Comprehensive Meta-Analysis on Drug-Eluting Stents versus Bare-Metal Stents during Extended Follow-up

CLINICAL RESEARCH STUDY

Comprehensive Meta-Analysis on Drug-Eluting Stents versus Bare-Metal Stents during Extended Follow-up Henri Roukoz, MD,a Anthony A. Bavry, MD, MPH,b Michael L. Sarkees, MD,c Girish R. Mood, MD,d Dharam J. Kumbhani, MD, SM,d Mark G. Rabbat, MD,e Deepak L. Bhatt, MD, MPHf a

Department of Cardiovascular Medicine, University of Minnesota, Minneapolis; bDivision of Cardiovascular Medicine, University of Florida, Gainesville; cDepartment of Internal Medicine and dDepartment of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio; eCardiovascular Institute, Loyola University Medical Center, Maywood, Ill; fVA Boston Healthcare System and Brigham and Women’s Hospital, Boston, Mass.

ABSTRACT BACKGROUND: Several observational reports have documented both increased and decreased cardiac mortality or Q-wave myocardial infarction with drug-eluting stents compared with bare-metal stents. METHODS: We sought to evaluate the safety and efficacy of drug-eluting stents compared with bare-metal stents early after intervention (⬍1 year) and late (⬎1 year) among a broad population of patients, using a meta-analysis of randomized clinical trials. RESULTS: We identified 28 trials with a total of 10,727 patients and a mean follow-up of 29.6 months. For early outcomes (⬍1 year), all-cause mortality for drug-eluting stents versus bare-metal stents was 2.1% versus 2.4% (risk ratio [RR] 0.91, [95% confidence interval (CI), 0.70-1.18]; P ⫽ .47), non-Q-wave myocardial infarction was 3.3% versus 4.4% (RR 0.78 [95% CI, 0.61-1.00]; P ⫽ .055), target lesion revascularization was 5.8% versus 18.4% (RR 0.28 [95% CI, 0.21-0.38]; P ⬍.001), and stent thrombosis was 1.1% versus 1.3% (RR 0.87 [95% CI, 0.60-1.26]; P ⫽ .47). For late outcomes (⬎1 year), all-cause mortality for drug-eluting stents versus bare-metal stents was 5.9% versus 5.7% (RR 1.03 [95% CI, 0.83-1.28]; P ⫽ .79), target lesion revascularization was 4.0% versus 3.3% (RR 1.22 [95% CI, 0.92-1.60]; P ⫽ .16), non-Q-wave myocardial infarction was 1.6% versus 1.2% (RR 1.36 [95% CI, 0.74-2.53]; P ⫽ .32) and stent thrombosis was 0.7% versus 0.1% (RR 4.57 [95% CI, 1.54-13.57]; P ⫽ .006). CONCLUSIONS: There was no excess mortality with drug-eluting stents. Within 1 year, drug-eluting stents appear to be safe and efficacious with possibly decreased non-Q-wave myocardial infarction compared with bare-metal stents. After 1 year, drug-eluting stents still have similar mortality, despite increased stent thrombosis. The reduction in target lesion revascularization with drug-eluting stents mainly happens within 1 year, but is sustained thereafter. Published by Elsevier Inc. • The American Journal of Medicine (2009) 122, 581.e1-581.e10 KEYWORDS: Bare-metal stent; Drug-eluting stent; Percutaneous coronary intervention; Stent thrombosis

Funding: None. Conflicts of interest: Dr. Deepak Bhatt discloses the following relationships: Research Grants (directly to the institution): Bristol Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, The Medicines Company; Honoraria (donated to non-profits for ⬎2 years): Astra Zeneca, Bristol Myers Squibb, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, Glaxo Smith Kline, Millennium, Paringenix, PDL, Sanofi Aventis, Schering Plough, The Medicines Company, tns Healthcare; Speaker’s bureau (⬎2 years ago): Bristol Myers Squibb, Sanofi Aventis, The Medicines Company; Consultant/Advisory Board (waived or donated to non-profits for ⬎2 years): Arena, Astellas, Astra Zeneca, Bristol Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, Glaxo Smith Kline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola,

0002-9343/$ -see front matter Published by Elsevier Inc. doi:10.1016/j.amjmed.2008.12.019

Sanofi Aventis, Schering Plough, Scios, Takeda, The Medicines Company, tns Healthcare, Vertex; Expert testimony about clopidogrel (⬎2 years ago; the compensation was donated to a non-profit organization). Dr. Anthony Bavry discloses the following relationships: Honoraria from Access Closure and Boston Scientific. Authorship: All authors had access to the data and a role in writing. Requests for reprints should be addressed to Deepak L. Bhatt, MD, MPH, VA Boston Healthcare System, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare System, TIMI Study Group, Harvard Medical School, 75 Francis St., PBB-146, Boston, MA, 02115. E-mail address: [email protected]

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The use of drug-eluting stents has become common practice exclusively diabetic patients. The indications for stent during coronary interventions, both for stable angina and placement included myocardial infarction, stable or unstaacute coronary syndromes. Their efficacy in reducing anble angina, and total coronary occlusion. We excluded studgiographic restenosis and the subsequent need for repeat ies that used nonpolymeric stent platforms, next-generation revascularization procedures has been well established.1-3 drug-eluting stents, venous bypass graft revascularization, Their ability to reduce target lesion treatment of in-stent restenosis, or revascularization also has been studhead to head comparison of pacliied in patients with ST-elevation taxel stents versus sirolimus stents. CLINICAL SIGNIFICANCE myocardial infarction.4-12 On the We also required that antiplatelet other hand, several meta-analyses therapy consist of lifelong aspirin ● Drug-eluting stents do not increase or documented increased late stent and a specified duration of a thiendecrease mortality compared with barethrombosis.2,3,13,14 Subsequent to opyridine (clopidogrel or ticlopimetal stents. these reports, several additional dine). Studies that used cilostazol ● The reduction in subsequent revascularreports have raised concerns about instead of a thienopyridine were ization procedures with drug-eluting increased mortality with drugexcluded. eluting stents,15,16 while more stents is mainly observed within 1 year recent studies have reported deData Abstraction and postprocedure, but is sustained up to 5 creased myocardial infarction,17 years of follow-up. Quality Assessment no change in mortality,2,17,18 or Two of the 4 reviewers (HR and ● Drug-eluting stents might decrease noneven decreased mortality.19-21 AAB) independently assessed apQ-wave myocardial infarction within 1 This controversy in outcomes propriate treatment allocation and year postprocedure. associated with drug-eluting stents adequacy of analysis in each speaks to the uncertainty with study. We used intention-to-treat ● After 1 year, drug-eluting stents increase these devices and the need for an analysis. For each outcome, 3 inthe risk of very late stent thrombosis. updated comprehensive metadependent reviewers (HR, MLS, analysis. Furthermore, the differand GM) recorded the interval ential effect on Q-wave and nonevents. Discrepancies were resolved Q-wave myocardial infarction and the early versus late through a fourth reviewer (AAB). The reviewers also tabueffects of drug-eluting stents on the safety and efficacy lated the baseline patient population and procedural characoutcomes have not been emphasized. We sought to confirm teristics. When trial results were available in both presenand explore new associations in a comprehensive metatation and peer-reviewed published articles, the latter was analysis of all randomized clinical trials that compared the considered for abstraction. commonly used paclitaxel- and sirolimus-eluting stents with bare-metal stents to assess their efficacy and safety in both Endpoints and Definitions short-term and long-term follow-up. The endpoints studied were all-cause mortality, cardiovascular mortality, Q-wave myocardial infarction, non-Q-wave METHODS myocardial infarction, target lesion revascularization, and stent thrombosis. Cardiovascular mortality was defined as Search Strategy death due to acute myocardial infarction, cardiac perforaWe searched the Medline database for randomized clinical tion or pericardial tamponade, arrhythmia or conduction trials in the English language from 2000 to 2007 using the abnormality, cerebrovascular accident before hospital dismedical subject heading terms “Angioplasty,” “Percutanecharge or suspected of being related to the procedure, and ous,” “Coronary,” “Bare metal,” and “stent,” along with all death in which a cardiac cause could not be excluded. A “Paclitaxel” or “Sirolimus.” The titles and abstracts were sudden death of unknown cause was considered a cardioreviewed on studies that presented original data from ranvascular death in the absence of another explanation. A domized clinical trials and compared paclitaxel-eluting myocardial infarction was defined as an elevation of creatstents or sirolimus-eluting stents with bare-metal stents. We ine kinase of at least 2 times the upper normal limit with a also searched relevant journal supplements for abstracts, positive creatine kinase MB enzyme. A Q-wave myocardial obtained abstract presentations from cardiology meetings, infarction was defined as the development of new pathologand used the Science Citation Index to cross-reference any ical Q-waves in 2 or more leads lasting 0.4 second or more. articles that met our selection criteria. An elevation of creatine kinase levels to at least 2 times Selection Criteria normal without new Q-waves was considered a non-Q-wave myocardial infarction. Target lesion revascularization was The main inclusion criteria were randomized clinical trials defined as any repeat percutaneous coronary intervention of that assigned patients to drug-eluting stents versus barethe target lesion or bypass surgery of the target vessel driven metal stents and reported at least 6 months of follow-up. We by a positive functional study, ischemic electrocardiogram included trials on a broad population of patients, including

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changes at rest, symptoms of myocardial ischemia referable to the target lesion, or an in-lesion stenosis of more than 70% of the reference luminal diameter by visual estimate. We followed the original per protocol definition for stent thrombosis. All events except stent thrombosis were tabulated into early (⬍1 year) and late (⬎1 year) events. Stent thromboses were divided into early (⬍30 days), late (30 days to 1 year) and very late (⬎1 year). The data also were dichotomized for subgroup analysis in the following categories: ST-elevation and non-ST-elevation myocardial infarction, exclusively diabetic patient trials, sirolimus- and paclitaxel-eluting stents, reference vessel diameter ⱖ2.75 mm and ⬍2.75 mm, stent length ⱖ22 mm and ⬍22 mm, and glycoprotein IIb/IIIa inhibitor use of ⱖ50% and ⬍50%. The cut-offs chosen for the subgroup analysis are based on the medians of each characteristic, with the intention to divide the studies evenly on each side of the cut-off point.

bare-metal stents (RR 0.98 [95% CI, 0.81-1.18]; P ⫽ .82). There also was no statistically significant difference in cardiovascular mortality, both in the overall and the subgroup analyses. Early and late mortality were not significantly different (Table 3). In the exclusively diabetic patient trials, all-cause mortality was 2.9% with drug-eluting stents and 3.5% with bare-metal stents (RR 0.95 [95% CI, 0.41-2.18]; P ⫽ .99), and cardiovascular mortality was 3.4% with drugeluting stents and 2.7% with bare-metal stents (RR 1.21 [95% CI, 0.36-4.08]; P ⫽ .76). In the ST-elevation myocardial infarction trials, only STRATEGY had a follow-up of more than 1 year; however, using all available data, allcause mortality was 4.1% with drug-eluting stents and 4.8% with bare-metal stents (RR 0.87 [95% CI, 0.62-1.23]; P ⫽ .44), with no significant difference in cardiovascular mortality (3.8% in drug-eluting stents vs 4.3% in bare-metal stents, RR 0.91 [95% CI, 0.59-1.40]; P ⫽ .67).

Statistical Analysis

Target Lesion Revascularization

We calculated the risk of an event for each type of stent as the number of patients with events that occurred during clinical follow-up divided by the number of individuals at risk for this event. Risk ratios (RR) were defined as the risk of an event for drug-eluting stents compared with baremetal stents. Each risk ratio was calculated according to DerSimonian-Laird, which employs a random effects model. Automatic “zero cell” correction was used for studies with no events for a particular outcome. The Q-statistic was computed to assess for heterogeneity between studies and publication bias was assessed by Begg’s method. All P values were 2-tailed, with statistical significance set at .05 and confidence intervals (CI) calculated at the 95% level. All analyses were performed using STATA software version 9.0 (STATA Corporation, College Station, Tex).

Target lesion revascularization was significantly decreased in the drug-eluting stent group compared with the baremetal stent group within the first year of follow-up, but there was no statistically significant difference in late target lesion revascularization (RR 1.22 [95% CI, 0.92-1.60]; P ⫽ .16); however, overall target lesion revascularization was still significantly decreased (Figure 2). The same pattern was present in all subgroup analyses (Figure 3). Overall target lesion revascularization also was decreased significantly both in the diabetes trials (7.1% with drug-eluting stents vs 31.3% with bare-metal stents, RR 0.23 [95% CI, 0.15-0.36]; P ⬍.001) and the ST-elevation myocardial infarction trials (5.6% in drug-eluting stents vs 14% in bare-metal stents, RR 0.38 [95% CI, 0.22-0.67]; P ⫽ .001).

Myocardial Infarction RESULTS Clinical Trials and Duration of Follow-up We identified 28 trials4-11,22-63 with a total of 10,727 patients in the analysis. The clinical follow-up was 26,479 patient-years with a weighted mean follow-up of 29.6 months. There were a total of 5534 patients with drugeluting stents and 5193 patients with bare-metal stents. Acute ST-elevation myocardial infarction was the indication for coronary stent placement in 9 trials (25% of all patients). Total coronary occlusion was the indication for stenting in one sirolimus-eluting stent trial, PRISON II.58 Stenting of unprotected left main coronary artery stenosis with paclitaxel-eluting stents was studied by Erglis et al.56 The baseline characteristics are presented in Table 1. The procedural characteristics, duration of follow-up and thienopyridine therapy are presented in Table 2.

Mortality During the entire follow-up available, all-cause mortality (Figure 1) was 5.3% for drug-eluting stents and 5.5% for

There were no statistically significant differences in Q-wave or non-Q-wave myocardial infarction (Table 3), with a tendency towards decreased early non-Q-wave myocardial infarction with drug-eluting stents (Figure 2). There were no significant differences in either Q-wave or non-Q-wave myocardial infarction in the diabetes trials. The ST-elevation myocardial infarction trials did not report Q-wave and non-Q-wave myocardial infarction separately. The overall re-infarction rate (both Q-wave and non-Q-wave myocardial infarction) was 3.1% in drug-eluting stents versus 4.2% in bare-metal stents (RR 0.77 [95% CI, 0.49-1.21]; P ⫽ .26). There was a significant difference in early non-Q-wave myocardial infarction in favor of drug-eluting stents in the studies where the mean stent length was ⬍22 mm (P ⫽ .01) and in studies that used glycoprotein IIb/IIIa inhibitors in more than 50% of the patients (P ⫽ .047) (Figure 3). In addition, there was a tendency towards decreased early non-Q-wave myocardial infarction in the sirolimus-eluting stents subgroup (P ⫽ .08) and in the studies where the reference vessel diameter was ⱖ2.75 mm (P ⫽ .07). On the other hand, there was a tendency towards increased late

581.e4 Table 1

The American Journal of Medicine, Vol 122, No 6, June 2009 Baseline Characteristics of Study Population

Trial Name

DES Patients Age, Women Type Indication n years n (%)

TAXUS I22 TAXUS II24 TAXUS IV28 TAXUS V31 TAXUS VI34 Erglis et al56 PASSION6 HAAMU-STENT8 SELECTION9

PES PES PES PES PES PES PES PES PES

Stable Stable Stable Stable Stable Stable STEMI STEMI STEMI

61 536 1314 1156 446 103 619 164 80

SIRIUS36 E-SIRIUS42 C-SIRIUS40 RAVEL44 SES-SMART46 SCANDSTENT47 DIABETES49 Pache et al52 DECODE51 SCORPIUS63 DESSERT60 STRATEGY53 TYPHOON5 SESAMI7 MISSION12 Diaz de la Llera et al4 FIBISTEMI10 PRISON II58 BASKET54 TOTAL

SES SES SES SES SES SES SES SES SES SES SES SES SES SES SES SES SES SES Both

Stable Stable Stable Stable Stable Stable Stable Stable Stable Stable Stable STEMI STEMI STEMI STEMI STEMI STEMI Stable Both

1058 352 100 238 257 322 160 500 83 200 150 175 715 320 316 120 156 200 826 10,727

DM n (%)

Smoking n (%)

Prior MI n (%)

65 60 62 63 63 62 61 63 61

7 234 367 353 106 17 149 46 14

(11.5) 11 (18.0) 31 (50.8) (43.7) 58 (10.8) 99 (18.5) (27.9) 318 (24.2) 286 (21.8) (30.5) 356 (30.8) 237 (20.5) (23.8) 88 (19.7) NA (16.5) 12 (11.6) 52 (50.5) (24.1) 68 (11.0) 319 (51.5) (28.0) 24 (14.6) 70 (42.7) (17.5) 10 (12.5) 43 (53.7)

17 160 397 333 187 50 32 15 3

62 62 60 61 64 63 66.5 67 61 66 70 63 59 62 59 65 58 59 64

307 103 31 57 73 75 60 109 27 78 67 47 157 60 38 25 30 41 176

(29.0) (29.3) (31.0) (23.9) (28.4) (23.3) (37.5) (21.8) (32.5) (39.0) (44.7) (26.9) (22.0) (18.7) (12.0) (20.8) (19.2) (20.5) (21.3)

328 147 45 86 74 168 59 157 29 65 46 19 0 30 12 9 NA 98 226

275 81 24 45 64 58 160 154 83 200 150 26 116 66 30 33 29 26 153

(26) (23) (24) (18.9) (24.9) (18.0) (100) (30.8) (100) (100) (100) (14.9) (16.3) (20.6) (9.5) (27.5) (18.6) (13) (19)

212 116 37 71 42 111 76 89 41 36 61 70 356 169 69 82 88 74 235

(20) (33) (37) (29.8) (16.3) (34.5) (47.5) (17.8) (49.4) (18) (40.7) (40.0) (50.0) (52.7) (53.5) (68.3) (56.4) (37) (28)

Prior PCI n (%)

Previous CABG n (%)

(27.9) NA NA (29.9) 59 (11.0)* (30.2) 254 (19.3)* (28.8) NA NA (41.9) 86 (19.3) 36 (8.1) (48.5) 40 (38.8) 6 (5.8) (5.2) 27 (4.4) 4 (0.6) (9.1) 13 (7.9) 5 (3.0) (3.7) None within 6 months pre-procedure (31) NA NA (42) 73 (21) 21 (6) (45) 8 (8) 4 (4) (36) 43 (18.1) 4 (1.7) (28.8) 55 (21.5) 21 (8.2) (52.2) 56 (17.4)* (36.9) 25 (15.6) 5 (3.1) (31.4) NA 37 (7.4) (34.9) 11 (13.2) 5 (6.0) (32.5) NA 8 (4) (30.7) 19 (12.7) 8 (5.3) (10.9) 6 (3.4) 4 (1.1) (0) 30 (4.2) (9.2) 31 (9.6) 5 (0.3) (3.8) 5 (1.6) 2 (0.6) (7.5) 7 (5.8) 1 (0.8) NA NA (49) 34 (17) 5 (2.5) (27) 133 (16) 105 (13)

Abbreviations: BMS ⫽ bare-metal stent; CABG ⫽ coronary artery bypass grafting; DES ⫽ drug-eluting stent; DM ⫽ diabetes mellitus; MI ⫽ myocardial infarction; NA ⫽ not available; PCI ⫽ percutaneous coronary intervention; PES ⫽ pacitaxel-eluting stent; SES ⫽ sirolimus-eluting stent; STEMI ⫽ STelevation MI; * ⫽ combined PCI and CABG.

non-Q-wave myocardial infarction in the paclitaxel-eluting stent subgroup (1.5% in drug-eluting stents vs 0.8% in bare-metal stents; RR 1.86 [95% CI, 0.97-3.55]; P ⫽ .06), but not in the sirolimus-eluting stent group.

Stent Thrombosis There was no significant difference in early stent thrombosis, but very late stent thrombosis was increased significantly with drug-eluting stents (Table 3). With the exception of DIABETES I, all exclusively diabetic patient trials did not have a follow-up of more than 1 year. There was no statistically significant difference in stent thrombosis in the diabetes trials and the ST-elevation myocardial infarction trials. There was a trend towards increased late stent thrombosis in all subgroups, but it reached statistical significance in each of the paclitaxeleluting stents and sirolimus-eluting stents subgroups, and in studies that used glycoprotein IIb/IIIa inhibitors in more than 50% of the patients (Figure 3).

DISCUSSION In this analysis of 28 studies in over 10,000 patients, we found no difference in all-cause mortality or cardiovascular mortality between drug-eluting stents and bare-metal stents. The overall reduction in target lesion revascularization in favor of drug-eluting stents was maintained up to 5 years. There was no difference in early or late mortality between drug-eluting stents and bare-metal stents. There was a trend towards decreased early non-Q-wave myocardial infarction in the drug-eluting stent group and no difference in late target lesion revascularization between the 2 groups. Late stent thrombosis was increased in the drug-eluting stent group. The reduction in target lesion revascularization with the use of drug-eluting stents happens mainly during the first year after implantation. Although the differential advantage is not detected beyond 1 year, the difference in target lesion revascularization is sustained through 5 years with no “catch up” phenomenon. This observation might have been

Roukoz et al Table 2

No Difference in Mortality between Drug-Eluting and Bare-Metal Stents

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Procedural Characteristics and Follow-up Data

Trial Name

Reference Vessel Diameter, mm

Lesion Length, mm

Mean Stent Diameter, mm

Mean Stent Length, mm

TAXUS I22 TAXUS II24 TAXUS IV28 TAXUS V31 TAXUS VI34 Erglis et al56 PASSION6 HAAMU-STENT8 SELECTION9 SIRIUS36 E-SIRIUS42 C-SIRIUS40 RAVEL44 SES-SMART46 SCANDSTENT47 DIABETES49 Pache et al52 DECODE51 SCORPIUS63 STRATEGY53 DESSERT60 TYPHOON5 SESAMI7 MISSION12 Diaz de la Llera et al4 FIBISTEMI10 PRISON II58 BASKET54

2.97 2.75 2.75 2.69 2.79 3.26 3.17 NA 2.86 2.8 2.55 2.63 2.62 2.2 2.86 2.34 2.7 2.51 2.6 2.3 2.66 2.81 NA 2.84 NA 2.93 2.56 NA

11.3 10.5 13.3 17.2 20.6 11.6 NA NA 11.4 14.4 15 13.6 9.6 11.8 18 15 12.6 15.05 11.4 13 14.9 NA NA 14.4 NA NA 16.2 NA

3-3.5* 3-3.5* 2.5-3.5* 3.1 3.13 3.7 3.24 NA 3.05 2.5-3.5* 2.5-3.0* 2.5-3.0* NA 2.48 NA 2.9 NA NA NA 3 3 3.1 3.08 NA 3.19 3.1 NA 2.5-3.5

15 15.4 21.6 28.4 33.1 17.5 19 NA 19.6 21.4 22.6 23.8 NA 15.9 24.4 22.5 18 20.9 18.5 23 19.9 21.2 18.1 26.5 29.6 30.9 30.4 34

Stents per Patient

Glycoprotein IIb/IIIa Inhibitor, n (%)

Duration Clopidogrel, Months

Follow-up, Months

1 1.1 1.1 1.4 1.4 1.0 1.3 NA NA 1.4 NA 1.5 NA NA 1.4 1.6 1.2 NA 1.2 NA 1.1 1.1 1 1.4 NA 1.4 1.4 1.9

0 (0) 92 (17.2) 752 (57.2) 487 (42.1) 89 (20.0) 79 (76.7) 457 (73.8) NA 80 (100) 635 (60) 56 (15.9) 53 (53) 23 (9.8) 19 (7.4) 103 (32.0) 94 (58.7) NA 26 (31.3) NA 175 (100) 150 (100) 509 (71.5) 240 (74.9) 309 (97.8) 120 (100) NA‡ NA 212 (26)

6 ⬎6 6 ⬎6 6 ⬎6 9 12 9 3 2 2 2 ⬎2 12 12 ⬎6 ⬎3 ⬎6 ⬎3 2-6 ⬎6 NA 12 1-9† ⬎9 ⬎6 6

60 60 60 36 48 6 12 12 7 60 60 60 60 8 12 24 12 6 12 36 12 12 12 12 12 12 12 18

Abbreviations: mm ⫽ millimeter; NA ⫽ not available. *Mean is not available and the range is presented. †At least 1 month for bare-metal stent and 9 months for sirolimus-eluting stent. ‡No use of GpIIb/IIIa mentioned in study.

amplified by the protocol-driven target lesion revascularization, because most studies had routine angiographic follow-up between 6 and 9 months. The decreased early nonQ-wave myocardial infarction might be explained by the lower restenosis rate in the drug-eluting stent group during the first year. This finding also was reported in diabetic patients in a recent meta-analysis.64 In a recent pooled analysis of the four major TAXUS trials, non-Q-wave myocardial infarction was the predominant presentation of ischemia-driven target lesion revascularization with nonfatal myocardial infarction.65 Additionally, bare-metal stent in-stent restenosis might not be a clinically benign phenomenon. Four recent studies have reported myocardial infarction rates between 3.5% and 19.4% in patients with symptomatic bare-metal stent restenosis.66-69 Furthermore, myocardial infarction related to bare-metal stent restenosis was associated with increased mortality in a recent retrospective study of 4503 patients with a 10-year follow-up.70 Our subgroup analysis also suggests decreased early non-

Q-wave myocardial infarction and increased very late stent thromboses with the subset of trials with more than 50% use of glycoprotein IIb/IIIa inhibitors. Given that glycoprotein IIb/IIIa inhibitors were used at the discretion of the operator, this subset of trials could represent higher-risk patients. There was tendency towards decreased early non-Qwave myocardial infarction in the sirolimus-eluting stent group (P ⫽ .08) and tendency towards increased late nonQ-wave myocardial infarction in the paclitaxel-eluting stent group (P ⫽ .06). While this finding might be due to chance, it is partly in agreement with a recently published network meta-analysis that showed decreased risk of total myocardial infarction with sirolimus-eluting stents compared with each of paclitaxel-eluting stents and bare-metal stents.17 Moreover, 2 recent non-randomized prospective studies demonstrated a higher incidence of angiographic restenosis with paclitaxel-eluting stents compared with sirolimus-eluting stents.71,72 These findings could be explained by the difference in drug-release kinetics, with the sirolimus-elut-

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Figure 1

Summary (Forest Plot) for all-cause mortality.

ing stent releasing almost all the sirolimus in the first 6 months, while more than 80% of the paclitaxel remains unreleased from the polymer coating of the paclitaxel-eluting stent, potentially resulting in more prolonged endothelial dysfunction and delayed healing with the latter.73,74 In concordance with most published studies,14,75 very late stent thrombosis (⬎1 year) was increased in the drugeluting stent group and with both paclitaxel-eluting stent and sirolimus-eluting stent trial subsets. While recent data have shown a steady rate of stent thrombosis of 0.6% per year up to 3 years after drug-eluting stent implantation,76,77 the highest incidence of stent thrombosis events in our study happened during the second year postprocedure. Although there is angioscopic evidence of incomplete neointimal coverage and thrombi with drug-eluting stents as many as 2 years after implantation, it remains uncertain whether reendothelialization with drug-eluting stents is just delayed or remains persistently incomplete.78 There were no significant differences in all-cause mortality or cardiovascular mortality between patients receiving either type of stents. While our findings agree with most published studies,2,17 they contradict other reports provided mainly by registries.15,19 As suggested by a recent study,65 this lack of difference in mortality might be due to a balance between more frequent but generally less adverse outcomes (early revascularization and non-Q-wave myocardial infarction) with less frequent but generally more adverse events driven by late stent thrombosis. Another hypothesis is that revascularization of stable atherosclerotic coronary lesions alone does not affect survival, as demonstrated by the COURAGE trial.79 Most patients included in our meta-analysis had stable coronary artery disease. If percutaneous coronary

intervention does not affect mortality in this patient population, the prevention of restenosis offered by drug-eluting stents would not be expected to change survival. Each of our ST-elevation myocardial infarction and exclusively diabetic patients’ analyses showed no difference in all-cause mortality, cardiovascular mortality, myocardial infarction, or stent thrombosis, along with significantly decreased target lesion revascularization in the drug-eluting stent group. Again we saw no significant difference in late target lesion revascularization between drug-eluting stents and bare-metal stents in ST-elevation myocardial infarction trials, but no conclusions can be made because these analyses were mainly limited by the lack of long-term followup. Longer-term follow-up is available only from registries at this time, showing no difference in target vessel revascularization at 3 years postprocedure.76 Our study faces several limitations. First, we had, in some instances, to rely on data published in abstract form due to lack of peer-reviewed manuscripts, sometimes limiting the number of outcomes available for each study. We did not include any observational studies. Although this would have increased the number of patients substantially, it may introduce significant bias given the nonrandomized design of these studies. Second, despite the increase in statistical power conferred by meta-analysis, the rarity of some events, the lack of patient level data and, in some instances, lack of long-term follow-up limit the capacity of our study to further describe the time distribution or detect possible differences of safety outcomes. Furthermore, outcomes like bleeding complications were not evaluated due to insufficient data. Third, due to lack of patient-level data, we were not able to use the Academic Research Consortium

Roukoz et al Table 3

No Difference in Mortality between Drug-Eluting and Bare-Metal Stents

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Results: Overall, Early, and Late Outcomes DES (%)

All-cause mortality Early (⬍1 year) Late (⬎1 year) Overall Cardiovascular mortality Early (⬍1 year) Late (⬎1 year) Overall Q-wave MI Early (⬍1 year) Late (⬎1 year) Overall Non-Q-wave MI Early (⬍1 year) Late (⬎1 year) Overall Target lesion revascularization Early (⬍1 year) Late (⬎1 year) Overall Stent thrombosis Early (⬍30 days) Late (30 days-⬍1 year) Very late (⬎1 year) Overall

BMS (%)

RR

95% CI

P Value

2.1% 5.9% 5.3%

2.4% 5.7% 5.5%

0.91 1.03 0.98

0.70-1.18 0.83-1.28 0.83-1.16

.47 .79 .82

1.6% 2.4% 3.1%

1.7% 2.1% 2.9%

0.95 1.26 1.08

0.68-1.31 0.89-1.77 0.86-1.35

.75 .19 .52

0.8% 0.8% 1.4%

0.7% 0.6% 1.2%

1.14 1.24 1.23

0.60-2.17 0.64-2.40 0.79-1.90

.68 .52 .36

3.3% 1.6% 4.7%

4.4% 1.2% 5.3%

0.78 1.36 0.90

0.61-1.00 0.74-2.53 0.72-1.11

.055 .32 .32

5.8% 4.0% 8.4%

18.4% 3.3% 20.9%

0.28 1.22 0.31

0.21-0.38 0.92-1.60 0.23-0.41

⬍.001 .16 ⬍.001

0.8% 0.3% 0.7% 1.4%

0.9% 0.4% 0.1% 1.3%

0.94 0.92 4.57 1.13

0.61-1.46 0.43-1.94 1.54-13.57 0.81-1.58

.79 .82 .006 .48

Abbreviations: BMS ⫽ bare-metal stent; CI ⫽ confidence interval; DES ⫽ drug-eluting stent; MI ⫽ myocardial infarction; RR ⫽ relative risk.

definitions of stent thrombosis. Using the Academic Research Consortium definitions may have attenuated or even eliminated any difference in stent thrombosis between drugeluting stents and bare-metal stents.80

CONCLUSION In conclusion, our study examined the safety and efficacy of drug-eluting stents compared with bare-metal stents in a

Figure 2

comprehensive conventional meta-analysis of all available randomized clinical trial data. Reassuringly, this study showed no excess all-cause mortality or cardiovascular mortality between drug-eluting stents and bare-metal stents. Within 1 year of follow-up, drug-eluting stents appear to be safe and efficacious with similar mortality, similar stent thrombosis, decreased revascularization, and possibly decreased non-Q-wave myocardial infarction compared with

Overall, early and late target lesion revascularization and non-Q-wave myocardial infarction.

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The American Journal of Medicine, Vol 122, No 6, June 2009

Figure 3 The subgroup analysis for NQMI, TLR and stent thrombosis. NQMI ⫽ non-Q-wave myocardial infarction; TLR ⫽ target lesion revascularization; PES ⫽ paclitaxel-eluting stent; SES ⫽ sirolimus-eluting stent; RVD ⫽ reference vessel diameter; GP IIb/ IIIa ⫽ glycoprotein IIb/IIIa inhibitor.

bare-metal stents. After 1 year, drug-eluting stents still have similar mortality compared with bare-metal stents; however, stent thrombosis is increased, and there is a possibility of increased non-Q-wave myocardial infarction with paclitaxel-eluting stents. The reduction in target lesion revascularization with drug-eluting stents is sustained in late follow-up. Longer-term follow-up is needed to assess the safety of drug-eluting stents in ST-elevation myocardial infarction.

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