Author + information
- Received August 8, 2013
- Revision received February 7, 2014
- Accepted February 13, 2014
- Published online July 1, 2014.
- Wouter S. Remkes, MD,
- Samer Somi, MD, PhD,
- Vincent Roolvink, MD,
- Saman Rasoul, MD, PhD,
- Jan Paul Ottervanger, MD, PhD,
- A.T. Marcel Gosselink, MD, PhD,
- Jan C.A. Hoorntje, MD, PhD,
- Jan-Henk E. Dambrink, MD, PhD,
- Menko-Jan de Boer, MD, PhD,
- Harry Suryapranata, MD, PhD,
- Arnoud W.J. van 't Hof, MD, PhD∗ (, )
- Acute Myocardial Infarction Study Group
- ↵∗Reprint requests and correspondence:
Dr. Arnoud W. J. van 't Hof, Department of Cardiology, Isala Klinieken, Dr. Van Heesweg 2, 8025 AB Zwolle, the Netherlands.
Objectives The aim was to investigate whether a strategy of direct drug-eluting stent (DES) implantation without pre-dilation is associated with a reduced incidence of restenosis compared with CS with pre-dilation or provisional stenting (PS).
Background Previous studies were performed comparing direct stenting (DS) with conventional stenting (CS) after pre-dilation; however, none of these in the DES era. Therefore, the STRESSED (direct Stenting To reduce REStenosis in Stent Era with Drug elution) study was designed and carried out.
Methods A total of 600 patients with angina pectoris or recent myocardial infarction were randomized to a DS, CS, or PS strategy. The primary endpoint was the mean minimal lumen diameter at 9-month follow-up angiography. Secondary endpoints were clinical procedural success defined as angiographic success without in-hospital major adverse cardiac events (MACE), and MACE at 9-month and 2-year follow-up.
Results Stent implantation in the DS group was 98%, 99% in the CS group, and 77% in the PS group. Percutaneous coronary intervention success was 99% in all groups. The minimal lumen diameter at 9-month follow-up was 2.12 ± 0.58 mm (DS), 2.17 ± 0.67 mm (CS), and 1.99 ± 0.69 mm (PS), p = 0.556 for comparison of DS with CS, p = 0.073 for comparison of DS with PS. The absolute difference was −0.05 (DS to CS), 95% confidence interval: −0.19 to −0.09, p = 0.48 and 0.13 (DS to PS), confidence interval: −0.02 to −0.27, p = 0.087. Restenosis was found in 3.4% (DS), 6.7% (CS), and 11.5% (PS), p = 0.025. At 9-month and 2-year follow-up, MACE occurred in 6.8% and 11.5% (DS), 4.6% and 10.3% (CS), and 7.6% and 13.8% (PS) (p = 0.439 and 0.536), respectively.
Conclusions Direct DES implantation compared with conventional DES implantation did not reduce restenosis. Provisional stenting, however, was associated with a higher rate of restenosis. This did not translate into a difference in the rate of MACE. (STRESSED study: direct Stenting To reduce REStenosis in Stent Era with Drug elution; ISRCTN41213536)
- direct stenting
- late lumen loss
- percutaneous coronary intervention
- provisional stenting
Direct stenting (DS), without pre-dilation, has been shown to be a safe and effective treatment modality in elective patients as well as in patients who undergo percutaneous coronary intervention (PCI) because of unstable angina. Success rates vary from 90% to 98% (1–8). DS may reduce procedure length, the use of contrast agent, and the number of balloons and wires needed, resulting in a reduction of procedure-related costs (9). It also has some potential disadvantages that might increase procedural risks and may lead to suboptimal clinical results. A higher risk of failure to initially cross the lesion, errors in stent placement, incorrect stent sizing, underexpansion, stent dislodgment, and embolization are possibilities. Furthermore, calcified, tortuous, or angulated lesions and chronic total occlusions are often not suitable for a DS approach and formed a reason for exclusion in all previous stent- trials comparing DS and conventional stenting (CS) strategies.
The potential advantage of DS in reducing the risk of in-stent-restenosis was suggested in an experimental study by Rogers et al. (10), who showed that undamaged remnant endothelial cells that remain between the stent struts regenerate, and therefore may reduce the degree of intimal hyperplasia compared with previous balloon dilation.
Furthermore, pre-dilation may induce dissection necessitating longer stents compared with DS without pre-dilation, and this may increase restenosis (11). On the other hand, after pre-dilation, a wider diameter stent may be chosen, resulting in a larger minimal luminal diameter (MLD) after intervention, which itself is associated with a lower rate of restenosis (12).
DES have been successful in reducing restenosis after percutaneous coronary intervention (PCI) by 50% to 90% (13,14). When a DES is placed after pre-dilation, it is of critical importance to cover the whole dilated area with the stent. This problem is not present with DS. Therefore, the concept of DS might be beneficial in patients receiving a DES. There are no randomized trials comparing DS with a conventional approach in the second-generation DES era, and no previous studies comparing DS with CS had a provisional arm included.
The aim of this study was to investigate whether a strategy of DS without pre-dilation is associated with a reduced incidence of restenosis at 9-month follow-up angiography compared with CS with pre-dilation or a strategy of provisional stenting (PS).
Eligible were men and women younger than 85 years of age with stable or unstable angina pectoris or a recent (<30 days) myocardial infarction with objective evidence of myocardial ischemia. Lesions were single American College of Cardiology/American Heart Association (ACC/AHA) Task Force classification type A, B1, or B2 noncalcified target lesions with >50% and <100% diameter stenosis according to the visual estimation of the investigator.
Exclusion criteria were acute ST-segment elevation myocardial infarction, unstable angina pectoris classified as Braunwald category IIIB or C, bifurcation lesions with a side branch >2.0 mm in diameter, left main coronary artery lesions, ostial lesions, left ventricular ejection fraction <30%, contraindications to inhibit platelet function with aspirin and clopidogrel, and contraindications to follow-up angiography (severe peripheral vessel disease or creatinine-clearance <30 ml/min).
Randomization to DES implantation without (DS group) and with (CS group) balloon pre-dilation or PS (PS group) was assigned by a sealed envelope, located in the catheterization laboratory.
In the CS group, coronary angioplasty was performed using standard techniques, with a balloon size chosen according to the angiographic arterial diameter. One or more inflations were performed to obtain a visually estimated residual vessel stenosis of <30%, after which the stent was implanted. Identical techniques were used in the DS group except for pre-dilation. Crossover to balloon pre-dilation was allowed when the stent could not be successfully advanced through the lesion. PS was allowed only if visual diameter stenosis after repeated balloon dilation was >30%, if there was a dissection grade D1 or higher occurred, or if there was decreased Thrombolysis In Myocardial Infarction (TIMI) flow after repeated dilation.
In all groups, an inflation pressure of at least 10 atm was recommended. DES were used in all patients. During this study, we used 2 second-generation DES; the zotarolimus- (Endeavour, Medtronic, Minneapolis, Minnesota) and the everolimus- (PROMUS, Boston Scientific, Natick, Massachusetts) coated stents. Stent dimension and length were chosen according to lesion length.
All patients received aspirin 160 mg/day and clopidogrel 300 mg bolus (preferably >12 h before angioplasty) and 75 mg/day for at least 6 months with the exception for patients who did not receive a stent but received 1-month treatment with clopidogrel. A single intravenous bolus of 5,000 U of heparin was given at the beginning of the procedure in all patients.
All patients signed informed consent. This trial was conducted in accordance with the Helsinki Declaration and approved by the Medical Ethics Committee of the Isala Clinics, Zwolle, the Netherlands.
Procedure time was defined as the interval between placement of the arterial sheath and removal of the guiding catheter. Immediate angiographic success was defined as angioplasty with or without stenting with a reduction in stenosis <50% by quantitative coronary analysis, in the absence of dissection higher than grade D1 according to the National Heart, Lung, and Blood Institute criteria (15) and a TIMI flow grade 3. Clinical procedural success was defined as immediate angiographic success without major in-hospital complication, including death, myocardial infarction, stent thrombosis, or emergency coronary artery bypass grafting (CABG). Myocardial infarction was defined by the presence of new Q waves or creatine kinase level or myocardial band fraction at least twice the upper limit of normal. Lesions were classified according to the definitions recommended by the ACC/AHA Task Force.
The primary endpoint was the mean MLD at follow-up angiography. Secondary endpoints were defined as clinical procedural success and rate of MACE at 9- and 2-year follow-up. Exploratory endpoints were the amount of post-procedural cardiac troponin T (cTnT) release and angiographic restenosis (>50%) at 9-month follow-up angiography.
Qualitative and quantitative coronary analysis
Coronary angiograms were obtained before and immediately after angioplasty and at 9-month follow-up. Standard acquisition procedures were followed for qualitative and quantitative coronary angiography analysis. To improve the accuracy and reproducibility of measurements, intracoronary isosorbide dinitrate (1 to 3 mg) was given before the initial and final post-stent placement angiograms. Angiograms were recorded on a CD-ROM. Matched orthogonal views were used for quantitative analysis at each control. Dye-filled guiding catheters were used for magnification calibration. Data collection included assessment of TIMI flow grade, lesion eccentricity, estimation of thrombus load, and ACC/AHA classification. An independent laboratory (DIAGRAM, Zwolle, the Netherlands) performed routine quantitative coronary angiography measurements using the Coronary Angiography Analysis II System. Two orthogonal angiographic views with minimized vessel foreshortening were obtained, and the angiogram showing the most severe stenosis was selected for quantitative coronary analysis. Post-procedure and follow-up angiograms, which duplicate the initial orthogonal views, were obtained after the removal of the balloon and guidewire.
Coronary angiography was required at 9 months in all patients with angiographic procedural success and no target lesion revascularization during hospital stay and follow-up. Coronary angiography could be prematurely performed on the basis of clinical indications; it was used as the follow-up angiogram in the case of restenosis or if performed after 4 months. When it was performed within 4 months without evidence of restenosis, angiographic control was repeated at 9 months. All major clinical events including death, myocardial infarction, readmission to hospital for unstable angina pectoris, and the need for additional revascularization of the target vessel were monitored at the time of repeated angiography or by phone at 9 months and 2 years for all patients.
The study was designed to demonstrate the superiority of DS based on the assumption that at follow-up angiography, the mean MLD in the DS group was at least 0.15 mm larger than the mean MLD in the CS group or that the mean MLD in the DS group is at least 0.15 mm larger than the mean MLD in the PS group (based on the preceding DIRECT-2 study [Direct Stenting Strategy vs Conventional or Provisional Stenting]).
Previous studies have shown that it is reasonable to assume that the MLD measurement follows a normal distribution. A group mean of ∼2.2 mm with an SD of ∼0.4 mm was expected, allowing for a type I error of 2.5%. A sample of 159 patients per group will give 90% power to prove superiority of DS compared with a strategy of pre-dilation stenting or PS stenting. To compensate crossover and losses for angiographic follow-up, the sample was enlarged by 25% to 600 patients. The data were evaluated by intention-to-treat analysis. Because of crossover, data were also analyzed under per-protocol approach.
For comparisons between groups, the chi-square test (or, in case of <5 expected observations, the Fisher exact test) was used. For comparisons of continuous variables, analysis of variance was used according to the type of data and their distribution. Statistical significance was considered by a 2-tailed p value <0.05. Relative risks were calculated with 95% confidence intervals. MACE survival Kaplan-Meier curves were obtained and compared by means of the log-rank test. In the pairwise comparisons, we adjusted for multiple testing by dividing the alpha by 2.
A 2-sided p value <0.025 was considered to be statistically significant in the pairwise test.
We enrolled 600 patients in this trial between 2005 and 2010 (Fig. 1). Patients were equally randomized into 3 groups; DS (n = 198), CS (n = 201), and PS (n = 201). All 3 arms were well matched with respect to demographic and angiographic characteristics at baseline (Table 1). In the DS group, 18% of the lesions required pre-dilation because of the inability of the stent to cross the lesion. In the PS group, a stent was implanted in 77% of the patients. No differences were observed in procedural time between DS and pre-dilation. PCI was successful in 99%, without differences between the groups. Five patients (0.8%) experienced in-hospital myocardial infarction (2 in the CS group and 3 in PS group) due to side branch occlusion and in 1 case due to dissection distal to the stent, requiring repeat PCI of the target vessel.
Before leaving the hospital, 6 patients (1.0%) underwent CABG after an initial unsuccessful PCI. There were no in-hospital deaths and no significant differences in in-hospital events among the 3 groups (Table 2).
The biochemical exploratory endpoint of cTnT release post-PCI (>0.05 ng/ml) occurred significantly more in the CS group: DS, 11.2%; CS, 24.8%; PS 21.9%; p = 0.008 for comparison of DS with CS, p = 0.031 for comparison of DS with PS, and p = 0.625 for comparison of CS with PS.
Follow-up angiography was performed at 9 months in 72.9% of the patients. Follow-up was missing because of patient refusal (21%), death (1%), or angiograms did not meet the qualitative criteria for accurate analysis (3%). At baseline, patients who declined follow-up angiography were older (65.3 ± 10.2 years vs. 63.1 ± 9.5 years, p = 0.007) and more often female (34.3 vs. 23.0%, p = 0.004). There were no differences in clinical and angiographic characteristics.
The primary endpoint, MLD at 9 months, was not significantly different when comparing DS with CS and PS (DS, 2.12 ± 0.58; CS, 2.17 ± 0.67; PS, 1.99 ± 0.69; p = 0.556 for comparison of DS with CS and p = 0.073 for comparison of DS with PS).
The absolute difference was −0.05 (DS to CS), 95% confidence interval: −0.19 to 0.09; p = 0.480 and 0.13 (DS to PS), 95% confidence interval: −0.02 to −0.27; p = 0.087.
The presented results are for the intention-to-treat population. Analysis under a per-protocol approach showed similar results: for the primary endpoint, DS, 2.15 ± 0.54; CS, 2.20 ± 0.64; PS, 2.07 ± 0.62; p = 0.651 for comparison of DS with CS and p = 0.145 for comparison of DS with PS.
Immediately after angioplasty, there was significantly larger diameter stenosis in the PS group (DS, 8.29 ± 10.62%; CS, 7.84 ± 10.06%; PS, 12.08 ± 13.37; p = 0.783 for comparison of DS with CS, p = 0.013 for comparison of DS with PS).
Late lumen loss in the PS group exceeded that in the DS group and the CS group (PS, 0.36 ± 0.49 mm vs. 0.24 ± 0.47 mm [CS] vs. 0.29 ± 0.55 mm [DS]; p = 0.526 for comparison of DS with CS and p = 0.017 for comparison of DS with PS) (Table 3). Figure 2 presents the cumulative distributions of acute gain, late loss, and net gain for the 3 treatment strategies.
The secondary endpoint, clinical procedural success without MACE, was encountered in 96.9% (DS), 97.5% (CS), and 96.0% (PS) (p = 0.614). The exploratory endpoint of angiographic restenosis at 9 months (stenosis ≥50%) was significantly more encountered within the PS group (DS, 3.4%; CS, 6.7%; PS, 11.5%; p = 0.190 for comparison of DS with CS and p = 0.008 for comparison of DS with PS. In the PS group, no stent was implanted in 23% of the patients. In this group, restenosis occurred in 32% at 9-month follow-up. In 77% of patients in whom a stent was implanted, the rate of restenosis was 5%.
In the PS group, no stent was implanted in 23% of the patients. In this group, restenosis occurred in 32% at 9-month follow-up. In the 77% of patients in whom a stent was implanted, the rate of restenosis was 5%.
Clinical outcome after 2-year follow-up
Clinical follow-up was complete in 98.3% (9 months) and 97% (2 years) of patients. During the 2-year follow up, 18 patients died (3.1%), 11 patients experienced a myocardial infarction (1.9%), 45 patients underwent repeat PCI of the target lesion (7.7%), and 13 patients underwent CABG (2.2%). There were no significant differences among the 3 groups at either the 9-month or the 2-year follow-up (Table 2). Kaplan-Meier event-free survival curves (Fig. 3) were similar (p = 0.450; log-rank test).
The main finding of the STRESSED study is that direct DES implantation does not reduce restenosis compared with conventional DES implantation.
Provisional DES implantation was associated with a higher rate of restenosis compared with DS or CS; however, this did not translate into a significant difference in the rate of MACE at 9-month and 20-year follow-up.
The provisional arm was included because the STRESSED trial is a continuation of the DIRECT-2 study, comparing DS with CS and PS in the BMS era. The study design was not changed. It was still thought to be interesting to compare differences between stenting groups and a provisional group, although previous studies have shown balloon angioplasty to be inferior to a stenting approach for restenosis (16). This most likely explains the high rate of DES implantation in the PS group. The acceptance of the result after balloon angioplasty (stenting was allowed only if visual diameter stenosis after repeated balloon dilation was >30%, if dissection was grade D1 or higher occurred, or if there was decreased TIMI flow after repeated dilation) was left to the discretion of the operator. It is likely that in case of any doubt, a DES would have been implanted, leading to the high crossover rate.
The TAXUS ATLAS DIRECT STENT study (17) showed similar amounts of neo-intimal hyperplasia after DS versus CS using DES, but DS was associated with reduced rates of binary angiographic restenosis and ischemia-driven target lesion revascularization. The patients in this trial, however, were not randomized but propensity matched and carefully selected for DS. The SIRIUS-DIRECT trial (18) showed noninferiority for both safety and efficacy in the DS versus CS approach using the sirolimus-eluting Cypher stent (Cordis, Bridgewater, New Jersey), and no differences in target lesion revascularization and MACE. This study, however, was nonrandomized, with significant differences in lesion characteristics between the 2 patient cohorts.
A recent meta-analysis by Piscione et al. (19) included 24 randomized trials comparing DS and CS strategies. Most of the included trials were originally designed to evaluate a possible role in reducing restenosis associated with DS technique.
The main finding of this study was a significantly lower MACE rate in the DS group. This was mainly due to the lower incidence of periprocedural myocardial infarction. None of the included trials showed a significant benefit in terms of target vessel revascularization or restenosis reduction.
The most likely mechanism of the release of troponin after PCI is the occlusion of side branches or microembolization of plaque debris (20); hence, the expected theoretical advantage of DS is that distal microembolization of plaque could be partly avoided, leading to a lower incidence of myocardial infarction related to the procedure and leading to a better TIMI flow (21).
The exploratory biochemical endpoint of cTnT release in our study showed a significantly lower amount of myocardial injury in the DS group. A meta-analysis by Feldman et al. (22) indicates that cardiac troponin I or cTnT elevation after nonemergent PCI is indicative of an increase in long-term all-cause mortality and myocardial infarction.
The proposed mechanism of myocardial injury that impairs left ventricular function promotes arrhythmias and congestive heart failure, therefore resulting in decreased long-term survival, is unlikely to play a role in patients with minor cTnT elevations. Other possible mechanisms for the decreased long-term survival in patients with cTnT elevation are the extent of unstable coronary artery disease on presentation, leading to more complex coronary interventions and the expectation that the amount of myocardial injury post-PCI acts as a marker for the severity of atherosclerosis, leading to a poorer long-term outcome. Considering these mechanisms, it is unlikely that periprocedural efforts to minimize small cTnT elevations after nonemergent PCI will result in improved long-term outcomes. This is also shown in recent publications by Pervaiz et al. (23) and Novack et al. (24). In large studies, they showed that troponin elevations after PCI of almost any amount have no prognostic relevance, and, based on these studies, the prognostic implications of troponin release after PCI (especially the small amounts noticed in the present study), are uncertain.
The myocardial infarction rate (defined as an increase in creatine kinase/creatine kinase-myocardial band more than twice the upper limit of normal) that we encountered in our study was 0.8%, without significant differences among groups. The rate of MI in the review article by Piscione et al. (19) was 3.6%, with a significant difference between DS (3.16%) and CS (4.04%). This is most likely caused by the different definitions of myocardial infarction that were used, which makes it difficult to compare different studies.
A limitation of our study was the higher-than-expected loss of angiographic follow-up at 9 months. It was assumed to be 25% (see sample size calculation in the Statistical Analysis section). After completion of the trial, this appeared to be somewhat higher (27%). Additionally, patients who declined angiographic follow-up were older and more often female. The acceptance rate after balloon angioplasty in the PS group was quite low, with 77% stent placement. Therefore, data were also analyzed with the per-protocol approach, which showed results similar to the intention-to-treat analysis. Furthermore, this study was not powered to show differences in MACE, and the results reflect the performance of a single institution.
Direct DES implantation compared with conventional DES implantation does not reduce restenosis. Provisional stenting, however, was associated with a higher rate of restenosis. This did not translate into a difference in the rate of MACE at short- and medium-term follow-up. Early and medium-term MACE rates were comparably low in this study, confirming that a systematic DS strategy with second-generation DES is associated with medium-term results as favorable as those associated with a systematic strategy of stenting after balloon pre-dilation.
The authors thank Vera Derks for her excellent editorial assistance.
The study was partly funded by an unrestricted grant from Medtronichttp://dx.doi.org/10.13039/100004374. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- American College of Cardiology/American Heart Association
- bare-metal stent(s)
- coronary artery bypass grafting
- conventional stenting
- cardiac troponin T
- drug-eluting stent(s)
- direct stenting
- major adverse cardiac event(s)
- minimal lumen diameter
- percutaneous coronary intervention
- provisional stenting
- Thrombolysis In Myocardial Infarction
- Received August 8, 2013.
- Revision received February 7, 2014.
- Accepted February 13, 2014.
- American College of Cardiology Foundation
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