High-Frequency Mechanical Vibration to Recanalize Chronic Total Occlusions after Failure to Cross with Conventional Guidewires

Percutaneous coronary intervention (PCI) of a chronic total occlusion (CTO) remains one of the more difficult technical challenges for interventional cardiologists, despite the progress made in the field of PCI in the past decade. CTOs (found in one-third of patients with significant coronary disease) represent only about 10% of all PCI cases.¹ Failure to revascularize a CTO often leaves the patient with either the more invasive option of coronary artery bypass graft surgery (CABG), or continuing medical therapy, which may or may not control anginal symptoms. In addition, leaving a vessel occluded may also have detrimental consequences on long-term survival.^2,3 The success rate of PCI for CTOs varies widely (range = 40–80%), depending on the location and characteristics of the CTO as well as the operator’s experience.^4,5 The main technical reason for an unsuccessful PCI for CTOs is the failure to cross the occlusion with the guidewire. Various specialized wires or adjunctive devices have been developed over the years to improve the chances of crossing a CTO successfully, albeit with variable success rates. Recently, we evaluated the CROSSER™ System (FlowCardia, Inc., Sunnyvale, California), which uses high-frequency mechanical vibrational energy in a pulsed mode (30 milliseconds on, 30 milliseconds off) to penetrate both calcific and noncalcific atherosclerotic plaque material. Methods Study population and inclusion/exclusion criteria. In this prospective registry, a total of 53 consecutive patients with 55 CTOs suitable for PCI were recruited from December 2002 through January 2004 in four European centers: the Heart Center in Siegburg, Germany, the EMO Centro Cuore Columbus in Milan, St. Raffaelle Hospital in Milan and Zurich University Hospital in Zurich. Local ethics committee approval was obtained prior to launching the study, and informed written consent was obtained from all patients. All patients entered into the study had a totally occlusive lesion that had been in existence for a minimum of 1 month, with associated TIMI 0 or 1 flow, and had a concurrent or previously documented, failed conventional percutaneous procedure to cross the total occlusion. The patients had either symptomatic angina of Canadian Cardiovascular Society Class II or higher, or objective evidence of myocardial ischemia. Other inclusion criteria included a reference vessel diameter of the target of lesion > 2.0 mm, and suitability for PCI or CABG. Exclusion criteria included the following: contraindication to aspirin, heparin or radiographic contrast agents; lesions in an aorto-ostial, ostial, unprotected left main or saphenous vein graft location; a myocardial infarction within the past 72 hours; left ventricular ejection fraction Study design and endpoints. The first 30 CTOs were chosen for the feasibility phase of the registry, while the subsequent 25 CTOs were chosen for the pivotal phase. The objective of the feasibility phase was to assess technology safety and identify possible opportunities for device improvement, while the objective of the pivotal phase was to evaluate the efficacy of the device (after improvements in device flexibility and the addition of a hydrophilic coating to the catheter). The endpoints were the same for both phases of the study. Technical success was defined as the success of the CROSSER device to facilitate crossing a CTO with a conventional 0.014 inch wire. The primary endpoint of the study was device efficacy, defined as advancement of the CROSSER into or through total occlusions in a native coronary artery or in-stent, and achievement of distal vessel guidewire position with any conventional 0.014 inch guidewire, with a resultant postprocedural residual restenosis of 2 times the upper normal limit, together with CK-MB fraction elevation], or target lesion revascularization (TLR) by either CABG or PCI through 30 days of follow up. Device. The CROSSER system consists of two components: a generator and a catheter (Figure 1). The generator delivers high-frequency current to the transducer, which converts the current into high-frequency mechanical vibration that is propagated to the distal tip of the catheter. The transducer operates at a frequency of approximately 21 kHz, and the vibrational energy provides for mechanical and cavitational effects that aid in the recanalization of the occluded artery. The monorail CROSSER catheter accepts a standard 0.014 inch guidewire through its central lumen, and can be advanced through standard 6 Fr guiding catheters. The generator is reusable and the CROSSER catheter is disposable. Both components are attached together and protected by a sterile drape during the interventional procedure. The primary difference between the feasibility and pivotal phases was the device being studied. In the initial design of the CROSSER catheter, the device was uncoated and had a shaft diameter of 1.3 mm. This version of the device often became stuck on proximal disease and tortuous anatomy. In the pivotal device, a hydrophilic coating was added to the distal end of the catheter and the profile was reduced to 1.1 mm, which dramatically improved deliverability. Procedure and follow up. Potential candidates for the study first underwent an attempt to cross the CTO with conventional percutaneous guidewire intervention for a minimum of 10 minutes of fluoroscopy time unless they had a previously documented failed PCI attempt. If the attempt with a conventional technique was unsuccessful, the patient could then be recruited into the study at the physician’s discretion. The CROSSER catheter was only used if conventional guidewires had failed to cross the CTO after this designated period of time. The CROSSER catheter was advanced over a guidewire of choice (generally a moderate or heavy support wire) to the proximal cap of the CTO. The guidewire was then withdrawn into the catheter guidewire lumen and the CROSSER catheter was energized and gently pushed forward against the proximal face of the lesion. In a majority of the cases, bilateral coronary injection was used to define coronary circulation proximal and distal to the CTO to estimate the length of the CTO and to provide a roadmap for the recanalization procedure. The operator was able to utilize the guidewire at any time as necessary during the procedure. Successful guidewire placement in the true distal lumen was followed by balloon angioplasty and/or stent placement. Each CROSSER catheter could be used for a maximum of 5 minutes of total activation time (the catheter was limited by its fatigue life to this time period), and additional catheters could be used as required to try to cross the CTO. If the CROSSER system was unsuccessful at crossing the occlusion within 15 minutes of catheter activation time, the procedure was considered a technical and procedural failure, and the patient was managed according to regular hospital procedures. The period of 15 minutes was chosen as a protocol maximum, as it was felt that if the CTO could not be crossed after the use of 3 CROSSER catheters, then it was unlikely that the use of additional catheters would bring success. CK and CK-MB fraction levels were monitored at 8 hours and 24 hours postprocedure. All patients were followed up with a phone interview at 30 days postprocedure. In this paper, continuous data are presented as mean with standard deviation, and nominal data as percentages. Results Fifty-one patients had a single-vessel CTO and 2 patients had two-vessel CTOs. Baseline patient characteristics are shown in Table 1. The population was predominantly male (90.2%). A total of 78.4% of the patients had multivessel disease (defined as those with 2 or more diseased vessels). Table 2 describes the lesion characteristics. The mean lesion length was 24.8 mm, and the overall CTO average age was 17.7 months. The CTO was located in a native vessel in 85.5% of patients and was in-stent in 14.5%. A total of 60% of the CTOs had been present for 3 months or more. A total of 45.5% (25/55) of the lesions in this study already had a documented unsuccessful prior PCI attempt. The various guidewires used unsuccessfully to cross the CTO before the deployment of the CROSSER device are summarized in Table 3. An average of 1.4 guidewires and 15.2 minutes of fluoroscopy time were used to attempt recanalization of the CTO prior to the introduction of the CROSSER device. Feasibility phase. Thirty CTO lesions were treated during the feasibility phase. The technical success rate was 46.7%, but the device efficacy was only 40.0%. In 2 patients with right coronary artery occlusions, the CROSSER device crossed the CTO, but only made progress into a marginal branch distal to the occlusion; the distal segment of the vessel could not be wired. No major adverse events or complications relating to vibrational energy, either clinical or angiographic, occurred during the procedure or within 30-day follow up. In particular, there was no device-related perforation, thrombosis, abrupt closure, coronary artery spasm, side branch loss, distal embolization, no-reflow, bradycardia or hypotension. One patient experienced discomfort during the entire procedure, both with vibrational energy application and during contrast injection and balloon inflation. From the experience gathered during this phase, the limitations of the device were noted and addressed accordingly, resulting in the final version of the CROSSER catheter that was used in the pivotal phase of the trial. Pivotal phase. Twenty-five CTO lesions were treated during the pivotal phase of the study. The technical success rate and device efficacy was 76.0%. Two patients had a non-Q wave myocardial infarction (NQMI). The first patient had a failed PCI attempt to open a CTO, and subsequently also underwent PCI of a left anterior descending artery stenosis through the left internal mammary artery graft. Chest pain was experienced periprocedurally and the patient’s cardiac enzymes were elevated. The second patient was asymptomatic, but had elevated cardiac enzymes following a successful recanalization of a CTO in the right coronary artery. No other serious adverse events were reported during the pivotal phase. The study endpoint results are summarized in Table 4. In the pivotal phase, using the final, improved version of the CROSSER device, the primary endpoint of device efficacy was 76.0%, and the secondary endpoint of clinical success was also 76.0%. Overall, combining the results from both phases of the study, the device efficacy and clinical success were 56.4%. An example of a successful case is shown in Figure 2. A MACE rate of 0% through 30-day follow up was reported for the study. There were 2 NQMIs (3.8%); however, the prespecified protocol definition of MACE in this trial did not include NQMI. No MACE events, such as death, Q-wave MI or TLR, were observed. In particular, no coronary perforation or pericardial tamponade occurred. Table 5 summarizes the various reasons for which the CROSSER device was unsuccessful in crossing the CTO. The subintimal passage of either the guidewire or CROSSER device was the main reason for failure. An example of an unsuccessful case is shown in Figure 3. The mean duration of CROSSER use during the study was 2 minutes 51 seconds. Stenting was performed in 29 of the 31 (93.5%) successfully treated lesions. Two lesions, as a result of excellent postprocedural angiographic appearance, were only treated with balloon angioplasty; 1 lesion was an in-stent restenosis that was treated with atherectomy followed by balloon angioplasty, and the other was a de novo lesion with a satisfactory residual 10% stenosis postangioplasty. The mean number of stents implanted was 2.2 ± 1.0 (range = 1–4), the mean diameter of stents implanted was 3.4 ± 0.5 mm (range = 2.5–5 mm), and the mean length of stented segments was 52.2 ± 26.4 mm (range = 11–116 mm). The mean volume of radiographic contrast used was 299.² ml (± 166.5 ml). The overall average procedure time was 83.0 ± 39.7 minutes, and average fluoroscopic time was 30.8 ± 18.5 minutes. Discussion PCI of a CTO is more difficult, costly and time-consuming, and also invariably comes with increased radiation exposure and contrast load. However, successful revascularization of a CTO confers symptomatic, physiological and mortality benefits. There is persuasive evidence of the prognostic importance of maintaining an open artery over the long term. Previous trials in postinfarct patients have shown that patients with occluded infarct arteries are more likely to have ventricular late potentials,^6,7 as well as inducible ventricular tachycardia,^8,9 and may therefore be at higher risk of sudden death. Analysis of a subset of patients from the SAVE trial demonstrated that patients with a patent infarct artery had a more favorable clinical outcome at up to 5 years’ follow up, irrespective of the number of vessels diseased or the left ventricular ejection fraction.² Long-term follow up results from the Mid-America Heart Institute study also showed that a successfully revascularized CTO confers a significant 10-year survival advantage when compared to failed revascularization (73.5% versus 65.1%; p = 0.001).³ A prerequisite for successful PCI of a CTO is to be able to cross the occlusion with a guidewire. A wide variety of techniques and devices to achieve this have been evaluated and used: specialized guidewires with hydrophilic or tapered tips,^10,11 optical coherence reflectometry-guided radiofrequency ablation guidewires,^12,13 mechanical approaches such as blunt microdissection,¹⁴ and ablative devices such as laser wires.^15,16 These varied methods have had variable success rates that may be somewhat dependent on experienced hands in tertiary centers, and may not be reproducible in the real world. The search for a simpler and reliably effective method continues unabated. In this study, we report a promising technology that utilizes mechanical vibrational energy topreferentially ablate plaque. The CROSSER system produces vibrational energy at the tip of the CROSSER catheter. It is hypothesized that the selective penetration of plaque with this catheter is dependent on the difference in elasticity between the atherosclerotic plaque and the adjacent media. Collagen, the major determinant of tissue elasticity, is abundant in the media of muscular arteries, while the collagen in atherosclerotic plaque is abnormal, making the elasticity of plaque significantly lower than that of the media. When vibrational energy is applied, a given level of energy causes more deformation and a greater disintegrative effect on the less elastic atherosclerotic plaque as opposed to the more elastic arterial wall. The precedent for this technology came from the use of catheter-delivered therapeutic ultrasound to treat lesions in coronary and peripheral arteries. In biological tissues, high-energy ultrasound causes local effects of acoustic cavitation, microstreaming, thermal warming and mechanical vibration. In vivo studies have shown that the results of ultrasound ablation of lesions were microscopic particulates, 90% of which were 17–18 The predominant effect that helps to disrupt the plaque is primarily mechanical as a result of the very rapid movement of the catheter tip on rigid plaque material. Normal segments of the arteries are not damaged by this action, as they are elastic and therefore move out of the way of the oscillating probe tip. Previously, the use of this modality in coronary arteries was limited by the large catheter size and lack of deliverability of the device.^19–21 The CROSSER system has a much smaller catheter tip size compared with the previous devices utilizing this modality, such as the SONICROSS (Guidant Corp., Indianapolis, Indiana).²⁰ Michalis et al. have also previously reported on an earlier variation of vibrational angioplasty. Their method involved attaching a battery-driven, motorized device to the proximal end of an over-the-wire catheter with a guidewire protruding slightly from the distal end, thereby imparting a low-frequency vibration to the guidewire tip to help facilitate crossing the CTO.²² However, this is a low-energy method, as the frequencies used are only 16–100 Hz, compared to much higher frequencies of 20 KHz used in the SONICROSS device²⁰ or 21 KHz in the CROSSER device. In addition, the CROSSER device involves the use of a specific crossing catheter; the conventional guidewire is used mainly to deliver the CROSSER catheter, but also allows the operator to probe the occlusion when required while the catheter is inactive. An important potential side effect of high-frequency vibrational angioplasty is the local heating of tissues resulting from the dissipation of the catheter’s mechanical energy. However, in the CROSSER system, 95% of this heating occurs at the proximal end of the catheter outside the body, and with continuous saline irrigation at a flow rate of 12 ml/minute, local heating at the catheter tip is maintained at Study limitations. Limitations of this study include the small number of patients involved, as well as the nonrandomized nature of the study which may give rise to case selection bias. In addition, 14.5% of the cases were of in-stent CTOs as a result of proliferative restenosis in which the occlusion was composed primarily of smooth muscle cell hyperproliferation rather than the denser fibrous connective tissue typically found in CTOs of de novo lesions. The enrollment period was lengthy for a couple of reasons. First, this study only enrolled patients who underwent failed conventional guidewire attempts. Second, there was a halt in the trial between the feasibility and pivotal phases. During this time, the device was modified and submitted for ethical committee review prior to initiation of the pivotal phase. There were no specific protocol instructions regarding a step-up in wire stiffness during the attempt to cross, and the exact order of wires used for each patient was also not recorded; we recognize this as a shortcoming of this study. The choice of wires was left to the operator’s discretion, but we believe that the range of wires used (as summarized in Table 3) demonstrated “good faith” attempts to cross the CTOs. This is supported by the observation of similar technical success rates both in the group of 25 lesions with a documented prior and separate unsuccessful PCI attempt to cross the CTO [60.0% (15/25)], and also in the other group of 30 lesions that had an unsuccessful PCI attempt with conventional wires during the same procedure preceding the use of the CROSSER device [60.0% (18/30)]. Conclusion The CROSSER system using high-frequency mechanical vibrational energy is a promising device to treat coronary CTO lesions. In this small pilot registry, we found the device to be safe and effective, and its potential should be further explored with a larger randomized trial. Acknowledgement. The authors would like to thank Dr. Donald Baim for his assistance with the manuscript.

1. Srinivas VS, Brooks MM, Detre KM, et al. Contemporary percutaneous coronary intervention versus balloon angioplasty for multi-vessel coronary artery disease. A comparison of the National Heart, Lung and Blood Institute Dynamic Registry and the Bypass Angioplasty Revascularization Investigation (BARI) Study. Circulation 2002;106:1627–1633. 2. Lamas GA, Flaker GC, Mitchell G, et al. Effect of infarct artery patency on prognosis after acute myocardial infarction. Circulation 1995;92:1101–1109. 3. Suero JA, Marso SP, Jones PG, et al. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: A 20-year experience. J Am Coll Cardiol 2001;38:409–414. 4. Puma JA, Sketch MH Jr, Tcheng J, et al. Percutaneous revascularization of chronic coronary occlusions: An overview. J Am Coll Cardiol 1995;26:1–11. 5. Serruys PW, Hamburger JN, Koolen JJ, et al. Total occlusion trial with angioplasty by using laser guidewire: The TOTAL trial. Eur Heart J 2000;21:1797–1805. 6. Gang ES, Lew AS, Hong M, et al. Decreased incidence of ventricular late potentials after successful thrombolytic therapy for acute myocardial infarction. N Engl J Med 1989;321:712–716. 7. Vatterott PJ, Hammill SC, Bailey KR, et al. Late potential on signal-average electrocardiograms and patency of the infarct-related artery in survivors of acute myocardial infarction. J Am Coll Cardiol 1991;17:330–337. 8. Sager PT, Perlmutter RA, Rosenfeld LE, et al. Electrophysiologic effects of thrombolytic therapy in patients with a transmural anterior myocardial infarction complicated by left ventricular aneurysm formation. J Am Coll Cardiol 1988;12:19–24. 9. Kersschot IE, Brugada P, Ramentol M, et al. Effects of early reperfusion in acute myocardial infarction on arrhythmias induced by programmed stimulation: A prospective, randomized study. J Am Coll Cardiol 1986;7:1234–1242. 10. Corcos T, Favereau X, Guerin Y, et al. Recanalization of chronic coronary occlusions using a new hydrophilic wire. Cathet Cardiovasc Diagn 1998;43:83–90. 11. Saito S, Tanaka S, Hiroe Y, et al. Angioplasty for chronic total occlusion by using tapered-tip guidewires. Catheter Cardiovasc Interv 2003;59:305–311. 12. Chen WH, Ng W, Lee PY, Lau CP. Recanalization of chronic and long occlusive in-stent restenosis using optical coherence reflectometry-guided radiofrequency ablation guidewire. Catheter Cardiovasc Interv 2003;59:223–229. 13. Hoye A, Ondewater E, Cummins P, et al. Improved recanalization of chronic total coronary occlusions using an optical coherence reflectometry-guided guidewire. Catheter Cardiovasc Interv 2004;63:158–163. 14. Whitbourn RJ, Cincotta M, Mossop P, Selmon M. Intraluminal blunt microdissection for angioplasty of chronic coronary total occlusions. Catheter Cardiovasc Interv 2003;58:194–198. 15. Hamburger J, Serruys PW, Scabra-Gomes R, et al. Recanalization of total coronary occlusions using a laser guide-wire (the European TOTAL surveillance study). Am J Cardiol 1997;80:1419–1423. 16. Hamburger JN, Gijsbers GHM, Ozaki Y, et al. Recanalization of chronic total coronary occlusions using a laser guide wire: A pilot study. J Am Coll Cardiol 1997;30:649–656. 17. Siegel RJ, Fishbein MC, Forrester J, et al. Ultrasound plaque ablation. A new method of recanalization of partially or totally occluded arteries. Circulation 1988;78:1443–1448. 18. Rosenscheim U, Bernstein JJ, Disegni E, Cumberland DC. Experimental ultrasound angioplasty: Disruption of atherosclerotic plaques and thrombi in vitro and arterial recanalization in vivo. J Am Coll Cardiol 1990;15:711–777. 19. Siegel RJ, Gunn J, Ahsan A, et al. Use of therapeutic ultrasound in percutaneous coronary angioplasty: Experimental in vitro studies and initial experience. Circulation 1994;89:1587–1592. 20. Cannon LA, John J, LaLonde J. Therapeutic ultrasound for chronic total coronary artery occlusions. Echocardiography 2001;18:219–223. 21. Siegel RJ, Gaines P, Crew JR, et al. Clinical trial of percutaneous peripheral ultrasound angioplasty. J Am Coll Cardiol 1993;22:480–488. 22. Michalis LK, Rees MR, Davis JAS, et al. Use of vibrational angioplasty for the treatment of chronic total coronary occlusions: Preliminary results. Catheter Cardiovasc Interv 1999;46:98–104.