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I n multiple randomized trials, the cobalt chro-mium everolimus-eluting stent (CoCr-EES)(Abbott Vascular, Santa Clara, California)
resulted in lower rates of ischemia-driven revascular-ization (TLR), stent thrombosis (ST), and myocardialinfarction (MI) when compared with first-generationdrug-eluting stents (1–7). The platinum-chromiumeverolimus-eluting stent (PtCr-EES) (Boston Scienti-fic, Marlborough, Massachusetts) uses the same poly-mer and everolimus concentration and elution rate asthe CoCr-EES, but with a denser alloy and modifiedstrut architecture designed to provide greater con-formability, radial strength, radiopacity, and fractureresistance (8,9). In the large-scale, randomized PLAT-INUM (PLATINUM Clinical Trial to Assess the PRO-MUS Element Stent System for Treatment of DeNovo Coronary Artery Lesions), the PtCr-EES wasnoninferior to CoCr-EES at 1 year with respect to theprimary outcome of target lesion failure (TLF) (3.4%for PtCr-EES vs. 2.9% for CoCr-EES, pnoninferiority ¼0.001) in patients undergoing percutaneous coronaryintervention (PCI) (10). In 2 concurrent single-armsubstudies, the PtCr-EES provided superior outcomesin small vessels (SV) and long lesions (LL) whencompared with historical data from studies ofplatinum-chromium paclitaxel-eluting stents (11). Itis important to describe the final long-term outcomesfrom these trials, because the favorable early safetyand effectiveness profile of some coronary stentswas not durable at late follow-up. The current reportprovides the final, 5-year follow-up results from therandomized PLATINUM trial and the single-arm SVand LL substudies.
METHODS
STUDY POPULATION. Patients were eligible for in-clusion if they presented with unstable angina, stableangina, or documented silent ischemia, and requiredPCI of an atherosclerotic lesion with estimated ste-nosis of 50% to 99% and Thrombolysis In MyocardialInfarction flow grade >1. Patients with 1 or 2lesions #24 mm in length and with reference vesseldiameter (RVD) 2.50 to 4.25 mm, as visually assessed,
been a speaker for and received consulting fees from Boston Scientific, Abbo
shareholder of Boston Scientific. Dr. Dubois serves on Boston Scientific’s s
honoraria from Boston Scientific; is stockholder of Boston Scientific; and se
consultant for and has received a research grant from Boston Scientific. Dr.
from Abbott Vascular, Boston Scientific, Medtronic, and Terumo. Drs. Alloc
Boston Scientific. All other authors have reported that they have no relationsh
Manuscript received March 9, 2017; revised manuscript received June 1, 201
were randomized in the main trial. Patientswith a single lesion with RVD $2.25 to <2.50mm and length #28 mm were enrolled in theSV study. Patients with a single lesion >24to #34 mm long with RVD 2.5 to 4.25 mmwere enrolled in the LL study. Generalexclusion criteria included acute or recentMI, recent PCI of the target vessel, left ven-tricular ejection fraction #30%, chronic totalocclusions, left main or ostial lesions, majorbifurcation disease, location of the targetlesion in or access through a saphenous veingraft, and presence of thrombus. The studieswere approved by the institutional reviewboard at each participating center, and allsubjects provided written informed consent.
INTERVENTION AND FOLLOW-UP. In themain trial, patients were randomized 1:1 inopen-label fashion after successful targetlesion pre-dilatation to PtCr-EES or CoCr-EES.Randomization was stratified by site. Theoperator was aware of the treatment assign-ment, but the patient and other providerswere blinded. In the SV and LL substudies, allpatients received PtCr-EES. Patients were
treated with loading doses of aspirin and clopidogrel.The choice of anticoagulant agent (unfractionatedheparin, enoxaparin, or bivalirudin) and use ofglycoprotein IIb/IIIa inhibitors were left to operatordiscretion. After PCI, all patients were required totake aspirin indefinitely and clopidogrel for at least 6months (12 months in the absence of high bleedingrisk). Prasugrel was an option for patients outside ofthe United States. Follow-up was performed at 1, 6,12, and 18 months, and then annually from 2 to 5years. Routine angiographic follow-up was not per-formed. Study monitors verified all case report formdata. An independent, blinded clinical events com-mittee adjudicated all death, MI, TLR, target vesselrevascularization (TVR), and ST events. An indepen-dent core laboratory evaluated all angiographic data.An independent Data Safety and MonitoringCommittee oversaw the trial performance andoutcomes.
tt, and Medtronic. Dr. Meredith is an employee and
cientific advisory board. Dr. Feldman has received
rves on their scientific advisory board. Dr. Dens is a
Saito is a consultant for and has received honoraria
co and Dawkins are employees and shareholders of
ips relevant to the contents of this paper to disclose.
7, accepted June 29, 2017.
TABLE 1 Baseline and Procedural Characteristics of Patients in the Randomized PLATINUM Trial and the SV and LL Substudies
Values are mean � SD, n (%), or n/N (%). *Requiring medication.
CoCr-EES¼ cobalt chromium everolimus-eluting stent(s); LL ¼ long lesion; PLATINUM¼ PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatmentof De Novo Coronary Artery Lesions; PtCr-EES ¼ platinum-chromium everolimus-eluting stent(s); SV ¼ small vessel.
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ENDPOINTS. The primary endpoint in each of thestudies was TLF at 1 year, a composite of cardiac deathrelated to the target vessel, MI related to the targetvessel, or ischemia-driven TLR. Cardiac deathincluded any death without a proven noncardiaccause. MI was defined as: 1) new Q waves lasting>0.04 s in $2 leads with biomarkers elevated abovenormal (creatine kinase-myocardial band [CK-MB] ortroponin); 2) elevated CK levels (>2� normal if spon-taneous, >3� normal if after PCI, >5� normal if aftercoronary artery bypass grafting [CABG]), with elevatedCK-MB; or 3) elevated troponin levels (>2� normal ifspontaneous, >3� normal if after PCI, >5� normal ifafter CABG) with electrocardiographic changesconsistent with ischemia (ST-segment or T-wavechanges, new left bundle branch block), imaging evi-dence of new loss of viable myocardium, and/or a newregional wall motion abnormality. Ischemia-drivenrevascularization was defined as revascularizationfor angiographic stenosis$70%, or stenosis$50%withclinical or functional evidence of ischemia. Secondaryendpoints included target vessel failure (TVF), a
composite of target vessel-related cardiac death,target vessel-related MI, or TVR; the components ofTLF and TVF; all-cause death; and ST (defined usingthe Academic Research Consortium criteria).
STATISTICAL ANALYSIS. For the randomized trial,principal analyses were performed in the intention-to-treat population; however, patients who did notreceive 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-ranktest. Landmark analyses were performed to examineevent rates from 1 to 5 years (after excluding eventsoccurring before 1 year). Hazard ratios (HRs) and 95%confidence intervals (CIs) were calculated using Cox’spartial likelihood method. Multivariable analysis wasperformed to determine the independent predictors ofTLF at 5 years in the entire population. Candidate pa-tient- and lesion-level predictors (Online Table 1) wereentered into the model using entry/exit criteria ofp < 0.10. All statistical analyses were conducted usingSAS software, version 8.2 or above (SAS Institute, Cary,
PLATINUM ¼ PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for
Treatment of De Novo Coronary Artery Lesions; PtCr-EES ¼ platinum-chromium ever-
olimus-eluting stent(s).
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North Carolina). For all tests, a p value of <0.05 wasconsidered statistically significant.
RESULTS
RANDOMIZED TRIAL. The PLATINUM trial random-ized 1,530 subjects at 132 sites in the United States,Europe, Japan, and other Asia-Pacific countries toPtCr-EES (n ¼ 768) versus CoCr-EES (n ¼ 762). Aspreviously reported (10), the patients were well-matched with respect to baseline demographic,lesion, and procedure characteristics (Table 1). A totalof 23 patients who did not receive a study stent werenot followed beyond the first year. After the exclusionof these patients, 5-year outcomes data were availablefor 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 patientsassigned to PtCr-EES and 9.3% of patients assigned toCoCr-EES (HR: 0.97, 95% CI: 0.69 to 1.37; p ¼ 0.87)(Figure 1A). Landmark analysis demonstrated similarrelative TLF rates from discharge to 1 year (HR: 1.12;p ¼ 0.70) and from 1 to 5 years (HR: 0.90; p ¼ 0.63)(Figure 1B). The groups did not significantly differ inthe rates of the components of the primary endpoint,or in any of the other pre-specified secondary end-points (Table 2), both at 5 years (Figure 2) and in thelandmark periods (Online Figure 2). ST at 5 yearsoccurred 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 occur-ring after 1 year in both groups. The use of antiplateletagents was similar in both groups throughout follow-up (Online Figure 3A). Subgroup analysis did notdemonstrate any statistically significant interactionsbetween baseline factors and stent type with respectto the primary outcome of TLF at 5 years (Figure 3).
By multivariable analysis, the independentpredictors of TLF at 5 years were previous CABG(p ¼ 0.0008), history of congestive heart failure(p ¼ 0.002), history of peripheral vascular disease(p ¼ 0.002), diabetes mellitus (p ¼ 0.005), and leftanterior descending coronary artery treatment(p ¼ 0.02). Randomized stent type was not a signifi-cant predictor of 5-year TLF (p ¼ 0.77).
SV SUBSTUDY. The SV substudy enrolled 94 patientsat 23 sites in the United States, Europe, Japan, andNew Zealand. The baseline patient, lesion, and pro-cedure characteristics have been previously reported(11) and are summarized in Table 1. Five patients didnot receive a study stent and were not followedbeyond the first year. Five-year outcomes data wereavailable 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 themajor secondary endpoints are shown in Figure 4Band Table 3. There were no definite or probablestent thromboses in this study cohort. At 5 years, therates of aspirin and thienopyridine use were 92.1%and 39.5%, respectively (Online Figure 3B).
LL SUBSTUDY. The LL substudy enrolled 102 patientsat 30 sites in the United States, Europe, Japan, andNew Zealand. The baseline characteristics are sum-marized in Table 1. Two patients did not receive astudy stent and were not followed beyond the firstyear. Five-year outcomes data were available for88.0% (88 of 100) of the remaining patients. The5-year TLF event rate was 13.6% (95% CI: 6.7% to20.6%) (Figure 4C). The 5-year event rates for the
Values are Kaplan-Meier estimated event rates expressed as % (n events) unless otherwise indicated.
CI ¼ confidence interval; MI ¼ myocardial infarction; PLATINUM ¼ PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo CoronaryArtery Lesions; TL ¼ target lesion; TLR ¼ target lesion revascularization; TVR ¼ target vessel revascularization.
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FIGURE 3 Subgroup Analyses for the Primary Outcome at 5 Years in the Randomized PLATINUM Trial
Interaction effects between stent type and baseline findings were determined for TLF at 5 years. Diamonds indicate relative risk, and
bars indicate 95% CIs. Abbreviations as in Figure 1.
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major secondary endpoints are shown in Figure 4Dand Table 3. There were no definite or probablestent thromboses in this study cohort. At 5 years, therates of aspirin and thienopyridine use were 93.6%and 38.5%, respectively (Online Figure 3C).
DISCUSSION
The 5-year data from the pivotal, multicenterPLATINUM trial demonstrate that: 1) PtCr-EES havecomparable short-term and long-term safety andeffectiveness to CoCr-EES; 2) both stents resulted invery low rates of adverse events in the types ofpatients and lesions studied, with no significantdifferences in the 5-year rates of cardiac death, MI,
or ST in the randomized trial; and 3) 5-year eventrates were also low after PCI with PtCr-EES of selectedlong lesions or lesions in small vessels.
The present report provides the longest follow-up todate of patients undergoing PCI with PtCr-EES. The5-year rates of ischemia-driven TLR with both stentswere favorable (6.2% for CoCr-EES and 5.3% for PtCr-EES), signifying long-term freedom from repeat TLR inw19 of 20 patients. Of note, the rates of ischemia-drivenTVR not related to the target lesion were also similarbetween stent types (4.8% and 5.8%, respectively),signifying that approximately as many non-TLR eventsas TLR events in the target vessel occur during long-termfollow-up. These findings are consistent with priorresearch (12) demonstrating an increasing proportion
FIGURE 4 5-Year Endpoints in the PLATINUM Substudies
Five-year time-to-event curves for the primary and major secondary outcomes in the small vessel substudy (A and B) and long lesion substudy
(C and D). Abbreviations as in Figures 1 and 2.
TABLE 3 5-Year Event Rates in the PLATINUM Substudies
SV Study(n ¼ 89)
LL Study(n ¼ 100)
Target lesion failure 7.0 (6) 13.6 (13)
Cardiac death 5.9 (5) 8.6 (8)
Related to target vessel 3.5 (3) 8.6 (8)
Not related to target vessel 2.5 (2) 0.0 (0)
Myocardial infarction 2.4 (2) 1.3 (1)
Related to target vessel 0.0 (0) 0.0 (0)
Not related to target vessel 2.4 (2) 1.3 (1)
Ischemia-driven TLR 3.6 (3) 7.5 (7)
All-cause death 8.1 (7) 10.6 (10)
All-cause death or MI 9.3 (8) 11.7 (11)
Ischemia-driven TVR 13.1 (11) 11.6 (11)
Ischemia-driven non-TL TVR 12.0 (10) 7.5 (7)
Target vessel failure 16.3 (14) 17.7 (17)
Stent thrombosis
Definite 0 0
Probable 0 0
Possible 0 1.0 (1)
Values are Kaplan-Meier estimated event rates expressed as % (n events).
Abbreviations as in Tables 1 and 2.
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of non-TLR events during long-term follow-up afterstent implantation due to progressive atherosclerosis innon-treated coronary segments.
In the SPIRIT III (Clinical Evaluation of theXIENCE V Everolimus Eluting Coronary Stent Systemin the Treatment of Patients With De Novo NativeCoronary Artery Lesions) trial (2), which enrolled asimilar patient population to the PLATINUM study,the 5-year rate of ischemia-driven TLR with CoCr-EESwas 8.6%, whereas in the all-comers COMPARE(A Trial of Everolimus-eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization inDaily Practice), the 5-year TLR rate with CoCr-EESwas 5.0%.
The 5-year rates of all-cause death or MI with bothstents in this trial were also favorable, and similar tothat previously reported (10.3% for both CoCr-EESand PtCr-EES in the PLATINUM study, 9.5% forCoCr-EES in the SPIRIT III trial, 14.6% for CoCr-EES inthe COMPARE trial). Of note, the 5-year ST rates in therandomized PLATINUM trial were particularly low(<1% with both devices), consistent with the low rateof ST with fluoropolymer-based everolimus-elutingstents reported in prior meta-analyses (13,14).
In patients treated with PtCr-EES in the single-armSV and LL substudies, the 5-year event rates were alsoacceptable, with no patients developing ST. Althoughprior studies have evaluated CoCr-EES in SV and
LL (defined using similar criteria), none has provided5-year follow-up. The single-arm SPIRIT SV trial(Spirit Small Vessel Registry) (15), which evaluatedCoCr-EES in SV, reported a 1-year TLF rate of 8.1%,numerically higher than both the 1-year (5.6%) and
PERSPECTIVES
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 ana-
lyses 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.
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5-year (7.0%) TLF rates with PtCr-EES in thePLATINUM SV substudy.
Likewise, the LONG-DES III (Percutaneous Treat-ment of Long Native Coronary Lesions With Drug-Eluting Stent-III) trial (16) reported a 1-year TLFrate of 12.9% after CoCr-EES in LL, higher than the1-year (3.1%) and 2-year (8.8%) rates, but comparableto the 5-year rate (13.6%) with PtCr-EES in thePLATINUM LL substudy. In the IVUS-XPL (Impact ofIntraVascular UltraSound Guidance on Outcomes ofXience Prime Stents in Long Lesions) trial (17), whichexamined the relative efficacy of angiography andIVUS 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 boththe IVUS-XPL (34.7 mm) and LONG-DES III (34.0mm) trials than the PLATINUM LL trial (24.4 mm),which may account for the higher event rates. Directcomparisons between these studies should be per-formed with caution, given the modest numbers ofenrolled patients, which adds imprecision to theevent rate estimates, and the differences in patientand lesion risk profiles and adjudication methods.Nonetheless, the findings from the randomized trialsand SV and LL substudies suggest that PtCr-EES andCoCr-EES likely have approximately comparableperformance in these lesion subtypes. Large ran-domized trials would be required for more mean-ingful comparisons.
PtCr-EES and CoCr-EES share the same polymer,with a similar concentration and elution rate ofeverolimus (8,9); however, differences in the under-lying metal alloy and its configuration give rise todifferences in radial and longitudinal strength andresistance to deformation, flexibility and deliver-ability, and radiopacity. The procedural and angio-graphic success rates were similar with both devicesin the randomized trial (10), and the similar long-termoutcomes in the present report suggest overall inter-changeability with respect to clinical performancewith both devices in noncomplex lesions.
STUDY LIMITATIONS. The major limitation of thePLATINUM randomized trial is the exclusion of high-risk patients and lesions, restricting the generaliz-ability of the results. Recent data from trials of PtCr-EES in less selected patients, however, are consis-tent with the present results. In the DUTCH PEERS(Durable Polymer-Based Stent Challenge of PromusElement Versus Resolute Integrity in an All ComersPopulation) trial (18,19), which randomized 1,811 all-comer patients to slow-release cobalt-chromiumzotarolimus-eluting stents or PtCr-EES, the rate ofTVF after PtCr-EES was 5.0% at 1 year and 10.3% at
3 years, whereas the rate of definite/probable ST was1% at 1 year and 1.1% at 3 years, with no significantdifferences from zotarolimus-eluting stents. The re-sults were consistent in high-risk patients presentingwith MI. In the PLATINUM PLUS trial (Trial to Assessthe Everolimus-Eluting Coronary Stent System(PROMUS Element) for Coronary Revascularization)(20), which randomized 2,980 all-comer patients toPtCr-EES versus CoCr-EES, the 1-year TVF rates were4.6% versus 3.2% (p ¼ 0.08), whereas the 1-year ratesof definite/probable ST were 0.8% and 0.5% (p ¼0.44), respectively. Similar results were seen in thesingle-arm PROMUS Element European Post-Approval Surveillance Study (21), which enrolled1,010 all-comers and reported a 1-year TVF rate of6.2% and ST rate of 0.6%. Long-term data from thesetrials are required to provide further evidence of theclinical performance of PtCr-EES in high-risk patients.
CONCLUSIONS
The 5-year results from the PLATINUM randomizedtrial demonstrate comparable long-term safety andeffectiveness of PtCr-EES and CoCr-EES, with notablylow rates of ST with both devices. Patients with SVand LL treated with PtCr-EES also had high rates ofevent-free survival at 5 years.
ADDRESS FOR CORRESPONDENCE: Dr. Gregg W. Stone,Columbia University Medical Center, The CardiovascularResearch Foundation, 1700 Broadway, 8th Floor, NewYork, New York 10019. E-mail: [email protected].
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KEY WORDS coronary artery disease,drug-eluting stent(s), percutaneous coronaryintervention, stent design
APPENDIX For supplemental tables andfigures, please see the online version of thispaper.
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