Author + information
- Received March 9, 2017
- Revision received June 1, 2017
- Accepted June 29, 2017
- Published online December 4, 2017.
- Christopher R. Kelly, MDa,
- Paul S. Teirstein, MDb,
- Ian T. Meredith, AM, MBBS, PhDc,
- Bruno Farah, MDd,
- Christophe L. Dubois, MD, PhDe,
- Robert L. Feldman, MDf,
- Joseph Dens, MD, PhDg,
- Nobuhisa Hagiwara, MDh,
- Abram Rabinowitz, MDi,
- Didier Carrié, MDj,
- Vincent Pompili, MDk,
- Alain Bouchard, MDl,
- Shigeru Saito, MDm,
- Dominic J. Allocco, MDn,
- Keith D. Dawkins, MDn and
- Gregg W. Stone, MDa,∗ ()
- aColumbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation, New York, New York
- bScripps Clinic, La Jolla, California
- cMonashHEART, Southern Health, Monash Medical Centre, Clayton, Victoria, Australia
- dClinique Pasteur–Toulouse, Toulouse, France
- eUniversity Hospital Leuven, Leuven, Belgium
- fMediquest Research at Munroe Regional Medical Center, Ocala, Florida
- gDepartment of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium
- hTokyo Women’s Medical University Hospital, Shinjuku, Tokyo, Japan
- iTexSan Heart Hospital, San Antonio, Texas
- jUniversité Paul Sabatier, Centre Hospitalier Universitaire Rangueil, Toulouse, France
- kUniversity of Nebraska Medical Center, Omaha, Nebraska
- lBaptist Medical Center–Princeton, Birmingham, Alabama
- mShonan Kamakura General Hospital, Kanagawa, Japan
- nBoston Scientific Corporation, Marlborough, Massachusetts
- ↵∗Address for correspondence:
Dr. Gregg W. Stone, Columbia University Medical Center, The Cardiovascular Research Foundation, 1700 Broadway, 8th Floor, New York, New York 10019.
Objectives The authors sought to evaluate the final 5-year safety and effectiveness of the platinum-chromium everolimus-eluting stent (PtCr-EES) in the randomized trial, as well as in 2 single-arm substudies that evaluated PtCr-EES in small vessels (diameter <2.5 mm; n = 94) and long lesions (24 to 34 mm; n = 102).
Background In the multicenter, randomized PLATINUM (PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions), the PtCr-EES was noninferior to the cobalt-chromium everolimus-eluting stent (CoCr-EES) at 1 year in 1,530 patients undergoing percutaneous coronary intervention.
Methods Patients with 1 or 2 de novo coronary artery lesions (reference vessel diameter 2.50 to 4.25 mm, length ≤24 mm) were randomized 1:1 to PtCr-EES versus CoCr-EES. All patients in the substudies received PtCr-EES. The primary endpoint was target lesion failure (TLF), a composite of target vessel-related cardiac death, target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization.
Results In the randomized trial, the 5-year TLF rate was 9.1% for PtCr-EES and 9.3% for CoCr-EES (hazard ratio [HR]: 0.97; p = 0.87). Landmark analysis demonstrated similar TLF rates from discharge to 1 year (HR: 1.12; p = 0.70) and from 1 to 5 years (HR: 0.90; p = 0.63). There were no significant differences in the rates of cardiac death, myocardial infarction, target lesion or vessel revascularization, or stent thrombosis. PtCr-EES had 5-year TLF rates of 7.0% in small vessels and 13.6% in long lesions.
Conclusions PtCr-EES demonstrated comparable safety and effectiveness to CoCr-EES through 5 years of follow-up, with low rates of stent thrombosis and other adverse events. The 5-year event rates were also acceptable in patients with small vessels and long lesions treated with PtCr-EES. (The PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions [PLATINUM]; NCT00823212; The PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions in Small Vessels [PLATINUM SV]; NCT01498692; The PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of Long De Novo Coronary Artery Lesions [PLATINUM LL]; NCT01500434)
In multiple randomized trials, the cobalt chromium everolimus-eluting stent (CoCr-EES) (Abbott Vascular, Santa Clara, California) resulted in lower rates of ischemia-driven revascularization (TLR), stent thrombosis (ST), and myocardial infarction (MI) when compared with first-generation drug-eluting stents (1–7). The platinum-chromium everolimus-eluting stent (PtCr-EES) (Boston Scientific, Marlborough, Massachusetts) uses the same polymer and everolimus concentration and elution rate as the CoCr-EES, but with a denser alloy and modified strut architecture designed to provide greater conformability, radial strength, radiopacity, and fracture resistance (8,9). In the large-scale, randomized PLATINUM (PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions), the PtCr-EES was noninferior to CoCr-EES at 1 year with respect to the primary outcome of target lesion failure (TLF) (3.4% for PtCr-EES vs. 2.9% for CoCr-EES, pnoninferiority = 0.001) in patients undergoing percutaneous coronary intervention (PCI) (10). In 2 concurrent single-arm substudies, the PtCr-EES provided superior outcomes in small vessels (SV) and long lesions (LL) when compared with historical data from studies of platinum-chromium paclitaxel-eluting stents (11). It is important to describe the final long-term outcomes from these trials, because the favorable early safety and effectiveness profile of some coronary stents was not durable at late follow-up. The current report provides the final, 5-year follow-up results from the randomized PLATINUM trial and the single-arm SV and LL substudies.
Patients were eligible for inclusion if they presented with unstable angina, stable angina, or documented silent ischemia, and required PCI of an atherosclerotic lesion with estimated stenosis of 50% to 99% and Thrombolysis In Myocardial Infarction flow grade >1. Patients with 1 or 2 lesions ≤24 mm in length and with reference vessel diameter (RVD) 2.50 to 4.25 mm, as visually assessed, were randomized in the main trial. Patients with a single lesion with RVD ≥2.25 to <2.50 mm and length ≤28 mm were enrolled in the SV study. Patients with a single lesion >24 to ≤34 mm long with RVD 2.5 to 4.25 mm were enrolled in the LL study. General exclusion criteria included acute or recent MI, recent PCI of the target vessel, left ventricular ejection fraction ≤30%, chronic total occlusions, left main or ostial lesions, major bifurcation disease, location of the target lesion in or access through a saphenous vein graft, and presence of thrombus. The studies were approved by the institutional review board at each participating center, and all subjects provided written informed consent.
Intervention and follow-up
In the main trial, patients were randomized 1:1 in open-label fashion after successful target lesion pre-dilatation to PtCr-EES or CoCr-EES. Randomization was stratified by site. The operator was aware of the treatment assignment, but the patient and other providers were blinded. In the SV and LL substudies, all patients received PtCr-EES. Patients were treated with loading doses of aspirin and clopidogrel. The choice of anticoagulant agent (unfractionated heparin, enoxaparin, or bivalirudin) and use of glycoprotein IIb/IIIa inhibitors were left to operator discretion. After PCI, all patients were required to take aspirin indefinitely and clopidogrel for at least 6 months (12 months in the absence of high bleeding risk). Prasugrel was an option for patients outside of the United States. Follow-up was performed at 1, 6, 12, and 18 months, and then annually from 2 to 5 years. Routine angiographic follow-up was not performed. Study monitors verified all case report form data. An independent, blinded clinical events committee adjudicated all death, MI, TLR, target vessel revascularization (TVR), and ST events. An independent core laboratory evaluated all angiographic data. An independent Data Safety and Monitoring Committee oversaw the trial performance and outcomes.
The primary endpoint in each of the studies was TLF at 1 year, a composite of cardiac death related to the target vessel, MI related to the target vessel, or ischemia-driven TLR. Cardiac death included any death without a proven noncardiac cause. MI was defined as: 1) new Q waves lasting >0.04 s in ≥2 leads with biomarkers elevated above normal (creatine kinase-myocardial band [CK-MB] or troponin); 2) elevated CK levels (>2× normal if spontaneous, >3× normal if after PCI, >5× normal if after coronary artery bypass grafting [CABG]), with elevated CK-MB; or 3) elevated troponin levels (>2× normal if spontaneous, >3× normal if after PCI, >5× normal if after CABG) with electrocardiographic changes consistent with ischemia (ST-segment or T-wave changes, new left bundle branch block), imaging evidence of new loss of viable myocardium, and/or a new regional wall motion abnormality. Ischemia-driven revascularization was defined as revascularization for angiographic stenosis ≥70%, or stenosis ≥50% with clinical or functional evidence of ischemia. Secondary endpoints included target vessel failure (TVF), a composite of target vessel-related cardiac death, target vessel-related MI, or TVR; the components of TLF and TVF; all-cause death; and ST (defined using the Academic Research Consortium criteria).
For the randomized trial, principal analyses were performed in the intention-to-treat population; however, patients who did not receive a study stent were not followed beyond 1 year. Kaplan-Meier analysis was used to determine time-to-event rates, which were compared using the log-rank test. Landmark analyses were performed to examine event rates from 1 to 5 years (after excluding events occurring before 1 year). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox’s partial likelihood method. Multivariable analysis was performed to determine the independent predictors of TLF at 5 years in the entire population. Candidate patient- and lesion-level predictors (Online Table 1) were entered into the model using entry/exit criteria of p < 0.10. All statistical analyses were conducted using SAS software, version 8.2 or above (SAS Institute, Cary, North Carolina). For all tests, a p value of <0.05 was considered statistically significant.
The PLATINUM trial randomized 1,530 subjects at 132 sites in the United States, Europe, Japan, and other Asia-Pacific countries to PtCr-EES (n = 768) versus CoCr-EES (n = 762). As previously reported (10), the patients were well-matched with respect to baseline demographic, lesion, and procedure characteristics (Table 1). A total of 23 patients who did not receive a study stent were not followed beyond the first year. After the exclusion of these patients, 5-year outcomes data were available for 94.6% (717 of 758) of the PtCr-EES group and 93.5% (700 of 749) of the CoCr-EES group (Online Figure 1).
At 5 years, TLF occurred in 9.1% of patients assigned to PtCr-EES and 9.3% of patients assigned to CoCr-EES (HR: 0.97, 95% CI: 0.69 to 1.37; p = 0.87) (Figure 1A). Landmark analysis demonstrated similar relative TLF rates from discharge to 1 year (HR: 1.12; p = 0.70) and from 1 to 5 years (HR: 0.90; p = 0.63) (Figure 1B). The groups did not significantly differ in the rates of the components of the primary endpoint, or in any of the other pre-specified secondary endpoints (Table 2), both at 5 years (Figure 2) and in the landmark periods (Online Figure 2). ST at 5 years occurred in only 6 patients in the PtCr-EES group (0.8%) and in 5 patients in the CoCr-EES group (0.7%), with approximately one-half of these events occurring after 1 year in both groups. The use of antiplatelet agents was similar in both groups throughout follow-up (Online Figure 3A). Subgroup analysis did not demonstrate any statistically significant interactions between baseline factors and stent type with respect to the primary outcome of TLF at 5 years (Figure 3).
By multivariable analysis, the independent predictors of TLF at 5 years were previous CABG (p = 0.0008), history of congestive heart failure (p = 0.002), history of peripheral vascular disease (p = 0.002), diabetes mellitus (p = 0.005), and left anterior descending coronary artery treatment (p = 0.02). Randomized stent type was not a significant predictor of 5-year TLF (p = 0.77).
The SV substudy enrolled 94 patients at 23 sites in the United States, Europe, Japan, and New Zealand. The baseline patient, lesion, and procedure characteristics have been previously reported (11) and are summarized in Table 1. Five patients did not receive a study stent and were not followed beyond the first year. Five-year outcomes data were available for 93.3% (83 of 89) of the remaining patients. The 5-year TLF event rate was 7.0% (95% CI: 1.6% to 12.4%) (Figure 4A). The 5-year rates for the major secondary endpoints are shown in Figure 4B and Table 3. There were no definite or probable stent thromboses in this study cohort. At 5 years, the rates of aspirin and thienopyridine use were 92.1% and 39.5%, respectively (Online Figure 3B).
The LL substudy enrolled 102 patients at 30 sites in the United States, Europe, Japan, and New Zealand. The baseline characteristics are summarized in Table 1. Two patients did not receive a study stent and were not followed beyond the first year. Five-year outcomes data were available for 88.0% (88 of 100) of the remaining patients. The 5-year TLF event rate was 13.6% (95% CI: 6.7% to 20.6%) (Figure 4C). The 5-year event rates for the major secondary endpoints are shown in Figure 4D and Table 3. There were no definite or probable stent thromboses in this study cohort. At 5 years, the rates of aspirin and thienopyridine use were 93.6% and 38.5%, respectively (Online Figure 3C).
The 5-year data from the pivotal, multicenter PLATINUM trial demonstrate that: 1) PtCr-EES have comparable short-term and long-term safety and effectiveness to CoCr-EES; 2) both stents resulted in very low rates of adverse events in the types of patients and lesions studied, with no significant differences in the 5-year rates of cardiac death, MI, or ST in the randomized trial; and 3) 5-year event rates were also low after PCI with PtCr-EES of selected long lesions or lesions in small vessels.
The present report provides the longest follow-up to date of patients undergoing PCI with PtCr-EES. The 5-year rates of ischemia-driven TLR with both stents were favorable (6.2% for CoCr-EES and 5.3% for PtCr-EES), signifying long-term freedom from repeat TLR in ∼19 of 20 patients. Of note, the rates of ischemia-driven TVR not related to the target lesion were also similar between stent types (4.8% and 5.8%, respectively), signifying that approximately as many non-TLR events as TLR events in the target vessel occur during long-term follow-up. These findings are consistent with prior research (12) demonstrating an increasing proportion of non-TLR events during long-term follow-up after stent implantation due to progressive atherosclerosis in non-treated coronary segments.
In the SPIRIT III (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) trial (2), which enrolled a similar patient population to the PLATINUM study, the 5-year rate of ischemia-driven TLR with CoCr-EES was 8.6%, whereas in the all-comers COMPARE (A Trial of Everolimus-eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice), the 5-year TLR rate with CoCr-EES was 5.0%.
The 5-year rates of all-cause death or MI with both stents in this trial were also favorable, and similar to that previously reported (10.3% for both CoCr-EES and PtCr-EES in the PLATINUM study, 9.5% for CoCr-EES in the SPIRIT III trial, 14.6% for CoCr-EES in the COMPARE trial). Of note, the 5-year ST rates in the randomized PLATINUM trial were particularly low (<1% with both devices), consistent with the low rate of ST with fluoropolymer-based everolimus-eluting stents reported in prior meta-analyses (13,14).
In patients treated with PtCr-EES in the single-arm SV and LL substudies, the 5-year event rates were also acceptable, with no patients developing ST. Although prior studies have evaluated CoCr-EES in SV and LL (defined using similar criteria), none has provided 5-year follow-up. The single-arm SPIRIT SV trial (Spirit Small Vessel Registry) (15), which evaluated CoCr-EES in SV, reported a 1-year TLF rate of 8.1%, numerically higher than both the 1-year (5.6%) and 5-year (7.0%) TLF rates with PtCr-EES in the PLATINUM SV substudy.
Likewise, the LONG-DES III (Percutaneous Treatment of Long Native Coronary Lesions With Drug-Eluting Stent-III) trial (16) reported a 1-year TLF rate of 12.9% after CoCr-EES in LL, higher than the 1-year (3.1%) and 2-year (8.8%) rates, but comparable to the 5-year rate (13.6%) with PtCr-EES in the PLATINUM LL substudy. In the IVUS-XPL (Impact of IntraVascular UltraSound Guidance on Outcomes of Xience Prime Stents in Long Lesions) trial (17), which examined the relative efficacy of angiography and IVUS for guiding the treatment of LL using CoCr-EES, the 1-year TLF rate in the angiography arm was 5.8%. Of note, the average lesion length was longer in both the IVUS-XPL (34.7 mm) and LONG-DES III (34.0 mm) trials than the PLATINUM LL trial (24.4 mm), which may account for the higher event rates. Direct comparisons between these studies should be performed with caution, given the modest numbers of enrolled patients, which adds imprecision to the event rate estimates, and the differences in patient and lesion risk profiles and adjudication methods. Nonetheless, the findings from the randomized trials and SV and LL substudies suggest that PtCr-EES and CoCr-EES likely have approximately comparable performance in these lesion subtypes. Large randomized trials would be required for more meaningful comparisons.
PtCr-EES and CoCr-EES share the same polymer, with a similar concentration and elution rate of everolimus (8,9); however, differences in the underlying metal alloy and its configuration give rise to differences in radial and longitudinal strength and resistance to deformation, flexibility and deliverability, and radiopacity. The procedural and angiographic success rates were similar with both devices in the randomized trial (10), and the similar long-term outcomes in the present report suggest overall interchangeability with respect to clinical performance with both devices in noncomplex lesions.
The major limitation of the PLATINUM randomized trial is the exclusion of high-risk patients and lesions, restricting the generalizability of the results. Recent data from trials of PtCr-EES in less selected patients, however, are consistent with the present results. In the DUTCH PEERS (Durable Polymer-Based Stent Challenge of Promus Element Versus Resolute Integrity in an All Comers Population) trial (18,19), which randomized 1,811 all-comer patients to slow-release cobalt-chromium zotarolimus-eluting stents or PtCr-EES, the rate of TVF after PtCr-EES was 5.0% at 1 year and 10.3% at 3 years, whereas the rate of definite/probable ST was 1% at 1 year and 1.1% at 3 years, with no significant differences from zotarolimus-eluting stents. The results were consistent in high-risk patients presenting with MI. In the PLATINUM PLUS trial (Trial to Assess the Everolimus-Eluting Coronary Stent System (PROMUS Element) for Coronary Revascularization) (20), which randomized 2,980 all-comer patients to PtCr-EES versus CoCr-EES, the 1-year TVF rates were 4.6% versus 3.2% (p = 0.08), whereas the 1-year rates of definite/probable ST were 0.8% and 0.5% (p = 0.44), respectively. Similar results were seen in the single-arm PROMUS Element European Post-Approval Surveillance Study (21), which enrolled 1,010 all-comers and reported a 1-year TVF rate of 6.2% and ST rate of 0.6%. Long-term data from these trials are required to provide further evidence of the clinical performance of PtCr-EES in high-risk patients.
The 5-year results from the PLATINUM randomized trial demonstrate comparable long-term safety and effectiveness of PtCr-EES and CoCr-EES, with notably low rates of ST with both devices. Patients with SV and LL treated with PtCr-EES also had high rates of event-free survival at 5 years.
WHAT IS KNOWN? The PtCr-EES had been previously shown in the PLATINUM trial to be noninferior to the CoCr-EES at 1 year in patients undergoing percutaneous coronary intervention. However, longer-term outcomes have not been reported.
WHAT IS NEW? The 5-year outcomes from the PLATINUM trial demonstrate comparable event rates for PtCr-EES and CoCr-EES throughout the study period, with low rates of stent thrombosis and other adverse cardiac events. Landmark analyses between 1 and 5 years did not show a difference in very late events between the stent types. Long-term event rates were also acceptable in registries evaluating small vessels and long lesions treated with PtCr-EES.
WHAT IS NEXT? Long-term data on PtCr-EES from ongoing trials of unselected patients are required to provide further evidence of the safety and efficacy of PtCr-EES in general clinical practice.
Funded by Boston Scientific Corp. Dr. Teirstein has been a speaker for and received consulting fees from Boston Scientific, Abbott, and Medtronic. Dr. Meredith is an employee and shareholder of Boston Scientific. Dr. Dubois serves on Boston Scientific’s scientific advisory board. Dr. Feldman has received honoraria from Boston Scientific; is stockholder of Boston Scientific; and serves on their scientific advisory board. Dr. Dens is a consultant for and has received a research grant from Boston Scientific. Dr. Saito is a consultant for and has received honoraria from Abbott Vascular, Boston Scientific, Medtronic, and Terumo. Drs. Allocco and Dawkins are employees and shareholders of Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery bypass grafting
- confidence interval
- cobalt chromium everolimus-eluting stent(s)
- hazard ratio
- long lesions
- myocardial infarction
- percutaneous coronary intervention
- platinum-chromium everolimus-eluting stent(s)
- reference vessel diameter
- stent thrombosis
- small vessels
- target lesion failure
- target lesion revascularization
- target vessel failure
- target vessel revascularization
- Received March 9, 2017.
- Revision received June 1, 2017.
- Accepted June 29, 2017.
- 2017 American College of Cardiology Foundation
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