Controlled Balloon Inflation Reduces Long-Term Restenosis After Percutaneous Transluminal Coronary Angioplasty

Stents have proven their benefits in an increasing number of transluminal coronary interventions.1,2 However, stents increase procedural costs and have the inherited problem of in-stent restenosis, particularly in patients with small-vessel disease, for which the optimal treatment modalities have not been settled.3–7 Moreover, after stand-alone angioplasty, there seem to be particular variables, such as optimal result after angiography,8,9 guidance by Doppler flow wire,10,11 guidance by intracoronary Doppler and quantitative angiography,12 and assessment by intravascular ultrasound,13,14 that achieve comparable restenosis rates to primary stenting. On the other hand, the vessel wall trauma that results with the process of balloon inflation plays a crucial role in determining long-term results15–19 even with the combination of stents and brachytherapy.20 The current mode of inflation using a hand-driven pump precludes a standardized inflation process. Controlled widening of the vessel wall, which limits traumatization of the vascular wall, is possible with a computer-assisted percutaneous transluminal coronary angioplasty system (CAPS), the reliability of which has been published elsewhere.21 METHODS Design. The primary endpoint of this single-center, prospective, randomized trial was the binary restenosis rate. Secondary endpoints at 6 months were acute success; target site revascularization; acute ischemic, vascular, and hemorrhagic complications; and angiographic late and percent minimal lumen diameter. Safety endpoints were combined late cardiac events [death, myocardial infarction (MI), and revascularization]. Inflation devices. A computer-assisted PTCA system (CAPS) has been developed for controlled dilatation and has been described elsewhere.21 Conventional balloon catheters are connected to a pressure sensor, which is connected to a readily available syringe. The syringe is clamped to a plastic housing which hosts the step motor for inflation and deflation. Pressure slope (0.1–1.0 bar/second), maximal pressure (0.1–20.0 bars) and inflation time (1–180 seconds) are preselected by means of a laptop computer (>= 386 SX 20 processor) which also displays the inflation process by a pressure/volume curve online. On a separate cart, the electronic components (e.g., the microcontroller, etc.) allow for adjustment of the parameters in closed loop mode 40 times per second. Extensive in vitro testing demonstrated the system’s technical reliability, high reproducibility of the inflation process, and safety.21 Hand-driven (manual) balloon inflation was performed by means of various readily available inflation pumps commonly used in clinical practice. Study population. After informed consent was obtained, a total of 454 unselected patients (82.6% men; mean age, 60.9 ± 9.0 years) scheduled for routine PTCA were assigned by computer-generated randomization to either computer-assisted dilatation with 0.2 bar/second (CAPS 0.2), 1.0 bar/second (CAPS 1.0) or standard inflation with a hand-driven pump (H). Inclusion criteria consisted of patients of either sex, aged 20–85 years, with the indication for PTCA in a native coronary artery with a significant lesion of >= 70% occlusion and 2.5 mg/dl; contraindication to both aspirin and ticlopidine; contraindication for emergent bypass operation; cerebral stroke Operator technique. The procedures were performed by three operators with an annual volume of about 1,000 interventions each. The procedure consisted of the administration of 200 IU/kg body weight of heparin after introduction of the sheath, and was supplemented by 100 IU/kg body weight in prolonged procedures. Following intracoronary injection of nitroglycerin (> 100 µg), baseline angiography of the involved vessel was performed in at least two near-orthogonal views, showing the target lesion free of foreshortening or vessel overlap, using an 8 French guiding catheter. The target lesion was crossed with a 0.014´´ exchange-length guidewire and dilated with an appropriately sized balloon (balloon/artery ratio, 1:1). Assessment of lesion severity and lesion length (and therefore, choice of the balloon) was based on visual estimation. The procedure was judged successful if the remaining diameter was less than or equal to 30%. Angiographic images were acquired pre-procedure, post-procedure and at 4-month follow-up examination. 35-mm cine angiography films, as well as the case report forms, were evaluated by the center’s angiographic core lab. The investigators only received the cine films and were thus blinded to the mode of balloon inflation. Regarding the number of balloon inflations, there was no significant difference in the maximal pressure or in the time span for which this pressure was exerted (i.e., peak pressure time) (Table 4). Concomitant medical therapy. All patients received aspirin 100 mg/day both pre-procedure and throughout the follow-up period. If aspirin was not tolerated, ticlopidine (250 mg twice daily) was given. Angiographic assessment.Angiograms were reviewed by two of the center’s angiographic core laboratory investigators using qualitative morphologic and quantitative angiographic methods by means of the CAAS II System (Pie-Medical, 6227 AJ Maastricht, The Netherlands). The contrast-filled diagnostic or guiding catheter served as the calibration standard, while the reference and minimal lumen diameters were determined using an automated edge-detection algorithm. Reference vessel diameters were calculated by selecting a smooth arterial segment 10 mm proximal and distal to the lesion. The reference vessel diameter, minimal lumen diameter, and percent diameter stenosis were taken from the worst view using a validated edge-detection algorithm. Follow-up. Follow-up procedures included baseline electrocardiogram, white blood cell count, hematocrit, hemoglobin, creatinine (CK) and CK-MB, repeat visit, exercise tolerance test, and catheterization at 4 months. Abrupt closure was defined as significantly reduced flow (TIMI grade 0 or 1) due to mechanical dissection, coronary thrombus, or severe microvascular spasm that resulted in either unplanned transluminal reintervention, emergent surgery, controlled MI or death. Acute myocardial infarction was defined as CK-MB levels >= 2 times the normal with significant CK-MB levels with or without electrocardiogram changes. Major vascular complications at the access site included those which required transfusion or surgery and pseudoaneurysms. Patient follow-up consisted of a repeat visit, an exercise tolerance test and catheterization at 4 months. The binary restenosis definition (> 50% reduction in lumen diameter at follow-up) was used. The referring cardiologist was contacted for follow-up data on patients. Statistical analysis. The Kolmogorov-Smirnov test was used to check the assumption of a Gaussian distribution. Mean and standard deviation were used to describe Gaussian distributions, whereas non-Gaussian distributions were described by median and range. Discriminant variables were evaluated with the 2-sided exact Fisher test using two-by-three contingency tables containing the three treatment groups. For all tests, the significance level a was 0.05. RESULTS Procedural outcome. For the patients with computer-assisted inflation at slow pressure increase (CAPS 0.2), procedural success was achieved in all but 2 (1.3%); due to severe dissections of NHLBI type F,22 these patients proceeded to emergent coronary bypass operation and had uneventful recoveries. Although acute MIs were most frequent in patients with conventional hand-driven inflation (4% versus 1.3% in CAPS 0.2 patients and 2.6% in CAPS 1.0 patients), total major adverse coronary events occurred in 4.6–8.6% in all groups (p = not significant). Flow reducing and non-flow reducing dissections were equally present in all groups (Table 5). Follow-up. Angiographic follow-up after 4.1 ± 3.2 months in 408/454 patients (89.9% of all patients and 90.3% if adjusted for the two patients who proceeded to emergent bypass operation) revealed similar binary restenosis rates of 65/133 (48.9%) in the hand-driven group and 62/140 (44.3%) in the CAPS 0.2 group. With rapid balloon inflation (CAPS 1.0), the recurrence rate of 32.6% (44/135) was significantly lower in comparison to manual inflation (p  70%. Twelve out of 454 patients (2.6%) who presented neither with angina pectoris nor ischemia during the symptom-limited exercise stress test refused follow-up angiography. One patient (0.2%) with 3-vessel disease died from sudden cardiac death. Thirty-three out of 454 patients (7.3%) were lost to follow-up. DISCUSSION Stents have become the treatment of choice in most percutaneous transluminal coronary interventions despite several disadvantages, including in-stent restenosis, risk of sidebranch occlusion, unsatisfactory results in bifurcational lesions, long lesions, and the treatment of small vessels; at this point, these issues remain unsolved.1,2 Moreover, after stand-alone balloon angioplasty, the optimal result as assessed angiographically,8,9 by Doppler flow-wire,10,11 by intracoronary Doppler and quantitative angiography,12 or by intravascular ultrasound13,14 was predictive of similar restenosis rates compared to primary stenting. In addition, the enhanced costs per procedure may not be covered by all of the patients. These issues still justify plain old balloon angioplasty as the treatment of choice in many patients. It is well known that the damage to the vessel wall following interventional procedures plays a crucial role in the occurrence of restenosis23–25 even after the application of brachytherapy.20 However, the mode of balloon inflation is not yet standardized. It is also unknown which mode of balloon angioplasty would be most suitable for a particular type of lesion.26–28 A lesion’s morphologic characteristics do not seem to determine the acute morphologic result. Intravascular ultrasound analysis did not reveal any significant relationship between pre-interventional plaque characteristics such as composition features and eccentricity, and the incidence, location, and extent of post-interventional dissections.29 As a first step, the present trial supports the hypothesis of vascular injury to determine the long-term outcome of PTCA15–18,24,30 and revealed another parameter8–14 which might identify subsets of patients in whom provisional stenting would result in a recurrence rate similar to primary stenting. The possible benefits and risks of two reproducible modes of balloon inflation were compared to the generally accepted, although non-standardized, hand-driven mode of PTCA. The reproducibility of inflation was ascertained by a computer-assisted system, the absolute reliability and safety of which has been reported elsewhere.21 In non-selected patients, there were no differences in minor or major procedural and post-procedural complications between the treatment groups, which is in accordance with previous results.26 At 4-month follow-up exam, however, the rapid pressure increase (1.0 bar/second) demonstrated a significant reduction in recurrence rates (32.6%) when compared to hand-driven balloon angioplasty (48.9%; p = 20%) was achieved by 5.4 ± 0.3/5.5 ± 0.3 inflations in the aforementioned work and thus differ considerably with the definition of success (

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