Author + information
- Received December 19, 2011
- Revision received February 6, 2012
- Accepted February 7, 2012
- Published online June 19, 2012.
- Anouar Belkacemi, MD⁎,
- Pierfrancesco Agostoni, MD, PhD⁎,
- Hendrik M. Nathoe, MD, PhD⁎,
- Michiel Voskuil, MD, PhD⁎,
- ChunLai Shao, MD⁎,
- Eric Van Belle, MD, PhD⁎,
- Thierry Wildbergh, MD⁎,
- Luigi Politi, MD†,
- Pieter A. Doevendans, MD, PhD⁎,
- Giuseppe M. Sangiorgi, MD† and
- Pieter R. Stella, MD, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Pieter R. Stella, Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands
Objectives The goal of this study was to compare angiographic, intravascular imaging, and functional parameters, as well as the clinical outcomes of patients treated with drug-eluting balloon (DEB) plus bare-metal stent (BMS) versus BMS versus drug-eluting stent (DES) for ST-segment elevated acute myocardial infarction (STEMI).
Background Concerns remain regarding the long-term safety of DES in STEMI. DEB could provide an attractive alternative in order to achieve potentially similar effectiveness but limiting the long-term hazards related to late-acquired stent malapposition and thus stent thrombosis.
Methods In this randomized, international, 2-center, single-blinded, 3-arm study, STEMI patients were randomly assigned to group A: BMS; group B: DEB plus BMS; or group C: DES after successful thrombus aspiration. The primary endpoint was 6-month angiographic in-stent late-luminal loss. Secondary endpoints were in-stent binary restenosis, major adverse cardiac events (MACE: cardiac death, myocardial infarction, target vessel revascularization). In a subgroup of patients, stent (mal)apposition (by optical coherence tomography) and endothelial function (by acetylcholine infusion) was assessed.
Results Overall, 150 patients were randomized. Procedural success was achieved in 96.7%. In groups A, B, and C, respectively, late-luminal loss was 0.74 ± 0.57 mm, 0.64 ± 0.56 mm, and 0.21 ± 0.32 mm (p < 0.01); binary restenosis was 26.2%, 28.6%, and 4.7% (p = 0.01); and MACE rates were 23.5%, 20.0%, and 4.1% (p = 0.02), respectively. The median percentage [25th to 75th interquartile range] of uncovered and malapposed stent struts per lesion was 0 [0 to 0.35], 2.84 [0 to 6.63], and 5.21 [3.25 to 14.5] (p < 0.01). Significant paradoxical vasoconstriction was seen in groups B and C.
Conclusions In STEMI patients, DEB followed by BMS implantation failed to show angiographic superiority to BMS only. Angiographic results of DES were superior to both BMS and DEB. Moreover, DEB before implantation induced more uncovered and malapposed stent struts than BMS, but less than after DES. (Drug-Eluting Balloon in Acute Myocardial Infarction [DEB-AMI]; NCT00856765)
Primary percutaneous coronary intervention (PCI) for the treatment of patients with ST-segment elevation myocardial infarction (STEMI) is well established (1). In this setting, drug-eluting stents (DES) reduce the need for repeat revascularization as compared with bare-metal stents (BMS). However, the revascularization benefit of DES is more pronounced in study settings than in routine clinical practice, partly due to protocol-mandated angiographic follow-up (2). Moreover, in patients without risk factors for restenosis such as diabetes mellitus, reference vessel diameter >3.0 mm, and lesion length <20 mm, DES and BMS result in similar revascularization rates (2).
Furthermore, with the use of DES in the STEMI setting, safety concerns remain regarding late acquired stent malapposition with consequently a possible increased risk of stent thrombosis (3). It is known that DES induce local inflammation due to the presence of polymers, drug-induced delayed endothelial healing, and vessel wall toxicity. Besides, in STEMI, the culprit lesions usually show a large necrotic core and high amount of thrombus formation, characteristics that can cause even more local toxicity, inflammation, and delayed vascular healing after DES implantation (4,5). These effects are also associated with an impaired vasomotor function in the treated vessel (6,7).
The paclitaxel drug-eluting balloon (DEB) is an emerging device that has shown promising results (8–11) by means of a high-concentration, rapid local release of an antirestenotic drug (paclitaxel) into the coronary vessel without using durable polymers (12). Therefore, it could provide a valid alternative treatment in STEMI patients by avoiding sustained drug/polymer interaction with the vessel wall.
The aim of the current study was to test the DIOR DEB (Eurocor, Bonn, Germany) combined with a modern cobalt chromium BMS in primary PCI with the goal of obtaining improved angiographic results and comparable vessel healing and preserved endothelial function with respect to BMS alone and less uncovered or malapposed stent struts than a paclitaxel-eluting DES.
The DEB-AMI (Drug Eluting Balloon in Acute Myocardial Infarction) trial was a randomized, international, 2-center, single-blinded, 3-arm study, aimed at comparing BMS implantation (group A), versus sequential DEB dilatation and BMS implantation (group B) and paclitaxel DES implantation (group C) in patients presenting with STEMI. In order to minimize confounding, in both group A and B, an identical stent platform was used, and the same drug (paclitaxel) was compared in groups B and C.
The study, conducted according to the Declaration of Helsinki, was approved by the ethics committees of both participating centers, and signed informed consent was obtained from all included patients.
Patients between 18 and 80 years of age, presenting in the first 12 h after the onset of STEMI (diagnosed by the presence of anginal symptoms associated with electrocardiographic ST-segment elevation of >1 mm in >2 contiguous leads or new left bundle branch block), and undergoing primary PCI, with angiographic evidence of a single culprit lesion in the target vessel, after successful thrombus aspiration (defined by no angiographically evident flow-limiting residual thrombus at the site of [sub]occlusion, and Thrombolysis In Myocardial Infarction [TIMI] flow grade >1) were deemed eligible for inclusion.
Major clinical and procedural exclusion criteria were contraindications to study medications (acetylsalicylic acid, clopidogrel, paclitaxel), life expectancy <12 months, lesion length >25 mm, reference vessel diameter <2.5 mm and >4.0 mm, severe triple vessel disease, left main stenosis >50%, and a combination of type C coronary lesion and diabetes mellitus (in which DES was favored).
The DEB used in this study was the second-generation DIOR coronary angioplasty balloon (8). This DEB has a coating consisting of a 1:1 mixture of paclitaxel with shellac applied to the balloon by a micro-pipetting procedure. This device is coated with 3 μg of paclitaxel/mm2 of balloon surface. The DIOR DEB is available in the following lengths: 15, 20, 25, and 30 mm; and diameters: 2.0, 2.25, 2.5, 2.75, 3.0, 3.5, and 4.0 mm. The shellac coating protects the drug from a wash-off effect during tracking in the guiding catheter and in the coronary vasculature. The minimal inflation time is 30 s (recommended 45 to 60 s) to allow sufficient drug release into the vessel wall in order to achieve the required effective tissue dosages of paclitaxel to inhibit smooth muscle cell proliferation (12).
The BMS (Genius Magic stent, Eurocor) is a new cobalt chromium stent platform with a strut thickness of 60 μm. The DES (Taxus Liberté, Boston Scientific, Natick, Massachusetts) has a stainless steel stent platform coated with a permanent polymer that allows the release of paclitaxel (1 μg/mm2). The total strut thickness including stent and polymer is 132 μm.
Randomization and interventional procedure
All patients received routinely in the ambulance or at the first medical contact a loading dose of acetylsalicylic acid (325 to 500 mg) and of clopidogrel (600 mg). Heparin was administered before and during the procedure in order to maintain an activated clotting time ≥250 s. Additional administration of glycoprotein IIb/IIIa inhibitors was recommended, but was left to the physician's discretion.
After fulfilling angiographic inclusion criteria, patients underwent mandated thrombus aspiration of the culprit lesion with a manual thrombus aspiration device. Sequentially, if thrombus aspiration was successful according to definition, patients were randomly assigned to 1 of the 3 treatment strategies: group A: pre-dilation with a standard balloon (balloon-to-artery ratio 0.8:1) followed by BMS implantation; group B: pre-dilation with a standard balloon (balloon-to-artery ratio 0.8:1) followed by sequential dilation with DEB (balloon-to-artery ratio 1:1 and at least 5 mm longer than the normal balloon in order to avoid geographic miss) for at least 30 s, and BMS implantation; or group C: pre-dilation with a standard balloon (balloon-to-artery ratio 0.8:1) followed by implantation of a paclitaxel-eluting DES. Randomization was obtained by means of sequentially numbered, opaque sealed envelopes containing the assigned group letter (A, B, or C). The coupling between number of the envelope and group letter was automatically generated by a computer, and the envelopes were sealed by an independent employee. The allocation ratio to the 3 groups was 1:1:1.
Concerning the DEB use, a 1:1 balloon-to-artery ratio, nominal inflation pressures, and an inflation time of >30 s were mandated. Special care was taken to center the DEB in the lesion and to use a DEB at least 5 mm longer than the normal balloon used and the intended stent length, in order to avoid potential geographic miss (13). In any group, additional bailout stenting (with stents of the same randomization group) was performed in case of residual edge dissections or incomplete lesion coverage. In this setting in group B, additional DEB were also mandated to cover the complete stented segment. In case of multiple DEB use, care was taken to avoid excessive DEB overlap (to avoid double-dose release). Additional post-dilation was left to the physician's discretion. Discharge medications included acetylsalicylic acid 80 to 100 mg per day lifelong and clopidogrel 75 mg for 12 months.
Follow-up and clinical endpoints
All patients were contacted by phone call 1 month after the procedure and underwent clinical and angiographic follow-up at 6 months. In case an event occurred, detailed review of the related hospital files was performed.
Major adverse cardiac events (MACE) were defined as a hierarchical composition of death, any myocardial infarction (MI), and target vessel revascularization (TVR). All definitions followed the Academic Research Consortium criteria (14). Target lesion revascularization (TLR) was defined as any repeat percutaneous or surgical intervention due to a restenosis in the treated segment (including the stent and 5 mm proximal and distal). A TLR was considered clinically indicated in case of restenosis >50% by quantitative coronary angiography (QCA), associated with recurrent angina and/or objective signs of silent ischemia (stress tests or fractional flow reserve), or in case of restenosis >70% by QCA without the aforementioned signs or symptoms. Stent thrombosis was defined as a definite, probable, or possible and early or late, also according to the Academic Research Consortium criteria (14). Angiographic success was defined as achievement of a TIMI flow grade 3 and final residual stenosis <30%, using any percutaneous method. Device success was defined as angiographic success using the randomized device. Procedural success was defined as angiographic success without the occurrence of in-hospital MACE. All patients' files were independently monitored and all outcomes were adjudicated by an independent clinical events committee.
Quantitative coronary angiography
QCA was performed according to standard procedures (15), using dedicated software (CAAS 5.9.1 research edition, Pie Medical Imaging, Maastricht, the Netherlands). Images were analyzed by an independent core laboratory with operators not involved with the procedure and blinded to randomization assignment. As the vessel was totally occluded in most of the baseline images, the pre-procedural images analyzed were those after thrombus aspiration. The number of patients with a total occlusion was assessed, and the values for diameter stenosis and minimal luminal diameter (MLD) were changed in these patients in 100% and 0 mm, respectively. In the post-procedural and follow-up images, the stent(s) and additional 5-mm segments proximal and distal to the stent(s) edges were analyzed. MLD and lesion length were directly measured by the QCA software, whereas reference vessel diameter was estimated by an interpolation method, and percent diameter stenosis was subsequently computed. Binary restenosis was defined as a diameter stenosis ≥50% at angiographic follow-up. Late-luminal loss was defined as the difference between post-procedural MLD and MLD at follow-up in the same segment (proximal to the stent, in-stent, distal to the stent, in-segment). In-stent late-luminal loss was the primary endpoint of the study.
Optical coherence tomography
At the same time as the main randomization, each patient was also randomized to undergo, at 6 months, only angiographic follow-up or optical coherence tomography (OCT) investigation and endothelial function testing together with the angiographic control (4:1 ratio).
Time-domain or frequency-domain OCT systems (M3 LightLab Imaging, Westford, Massachusetts, or C7XR, St. Jude Medical, St. Paul, Minnesota) were used. All images were analyzed by an independent core laboratory.
OCT imaging of the target lesion was obtained after 200-μg intracoronary nitroglycerin infusion, and OCT pullback images were acquired during continuous infusion of contrast from the guiding catheter, by means of a controlled injection (2 to 4 ml/s contrast with 200 to 300 psi, depending on the coronary assessed), as previously described (16). Images were acquired with automated pullback at a rate of 2, 3, or 20 mm/s (according to the type of OCT system). All cross-sectional images (frames) were initially screened for quality assessment and excluded if any portion of the stent was out of the screen, images were not analyzable due to side branches, or images had poor quality caused by residual blood, artifacts, or reverberation (17).
A dedicated semiautomated contour-detection system (Curad BV, Wijk bij Duurstede, the Netherlands) was used. Two contours were delineated: the lumen contour (for each cross-sectional image) and the stent contour (every 0.2 to 0.3 mm, depending on the pullback speed, thus, for example, every 5 frames for 2 to 3 mm/s). For stent analysis, an automated stent contour interpolation was performed between frames. Manual corrections were applied if needed. Lumen, stent, and neointimal hyperplasia diameters, areas, and volumes were automatically calculated. Stent struts were semiautomatically classified as covered embedded, covered protruding, uncovered apposed, and malapposed. Covered embedded struts were defined as covered by tissue and not otherwise interrupting the smooth lumen contour; covered protruding struts were defined as covered with tissue but extending into the lumen (however, not greater than the stent strut thickness: 132 μm for DES and 60 μm for BMS); uncovered apposed struts were defined by the same distance from the lumen border as covered protruding struts, without the presence of tissue coverage, however; malapposed struts were defined as those not abutting the lumen border: ≥132 μm for DES and ≥60 μm for BMS (18). The distance was measured between the center of the stent strut and the lumen border, and was preset in the software and manually corrected if necessary. Hence, all struts were semiautomatically defined depending on their distance.
Endothelial function testing
The assessment of the endothelium-dependent vasomotor function was performed by the selective infusion of the endothelium-dependent vasodilator acetylcholine into the target coronary artery. After baseline angiography, acetylcholine was infused via an infusion microcatheter located at the level of the stent into the target coronary artery at incremental concentrations of 10−6, 10−5, and 10−4 mol/l/ml. Acetylcholine was infused for 3 min at each concentration, with a 3-min interval between each infusion. Angiography was obtained after each infusion. The infusion was terminated when the largest dose of acetylcholine was reached or in case of coronary vasoconstriction >50% by visual estimation. Nitroglycerin was then injected as an intracoronary bolus (100 μg) through the guiding catheter to evaluate the endothelium-independent coronary vasoactive response of the coronary artery. Angiography was also performed after nitroglycerin infusion.
Coronary responses to acetylcholine and nitroglycerin were analyzed offline, using dedicated QCA software allowing for segmental analysis by the same core laboratory. All images were recorded in identical gantry position, allowing for accurate consecutive analysis, and were analyzed during diastole. The images obtained at baseline and after each infusion were analyzed for MLD in consecutive 5-mm segments, distal to the stent. Shoulder patterns on QCA analysis were used to identify the distal stent edge (15). The first 15 mm were considered in the analysis, and the worst MLD per each 5-mm segment was chosen. The MLD obtained after each infusion was compared with baseline values. Baseline MLD was set as 0. Endothelial function was quantified as percentage change of MLD from baseline, with negative values expressing paradoxical vasoconstriction and positive values representing physiological vasodilatation.
The primary endpoint of the study was in-stent late-luminal loss. The sample size calculation was based on the direct comparison between BMS (group A) and DEB plus BMS (group B). The study tested the hypothesis that late-luminal loss in group B would be significantly better than in group A. A sample size of 43 subjects per group was estimated to show a significant reduction in late-luminal loss of 50% (from 0.70 to 0.35 mm) with a 2-tailed p value of 0.05 and a power of 90%, assuming a standard deviation of 0.50 mm. To accommodate a 15% loss in angiographic follow-up, 50 patients per group were enrolled. A third DES arm with the same number of patients was added as an exploratory arm, to test at the same time this device in the same setting. Concerning OCT and endothelial function, the number of patients for the substudy was 10 per group, and the substudy was specifically powered (Online Appendix).
Continuous variables are presented as mean ± SD if normally distributed, or median [interquartile range] if not normally distributed. Categorical variables are presented as counts and percentages. Continuous variables were compared between 2 groups using the Student t test or its nonparametric equivalent Mann-Whitney U test. In case of a between-groups comparison (A vs. B vs. C), analysis of variance or its nonparametric equivalent Kruskal-Wallis test was applied. Categorical variables were compared using the chi-square or Fischer exact test. All analyses were performed according to the intention-to-treat> principle. A 2-tailed p value of 0.05 was considered statistically significant.
Patient and procedural characteristics
Overall, 150 patients were included and underwent primary PCI for STEMI according to the protocol between February 2009 and November 2010 (Fig. 1). Baseline clinical characteristics are shown in Table 1. Procedural and angiographic characteristics are shown in Tables 2 and 3.⇓⇓The groups were well balanced for all variables. Both angiographic and device success were achieved in 50 (98.0%), 49 (98.0%), 48 (98.0%), and procedural success in 49 (96.1%), 48 (96.0%), 48 (98.0%) of patients in the BMS, DEB, and DES groups, respectively (overall p = 1.00 and p = 0.83, respectively).
In-hospital adverse events
Two MACE occurred during hospitalization. A subacute stent thrombosis occurred 4 days post-procedure in a 61-year-old man randomized to group B. This caused a recurrent MI and a TLR with successful thrombus aspiration and implantation of an additional BMS distal to the previous stent placed because of a missed edge dissection after the index treatment. This patient was initially treated with a single BMS that was pre-dilated (before DEB) with a normal balloon. The second patient, randomized to group A, was an 86-year-old woman who died 1 day post-procedure due to cardiogenic shock, developed shortly after the index procedure.
At 6 months, 23 patients (15%) did not undergo angiographic control: 19 refused due to lack of symptoms, 2 patients died before angiographic follow-up, and 2 patients were recommended not to undergo it for clinical reasons (renal failure and intracranial hemorrhage with severe sequelae). Hence, 6-month QCA was available in 43 (84.3%), 42 (84.0%), and 42 (85.7%) group A, B, and C patients, respectively (overall p = 0.75).
The QCA data are presented in Table 3. The primary endpoint, reduction of in-stent late-luminal loss, was not met: 0.74 ± 0.57 mm in group A versus 0.64 ± 0.56 mm in group B (p = 0.39). Late-luminal loss in group C was significantly less compared with both groups A and B: 0.21 ± 0.32 mm (overall p < 0.01).
No significant differences were shown in binary restenosis rates between groups A (26.2%) and B (28.6%), whereas group C (4.7%) showed a significantly lower rate compared with the other groups (overall p = 0.01).
Adverse events at 6-month follow-up
Clinical events are shown in Table 4. A total of 28 MACE occurred in 24 patients. In group A, 12 (23.5%) patients had a MACE: 9 (17.6%) TLR (all due to restenosis and all treated with repeated PCI), 1 (2.0%) TVR non-TLR (due to disease progression), and 2 (3.9%) cardiac deaths (the first due to cardiogenic shock, shortly after the index procedure as already described, and the second after 5 months because of progressive heart failure). In group B, MACE occurred in 10 (20.0%) patients. Ten (20.0%) cases of TLR were reported: 8 due to restenosis and all treated percutaneously, and 2 due to early definite stent thrombosis. The first was a subacute stent thrombosis 4 days post-procedural, as has been already described. The second occurred 5 days after the index procedure, causing a recurrent MI treated with successful thrombus aspiration and balloon redilation of the previous stent, probably undersized. This patient was initially treated with a single BMS without pre-dilation with a normal balloon. Further, 1 (2.0%) TVR non-TLR (due to disease progression) and 2 (4.0%) MI (both caused by stent thrombosis as previously mentioned) occurred. In the DES group, 1 (2.0%) TLR (due to restenosis and treated percutaneously) and 1 (2.0%) TVR non-TLR (due to disease progression) occurred in 2 patients. Finally, in 2 patients, both in the DEB group, repetitive events of the same type occurred in the first 6 months. The first patient had a stent thrombosis 5 days post-procedure, causing an MI and TLR (as previously described), and underwent a new TLR because of restenosis 3 months later. The second patient underwent a clinically driven TLR because of restenosis at 10 weeks and again at 6 months.
OCT and endothelial function testing
After the index procedure, 31 patients were randomized to undergo OCT and endothelial function testing. An additional patient was randomized, above the 30 planned patients, because of the death of 1 patient before the follow-up procedure. During the 6-month angiographic follow-up, 27 patients underwent OCT and 21 patients underwent endothelial function testing. Thus, of these 31 randomized patients, 3 refused angiographic follow-up and 1 died before it. In an additional 6 patients, only OCT was performed, without endothelial function testing: in 3 patients, severe in-stent restenosis was evident, in 2, the temporary pacemaker lead (routinely placed during this test for safety purposes) could not be placed, and in 1, a new severe lesion distal to the stent was detected. The OCT and endothelial function findings at 6-month follow-up are presented in Table 5.
The average percentage of uncovered and malapposed stent struts per lesion was 0% [0 to 0.35], 2.84% [0 to 6.63], and 5.21% [3.25 to 14.5] in groups A, B, and C, respectively (overall p < 0.01). On cross-sectional analysis, vessel size was not statistically different between groups with stent diameters of 3.57 [2.75 to 3.77], 3.07 [2.75 to 3.40], and 3.19 [2.92 to 3.34] mm in the BMS, DEB, and DES groups, respectively (overall p = 0.25). Moreover, the stent length was also not statistically different between groups 25.3 [19.2 to 35.3], 22.9 [18.3 to 28.3], and 19.4 [14.5 to 27.9] mm, respectively (overall p = 0.42). Maximum neointimal area and neointimal volume were higher in the BMS group, compared with DEB and DES: 6.25 [4.53 to 9.37], 4.91 [4.23 to 5.28], and 2.70 [1.97 to 3.52] mm2 (overall p < 0.01) and 101.3 [63.5 to 101.3], 60.0 [46.7 to 80.4], and 24.2 [11.5 to 47.4] mm3 (overall p < 0.01), respectively.
Concerning endothelial function, no effect was seen in the BMS group, with substantial stability of the vascular dimensions. By contrast, both DEB and DES showed a paradoxical vasoconstriction related to incremental doses of acetylcholine. The degree of endothelial-dependent vascular response to incremental acetylcholine doses, expressed as percentage change of in-segment MLD, was significantly diminished in the DES group in comparison to the control group BMS for low, medium, and high acetylcholine infusions in the first 5 mm distal to the stent (Fig 2). In the DEB group, more paradoxical vasoconstriction was seen for medium and high acetylcholine infusions in comparison to BMS. The endothelial-independent vascular response, after nitroglycerin infusion, was similar between all 3 groups.
The main findings of this randomized, multicenter study are: 1) DIOR DEB failed to demonstrate angiographic superiority over BMS, with similar late-luminal loss and binary restenosis rates; 2) DES showed significantly better angiographic and clinical results compared with both DEB and BMS; and 3) DEB had significantly more combined uncovered and malapposed struts compared with BMS, but less compared with the DES group.
DES were developed with the knowledge that the process of restenosis after stent implantation is gradual and progressive. Therefore, drug release from the stent was deliberately prolonged with the use of polymer coatings, providing a long-term and sustained drug release. On the other hand, laboratory results have shown that even short contact between taxol compounds with vascular smooth muscle cells can inhibit the proliferation of these cells for a long period, suggesting that stent-based sustained drug release may not be necessary (19). With this knowledge, a DEB was developed and tested in trials, which confirmed this inhibitory effect on neointimal hyperplasia. This effect was demonstrated for the currently used DIOR DEB (8,20), and for the Sequent Please paclitaxel-coated balloon (Braun Melsungen AG, Melsungen, Germany) (10,11).
An appealing extension of the use of DEB appeared to be the treatment of STEMI, combining DEB with a BMS. Specific advantages of this approach might theoretically be: 1) homogeneous administration of the drug to the vessel wall, especially at the area of the culprit plaque, whereas the DES delivers the drug only in the proximity of its struts; 2) better angiographic results, and hence less need for TLR; 3) less malapposition, with potentially less stent thrombosis with respect to DES; 4) preservation of endothelial function with respect to DES; and 5) possibly less prone to the potential clinical consequences in case of shortened dual antiplatelet duration, or in patients incapable of adhering to 12-month dual antiplatelet therapy.
Notwithstanding these potential advantages, the DEB used in this study failed to prove superior angiographic outcomes. We were not able to demonstrate a beneficial effect of pre-treatment with DEB in STEMI. Interestingly, however, the percentage of uncovered and malapposed struts as seen on OCT suggest that there is a drug effect induced by DEB that shows morphological changes compared with BMS alone. The DES group showed even more pronounced morphological changes. These findings are in line with a recent OCT study in STEMI patients (5). These results may suggest that the DEB did induce some effects on neointimal proliferation as demonstrated by OCT; however, they were insufficient to cause enough inhibition of the process to reduce late-luminal loss as compared with the BMS group. As has been previously demonstrated for DES in OCT studies, effective inhibition of late-luminal loss seems to be accompanied by specific morphological changes, seen as uncovered and malapposed struts. These delayed healing processes may contribute to an increased risk of stent thrombosis (21,22). Also, the acetylcholine testing findings in the present study point toward a drug effect in DEB-treated patients. After incremental acetylcholine infusions, paradoxical vasoconstriction occurred in the DEB- and DES-treated patients, with nonsignificantly more pronounced vasoconstriction in DEB compared with DES. By contrast, endothelial function in the BMS group was stable after incremental acetylcholine concentrations.
A possible explanation of the findings relies on the fact that the currently used DEB may have failed to warrant sufficient bioavailability of paclitaxel at the lesion site (23). A clarification for this might be the excipient used, which consists of shellac. Recently, a side-by-side comparison in a porcine model of various DEB relying on different excipients demonstrated differences in late-luminal loss in one DEB over the other. In that same study, fibrin deposition and inflammatory response were more pronounced in the most effective DEB in comparison to a normal angioplasty balloon and the less effective DEB (24). Although the currently used DEB was not specifically used in that study, the study itself shows the importance of the excipient or drug carrier in DEB technology.
A second justification might be the fact that although mandatory per protocol, only 60% of patients in the DEB group underwent pre-dilation with a regular balloon. Pre-dilation before using a DEB should improve drug uptake by the vessel wall due to the creation of micro-dissections and thus facilitate drug transport through the intima and media. Third, in case of calcified lesions, pre-dilation will facilitate lesion crossing with the usually more bulky DEB and prevent potential scrape-off of the drug. Therefore, in order to understand the results obtained, we performed a series of post hoc “hypothesis-generating” analyses focused on the DEB group. Of 25 patients who had pre-dilation, the late-luminal loss was 0.49 ± 0.52 mm versus 0.85 ± 0.56 mm in the 17 patients without pre-dilation in the same DEB group (p = 0.04). Finally, in 10 patients in whom more than 1 stent was placed at the lesion site, a protocol-mandated DEB dilation was not performed in the segment where the additional BMS was placed. In these 10 patients with additional BMS and without an extra DEB dilation, the late-luminal loss was 1.01 ± 0.75 mm versus 0.52 ± 0.44 mm in the 32 patients without an additional stent (i.e., no geographical mismatch) (p = 0.01). Noticeably, 5 of these 10 patients (50%) had a TLR.
Considering the patients who had pre-dilation with a normal balloon and 1 stent (i.e., no geographical mismatch of DEB and BMS), late-luminal loss was 0.74 ± 0.60 mm (n = 29), 0.43 ± 0.45 mm (n = 19), and 0.19 ± 0.30 (n = 35) in the BMS, DEB, and DES groups, respectively. In this specific subgroup, the DEB had a significantly lower late-luminal loss than the BMS subgroup (Table 6).
It remains difficult to judge the impact of these protocol deviations on the outcomes in the DEB arm. Nevertheless, it is important to consider these results as “hypothesis-generating” and possibly useful when applying DEB in future studies.
Furthermore, whereas in DES the release of paclitaxel is regulated by a polymer coating that ensures a sustained and gradual release over time, DEB are applied by a single short exposure to the vessel. This may still have an impact on the long-term outcomes in patients with de novo lesions. However, it has been demonstrated that with a short exposure to DEB, the amount of paclitaxel in the vessel wall was still in a bio-effective range after 7 days (24). Therefore, we do not believe that the half-life of paclitaxel significantly contributed to the negative results of this study.
This study was powered for angiographic outcomes and not aimed at detecting clinical differences between groups. Hence, no firm conclusions can be drawn on the safety of DEB. Since this was the first study with DEB in STEMI, no reference late-luminal loss for the DEB group was available for the power calculation. Because late-luminal loss was higher in the DEB group than assumed, the study might have been insufficiently powered to detect smaller differences in angiographic outcomes between the BMS and DEB groups. Therefore, even a reduction in late-luminal loss <50% (as the original assumption of this study was) could be of clinical significance when applied to a larger cohort of patients. The OCT outcomes with a reduction of neointimal hyperplasia in the DEB group seem to suggest that the changes induced by DEB might indeed have clinical significance when applied to an appropriate number of patients. Hence, future larger randomized studies should be performed in order to put the current findings into perspective. Second, the study was single blinded, thus potentially resulting in treatment bias. Third, a risk of selection bias, which however should equally apply to all 3 treatment arms, could not be completely ruled out. Finally, the deviations from the protocol regarding the lack of pre-dilation in the DEB arm, as well as the lack of additional DEB dilation in case of additional BMS implantation, may have influenced the results negatively. Nevertheless, the consequences of these post-hoc analyses should be applied with thought and used as hypothesis-generating outcomes.
Local drug delivery with a DEB to the culprit plaque of a STEMI at the moment of highest inflammation remains an attractive treatment opportunity. Nevertheless, the DIOR DEB in combination with BMS failed to show angiographic superiority to BMS alone, and with more evident morphological and functional changes on OCT and acetylcholine testing, respectively. These morphological changes suggest a drug effect, however, one that is insufficient to result in superior angiographic results. Finally, the angiographic results of DES were superior to both BMS and DEB; however, DES induced delayed healing and endothelial dysfunction.
The authors thank the nurses of the Department of Cardiac Clinical Research for their cooperation. Yvonne Breuer-Otten has especially contributed to the successful implementation of the program and completion of the study. They also thank Mirza Becirovic (Cardiology Department, Modena) for his contribution and the dedication he has put into this study. Finally, the authors thank Ronald Hamers (Curad BV) for the devotion he has put into optimizing the OCT software and for the pleasant collaboration, and Stefanie Stahnke (Eurocor GmbH), who made sure all collected data were referred for analysis.
For a description of the power analysis for the OCT and endothelial function substudy, please see the online version of this article.
This study was funded by a research grant from Eurocor GmbH (Bonn, Germany). The DEB-AMI was a “physician-initiated study.” Eurocor GmbH gave a financial grant to support the research activities (development of the electronic case report form) and provided both centers with drug-eluting balloons. Dr. Stella is a member of the scientific advisory board of Eurocor GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Belkacemi and Agostoni contributed equally to this work.
- Abbreviations and Acronyms
- bare-metal stent(s)
- drug-eluting balloon(s)
- drug-eluting stent(s)
- major adverse cardiac event(s)
- myocardial infarction
- minimal luminal diameter
- optical coherence tomography
- percutaneous coronary intervention
- quantitative coronary angiography
- ST-segment elevation myocardial infarction
- target lesion revascularization
- target vessel revascularization
- Received December 19, 2011.
- Revision received February 6, 2012.
- Accepted February 7, 2012.
- American College of Cardiology Foundation
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