European Heart Journal (2013) 34, 909–919 doi:10.1093/eurheartj/ehs460

CLINICAL RESEARCH Interventional cardiology

Marco Valgimigli 1,2*, Marco Borghesi 1, Matteo Tebaldi 1, Pascal Vranckx 3, Giovanni Parrinello 4, and Roberto Ferrari 1,2, for the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY) Investigators 1 Cardiology Department, Cardiovascular Institute, University of Ferrara, Arcispedale S. Anna Hospital, C.rso Giovecca 203, 44100 Ferrara, Italy; 2Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS, Lumezzane (BS), Italy; 3Virga Jesse Ziekenhuis, Hasselt, Belgium; and 4Medical Statistics Unit, University of Brescia, Italy

Received 29 August 2012; revised 14 November 2012; accepted 6 December 2012; online publish-ahead-of-print 12 January 2013

See page 872 for the editorial comment on this article (doi:10.1093/eurheartj/eht026)

Aims

The purpose of this pre-specified analysis of the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY) was to assess device-specific outcomes relative to different duration of dual antiplatelet therapy (DAPT) after Everolimus- (EES), Paclitaxel (PES), Zotarolimus- (ZES-S) eluting, or bare metal stents (BMS). ..................................................................................................................................................................................... Methods We randomized 2013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group underwent up and results to 6 or 24 months clopidogrel therapy. The primary endpoint, which was a composite of death, myocardial infarction, or cerebrovascular accident, did not differ in patients receiving BMS [HR: 0.89 (95%CI: 0.54–1.45)], PES [HR: 0.74 (95%CI: 0.43–1.25)], or EES [HR: 0.63 (95%CI: 0.33 –1.21)] implantation across DAPT groups, whereas it was significantly higher in ZES-S patients undergoing long when compared with short-term DAPT therapy (HR: 2.85, P ¼ 0.0018), with positive interaction testing (P-value ¼ 0.004). At the 6-month landmark analysis, heterogeneity across stent types persisted for the primary study endpoint and other secondary clinical outcomes, whereas patients receiving PES showed a significantly higher rate of definite, probable and definite, probable, possible stent thrombosis in the short DAPT regimen. No association in absolute or relative terms was noted between stent potency in inhibiting intimal hyperplasia and greater vulnerability to shorter DAPT therapy. ..................................................................................................................................................................................... Conclusion Our study suggests that optimal duration of DAPT may be stent-specific and it does not support a clear association between stent potency and vulnerability to shorter DAPT therapy. Trial Registration clinicaltrials.gov Identifier: NCT00611286. http://clinicaltrials.gov/ct2/show/NCT00611286?term= prodigy&rank=2.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Dual antiplatelet therapy † Clopidogrel † Stent † Percutaneous coronary intervention

* Corresponding author. Tel: +39 0532 236874, Fax: +39 0532 236593, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]

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Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY)

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Introduction

Methods Study design and population PRODIGY is a 4-by-2 randomized, multicentre, open-label clinical trial designed to evaluate the efficacy and safety of prolonging the duration of clopidogrel therapy for up to 24 months in all comer patients receiving a balanced mixture of stents with various anti-intimal hyperplasia potency and belonging to both first and second generation drug-eluting stents.8 Patients undergoing elective, urgent, or emergent coronary angioplasty with intended stent implantation at three referral Italian sites were randomly assigned in a 1:1:1:1 fashion to one of four stent types, including everolimus-eluting stent (EES), paclitaxel-eluting stent (PES), zotarolimus-eluting Endeavor Sprintwstent (ZES-S), or thin-strut bare metal stent. As stent chronic recoil is negligible, late lumen loss (LLL, i.e. the difference in minimal lumen diameter at quantitative coronary angiography undertaken after stent implantation and at 6 – 9 month follow-up) of a given stent quantifies the amount of neontimal hyperplasia, which has grown towards the lumen, thereby determining in-stent restenosis. Typical average late loss figures for the stents, which were used in the present study, are 1.00 mm for BMS (i.e. no active inhibition of stent-induced intimal hyperplasia), 0.65 mm for ZES-S, 0.4 mm for PES, and 0.20 mm for EES. At 30 days, patients in each stent group were randomized in a balanced fashion to either 6 or 24 months of dual antiplatelet treatment. In the 6-month DAPT group, clopidogrel discontinuation at any time after 30 days was allowed in patients who were randomized to bare metal stent if

coronary intervention was indicated by the presence of stable coronary artery disease. Individuals eligible for enrolment were patients 18 years of age or older with chronic stable coronary artery disease or acute coronary syndromes, including non-ST-elevation and ST-elevation myocardial infarction. They were eligible if they had at least one lesion with a diameter stenosis of 50% or more that was suitable for coronary stent implantation in a vessel with a reference vessel diameter of at least 2.25 mm. Selection criteria were broad, reflecting routine clinical practice. We set no limit for the number of treated lesions, vessels, or lesion length, and excluded no patients on the basis of comorbid disorders or age, apart from the following pre-specified criteria: known allergy to acetyl salicylic acid or clopidogrel; planned surgery within 24 months of percutaneous coronary intervention unless the DAPT could be maintained throughout the perisurgical period; history of bleeding diathesis; major surgery within 15 days; active bleeding or previous stroke in the last 6 months; concomitant or foreseeable need for oral anticoagulation therapy; pregnancy; life expectancy ,24 months; participation in another trial; and inability to provide informed consent. The Ethics Committees of the three participating centres independently approved the protocol and all participants gave written informed consent.

Treatment protocol and follow-up procedures All patients received aspirin (160 – 325 mg orally or 500 mg i.v. as a loading dose and then 80 – 160 mg orally indefinitely) and clopidogrel (300 or 600 mg orally as a loading dose), and then 75 mg/day for the treatment duration according to the randomization scheme as follows: for either 6 months in the 6-month dual antiplatelet group—in patients randomized to bare metal stent and presenting stable coronary artery disease, a shorter (but not ,30 day) duration of dual antiplatelet treatment was allowed to comply with available evidence—or 24 months in the 24-month dual antiplatelet arm irrespective of the previously implanted stent type or indication to the coronary procedure. Anticoagulation during coronary intervention was accomplished through administration of either unfractionated heparin or bivalirudin. All interventions were performed according to current standard guidelines2 and the final interventional strategy, including administration of glycoprotein IIb/IIIa antagonists, pre- or post-dilatation or use of intravascular imaging techniques, was left entirely to the discretion of the operator, except for the stent utilization. Angiographic success was defined as residual stenosis , 30% by visual analysis in the presence of TIMI 3 grade flow.

Follow-up All randomized patients who were not lost-to-follow-up, irrespective of their compliance to the assigned treatment schedule, returned for study visits at 30 days, and then every 6 months up to 2 years. During follow-up visits, patients were examined, assessed for adverse events and 12-lead ECG recordings. At all follow-up timepoints, patients were questioned on their compliance with the study medication. Any interruptions or termination as well as the reasons for this were documented. To ensure a high adherence rate to the assigned study treatment, a dedicated study nurse per site was telephonically contacting each patient on a monthly basis.

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Based on the concerns that delayed vessel healing may be responsible for late or very late stent thrombosis, drug-eluting stent implantation (DES), irrespective of which type, should prompt at least 121 or at least 6–12-month2 dual antiplatelet therapy (DAPT) duration. Recent data suggest that at least some newer generation DES lead to a more favourable healing profile3 and they are associated to a lower incidence of early, late, and very late stent thrombosis compared with first generation DES.4,5 Therefore, the need for prolonged DAPT may differ based on the type of implanted stent. Retrospective analyses of randomized controlled trials and registry data have shown that 6-month or even shorter DAPT duration was not associated with increased likelihood of thrombotic events at long-term follow-up after everolimus- or zotarolimus (Endeavor sprint)-eluting stent implantation.6,7 These observations have recently led to a CE Mark in Europe for 3-month only DAPT duration after Xience Prime or the Xience V everolimus-eluting coronary stent systems. Yet, whether the need for prolonged DAPT should differ based on the type of implanted stent remains a controversial issue due to the paucity of prospective randomized data. The purpose of this pre-specified analysis of the PROlonging Dual antiplatelet treatment after Grading stent-Induced Intimal hyperplasia studY (PRODIGY)8,9 was to assess device-specific outcomes relative to DAPT duration in an all-comer patient population randomly allocated to paclitaxel (PES), Zotarolimus- (ZES-S) or everolimus- (EES) eluting, or bare metal stents (BMS) at the time of intervention.

M. Valgimigli et al.

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Dual antiplatelet therapy and stent-type

Study endpoints The primary endpoint of this analysis was to evaluate the interaction with stent type on the effect of short- vs. long-term DAPT and outcomes with respect to the incidence of death from any cause, non-fatal myocardial infarction, or cerebrovascular accident. As the therapy did not differ between the two groups in the first month after stenting, the time frame of major interest for the primary endpoint was from 30 days to 24 months. Secondary endpoints included each component of the primary endpoint, cardiovascular death, the incidence of stent thrombosis defined based on the Academic Research Consortium (ARC) criteria10 for the entire duration of follow-up or from 6 months onwards. All study endpoints were confirmed on the basis of documentation collected at each hospital and were centrally adjudicated by the clinical events committee, whose members were unaware of patients’ treatment-group assignments.

Statistical analysis

Results From December 2006 to December 2008, a total of 2789 patients underwent screening and 2013 were finally recruited into the study and randomized to receive one of the four stent types. Thirty-three (1.6%) patients died within 30 days and 10 patients

Follow-up and clinical outcomes Clinical follow-up at 2 years was complete for 99.7% of patients in the long-term clopidogrel group and for 99.6% of those in the short-term clopidogrel group. Table 4 shows cumulative 24-month event rates for each stent group. There was a clear signal of heterogeneity for the primary endpoint of death for any cause, non-fatal myocardial infarction, and cerebrovascular accident across stent groups with respect to the duration of DAPT (P-value for interaction ¼ 0.004). The primary outcomes did not formally differ in patients receiving BMS [HR: 0.89 (95%CI: 0.54–1.45), P ¼ 0.64], PES [HR: 0.74 (95%CI: 0.43 –1.25), P ¼ 0.26], or EES [HR: 0.63 (95%CI: 0.33– 1.21), P ¼ 0.17] implantation across DAPT groups, whereas it was significantly lower in ZES-S patients undergoing short- when compared with long-term DAPT therapy [HR: 2.85 (95%CI: 1.49 –5.45), P ¼ 0.0018] (Figure 1). Consistent findings were observed with respect to the composite of death for any cause or MI and for cardiovascular death or MI (Figure 1). The analysis of stent thrombosis endpoints did not formally disclose heterogeneity across stent groups. The analysis of definite and definite or probable ST showed no event in the short-term DAPT group of patients receiving ZES-S and an excess of thrombotic events in patients treated with PES receiving a short when compared with a long course of DAPT therapy, which did not reach statistical significance (HR: 0.20 95%CI: 0.02–1.69, P ¼ 0.14 and HR: 0.44 95%CI: 0.14–1.43, P ¼ 0.15, respectively, Figure 2).

Landmark and per protocol analysis There were 1924 patients reaching the 6-month follow-up of whom 963 were allocated to the 24-month DAPT group and 961 to the short-term clopidogrel duration arm. The incidence of the primary composite endpoint from 6 to 24 months consistently showed heterogeneity with respect to the primary composite endpoint (P-value for interaction ¼ 0.05), as well as for any death or MI (P-value for interaction ¼ 0.10) or cardiovascular death or MI (P-value for interaction ¼ 0.03) with patients receiving ZES-S showing lower event rates in the shortwhen compared with the long-term DAPT duration groups (Figure 3). Results were consistent when the primary study endpoint from 30 days (P-value for interaction 0.0002) or from 6 to 24 months (P-value for interaction 0.01) was assessed at per protocol analysis.

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Categorical variables were expressed as frequency (percentage), whereas continuous variables were expressed as mean + SD. Baseline continuous variables were compared between randomized groups using the Wilcoxon’s rank sums test or the ANOVA test, whereas for baseline binary variables the likelihood-ratio chi-square test or Fisher’s exact test was used. Estimation of the cumulative major adverse cardiovascular event rate was done with the Kaplan– Meier method, and events were compared by the log rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated as long-term clopidogrel vs. short-term clopidogrel (i.e. values .1 indicating increased hazard in the long-term group), using a proportional hazards model. The proportionality assumptions were met as they were checked by visual estimation after plotting the log Cumulative Hazard vs. (log) time at follow-up after index procedure and by applying a test for non-proportional hazards using the Schoenfeld residuals as previously described,11 which failed to reject the null hypothesis that event rate was affected by time. We performed a univariate Cox-regression analysis with interaction testing to determine whether the effect of duration of DAPT on the efficacy and safety endpoints at 2 year was consistent across stent types. Interaction tests were done with likelihood-ratio tests of the null hypothesis that the interaction coefficient is zero. In our analyses, we define landmark time and study outcomes in terms of their elapsed time from a patient’s index procedure. One landmark was used in this study at 6-months: alive patients completing 6-month follow-up were analysed with respect to events occurring after this timepoint and up to 24 months as per randomization scheme (i.e. by stent type and DAPT duration) according to the intention to treat principle. Finally, an explorative per protocol analysis focusing on patients who permanently discontinued clopidogrel after 6 months in the 6-month DAPT group vs. those who never interrupted clopidogrel therapy either permanently or temporarily during the course of follow-up in the 24-month DAPT arm was also performed. A two-sided P-value ,0.05 was considered significant. All analyses, carried out based on the intention to treat principle, were performed using STATA, version 11.1 (Stata Corp, College Station, TX, USA).

withdrew consent, therefore 1970 patients were randomly allocated at 1 month to undergo 24-month vs. 6-month duration of clopidogrel therapy. The four-stent groups, further stratified based on the different DAPT duration arms, were well balanced with regards to baseline and angiographic characteristics (Tables 1 and 2), with the only exception of circumflex artery being more frequently treated in the paclitaxel- and everolimus-eluting stent groups undergoing 6-month DAPT compared with other treatment groups. Adherence to aspirin therapy during the course of the study was high and it did not differ across stent groups, whereas the vast majority of BMS- and DES-treated patients in short-term DAPT arm discontinued clopidogrel before or at 6-month follow-up, respectively (Table 3).

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Table 1

Base-line characteristics of the patients

Characteristics

24-month clopidogrel

6-month clopidogrel

............................................................ ............................................................ BMS (n 5 246)

ZES (n 5 248)

PES (n 5 245)

EES (n 5 248)

BMS (n 5 246)

ZES (n 5 245)

PES (n 5 245)

P-value

EES (n 5 247)

............................................................................................................................................................................... Age (year) Male sex, n (%) Body mass index (kg/m2) Diabetes, n (%)

69 + 11

67 + 11

181 (74) 29 + 5

195 (79) 27 + 4

67 + 12

68 + 11

68 + 11

191 (78) 27 + 4

197 (79) 28 + 4

174 (71) 27 + 4

68 + 12 190 (78) 28 + 4

68 + 11 187 (76) 28 + 5

68 + 11 196 (79) 27 + 4

0.32 0.26 0.67

62 (25)

60 (24)

68 (28)

54 (22)

48 (20)

58 (24)

69 (28)

58 (24)

0.36

Insulin-dependent, n (%) Hypertension, n (%)

12 (5) 180 (73)

20 (8) 177 (71)

18 (7) 181 (74)

9 (4) 183 (74)

9 (4) 188 (76)

17 (7) 159 (65)

12 (5) 177 (72)

17 (7) 169 (68)

0.24 0.19

Hyperlipidaemia, n (%)

124 (50)

138 (56)

137 (56)

154 (62)

124 (50)

122 (50)

140 (57)

139 (56)

0.09

61 (25) 77 + 31

58 (23) 80 + 36

49 (20) 81 + 33

54 (22) 80 + 34

63 (26) 78 + 29

67 (28) 79 + 31

60 (24) 77 + 29

57 (23) 77 + 32

0.56 0.53

Prior MI, n (%)

61 (25)

64 (26)

82 (33)

63 (25)

56 (23)

67 (27)

56 (23)

79 (32)

0.51

Prior CABG, n (%) Prior stroke or TIA, n (%)

24 (10) 9 (4)

23 (9) 8 (3)

31 (13) 9 (4)

32 (13) 11 (4)

19 (8) 11 (4)

34 (14) 9 (4)

23 (9) 9 (4)

29 (12) 10 (4)

0.29 0.87

LVEF

50 + 11

52 + 10

50 + 10

51 + 10

51 + 10

50 + 11

51 + 11

50 + 10

0.16

...............................................................................................................................................................................

Clinical presentation, n (%) Stable angina pectoris Acute Coronary syndrome

57 (23) 189 (77)

65 (26) 183 (74)

75 (31) 170 (69)

58 (23) 190 (77)

56 (23) 191 (78)

65 (27) 180 (73)

68 (28) 176 (72)

61 (25) 186 (76)

0.49 0.58

Non-ST-elevation ACS

107 (43)

95 (38)

101 (41)

108 (44)

102 (41)

96 (39)

102 (42)

106 (43)

0.66

Unstable angina Non-ST-elevation MI

50 (19) 57 (23)

39 (16) 56 (23)

44 (18) 57 (23)

52 (21) 56 (23)

43 (17) 59 (24)

53 (22) 43 (18)

39 (16) 63 (26)

47 (19) 59 (24)

0.55 0.68

ST-segment-elevation MI

82 (33)

88 (35)

69 (28)

82 (33)

89 (36)

84 (34)

74 (30)

80 (32)

0.76

0.18

............................................................................................................................................................................... Angiographic features, n (%) Single-vessel disease Multi-vessel disease

87 (35)

78 (32)

69 (28)

68 (27)

83 (34)

61 (25)

79 (32)

76 (31)

159 (65)

170 (69)

176 (72)

180 (73)

163 (66)

184 (75)

166 (68)

171 (69)

ACS, acute coronary syndrome; LVEF, left-ventricular ejection fraction.

The composite of definite or probable [HR: 0.12 (95%CI: 0.02 – 1.00), P ¼ 0.049] and definite, probable or possible ST [HR: 0.25 (95%CI: 0.07–0.88), P ¼ 0.031] were both significantly lower in the 24-month DAPT arm in patients receiving PES, but not in those treated for the other stent types (Figure 4). Yet, no formal signal for interaction was noted for stent thrombosis endpoints across DAPT groups for each stent-type, which suggests a lack of study power for this analysis (there were only three definite, probable, or possible ST events in the long when compared with 12 in the short-term DAPT group in the PES arm) or the fact that results for stent thrombosis endpoints across stent groups are consistent with the overall study findings. At per protocol analysis, a consistent signal of heterogeneity across stent types for the definite, probable, or possible ST was also observed (P-value ¼ 0.07).

based on previously reported stent-specific late loss figures. Setting BMS as reference group, ZES-S, PES, or EES implantation resulted in a relative risk reduction for TLR in the range of 29% (95%CI: 12.9– 55.5), 63% (95%CI: 38.4–87.3), or 69% (95%CI: 46.0–93.6%), respectively (Figure 5). As shown in Figure 5, the relative risks of death, non-fatal myocardial infarction, or non-fatal stroke from 6 months onwards (i.e. when DAPT largely differed in the two DAPT treatment groups) as well as the 6-month landmark definite probable or possible stent thrombosis rates in the short when compared with the long-term DAPT group was not affected by the actual (i.e based on the observed TLR rates in the study) or expected (i.e. based on late loss figures in previously reported studies) potency of each stent type to inhibit intimal hyperplasia.

Stent potency and outcomes in relation to DAPT duration

Discussion

The re-intervention rates in the target lesion(s) from 30 days onwards was 15.9% in the BMS, 11.4% in the ZES-S, 6.0% in the PES, and 4.9% in the EES groups (P,0.0001 for the trend), which is consistent with the expected stent efficacy profiles

We found that the composite of death, myocardial infarction, or cerebrovascular accident did not differ in patients receiving BMS, PES, or EES implantation across DAPT groups, whereas it was significantly lower in ZES-S patients undergoing short when compared with long-term DAPT therapy, with positive interaction

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Current smoking, n (%) Creatinine clearance (mL/min)

Characteristic

24-month clopidogrel

......................................................................................

BMS (n 5 246)

ZES (n 5 248)

PES (n 5 245)

EES (n5 248)

6-month clopidogrel

......................................................................................

BMS (n5 246)

ZES (n 5 245)

PES (n 5 245)

P-value

EES (n 5 247)

............................................................................................................................................................................................................................................. Number of treated lesions ≥2 treated lesions, n (%)

1.47 + 0.8 85 (35)

1.53 + 0.9 97 (39)

1.51 + 0.9 83 (34)

1.51 + 0.8 100 (40)

1.48 + 0.8 83 (34)

1.60 + 1.0 92 (38)

1.64 + 1.0 104 (42)

1.56 + 0.9 92 (37)

0.35 0.38

≥3 treated lesions, n (%)

23 (9)

28 (11)

29 (12)

28 (11)

23 (9)

31 (13)

33 (14)

28 (11)

0.82

≥4 treated lesions, n (%) LAD treated, n (%)

8 (3) 150 (61)

13 (5) 146 (59)

12 (5) 136 (56)

5 (2) 141 (57)

7 (3) 137 (56)

14 (6) 149 (61)

11 (4) 142 (58)

12 (5) 146 (59)

0.34 0.43

CFX treated, n (%)

66 (27)

69 (28)

84 (34)

102 (41)

81 (33)

78 (32)

76 (31)

83 (34)

0.03

RCA treated, n (%) SVG treated, n (%)

87 (35) 5 (2)

92 (37) 6 (2)

88 (36) 6 (2)

79 (32) 6 (2)

98 (40) 4 (2)

86 (35) 5 (2)

84 (34) 3 (1)

95 (38) 5 (2)

0.70 0.73

At least one complex (type B2 or C) lesion, n (%)a Total ACC/AHA scorea,b

152 (62)

168 (68)

164 (67)

158 (64)

160 (65)

175 (71)

175 (71)

154 (62)

0.14

3.7 + 2.1

3.7 + 2.2

3.8 + 2.3

3.9 + 2.2

3.7 + 2.2

3.9 + 2.3

3.9 + 2.3

4.0 + 2.4

0.28

Number of stents implanted

1.82 + 1.2

1.91 + 1.3

1.81 + 1.3

1.77 + 1.1

1.77 + 1.1

1.96 + 1.3

1.88 + 1.2

1.96 + 1.3

0.34

39 + 35

41 + 32

39 + 29

37 + 24

36 + 25

42 + 30

40 + 27

42 + 32

0.13

Lesion length (mm)

13.07 + 8.45

13.18 + 8.32

14.09 + 9.51

13.13 + 8.35

13.51 + 8.25

13.23 + 8.24

13.75 + 8.98

14.27 + 8.64

0.49

RVD, before (mm) MLD, before (mm)

2.64 + 0.54 0.60 + 0.39

2.64 + 0.51 0.61 + 0.38

2.69 + 0.53 0.58 + 0.41

2.63 + 0.56 0.59 + 0.41

2.67 + 0.53 0.56 + 0.41

2.61 + 0.63 0.56 + 0.41

2.60 + 0.53 0.55 + 0.37

2.68 + 0.53 0.58 + 0.36

0.31 0.66

Length of stent (mm)

Dual antiplatelet therapy and stent-type

Table 2 Procedural results

.............................................................................................................................................................................................................................................

Quantitative coronary analysis

78 + 14

77 + 13

79 + 14

78 + 16

79 + 14

77 + 17

78 + 14

79 + 12

0.55

RVD, after (mm) MLD, after (mm)

2.76 + 0.50 2.42 + 0.56

2.74 + 0.42 2.46 + 0.46

2.86 + 0.47 2.53 + 0.46

2.76 + 0.50 2.45 + 0.49

2.79 + 0.46 2.44 + 0.49

2.79 + 0.54 2.47 + 0.54

2.79 + 0.51 2.42 + 0.53

2.79 + 0.48 2.52 + 0.46

0.47 0.27

Stenosis, after (%)

10.57 + 8.25

9.68 + 8.74

10.01 + 7.48

11.04 + 8.67

11.29 + 8.41

10.25 + 7.99

11.13 + 8.76

11.45 + 9.33

0.32

Stenosis, before (%)

a

Calculated in 952 patients in the 24-month clopidogrel arm and in 943 patients in the 6-month clopidogrel arm who presented at least one de-novo lesion; ACC/AHA score was missing in three patients. LAD, left anterior descending artery; CFX, circumflex artery; RCA, right coronary artery; LMCA, left main coronary artery; SVG, saphenous vein graft. b As previously described,18 type A stenoses were coded 1 point, typeB1 stenoses 2 points, type B2 stenoses 3 points, and type C stenoses 4 points.

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Table 3

Use of anti-platelet medications during the trial 24-month clopidogrel

6-month clopidogrel

................................................................... ................................................................... BMS (n 5 246)

ZES (n 5 248)

PES (n 5 245)

EES (n 5 248)

BMS (n 5 246)

ZES (n 5 245)

PES (n 5 245)

EES (n 5 247)

P-value

............................................................................................................................................................................... Anti-platelet therapy at 30 days, n (%) Number evaluated

246

248

245

248

246

245

245

247

Aspirin Clopidogrel

246 (100) 245 (99.6)

248 (100) 247 (99.6)

245 (100) 245 (100)

248 (100) 248 (100)

246 (100) 246 (100)

245 (100) 244 (99.6)

245 (100) 245 (100)

247 (100) 247 (100)

.0.99 0.55

Aspirin and clopidogrel

245 (99.6)

247 (99.6)

245 (100)

248 (100)

246 (100)

244 (99.6)

245 (100)

247 (100)

0.55

............................................................................................................................................................................... Anti-platelet therapy at 6 months, n (%) 241

241

238

246

240

244

239

240

Aspirin

240 (99.6)

240 (99.6)

234 (98.3)

246 (100)

236 (98.3)

241 (98.8)

238 (99.6)

238 (99.6)

0.24

Clopidogrel Aspirin and clopidogrel

239 (99.2) 238 (98.8)

239 (99.2) 238 (98.8)

237 (97.6) 233 (97.9)

245 (99.6) 245 (99.6)

94 (39.2) 97 (39.2)

241 (98.8) 238 (97.6)

234 (97.9) 233 (97.5)

236 (98.3) 235 (97.9)

,0.001 ,0.001

............................................................................................................................................................................... Anti-platelet therapy at 12 months, n (%) Number 236 238 evaluated total Aspirin 233 (98.7) 237 (99.6)

231

243

232

240

233

237

236 (98.3)

226 (97.8)

243 (100)

223 (96.1)

231 (99.1)

235 (99.2)

0.12

Clopidogrel

233 (98.7)

232 (97.5)

228 (98.7)

239 (98.3)

8 (3.5)

12 (5)

7 (3)

6 (2.5)

,0.001

Aspirin and Clopidogrel

230 (97.5)

231 (97.1)

223 (96.5)

239 (98.4)

8 (3.5)

12 (5)

6 (2.6)

6 (2.5)

,0.001

............................................................................................................................................................................... Anti-platelet therapy at 18 months, n (%) Number evaluated total

234

234

227

238

231

239

228

234

0.34

Aspirin Clopidogrel

232 (99.2) 231 (98.7)

232 (99.2) 222 (98.9)

223 (98.2) 220 (96.9)

234 (98.3) 231 (97.1)

221 (95.7) 2 (0.9)

232 (97.1) 2 (0.9)

226 (99.2) 3 (1.3)

233 (99.6) 1 (0.4)

0.12 ,0.001

Aspirin and clopidogrel

229 (97.9)

221 (94.4)

216 (95.2)

229 (96.2)

2 (0.9)

1 (0.4)

2 (0.9)

1 (0.4)

,0.001

............................................................................................................................................................................... Anti-platelet therapy at 24 months, n (%) Number evaluated total

230

228

224

238

227

237

226

230

Aspirin

228 (99.1)

224 (98.3)

219 (97.8)

234 (98.3)

216 (95.2)

230 (97.1)

221 (97.8)

229 (99.6)

Clopidogrel Aspirin and clopidogrel

226 (98.3) 224 (97.4)

212 (93) 210 (92.1)

214 (95.5) 211 (94.2)

228 (95.8) 226 (94.7)

2 (0.8) 1 (0.4)

3 (1.3) 2 (0.9)

testing. At the 6-month landmark analysis, heterogeneity across stent types persisted, whereas patients receiving PES showed a significantly higher rate of stent thrombosis in the short DAPT regimen. No association was noted between expected or actual stent potency in inhibiting intimal hyperplasia and greater vulnerability to shorter DAPT therapy. The main findings of our analysis challenge current recommendations endorsing a clear-cut dichotomy of BMS vs. DES for the need of prolonged DAPT after stenting. Furthermore, our data suggest minimal duration of clopidogrel therapy may differ among DES, irrespective of stent potency in inhibiting intimal hyperplasia.

0 0

0 0

0.19 ,0.001 ,0.001

As previously reported,9 no interaction was noted between BMS and the three different DES type clustered together with respect to duration of DAPT therapy. On the other hand, in the current analysis focusing on each DES type individually, a clear and formal signal of heterogeneity with respect to overall death, myocardial infarction, or cerebrovascular accidents was noted for the need of prolonged therapy with clopidogrel after intervention. This was driven by ZES-S treated patients showing an improved primary study and other secondary clinical outcomes with shortterm DAPT when compared with 24-month duration of therapy and by an excess of stent thrombosis events, particularly definite or probable and definite, probable, or possible ST in patients

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Number evaluated total

915

Dual antiplatelet therapy and stent-type

Table 4

Outcome rates at 24 months according to treatment group

Outcome

24-month clopidogrel

6-month clopidogrel

................................................................. .................................................................

BMS (n 5 246)

ZES (n 5 248)

PES (n 5 245)

EES (n 5 248)

BMS (n 5 246)

ZES (n 5 245)

PES (n 5 245)

EES (n 5 247)

Death for any cause, myocardial infarction, or cerebrovascular accident Death for cardiovascular cause, myocardial infarction, or cerebrovascular accident

29 (11.8)

33 (13.3)

23 (9.4)

15 (6.1)

32 (13)

12 (4.9)

31 (12.7)

23 (9.1)

19 (7.7)

21 (8.5)

15 (6.1)

8 (3.2)

22 (8.9)

11 (4.5)

23 (9.4)

13 (5.6)

Death for any cause or myocardial infarction

25 (10.2)

27 (10.9)

22 (8.9)

14 (5.7)

30 (12.2)

12 (4.9)

31 (12.7)

21 (8.5)

Death for cardiovascular cause, myocardial infarction

19 (7.7)

21 (8.5)

15 (6.1)

8 (3.2)

22 (8.9)

11 (4.5)

23 (9.4)

13 (5.3)

Death for any cause

16 (6.5)

20 (8.1)

19 (7.8)

20 (8.1)

8 (3.3)

20 (8.2)

17 (6.9)

Death for cardiovascular cause Myocardial infarction

9 (3.7) 14 (5.7)

13 (5.2) 12 (4.8)

10 (4.1) 9 (3.7)

4 (1.6) 4 (1.6)

12 (4.9) 15 (6.1)

7 (2.9) 4 (1.6)

12 (4.9) 14 (5.7)

6 (2.4) 8 (3.2)

Cerebrovascular accident

7 (2.8)

7 (2.8)

5 (2)

1 (0.4)

5 (2)

1 (0.4)

4 (1.6)

2 (0.8)

Definite stent thrombosis Late

...............................................................................................................................................................................

10 (4)

3 (1.2)

2 (0.8)

1 (0.4)

0 (0)

1 (0.4)

0 (0)

2 (0.8)

Very late

0 (0)

1 (0.4)

0 (0)

1 (0.4)

0 (0)

0 (0)

3 (1.3)

Cumulative

3 (1.2)

3 (1.2)

1 (0.4)

1 (0.4)

1 (0.4)

0 (0)

5 (2)

1 (0.4) 0 (0) 1 (0.4)

............................................................................................................................................................................... Definite or probable stent thrombosis Late 5 (2)

2 (0.8)

3 (1.2)

0 (0)

5 (2)

0 (0)

3 (1.2)

Very late

0 (0)

1 (0.4)

1 (0.4)

1 (0.4)

0 (0)

0 (0)

6 (2.6)

Cumulative

5 (2)

3 (1.2)

4 (1.6)

1 (0.4)

5 (2)

0 (0)

9 (3.7)

1 (0.4) 0 (0) 1 (0.4)

............................................................................................................................................................................... Definite, probable, or possible stent thrombosis Late 7 (2.8)

8 (3.2)

8 (3.2)

3 (1.2)

10 (4.1)

4 (1.6)

10 (4.1)

4 (1.6)

Very late

2 (0.8)

5 (2.1)

3 (1.3)

2 (0.8)

5 (2.1)

3 (1.3)

8 (3.4)

2 (0.8)

Cumulative

9 (3.7)

13 (5.2)

11 (4.5)

15 (6.1)

7 (2.9)

18 (7.4)

6 (2.4)

undergoing 6-month clopidogrel therapy after PES implantation compared with a longer duration of therapy. In our study, adherence to aspirin and clopidogrel was similarly high in the first 6 months after DES implantation in the two DAPT groups. Therefore, events occurring during this time period in the three DES groups may potentially confound the outcomes of the two different DAPT regimens tested in the study. Based on this notion, a landmark analysis focusing on events occurring after a 6 month-follow-up has been pre-specified and previously reported for the whole patient population or for all DES treated patients clustered together. When the three tested DES types were analysed separately at the 6-month landmark analysis, the results were largely consistent with the findings observed for the entire follow-up duration: (i) patients treated with ZES-S showed a better ischaemic outcomes in the 6-month when compared with the 24-month DAPT groups; (ii) event rates for the primary or secondary ischaemic clinical endpoints were similar between DAPT groups after BMS or EES implantation; (iii) the primary clinical composite endpoint trended higher and the ST rates were significantly increased in PES treated patients receiving PES and

5 (2)

undergoing 6-month when compared with 24-month duration of clopidogrel. Kandzari et al.6 recently analysed outcomes in 2032 patients undergoing coronary revascularization with ZES-S in five trials who for various reasons discontinued DAPT at 6 months and found that outcomes did not differ compared with patients who received longer clopidogrel therapy (up to 12 or 24 months). In the Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy Following Zotarolimus-Eluting Stent Implantation (RESET) trial of 2148 patients randomized to the ZES-S stent and three months of DAPT and 1058 patients treated with standard 12-month DAPT and other DES, the combined endpoint of any death, MI, stent thrombosis, occurred in 1.3% in the standard therapy arm vs. 0.8% in the 3-month group (P ¼ 0.48).12 Interestingly, prospective studies undertaken to evaluate the degree of ZES-S stent coverage have consistently showed a very low rate of uncovered/malapposed struts at 6- or even 3-month optical coherence tomography evaluation, which favourably compared with both first generation DES or even BMS.13 – 15 Based on this finding, the Zotarolimus-eluting stent in uncertain DES candidates

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...............................................................................................................................................................................

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M. Valgimigli et al.

ratios and 95% confidence intervals, for the primary end point of death for any cause, myocardial infarction (MI) or cerebrovascular accident (CVA), death or MI, and cardiovascular (CV) death or MI among patients randomly assigned to either the six or the 24-month clopidogrel therapy. The P-value for interaction represents the likelihood of interaction between the variable and the relative treatment effect.

Figure 2 Stent analyses of the stent thrombosis endpoints. Stent-specific analyses are shown, with hazard ratios and 95% confidence intervals, for the definite, definite, probable and definite, probable, possible stent thrombosis (ST) among patients randomly assigned to either the 6 or the 24-month clopidogrel therapy. The P-value for interaction represents the likelihood of interaction between the variable and the relative treatment effect.

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Figure 1 Stent analyses of the primary study endpoint and other secondary clinical outcomes. Stent-specific analyses are shown, with hazard

Dual antiplatelet therapy and stent-type

917

Figure 4 Stent analyses of the 6-month landmark stent thrombosis endpoints. Stent-specific analyses are shown, with hazard ratios and 95% confidence intervals, for the 6-month landmark analyses of definite, definite, probable and definite, probable, possible stent thrombosis (ST) among patients randomly assigned to either the 6 or the 24-month clopidogrel therapy. The P-value for interaction represents the likelihood of interaction between the variable and the relative treatment effect.

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Figure 3 Stent analyses of the 6-month landmark primary study endpoint and other secondary clinical outcomes. Stent-specific analyses are shown, with hazard ratios and 95% confidence intervals, for the 6-month landmark analyses of the primary endpoint of death for any cause, myocardial infarction (MI) or cerebrovascular accident (CVA), death or MI, and cardiovascular (CV) death or MI among patients randomly assigned to either the 6 or the 24-month clopidogrel therapy. The P-value for interaction represents the likelihood of interaction between the variable and the relative treatment effect.

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(ZEUS) study is comparing ZES-S vs. BMS in patients at high thrombotic, bleeding, or low restenosis risk allowing 1-month DAPT duration in both stent arms in patients who cannot tolerate longer duration of therapy (NCT01385319). Reassuring data on the safety of early DAPT discontinuation after EES have also been reported by a retrospective analysis of registry data.7 Moreover, the pooled analysis of SPIRIT II, III, IV, and COMPARE Trials of 6789 patients showed a persistently low ST rate in patients treated with EES but not PES who discontinued DAPT after 6 months, which is consistent with our current findings.16 Indeed, while our analysis on primary study endpoint and other secondary clinical outcomes numerically favoured longterm DAPT after EES implantation, the stent thrombosis endpoints and 6-month clinical landmark analyses revealed no excess of events in the 6-month DAPT group compared with longer-term clopidogrel therapy which is at variance with the results observed after PES implantation. The need for prolonged DAPT has been suggested to be inversely related to stent late loss.17 Potent inhibition of intimal

hyperplasia might more frequently lead to incomplete stent coverage and/or late stent mal-apposition, requiring a more prolonged course of intensified anti-platelet therapy to maintain stent safety.17 Our study, by randomizing patients to a balanced mixture of stents with various anti-intimal hyperplasia and each stent group to 6- vs. 24-month DAPT duration offers no evidence supporting the association between stent-related late-loss and need for prolonged DAPT. On the contrary, the results of our explorative yet pre-specified analysis suggest that the minimal DAPT duration may be stent-specific and not clearly related to stent potency towards inhibition of intimal hyperplasia. Several limitations of our study should be considered. Our study was not powered to assess outcomes with respect to the different DAPT regimens tested in our study for each stent type. Similarly, our study was overall underpowered to assess the effect of DAPT duration on stent thrombosis endpoints. Therefore, our findings should be considered exploratory and hypothesis generating. Our observation that primary study endpoint and other secondary clinical ischaemic endpoints may be significantly lower after 6-month compared with 24-month DAPT duration in ZES-S treated patients is intriguing, but it should be interpreted with caution. In light of the limitations outlined above, this finding should be reassuring on the safety of early DAPT discontinuation in patients treated with ZES-S. Yet, a new paradigm has been recently proposed by the results of the WOEST study (clinicaltrials. gov NCT00769938) according to which lessening intensity of antiplatelet inhibition via dropping aspirin has resulted in a dramatic reduction of not only bleeding but also ischaemic endpoints, including overall and cardiac mortality. This paradigm has also been shown to apply to periprocedural anti-thrombotic therapy and it will be further investigated in the ongoing comparative effectiveness of 1 month of ticagrelor plus aspirin followed by ticagrelor monotherapy vs. a current-day intensive DAPT in all-comer patients undergoing percutaneous coronary intervention with unrestricted Biolimus A9-eluting stent (GLOBAL LEADERS) study. In conclusion, our study offers preliminary evidence that optimal duration of DAPT may be stent-specific with no clear association between late loss potency and vulnerability to shorter DAPT duration. DES-specific studies aiming at unraveling the optimal DAPT duration after stent implantation are eagerly required and some of them are currently ongoing. Conflict of interest: M.V. has received honoraria for lectures/advisory board and research grants from Merck, Iroko, Eli Lilly, and Medtronic; honoraria for advisory board and lectures from The Medicines Company and Eli Lilly Co; Daiichi Sankyo, Inc., St Jude and Abbott Vascular; lectures from Cordis, CID, and Terumo.

Funding The study is an investigator-driven clinical trial. The conduct of this study did not receive any direct or indirect external funding but was entirely supported by the University of Ferrara, which employed dedicated personnel for data monitoring, data management, events adjudication, and independent statistical analysis.

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Figure 5 Stent potency in inhibiting repeated intervention and relative risks of adverse outcomes after 6-month dual antiplatelet therapy. Relative risk reductions and corresponding 95% confidence intervals (vertical bars) for target lesion revascularization from 30 days onwards for each drug-eluting stent employed in the study when compared with bare metal stent group (reference group) is shown to the left. In the middle, relative risk reductions and corresponding 95% confidence intervals (vertical bars) for 6-month landmark analysis of death, myocardial infarction, or stroke in the 6-month when compared with 24-month dual antiplatelet group is shown for each stent. In the right portion of the figure, relative risk reductions and corresponding 95% confidence intervals (vertical bars) for 6-month landmark analysis of definite, probable, or possible stent thrombosis (ST) in the 6-month when compared with 24-month dual antiplatelet group is shown for each stent. Note that a negative relative risk reduction, such as that observed for PES or BMS groups, implies the possibility of a relative risk increase in the study arm when compared with reference group. EP, endpoint; TLR, target lesion revascularization from 30 days onwards; D, death; MI, myocardial infarction; CV, cerebrovascular accident; DAPT, dual antiplatelet therapy; ST, stent thrombosis; Ref, reference arm; BMS, bare metal stent; ZES-S, zotarolimus-eluting stent Endeavor Sprint; PES, paclitaxel-eluting stent; EES, everolimuseluting stent.

M. Valgimigli et al.

Dual antiplatelet therapy and stent-type

Clinical sites Azienda Ospedaliero Universitaria di Ferrara, Italy—M. Valgimigli, G. Campo, M. Tebaldi, C. Tumscitz, C. Cavazza, E. Cangiano, M. Minarelli, C. Arcozzi, A Scalone, M. Borghesi, J. Marchesini, M. Monti; Valle Oppio Hospital— G.F. Percoco, M. Kubbajeh, A. Frangione; Villa Maria Cecilia Hospital— A. Cremonesi, F. Castriota, F. Colombo, K. Oshoala, C. Garattoni, P. Sbarzaglia; Cento Hospital—G. Fuca’.

Appendix

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5. Stone GW, Rizvi A, Newman W, Mastali K, Wang JC, Caputo R, Doostzadeh J, Cao S, Simonton CA, Sudhir K, Lansky AJ, Cutlip DE, Kereiakes DJ. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010;362:1663 –1674. 6. Kandzari DE, Barker CS, Leon MB, Mauri L, Wijns W, Fajadet J, Mehran R. Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents. JACC. Cardiovasc Interven 2011;4:1119 –1128. 7. Naidu SS, Krucoff MW, Rutledge DR, Mao VW, Zhao W, Zheng Q, Wilburn O, Sudhir K, Simonton C, Hermiller JB. Contemporary Incidence and Predictors of Stent Thrombosis and Other Major Adverse Cardiac Events in the Year After XIENCE V Implantation: Results From the 8,061-Patient XIENCE V United States Study. JACC. Cardiovasc Interven 2012;5:626 –635. 8. Valgimigli M, Campo G, Percoco G, Monti M, Ferrari F, Tumscitz C, Zuffi A, Colombo F, Kubbajeh M, Cavazza C, Cangiano E, Tebaldi M, Minarelli M, Arcozzi C, Scalone A, Frangione A, Borghesi M, Marchesini J, Parrinello G, Ferrari R. Randomized comparison of 6- vs. 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention Design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY). Am Heart J 2010;160:804 –811. 9. Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G, Tumscitz C, Castriota F, Colombo F, Tebaldi M, Fuca G, Kubbajeh M, Cangiano E, Minarelli M, Scalone A, Cavazza C, Frangione A, Borghesi M, Marchesini J, Parrinello G, Ferrari R. Shortvs. long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015 –2026. 10. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –51. 11. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer-Verlag; 2000. 12. Hong MK. A New Strategy for Discontinuation of Dual Antiplatelet Therapy: Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy Following Zotarolimus-Eluting Stent Implantation: RESET Trial ACC, 2012;Chicago(24 March):oral presentation. 13. Guagliumi G, Ikejima H, Sirbu V, Bezerra H, Musumeci G, Lortkipanidze N, Fiocca L, Tahara S, Vassileva A, Matiashvili A, Valsecchi O, Costa M. Impact of drug release kinetics on vascular response to different zotarolimus-eluting stents implanted in patients with long coronary stenoses: the LongOCT study (Optical Coherence Tomography in Long Lesions). JACC. Cardiovasc Interven 2011;4:778 –785. 14. Guagliumi G, Musumeci G, Sirbu V, Bezerra HG, Suzuki N, Fiocca L, Matiashvili A, Lortkipanidze N, Trivisonno A, Valsecchi O, Biondi-Zoccai G, Costa MA. Optical coherence tomography assessment of in vivo vascular response after implantation of overlapping bare-metal and drug-eluting stents. JACC. Cardiovasc Interven 2010;3: 531 –539. 15. Kim JS, Jang IK, Fan C, Kim TH, Park SM, Choi EY, Lee SH, Ko YG, Choi D, Hong MK, Jang Y. Evaluation in 3 months duration of neointimal coverage after zotarolimus-eluting stent implantation by optical coherence tomography: the ENDEAVOR OCT trial. JACC. Cardiovasc Interven 2009;2:1240 –1247. 16. Kedhi E, Stone GW, Kereiakes DJ, Serruys PW, Parise H, Fahy M, Simonton CA, Krishnankutty S, Soodll P, Smits PS. Stent thrombosis: insights on outcomes, predictors and impact of dual antiplatelet therapy interruption from the SPIRIT II, SPIRIT III, SPIRIT IV and COMPARE Trials. Eurointervention 2012;8:599 –606. 17. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of firstgeneration drug-eluting stents: a cause for concern. Circulation 2007;115: 1440 –55. discussion 1455. 18. Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, Bulle TM. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection. Multivessel Angioplasty Prognosis Study Group. Circulation 1990;82:1193 – 1202.

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The following investigators participated in the study: Executive Committee—M. Valgimigli (principal investigator), G. Campo, G. Percoco, R. Ferrari; Data and Safety Monitoring Board—N. Avigni, R. Mazzucco; Clinical Events Committee—P. Vranckx (chair), Belgium; S. Curello, Italy; G. Guardigli, Italy; Data Management and Monitoring—Medial trial Analysis, Switzerland and Eustrategy Research Coordination, Italy— M. Monti, S. Gambetti and L. Bristot; Statistical Committee—G.Parrinello (chair), University of Brescia.

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