)
Duration of DAPT, d	n=6492, 290±185	n=5477, 235±181	n=5519, 292±177	n=4950, 248±173

BMS indicates bare‐metal stent; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DES, drug‐eluting stent; LAD, left anterior descending artery; LM, left main artery; MI, myocardial infarction; and PCI, percutaneous coronary intervention.

Outcomes in Patients Undergoing PCI on LAD/LM Versus No‐LAD/LM Artery

As depicted in Figure 1 and Figure S1, the multivariable regression model showed that patients undergoing PCI in the LAD/LM artery had a higher risk of the primary outcome of cardiac death or MI compared with those undergoing PCI in other vessels (16.11% versus 14.67%; adjusted HR, 1.18; 95% CI, 1.06–1.32; P=0.003). This risk increase emerged at 1 year and remained significant throughout the follow‐up period. The risks of cardiac death, MI, TVR, and definite stent thrombosis were all higher in patients undergoing PCI in the LAD/LM artery. However, there was no evidence of a difference between the LAD/LM versus the no‐LAD/LM group in terms of all‐cause mortality.

Figure 1

Clinical outcomes in patients undergoing percutaneous coronary intervention in the LAD/LM vs no‐LAD/LM territory.

Squares indicate the HR (black for the longest follow‐up, white for 5‐ and 1‐year follow‐up) and bars indicate 95% CI. HR indicates hazard ratio; LAD, left anterior descending artery; LM, left main artery; MI, myocardial infarction; and TVR, target‐vessel revascularization.

Treatment Effect of DES Versus BMS by Target‐Vessel Location

There was evidence for interaction (P=0.024) between randomized treatment (DES versus BMS) and the intervened artery (LAD/LM versus no‐LAD/LM) with respect to the primary outcome of cardiac death or MI (Figures 2, 3 Panels A‐B). At longest follow‐up, DES, as compared with BMS, were associated with a greater reduction in the risk of cardiac death or MI in the LAD/LM (HR, 0.76; 95% CI, 0.68–0.85; P<0.001) than the no‐LAD/LM territory (HR, 0.93; 95% CI, 0.83–1.05; P=0.241). For the individual components of the primary outcome (Figures 2 and 3 Panels C‐F), although interaction testing was not significant, DES were associated with a lower risk of cardiac death (HR, 0.83; 95% CI, 0.70–0.98; P=0.030; P‐interaction=0.135) and MI (HR, 0.74; 95% CI, 0.65–0.85; P<0.001; P‐interaction=0.077) in the LAD/LM group. Heterogeneity in the treatment effect of DES versus BMS was more evident at 1‐year follow‐up, resulting in a significant interaction for both cardiac death (HR, 0.72; 95% CI, 0.58–0.88 in LAD/LM versus HR, 1.09; 95% CI, 0.83–1.42 in no‐LAD/LM; P‐interaction=0.022) and MI (HR, 0.55; 95% CI, 0.46–0.66 in LAD/LM versus HR, 0.74; 95% CI, 0.60–0.91 in no‐LAD/LM; P‐interaction=0.041).

Figure 2

Effect of drug‐eluting stents (DES) vs bare‐metal stents (BMS) in patients undergoing percutaneous coronary intervention in the LAD/LM vs no‐LAD/LM territory.

Data are shown at maximum, 5‐y, and 1‐y follow‐up. HR indicates hazard ratio; LAD, left anterior descending artery; LM, left main artery; MI, myocardial infarction; and TVR, target‐vessel revascularization.

Figure 3

Kaplan‐Meier curves for the primary outcome of cardiac death or myocardial infarction and its components in patients undergoing percutaneous coronary intervention in the LAD/LM vs no‐LAD/LM territory and randomized to new‐generation drug‐eluting stents (red line) or bare‐metal stents (blue line).

BMS indicates bare‐metal stents; DES, drug‐eluting stents; HR, hazard ratio; LAD, left anterior descending artery; and LM, left main artery.

At maximum follow‐up, we found also strong evidence for an interaction (P=0.004) with respect to all‐cause mortality (Figures 2 and 4 Panels A‐B), which was significantly reduced with DES among patients undergoing PCI in the LAD/LM artery (HR, 0.86; 95% CI, 0.76–0.97; P=0.013) but not among patients undergoing PCI in other vessels (HR, 1.12; 95% CI, 0.98–1.28; P=0.086). The interaction effect for all‐cause mortality was stronger at 1‐year follow‐up (P‐interaction=0.001) with a signal of benefit (HR, 0.77; 95% CI, 0.65–0.91) and harm (HR, 1.24; 95% CI, 1.01–1.53) with DES instead of BMS in the LAD/LM versus no‐LAD/LM arteries, respectively.

Figure 4

Kaplan‐Meier curves for the secondary outcomes in patients undergoing percutaneous coronary intervention in the LAD/LM vs no‐LAD/LM territory and randomized to new‐generation drug‐eluting stents (red line) or bare‐metal stents (blue line).

BMS indicates bare‐metal stent; DES, drug‐eluting stents; HR, hazard ratio; LAD, left anterior descending artery; LM, left main artery; and ST, stent thrombosis.

As shown in Figures 2 and 4, a consistently beneficial effect of DES, as compared with BMS, with regard to target‐vessel revascularization (P‐interaction=0.329) was found in both LAD/LM (HR, 0.53; 95% CI, 0.47–0.59) and no‐LAD/LM group (HR, 0.56; 95% CI, 0.49–0.64). The risk of definite stent thrombosis was also similarly reduced by DES (P‐interaction=0.721) in the LAD/LM (HR, 0.61; 95% CI, 0.44–0.83) and no‐LAD/LM artery (HR, 0.64; 95% CI, 0.44–0.93).

Landmark Analyses

In the landmark analyses (Table 2), analyzing the HRs from 0 to 365 days and from 365 days to the end of follow‐up, we found that the heterogeneity by vessel location was mainly attributable to stronger effects of DES in the LAD/LM group within the first year after PCI. In a sensitivity analysis with 2 landmark points, the time window of greatest benefit from DES instead of BMS for the LAD/LM vessels was observed from 1 to 12 months after PCI (Table S6).

Table 2

Landmark Analysis at 1‐Year Follow‐Up

	Patients with LAD/LM (n=13 650)				Patients without LAD/LM (n=12 373)				P‐interaction between subgroups
	DES (n=7346)	BMS (n=6304)	HR (95% CI)	P value	DES (n=6521)	BMS (n=5852)	HR (95% CI)	P value
Cardiac death or MI
0–365 d	446 (6.12)	573 (9.17)	0.62 (0.53–0.71)	<0.001	362 (5.61)	375 (6.46)	0.85 (0.72–1.01)	0.059	0.008
>365 d	262 (9.14)	226 (9.42)	1.06 (0.89–1.27)	0.503	277 (9.04)	255 (9.44)	1.02 (0.86–1.22)	0.788	0.823
All‐cause death
0–365 d	255 (3.50)	296 (4.73)	0.77 (0.65–0.91)	0.003	228 (3.53)	172 (2.96)	1.24 (1.01–1.53)	0.037	0.001
>365 d	258 (7.60)	251 (7.98)	0.96 (0.80–1.14)	0.62	271 (7.70)	250 (8.69)	1.04 (0.88–1.24)	0.644	0.533
Cardiac death
From 0–365 d	165 (2.30)	207 (3.36)	0.72 (0.58–0.88)	0.002	128 (2.02)	111 (1.96)	1.09 (0.83–1.42)	0.545	0.022
>365 d	100 (2.73)	81 (2.73)	1.10 (0.82–1.47)	0.546	93 (2.52)	91 (3.48)	0.96 (0.72–1.29)	0.781	0.512
MI
0–365 d	322 (4.43)	431 (6.94)	0.55 (0.46–0.66)	<0.001	260 (4.04)	291 (5.03)	0.74 (0.60–0.91)	0.004	0.041
>365 d	204 (7.78)	174 (8.01)	1.09 (0.89–1.34)	0.391	223 (7.70)	202 (8.02)	1.04 (0.86–1.26)	0.684	0.760
TVR
0–365 d	316 (4.40)	589 (9.60)	0.43 (0.38–0.50)	<0.001	212 (3.32)	430 (7.48)	0.41 (0.34–0.48)	<0.001	0.766
>365 d	180 (5.17)	191 (7.11)	0.81 (0.66–0.99)	0.044	191 (6.38)	182 (6.42)	0.93 (0.76–1.14)	0.472	0.349
Definite stent thrombosis
0–365 d	57 (0.79)	84 (1.36)	0.57 (0.40–0.82)	0.003	24 (0.38)	50 (0.87)	0.36 (0.22–0.61)	<0.001	0.200
>365 d	15 (0.37)	19 (0.68)	0.74 (0.38–1.43)	0.364	26 (0.81)	17 (0.53)	1.40 (0.76–2.59)	0.286	0.128

BMS indicates bare‐metal stent; CAD, coronary artery disease; DES, drug‐eluting stent; HR, hazard ratio; LAD, left anterior descending artery; LM, left main artery; MI, myocardial infarction; and TVR, target‐vessel revascularization.

Sensitivity Analysis and Heterogeneity

We did not find clinically relevant heterogeneity between trials in both study groups (Table S7). When appraised separately (Figure 5), the treatment effect of DESs versus BMSs was homogenous for both LAD and LM subgroups. Results remained similar after excluding patients receiving early‐generation DES (Table S8). A 2‐stage meta‐analysis yielded similar results to the 1‐stage model (Figures S2 and S3).

Figure 5

Effect of drug‐eluting stents (DES) vs bare‐metal stents (BMS) in patients undergoing percutaneous coronary intervention in the LAD vs LM artery.

HR indicates hazard ratio; LAD, left anterior descending artery; LM, left main artery; MI, myocardial infarction; and TVR, target‐vessel revascularization.

Discussion

The main findings of this IPD analysis that included the totality of randomized trials comparing new‐generation DES versus BMS are that (1) DES were associated with a greater reduction in the risk of the primary outcome of cardiac death or MI as compared with BMS, when PCI was performed in the LAD or LM artery in comparison with other vessels; (2) patients receiving DES instead of BMS in the LAD/LM territory had also a lower risk of all‐cause mortality; (3) irrespective of the intervened artery, DES were safer and more effective than BMS by reducing the risk of MI, target‐vessel revascularization, and definite stent thrombosis; and (4) among patients undergoing PCI in the LAD/LM, we found a consistently beneficial effect of DES versus BMS for both LAD and LM subgroups with respect to primary and secondary outcomes.

Although new‐generation DES have replaced BMS in contemporary practice, the evidence from individual randomized trials in supporting their use is essentially based on a lower risk of repeat revascularization procedures and stent thrombosis or MI. This latter effect has been demonstrated only in a minority of studies. , The CST Collaboration was developed to comprehensively evaluate the efficacy and safety of new‐generation DES compared with BMS. By including 26 616 patients in 20 randomized trials, we found a 26% relative reduction in the risk of cardiac death or MI in favor of DES because of a reduced risk of MI and to a lesser extent cardiac death. The present analysis extends earlier results showing that new‐generation DES provide differential benefits among patients undergoing PCI of coronary segments with a larger area at risk, such as the LAD or LM arteries. We found that LAD‐ and/or LM‐treated patients experienced a 24% relative reduction in the hazard of cardiac death or MI at maximum follow‐up when treated with DES, whereas a nonsignificant 7% relative risk reduction was observed in the no‐LAD/LM group. At 1‐year follow‐up, the relative reduction in the risk of cardiac death or MI attested to 38% and 15% in the LAD/LM and no‐LAD/LM groups, respectively. The superiority of new‐generation DES over BMS for LAD/LM was driven by a decreased risk of both cardiac death (17% relative reduction) and MI (26% relative reduction). Conversely, only the MI component of the primary composite outcome was borderline reduced by 12% in the no‐LAD/LM group at the time of longest follow‐up. All‐cause mortality was also reduced among patients in the LAD/LM group but not in the no‐LAD/LM group, in whom all‐cause mortality was apparently higher with DES (HR at 1‐year follow‐up, 1.24; P=0.037). We do not have a mechanistically plausible explanation for this finding, which might simply be a chance finding.

Cardiac fatalities and MIs were robustly decreased by DES allocation solely in LAD/LM recipients, even though the magnitude of treatment response associated with DESs versus BMSs was comparable for both LAD/LM and no‐LAD/LM groups in terms of efficacy (HRs for TVR, 0.53 versus 0.56) and safety outcomes (HRs for stent thrombosis, 0.61 versus 0.64). This might be explained by more prognostically relevant implications of stent‐related failures in LAD or LM arteries in view of larger myocardium at risk. Patients in the LAD/LM group had also a higher risk of all study outcomes, excepting all‐cause death, suggesting a greater ischemic burden and thus benefit from safer and more effective coronary devices. In keeping with this, untreated LM stenosis as well as incomplete revascularization involving the LAD, especially in its proximal segment, are conditions associated with a higher risk of mortality. ,

Serial assessments of outcomes at 1‐year, 5‐year, and longest follow‐up as well as landmark analyses allowed for the evaluation of interactions between device type and lesion location over time. In line with prior findings, we saw that the beneficial effects of DES on efficacy and safety end points accrued principally within the first year after PCI, even within 30 days, with no further incremental benefit or loss thereafter. Consistently, there was a stronger evidence of a difference between LAD/LM and no‐LAD/LM groups at 1‐year follow‐up with the heterogeneity in treatment response among the 2 groups reaching the strongest effect at 1 year. This again suggests that the observation of a larger benefit in the LAD/LM group with DES instead of BMS could be explained by the potentially more detrimental sequelae of TVR and stent thrombosis in these coronary tree segments, notwithstanding the comparable treatment effect of device type in LAD/LM and no‐LAD/LM groups with respect to both TVR and stent thrombosis.

Limitations

Our study has a number of caveats and limitations. First, as an important limitation to the study, we did not collect lesion location in our IPD and therefore were unable to disentangle the treatment effect between proximal versus nonproximal LAD. Second, the study has limitations inherent in patient‐level, pooled analyses reflecting the shortcomings of the original studies. Third, a mixture of new‐generation DESs was used in the experimental arm, despite the fact that a limited number of DESs were implanted as previously described. Fourth, although outcomes were assessed at the maximum follow‐up of 6 years, the mean follow‐up of the study was about 3 years. Whether differences between DES and BMS exist in the late follow‐up and, importantly, whether the benefit of DES in the LAD/LM segments in terms of mortality is eroded in the long‐term remain unaddressed by this study. However, other trials comparing new‐generation DES with BMS are unlikely. Finally, we did not adjust or account for postrandomization covariates, such as actual duration of dual antiplatelet therapy, to avoid violating the principle of randomization.

In conclusion, our collaborative meta‐analysis based on the totality of available randomized data showed that the use of new‐generation DES rather than BMS in patients requiring PCI in the left anterior descending artery or in the left main system conferred additional benefits, with larger reductions in the risk of the composite outcome of cardiac death or MI, attributable to a reduction of both cardiac death and MI within the first year after intervention, without trade‐off between efficacy and safety thereafter. The use of new‐generation DES in the LAD artery and/or in the LM coronary artery was associated with a sustained decrease in the risk of all‐cause mortality at long‐term follow‐up.

Sources of Funding

There was no industry involvement in the design, analysis, or funding of this study. This study was funded by institutional support of the Department of Cardiology at Bern University Hospital, Bern, Switzerland.

Disclosures

Dr Piccolo reports personal fees from Abbott Vascular and nonfinancial support from Chiesi, outside the submitted work. Dr Varenne reports grants from Boston Research Grant (institution), personal fees from Abbott Vascular (lecture), personal fees from Biosensors (transportation), personal fees from AstraZeneca (lecture), personal fees from Servier (lecture), outside the submitted work. Dr Urban reports personal fees from Biosensors; other from CERC, Massy, France; personal fees from Edwards Lifesciences; and other from MedAlliance, outside the submitted work. Dr Raber reports grants from Abbott Vascular, Biotronik, Boston Scientific, Heartflow, Sanofi, and Regeneron; and personal fees from Abbott Vascular, Amgen, AstraZeneca, CSL Behring, Occlutech, Sanofi, and Vifor, outside the submitted work. Dr Lemos reports grants from Scietch, outside the submitted work. Dr Serruys reports personal fees from Abbott Laboratories, AstraZeneca, Biotronik, Cardialysis, GLG Research, Medtronic, Sino Medical Sciences Technology, Société Europa Digital Publishing, Stentys France, Svelte Medical Systems, Philips/Volcano, St Jude Medical, Qualimed, and Xeltis, outside the submitted work. Dr Sabate reports personal fees from Abbott Vascular and IVascular, outside the submitted work. Dr Byrne reports personal fees from B. Braun Melsungen AG and Biotronik; grants from Boston Scientific and Celonova Biosciences, outside the submitted work; unrestricted grants for research from Amgen, Biotronik, Abbott, and Bristol‐Myers‐Squibb; payments for advisory from Medtronic, Boston Scientific, AstraZeneca, and Daiichi Sankyo. Dr Wijns reports grants and personal fees from Biotronik; grants from Medtronic, Terumo, Mi‐Cell, Micro‐Port, and Medical Advisor Rede Optimus Research; and other from Argonauts, outside the submitted work. Dr Jüni serves as an unpaid member of the steering group of trials funded by AstraZeneca, Biotronik, Biosensors, St. Jude Medical, and The Medicines Company; and has participated in advisory boards and/or consulting from Amgen, Ava, and Fresenius. Dr Windecker reports grants from Abbott, Amgen, BMS, Bayer AG, Boston Scientific, Biotronik, Cardinal Health, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Johnson & Johnson, Medtronic, Quebert, Polares, Sanofi, and Terumo, outside the submitted work. Dr Valgimigli reports grants and personal fees from Abbott, Terumo, and AstraZeneca; and personal fees from Chiesi, Bayer, Daiichi Sankyo, Amgen, Alvimedica, Medicure, Biosensors, and Idorsia, outside the submitted work. The remaining authors have no disclosures to report.

Data S1

Tables S1–S8

Figures S1–S3

Click here for additional data file.