- Email: [email protected]
Usefulness of intracoronary brachytherapy for in-stent restenosis with a 188Re liquid-filled balloon
Usefulness of Intracoronary Brachytherapy for In-Stent Restenosis With a 188Re Liquid-Filled Balloon Helmut Schu¨hlen, MD, Neal Eigler, MD, James S. Whiting, PhD, Roland Haubner, Jo ¨ rg Hausleiter, MD, Josef Dirschinger, MD, Adnan Kastrati, MD, Markus Schwaiger, MD, and Albert Scho ¨ mig, MD
I
n-stent restenosis is a dominant problem of interventional cardiology. There is growing evidence for the efficacy of intracoronary brachytherapy as preventive treatment. After initial clinical feasibility studies,1,2 randomized trials have shown efficacy for ␥radiation3–5 and -radiation.6 Recently, the feasibility and safety of -radiation with a rhenium-188-(188Re) liquid-filled balloon catheter has been shown.7,8 This modality requires only standard percutaneous transluminal coronary angioplasty (PTCA) techniques, and has a number of advantages9: a balloon is self-centering, and ensures a close contact of the -emitting source with the vessel wall. Furthermore, identical doses will be given to equidistant points from the lumen surface in the vessel wall independent of vessel size and morphology. This appears to be the optimal delivery of -radiation considering its fast radial dose decrease. The present study reports on the pilot phase of a randomized trial with a 188Re-liquid filled balloon designed to show the efficacy for the treatment of in-stent restenosis. •••
The system consists of a slightly modified monorail PTCA balloon, a standard inflation device and the Isolation and Transfer Device (ISAT) developed by Vascular Therapies (Menlo Park, California; division of United States Surgical Corporation, Norwalk, Connecticut) and previously described.10 Briefly, the ISAT’s primary purpose is to provide shielding for the 188 Re fluid, and to allow for safe transportation and handling. It contains a 2-sided syringe with 2 completely separated chambers. After the balloon catheter has been placed in the coronary artery, it is securely connected to the “hot” chamber of the ISAT containing the 188Re fluid. The other “cold” chamber containing a saline solution gets connected to the PTCA inflation device. By engaging the ISAT, 188Re fluid enters the balloon lumen, and pressurizing the PTCA inflation device will hydraulically push 188Re fluid from the ISAT into the catheter. Balloon inflation pressures are only 2.5 to 3 atm; higher pressures would set off a safety valve on the cold side of the device. Drawing vacuum on the inflation device deflates the balloon by reverse hydraulic movement. From the 1. Medizinische Klinik and the Nuklearmedizinische Klinik of the Klinikum rechts der Isar, Technische Universita¨t, Munich, Germany; and Cedars-Sinai Medical Center, Los Angeles, California. Dr. Schu¨hlen’s address is: Medizinische Klinik, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 Mu¨nchen, Germany. E-mail: [email protected]. Manuscript received June 30, 2000; revised manuscript received and accepted August 22, 2000. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 February 15, 2001
PhD,
The source is a liquid 188Re solution (NaReO4 in a normal saline). It is primarily a -emitter with a physical half-life of 17 hours and a maximum energy of 2.1 MeV. The source is produced daily in the nuclear lab by eluting a 188W/188Re generator.11 The effluent is concentrated to approximately 100 Ci/ml, calibrated, and loaded into the ISAT. Previous animal experiments with this device have determined an optimal dose response with 28 Gy (Gray) at 0.5 mm into the vessel wall.10 For the individual treatment protocol, the time of the elution, volume, and activity are entered into a computer worksheet.10 This generates a list of calculated treatment times for the next 12 hours for different balloon diameters (2 to 4 mm), constituting the individual treatment protocol. All patients had to have at least the second in-stent restenosis either with symptoms or a positive stress test. The target lesion of ⬎50% diameter stenosis had to be in a vessel of 2.0 to 4.0 mm in diameter; the maximum length was 30 mm to allow 5 mm safety margins on both ends (treatment balloon, diameter 2.0 to 4.0 mm; length 20 to 40 mm). For each protocol, we excluded patients with severe hematologic disorders, acute myocardial infarction ⬍72 hours ago, left ventricular ejection fraction ⬍30%, bifurcation lesions, unprotected left main disease, visible intracoronary thrombus, abrupt vessel closure during PTCA, a residual stenosis after PTCA of ⬎30%, or Thrombolysis In Myocardial Infarction flow ⱕ2, or patients who did not tolerate balloon inflations of ⬎1 minute without severe symptoms or a decrease in systolic blood pressure. All procedures were performed according to our current standard practice with 7Fr guide catheters. It was at the operator’s discretion to place additional stents or use glycoprotein IIb/IIIa inhibitors. Randomization to brachytherapy or no further treatment was performed after a successful result was achieved. Radiation treatment was begun to deliver the prescribed dose of 28 Gy at 0.5 mm into the vessel wall. Total treatment time as determined by the dosimetry work sheet was typically fractionated into inflations of 2-minute duration, with 1- to 2-minute pauses. During the procedure, routine x-ray protective measures were used, and radiation exposure at various distances and positions was measured continuously. To exclude potential undetected minor balloon leaks (without noticeable pressure loss), two 10-ml syringes of blood were obtained drawn (1 before and 1 after brachytherapy) and monitored for radioactive contamination. After treatment, the balloon catheter was withdrawn, placed in a shielded container without disconnecting it 0002-9149/01/$–see front matter PII S0002-9149(00)01406-5
463
TABLE 1 Baseline Clinical and Angiographic Characteristics
Men Mean age (yrs) Cardiovascular risk factors Hypercholesterolemia (⬎240 mg/dl) Active smokers Arterial hypertension Diabetes Target coronary vessel Left anterior descending Left circumflex Right Venous bypass graft No. of previous interventions No. of stents implanted at previous interventions
Radiation (n ⫽ 11)
No Radiation (n ⫽ 10)
8 65 ⫾ 13
6 66 ⫾ 10
11
8
6 10 2
4 9 4
Leiden, The Netherlands). At follow-up, analysis was extended to include the edges 5 mm proximal and distal to the radiated segment. Data were analyzed on an intention-to-treat basis. For comparison of the 2 groups, we used t tests for continuous variables, Fisher’s exact test for discrete variables, and a Kaplan-Meier method for survival analysis. Statistical significance was assumed at p ⬍0.05. •••
This study reports on patients enrolled in a trial initially planned to include 250 patients with in-stent 4 2 restenosis. This trial was terminated prematurely after 2 3 Vascular Therapies withdrew its support. Between 4 5 1 0 September 1998 and January 1999, 21 patients were 3.7 ⫾ 0.9 3.7 ⫾ 1.2 randomized, 11 to radiation and 10 to no further 4.0 ⫾ 2.1 2.6 ⫾ 1.4 therapy. There were no significant differences in patient characteristics (Table 1). During the initial PTCA, additional stent placement was performed in 4 patients randomized to radiation, and in none in the group TABLE 2 Quantitative Coronary Measurements without radiation. Glycoprotein IIb/ Radiation No Radiation IIIa inhibitors were administered in 4 (n ⫽ 11) (n ⫽ 10) p Value and 2 patients, respectively. In the 11 Measurements before coronary angioplasty patients randomized to radiation, Vessel size (mm) 3.09 ⫾ 0.35 2.91 ⫾ 0.41 0.29 brachytherapy of the prescribed dose Minimal lumen diameter (min) 0.35 ⫾ 0.26 0.36 ⫾ 0.30 0.92 was successfully delivered to 10 paDiameter stenosis (%) 89 ⫾ 9 87 ⫾ 12 0.71 tients. In 1 patient no radioactive Lesion length (mm) 13.3 ⫾ 7.3 14.6 ⫾ 7.4 0.71 Coronary angioplasty procedure fluid entered the balloon due to inNominal balloon size (mm) 3.14 ⫾ 0.50 3.15 ⫾ 0.53 0.95 correct handling of the ISAT. Total Balloon/vessel ratio 1.02 ⫾ 0.15 1.08 ⫾ 0.12 0.12 treatment time was 5:20 to 12:50 Maximum balloon pressure (atm) 14.9 ⫾ 3.0 14.1 ⫾ 2.9 0.51 minutes (mean 8:35 ⫾ 2:27). TreatFinal measurements after procedure Minimal lumen diameter (mm) 2.7 ⫾ 0.4 2.5 ⫾ 0.3 0.26 ment was fractionated in 8 patients. Diameter stenosis (%) 15 ⫾ 13 16 ⫾ 9 0.94 There were no significant differAcute lumen gain 2.30 ⫾ 0.42 2.10 ⫾ 0.41 0.29 ences in quantitative angiographic Measurements at follow-up measurements before PTCA and in Minimal lumen diameter (mm) 1.84 ⫾ 0.99 0.55 ⫾ 0.35 0.001 procedural data (Table 2). After 6 Diameter stenosis (%) 39 ⫾ 31 81 ⫾ 12 ⬍0.001 Late lumen loss (mm) 0.81 ⫾ 0.93 1.91 ⫾ 0.41 0.003 months, there were significant differLoss index 0.33 ⫾ 0.43 0.93 ⫾ 0.21 ⬍0.001 ences in all indexes of restenosis. All Restenosis rate (%) 18 100 ⬍0.001 10 patients without radiation had ⬎50% diameter stenosis compared with only 2 of 11 patients with radifrom the ISAT, and returned to the Department of ation (1 of these 2 patients had actually not received Nuclear Medicine. After 1 week of storage, 188Re brachytherapy; see above). No total occlusion was activity decayed to allow its disposal with regular seen in any patient, and no restenosis was seen at the borders of the treatment/irradiation zone (edge stenohospital waste. All patients received ticlopidine (500 mg/day) for 2 sis). All patients remained asymptomatic and free of weeks in addition to a continuous regimen with aspirin (200 mg/day). Ticlopidine treatment was extended to adverse cardiac events during the first month. With 4 weeks in case of additional stent placement. Patients repeat angiography scheduled after 6 months, 1 pawere contacted by telephone 1 and 12 months after the tient in the group with and 6 in the group without procedure; all were scheduled for a repeat angiogram brachytherapy returned earlier due to recurrent symptoms. Complete follow-up of 1 year is illustrated in after 6 months. The primary end point of the trial was angiographic Figure 1. All events were repeat PTCAs, and no late lumen loss at 6 months. Secondary end points deaths or myocardial infarctions occurred. After 1 were angiographic restenosis at 6 months, and major year, 8 of 11 patients with brachytherapy were event adverse cardiac events at 1 year (death, myocardial free versus 2 of 10 patients in the group without infarction, and repeat target vessel revascularization). brachytherapy (p ⫽ 0.045). All quantitative angiographic measurements were ••• obtained by off-line analysis with an automated edgeThe clinical feasibility and safety of -radiation detection system (Medis Medical Imaging Systems, with a 188Re liquid-filled balloon catheter has been 464 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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FEBRUARY 15, 2001
gested that the biologic processes leading to restenosis are partially delayed, with an increase in the rate of revascularization procedures beyond 6 months.4,20 In the period between the sixth and 12th month of our study, 1 patient in the radiation group underwent repeat PTCA, versus 3 patients in the group without radiation, providing no support for a delayed restenosis development. However, our patient cohort is too small to provide reliable data for these issues.
FIGURE 1. One-year clinical outcome.
demonstrated in previous studies.7,8 The present randomized trial adds to the evidence, that this modality as adjunct therapy to repeat PTCA of in-stent restenosis may significantly reduce the incidence of restenosis. In our study, brachytherapy reduced angiographic late lumen loss by approximately 60% and restenosis by approximately 80%. The trial, initially planned to include 250 patients, had to be stopped after the company, which had developed integral parts of the radiation delivery system, withdrew its support and discontinued all research activities with this system. The reason was unrelated to this trial. For safety concerns during the pilot phase of this initially planned large randomized trial, we had intentionally included only patients with at least the second in-stent restenosis. With a mean of 3.7 previous interventions, these patients were at very high risk for developing recurrent restenosis.12–16 This explains the high rates of restenosis in the group without radiation, as well as the high angiographic late lumen loss and loss index. However, this high risk of the study population has facilitated the discrimination of a statistical difference. There are several current issues of brachytherapy. There has been concern about the risk of late thrombotic occlusion (⬎30 days) due to delayed healing,17,18 which appears to be particularily high with additional stent placement.5 Although 4 of the 11 patients in the radiation group received additional stents in our study, we did not see any total occlusion after 6 months. A recognized limitation of vascular brachytherapy is the development of stenoses at the edges of the irradiated segment.19 The primary cause is assumed to be a mismatch of the length of the vessel segment injured by angioplasty and the length of the brachytherapy source. Our maximal source (i.e., balloon) length was 40 mm, and stenoses ⬎30 mm long were excluded from this trial. Therefore, we were able to avoid this “geographical miss,” and we did not see a particular narrowing at the edges that were included in our quantitative analyses. Other trials have sug-
In summary, these data provide further evidence that intracoronary brachytherapy can be safely administered with a 188Re liquid-filled balloon system. In this study of a high-risk group of 21 patients with multiple recurrent in-stent restenoses, a significant benefit was seen with respect to angiographic indexes of restenosis as well as the clinical course of 12 months.
1. King SB III, Williams DO, Chougule P, Klein JL, Waksman R, Hilstead R,
Macdonald J, Anderberg K, Crocker IR. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: results of the beta energy restenosis trial (BERT). Circulation 1998;97:2025–2030. 2. Condado JA, Waksman R, Gurdiel O, Espinosa R, Gonzalez J, Burger B, Villoria G, Acquatella H, Crocker IR, Seung KB, Liprie SF. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997;96:727– 732. 3. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheterbased radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697–1703. 4. Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 5. Leon MB, Moses JW, Lansky A, Wong SC, Nawaz DM, Whitlow PL, Fish DR, Kluck B, Gorgianni J, Kuntz RE, Teirstein PS. Intracoronary gamma radiation for the prevention of recurrent in-stent restenosis: final results from the Gamma-1 Trial. Circulation 1999;100(suppl I):I–75. 6. Waksman R, Bhargava B, White L, Chan RC, Mehran R, Lansky AJ, Mintz GS, Satler LF, Pichard AD, Leon MB, Kent KK. Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000;101:1895– 1898. 7. Ho¨her M, Wo¨hrle J, Wohlfrom M, Hanke H, Voisard R, Osterhues HH, Kochs M, Reske SN, Hombach V, Kotzerke J. Intracoronary beta-irradiation with a liquid (188)Re-filled balloon: six-month results from a clinical safety and feasibility study. Circulation 2000;101:2355–2360. 8. Makkar R, Whiting JS, Li A, Hausleiter J, Robinson A, Eigler NL. Intravascular brachytherapy with Rhenium-188 balloon: RADIANT pilot study (abstr). J Am Coll Cardiol 2000;35(suppl A):2A. 9. Weinberger J. Intracoronary radiation using radioisotope solution-filled balloons. Herz 1998;23:366 –372. 10. Makkar R, Whiting JS, Li A, Honda H, Fishbein MC, Knapp FF, Hausleiter J, Litvack F, Eigler NL. Effects of a beta-emitting liquid isotope (rhenium-188) filled balloon in stented porcine coronaries: an angiographic, intravascular ultrasound and histomorphometric follow-up study. Circulation 2000;102: in press. 11. Knapp FF, Guhlke S, Beets AL, Lin W, Stabin M, Amols H, Weinberger J. Endovascular beta irradiation for prevention of restenosis using solution radioisotopes: pharmacologic and dosimetric properties of rhenium-188 compounds. Cardiovasc Rad Med 1999;1:86 –97. 12. Teirstein PS, Hoover CA, Ligon RW, Giorgi LV, Rutherford BD, McConahay DR, Johnson WL, Hartzler GO. Repeat coronary angioplasty: efficacy of a third angioplasty for a second restenosis. J Am Coll Cardiol 1989;13:291–296. 13. Meier B, King SB, Gru¨ntzig AR, Douglas JS, Hollman J, Ischinger T, Galan K, Tankersley R. Repeat coronary angioplasty. J Am Coll Cardiol 1984;4:463– 466. 14. Kastrati A, Scho¨mig A, Elezi S, Schu¨hlen H, Dirschinger J, Hadamitzky M, Wehinger A, Hausleiter J, Walter H, Neumann FJ. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol 1997;30:1428 –1436. 15. Scho¨mig A, Kastrati A, Mudra H, Blasini R, Schu¨hlen H, Klauss V, Richardt G, Neumann FJ. Four-year experience with Palmaz-Schatz stenting in coronary angioplasty complicated by dissection with threatened or present vessel closure. Circulation 1994;90:2716 –2724. 16. Bossi I, Klersy C, Black AJ, Cortina R, Choussat R, Cassagneau B, Jordan C,
BRIEF REPORTS
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Laborde JC, Laurent JP, Bernies M, Fajadet J, Marco J. In-stent restenosis: long-term outcome and predictors of subsequent target lesion revascularization after repeat balloon angioplasty. J Am Coll Cardiol 2000;35:1569 –1576. 17. Costa MA, Sabat M, van der Giessen WJ, Kay IP, Cervinka P, Ligthart JM, Serrano P, Coen VL, Levendag PC, Serruys PW. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789 –792. 18. Waksman R. Late thrombosis after radiation. Sitting on a time bomb. Circulation 1999;100:780 –782.
19. Sabate M, Costa MA, Kozuma K, Kay IP, van Der Giessen WJ, Coen VL, Ligthart JM, Serrano P, Levendag PC, Serruys PW. Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation 2000;101:2467–2471. 20. Teirstein PS, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Cloutier DA, Leon MB, Tripuraneni P. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2000;101:360 –365.
Results and Significance of Holter Monitoring After Direct Percutaneous Transluminal Coronary Angioplasty for Acute Myocardial Infarction Joerg O. Schwab, MD, Heiko Schmitt, MD, Michael Coch, MD, Frank Bernhoeft, MD, Wolfgang Waas, MD, Tanja Raedle-Hurst, MD, Harald H. Tillmanns, MD, and Bernd Waldecker, MD esides intravenous fibrinolysis, direct percutaneous transluminal coronary angioplasty (PTCA) is B an effective method to reopen occluded coronary arteries in patients with acute myocardial infarction (AMI).1– 4 Because direct PTCA restores brisk coronary flow in ⬎85% of patients, early survival after AMI is favorable, and left ventricular function is well preserved in many patients.4,5 In the past, nonsustained ventricular tachycardia (VT) during Holter monitoring has been related to increased late mortality.6,7 However, the prognostic value of nonsustained VT was questioned6,8 after the advent of fibrinolysis. The incidence of nonsustained VT and its clinical significance is unknown in post-AMI patients who had direct PTCA (i.e., early and effective reperfusion in almost all cases). One might speculate that nonsustained VT might occur less frequently and/or that it would become a finding of minor clinical relevance. The impact of such a change not only on every day practice, but also on the design of secondary prevention trials, is obvious. Therefore, we prospectively and systematically evaluated the incidence of ventricular arrhythmias and the prognostic significance of Holter findings after direct PTCA for AMI in a cohort of 400 patients that was followed for a mean of 4 years. •••
The study was designed to perform Holter monitoring in all patients who underwent coronary angiography and direct PTCA within 12 hours after onset of AMI and survived the acute infarct phase for ⬎10 days. A total of 400 unselected consecutive patients were enrolled (Table 1). Holter monitoring was performed in all of the 400 patients 10 to 30 days after the index AMI. Thereafter, patients were followed. Three end points were predefined: (1) death from any cause, (2) cardiac death, and (3) arrhythmia morbidity, defined as sudden death, resuscitation from documented From Medizinische Klinik I, University of Giessen, Giessen, Germany. Dr. Schwab’s address is: Mediz. Klinik I, Justus-Liebig University Giessen, Klinikstr. 36, 35385 Giessen, Germany. E-mail: joerg.o.schwab @med.uni-giessen.de. Manuscript received May 22, 2000; revised manuscript received and accepted August 29, 2000.
466
©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 February 15, 2001
ventricular fibrillation, or development of sustained VT. Diagnosis of AMI required the presence of typical chest pain and diagnostic ST-segment elevation in patients with supraventricular arrrhythmias and no left bundle branch block. The clinical presentation was decisive in patients with other arrhythmias or conduction defects. Diagnosis of AMI currently prompts treatment with intravenous heparin, acetylsalicylic acid (500 mg), and  blockers, if not contraindicated. Thereafter, all patients routinely undergo angiography at our institution and direct PTCA (if Thrombolysis In Myocardial Infarction [TIMI] grade flow is ⬍39 in the infarct-related artery). Direct PTCA is considered successful if the occluded vessel can be reopened and the residual stenosis is reduced to ⱕ50%. All 400 patients or the closest relatives gave informed consent to this invasive approach. Hospital care followed recent guidelines until discharge.10 Left ventricular function was assessed 10 to 30 days after the index AMI. It was determined angiographically in 176 patients and echocardiographically in 193 patients. Beta-blocker medication was given to 296 of 400 patients (74%) and angiotensin-converting enzyme inhibitors to 225 of 400 patients (56%) at the time of discharge. Antiarrhythmic medication was used in 4 patients: amiodarone to control recurrent atrial fibrillation (2 patients) and sotalol to suppress inducible VT (2 patients). The Reynolds Pathfinder (Nuernberg, Germany) as well as the Oxford Excel 2 systems (Wiesbaden, Germany) were used to record ventricular ectopy over 24 hours between days 10 and 30 after the index AMI. The patient‘s arrhythmia status during Holter monitoring was classified according to Lown’s classification.11 Patients who had long runs (⬎10 cycles) of nonsustained VT at a rate ⬎140 beats/min underwent invasive electrophysiologic testing (17 patients). If no sustained monomorphic VT was inducible, these patients (n ⫽ 13), along with all other patients, were discharged without specific antiarrhythmic drugs. Otherwise, antiarrhythmic therapy was individually tailored: an implantable cardioverter defibrillator was 0002-9149/01/$–see front matter PII S0002-9149(00)01407-7
I
n-stent restenosis is a dominant problem of interventional cardiology. There is growing evidence for the efficacy of intracoronary brachytherapy as preventive treatment. After initial clinical feasibility studies,1,2 randomized trials have shown efficacy for ␥radiation3–5 and -radiation.6 Recently, the feasibility and safety of -radiation with a rhenium-188-(188Re) liquid-filled balloon catheter has been shown.7,8 This modality requires only standard percutaneous transluminal coronary angioplasty (PTCA) techniques, and has a number of advantages9: a balloon is self-centering, and ensures a close contact of the -emitting source with the vessel wall. Furthermore, identical doses will be given to equidistant points from the lumen surface in the vessel wall independent of vessel size and morphology. This appears to be the optimal delivery of -radiation considering its fast radial dose decrease. The present study reports on the pilot phase of a randomized trial with a 188Re-liquid filled balloon designed to show the efficacy for the treatment of in-stent restenosis. •••
The system consists of a slightly modified monorail PTCA balloon, a standard inflation device and the Isolation and Transfer Device (ISAT) developed by Vascular Therapies (Menlo Park, California; division of United States Surgical Corporation, Norwalk, Connecticut) and previously described.10 Briefly, the ISAT’s primary purpose is to provide shielding for the 188 Re fluid, and to allow for safe transportation and handling. It contains a 2-sided syringe with 2 completely separated chambers. After the balloon catheter has been placed in the coronary artery, it is securely connected to the “hot” chamber of the ISAT containing the 188Re fluid. The other “cold” chamber containing a saline solution gets connected to the PTCA inflation device. By engaging the ISAT, 188Re fluid enters the balloon lumen, and pressurizing the PTCA inflation device will hydraulically push 188Re fluid from the ISAT into the catheter. Balloon inflation pressures are only 2.5 to 3 atm; higher pressures would set off a safety valve on the cold side of the device. Drawing vacuum on the inflation device deflates the balloon by reverse hydraulic movement. From the 1. Medizinische Klinik and the Nuklearmedizinische Klinik of the Klinikum rechts der Isar, Technische Universita¨t, Munich, Germany; and Cedars-Sinai Medical Center, Los Angeles, California. Dr. Schu¨hlen’s address is: Medizinische Klinik, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 Mu¨nchen, Germany. E-mail: [email protected]. Manuscript received June 30, 2000; revised manuscript received and accepted August 22, 2000. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 February 15, 2001
PhD,
The source is a liquid 188Re solution (NaReO4 in a normal saline). It is primarily a -emitter with a physical half-life of 17 hours and a maximum energy of 2.1 MeV. The source is produced daily in the nuclear lab by eluting a 188W/188Re generator.11 The effluent is concentrated to approximately 100 Ci/ml, calibrated, and loaded into the ISAT. Previous animal experiments with this device have determined an optimal dose response with 28 Gy (Gray) at 0.5 mm into the vessel wall.10 For the individual treatment protocol, the time of the elution, volume, and activity are entered into a computer worksheet.10 This generates a list of calculated treatment times for the next 12 hours for different balloon diameters (2 to 4 mm), constituting the individual treatment protocol. All patients had to have at least the second in-stent restenosis either with symptoms or a positive stress test. The target lesion of ⬎50% diameter stenosis had to be in a vessel of 2.0 to 4.0 mm in diameter; the maximum length was 30 mm to allow 5 mm safety margins on both ends (treatment balloon, diameter 2.0 to 4.0 mm; length 20 to 40 mm). For each protocol, we excluded patients with severe hematologic disorders, acute myocardial infarction ⬍72 hours ago, left ventricular ejection fraction ⬍30%, bifurcation lesions, unprotected left main disease, visible intracoronary thrombus, abrupt vessel closure during PTCA, a residual stenosis after PTCA of ⬎30%, or Thrombolysis In Myocardial Infarction flow ⱕ2, or patients who did not tolerate balloon inflations of ⬎1 minute without severe symptoms or a decrease in systolic blood pressure. All procedures were performed according to our current standard practice with 7Fr guide catheters. It was at the operator’s discretion to place additional stents or use glycoprotein IIb/IIIa inhibitors. Randomization to brachytherapy or no further treatment was performed after a successful result was achieved. Radiation treatment was begun to deliver the prescribed dose of 28 Gy at 0.5 mm into the vessel wall. Total treatment time as determined by the dosimetry work sheet was typically fractionated into inflations of 2-minute duration, with 1- to 2-minute pauses. During the procedure, routine x-ray protective measures were used, and radiation exposure at various distances and positions was measured continuously. To exclude potential undetected minor balloon leaks (without noticeable pressure loss), two 10-ml syringes of blood were obtained drawn (1 before and 1 after brachytherapy) and monitored for radioactive contamination. After treatment, the balloon catheter was withdrawn, placed in a shielded container without disconnecting it 0002-9149/01/$–see front matter PII S0002-9149(00)01406-5
463
TABLE 1 Baseline Clinical and Angiographic Characteristics
Men Mean age (yrs) Cardiovascular risk factors Hypercholesterolemia (⬎240 mg/dl) Active smokers Arterial hypertension Diabetes Target coronary vessel Left anterior descending Left circumflex Right Venous bypass graft No. of previous interventions No. of stents implanted at previous interventions
Radiation (n ⫽ 11)
No Radiation (n ⫽ 10)
8 65 ⫾ 13
6 66 ⫾ 10
11
8
6 10 2
4 9 4
Leiden, The Netherlands). At follow-up, analysis was extended to include the edges 5 mm proximal and distal to the radiated segment. Data were analyzed on an intention-to-treat basis. For comparison of the 2 groups, we used t tests for continuous variables, Fisher’s exact test for discrete variables, and a Kaplan-Meier method for survival analysis. Statistical significance was assumed at p ⬍0.05. •••
This study reports on patients enrolled in a trial initially planned to include 250 patients with in-stent 4 2 restenosis. This trial was terminated prematurely after 2 3 Vascular Therapies withdrew its support. Between 4 5 1 0 September 1998 and January 1999, 21 patients were 3.7 ⫾ 0.9 3.7 ⫾ 1.2 randomized, 11 to radiation and 10 to no further 4.0 ⫾ 2.1 2.6 ⫾ 1.4 therapy. There were no significant differences in patient characteristics (Table 1). During the initial PTCA, additional stent placement was performed in 4 patients randomized to radiation, and in none in the group TABLE 2 Quantitative Coronary Measurements without radiation. Glycoprotein IIb/ Radiation No Radiation IIIa inhibitors were administered in 4 (n ⫽ 11) (n ⫽ 10) p Value and 2 patients, respectively. In the 11 Measurements before coronary angioplasty patients randomized to radiation, Vessel size (mm) 3.09 ⫾ 0.35 2.91 ⫾ 0.41 0.29 brachytherapy of the prescribed dose Minimal lumen diameter (min) 0.35 ⫾ 0.26 0.36 ⫾ 0.30 0.92 was successfully delivered to 10 paDiameter stenosis (%) 89 ⫾ 9 87 ⫾ 12 0.71 tients. In 1 patient no radioactive Lesion length (mm) 13.3 ⫾ 7.3 14.6 ⫾ 7.4 0.71 Coronary angioplasty procedure fluid entered the balloon due to inNominal balloon size (mm) 3.14 ⫾ 0.50 3.15 ⫾ 0.53 0.95 correct handling of the ISAT. Total Balloon/vessel ratio 1.02 ⫾ 0.15 1.08 ⫾ 0.12 0.12 treatment time was 5:20 to 12:50 Maximum balloon pressure (atm) 14.9 ⫾ 3.0 14.1 ⫾ 2.9 0.51 minutes (mean 8:35 ⫾ 2:27). TreatFinal measurements after procedure Minimal lumen diameter (mm) 2.7 ⫾ 0.4 2.5 ⫾ 0.3 0.26 ment was fractionated in 8 patients. Diameter stenosis (%) 15 ⫾ 13 16 ⫾ 9 0.94 There were no significant differAcute lumen gain 2.30 ⫾ 0.42 2.10 ⫾ 0.41 0.29 ences in quantitative angiographic Measurements at follow-up measurements before PTCA and in Minimal lumen diameter (mm) 1.84 ⫾ 0.99 0.55 ⫾ 0.35 0.001 procedural data (Table 2). After 6 Diameter stenosis (%) 39 ⫾ 31 81 ⫾ 12 ⬍0.001 Late lumen loss (mm) 0.81 ⫾ 0.93 1.91 ⫾ 0.41 0.003 months, there were significant differLoss index 0.33 ⫾ 0.43 0.93 ⫾ 0.21 ⬍0.001 ences in all indexes of restenosis. All Restenosis rate (%) 18 100 ⬍0.001 10 patients without radiation had ⬎50% diameter stenosis compared with only 2 of 11 patients with radifrom the ISAT, and returned to the Department of ation (1 of these 2 patients had actually not received Nuclear Medicine. After 1 week of storage, 188Re brachytherapy; see above). No total occlusion was activity decayed to allow its disposal with regular seen in any patient, and no restenosis was seen at the borders of the treatment/irradiation zone (edge stenohospital waste. All patients received ticlopidine (500 mg/day) for 2 sis). All patients remained asymptomatic and free of weeks in addition to a continuous regimen with aspirin (200 mg/day). Ticlopidine treatment was extended to adverse cardiac events during the first month. With 4 weeks in case of additional stent placement. Patients repeat angiography scheduled after 6 months, 1 pawere contacted by telephone 1 and 12 months after the tient in the group with and 6 in the group without procedure; all were scheduled for a repeat angiogram brachytherapy returned earlier due to recurrent symptoms. Complete follow-up of 1 year is illustrated in after 6 months. The primary end point of the trial was angiographic Figure 1. All events were repeat PTCAs, and no late lumen loss at 6 months. Secondary end points deaths or myocardial infarctions occurred. After 1 were angiographic restenosis at 6 months, and major year, 8 of 11 patients with brachytherapy were event adverse cardiac events at 1 year (death, myocardial free versus 2 of 10 patients in the group without infarction, and repeat target vessel revascularization). brachytherapy (p ⫽ 0.045). All quantitative angiographic measurements were ••• obtained by off-line analysis with an automated edgeThe clinical feasibility and safety of -radiation detection system (Medis Medical Imaging Systems, with a 188Re liquid-filled balloon catheter has been 464 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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gested that the biologic processes leading to restenosis are partially delayed, with an increase in the rate of revascularization procedures beyond 6 months.4,20 In the period between the sixth and 12th month of our study, 1 patient in the radiation group underwent repeat PTCA, versus 3 patients in the group without radiation, providing no support for a delayed restenosis development. However, our patient cohort is too small to provide reliable data for these issues.
FIGURE 1. One-year clinical outcome.
demonstrated in previous studies.7,8 The present randomized trial adds to the evidence, that this modality as adjunct therapy to repeat PTCA of in-stent restenosis may significantly reduce the incidence of restenosis. In our study, brachytherapy reduced angiographic late lumen loss by approximately 60% and restenosis by approximately 80%. The trial, initially planned to include 250 patients, had to be stopped after the company, which had developed integral parts of the radiation delivery system, withdrew its support and discontinued all research activities with this system. The reason was unrelated to this trial. For safety concerns during the pilot phase of this initially planned large randomized trial, we had intentionally included only patients with at least the second in-stent restenosis. With a mean of 3.7 previous interventions, these patients were at very high risk for developing recurrent restenosis.12–16 This explains the high rates of restenosis in the group without radiation, as well as the high angiographic late lumen loss and loss index. However, this high risk of the study population has facilitated the discrimination of a statistical difference. There are several current issues of brachytherapy. There has been concern about the risk of late thrombotic occlusion (⬎30 days) due to delayed healing,17,18 which appears to be particularily high with additional stent placement.5 Although 4 of the 11 patients in the radiation group received additional stents in our study, we did not see any total occlusion after 6 months. A recognized limitation of vascular brachytherapy is the development of stenoses at the edges of the irradiated segment.19 The primary cause is assumed to be a mismatch of the length of the vessel segment injured by angioplasty and the length of the brachytherapy source. Our maximal source (i.e., balloon) length was 40 mm, and stenoses ⬎30 mm long were excluded from this trial. Therefore, we were able to avoid this “geographical miss,” and we did not see a particular narrowing at the edges that were included in our quantitative analyses. Other trials have sug-
In summary, these data provide further evidence that intracoronary brachytherapy can be safely administered with a 188Re liquid-filled balloon system. In this study of a high-risk group of 21 patients with multiple recurrent in-stent restenoses, a significant benefit was seen with respect to angiographic indexes of restenosis as well as the clinical course of 12 months.
1. King SB III, Williams DO, Chougule P, Klein JL, Waksman R, Hilstead R,
Macdonald J, Anderberg K, Crocker IR. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: results of the beta energy restenosis trial (BERT). Circulation 1998;97:2025–2030. 2. Condado JA, Waksman R, Gurdiel O, Espinosa R, Gonzalez J, Burger B, Villoria G, Acquatella H, Crocker IR, Seung KB, Liprie SF. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997;96:727– 732. 3. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheterbased radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697–1703. 4. Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 5. Leon MB, Moses JW, Lansky A, Wong SC, Nawaz DM, Whitlow PL, Fish DR, Kluck B, Gorgianni J, Kuntz RE, Teirstein PS. Intracoronary gamma radiation for the prevention of recurrent in-stent restenosis: final results from the Gamma-1 Trial. Circulation 1999;100(suppl I):I–75. 6. Waksman R, Bhargava B, White L, Chan RC, Mehran R, Lansky AJ, Mintz GS, Satler LF, Pichard AD, Leon MB, Kent KK. Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000;101:1895– 1898. 7. Ho¨her M, Wo¨hrle J, Wohlfrom M, Hanke H, Voisard R, Osterhues HH, Kochs M, Reske SN, Hombach V, Kotzerke J. Intracoronary beta-irradiation with a liquid (188)Re-filled balloon: six-month results from a clinical safety and feasibility study. Circulation 2000;101:2355–2360. 8. Makkar R, Whiting JS, Li A, Hausleiter J, Robinson A, Eigler NL. Intravascular brachytherapy with Rhenium-188 balloon: RADIANT pilot study (abstr). J Am Coll Cardiol 2000;35(suppl A):2A. 9. Weinberger J. Intracoronary radiation using radioisotope solution-filled balloons. Herz 1998;23:366 –372. 10. Makkar R, Whiting JS, Li A, Honda H, Fishbein MC, Knapp FF, Hausleiter J, Litvack F, Eigler NL. Effects of a beta-emitting liquid isotope (rhenium-188) filled balloon in stented porcine coronaries: an angiographic, intravascular ultrasound and histomorphometric follow-up study. Circulation 2000;102: in press. 11. Knapp FF, Guhlke S, Beets AL, Lin W, Stabin M, Amols H, Weinberger J. Endovascular beta irradiation for prevention of restenosis using solution radioisotopes: pharmacologic and dosimetric properties of rhenium-188 compounds. Cardiovasc Rad Med 1999;1:86 –97. 12. Teirstein PS, Hoover CA, Ligon RW, Giorgi LV, Rutherford BD, McConahay DR, Johnson WL, Hartzler GO. Repeat coronary angioplasty: efficacy of a third angioplasty for a second restenosis. J Am Coll Cardiol 1989;13:291–296. 13. Meier B, King SB, Gru¨ntzig AR, Douglas JS, Hollman J, Ischinger T, Galan K, Tankersley R. Repeat coronary angioplasty. J Am Coll Cardiol 1984;4:463– 466. 14. Kastrati A, Scho¨mig A, Elezi S, Schu¨hlen H, Dirschinger J, Hadamitzky M, Wehinger A, Hausleiter J, Walter H, Neumann FJ. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol 1997;30:1428 –1436. 15. Scho¨mig A, Kastrati A, Mudra H, Blasini R, Schu¨hlen H, Klauss V, Richardt G, Neumann FJ. Four-year experience with Palmaz-Schatz stenting in coronary angioplasty complicated by dissection with threatened or present vessel closure. Circulation 1994;90:2716 –2724. 16. Bossi I, Klersy C, Black AJ, Cortina R, Choussat R, Cassagneau B, Jordan C,
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Laborde JC, Laurent JP, Bernies M, Fajadet J, Marco J. In-stent restenosis: long-term outcome and predictors of subsequent target lesion revascularization after repeat balloon angioplasty. J Am Coll Cardiol 2000;35:1569 –1576. 17. Costa MA, Sabat M, van der Giessen WJ, Kay IP, Cervinka P, Ligthart JM, Serrano P, Coen VL, Levendag PC, Serruys PW. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789 –792. 18. Waksman R. Late thrombosis after radiation. Sitting on a time bomb. Circulation 1999;100:780 –782.
19. Sabate M, Costa MA, Kozuma K, Kay IP, van Der Giessen WJ, Coen VL, Ligthart JM, Serrano P, Levendag PC, Serruys PW. Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation 2000;101:2467–2471. 20. Teirstein PS, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Cloutier DA, Leon MB, Tripuraneni P. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2000;101:360 –365.
Results and Significance of Holter Monitoring After Direct Percutaneous Transluminal Coronary Angioplasty for Acute Myocardial Infarction Joerg O. Schwab, MD, Heiko Schmitt, MD, Michael Coch, MD, Frank Bernhoeft, MD, Wolfgang Waas, MD, Tanja Raedle-Hurst, MD, Harald H. Tillmanns, MD, and Bernd Waldecker, MD esides intravenous fibrinolysis, direct percutaneous transluminal coronary angioplasty (PTCA) is B an effective method to reopen occluded coronary arteries in patients with acute myocardial infarction (AMI).1– 4 Because direct PTCA restores brisk coronary flow in ⬎85% of patients, early survival after AMI is favorable, and left ventricular function is well preserved in many patients.4,5 In the past, nonsustained ventricular tachycardia (VT) during Holter monitoring has been related to increased late mortality.6,7 However, the prognostic value of nonsustained VT was questioned6,8 after the advent of fibrinolysis. The incidence of nonsustained VT and its clinical significance is unknown in post-AMI patients who had direct PTCA (i.e., early and effective reperfusion in almost all cases). One might speculate that nonsustained VT might occur less frequently and/or that it would become a finding of minor clinical relevance. The impact of such a change not only on every day practice, but also on the design of secondary prevention trials, is obvious. Therefore, we prospectively and systematically evaluated the incidence of ventricular arrhythmias and the prognostic significance of Holter findings after direct PTCA for AMI in a cohort of 400 patients that was followed for a mean of 4 years. •••
The study was designed to perform Holter monitoring in all patients who underwent coronary angiography and direct PTCA within 12 hours after onset of AMI and survived the acute infarct phase for ⬎10 days. A total of 400 unselected consecutive patients were enrolled (Table 1). Holter monitoring was performed in all of the 400 patients 10 to 30 days after the index AMI. Thereafter, patients were followed. Three end points were predefined: (1) death from any cause, (2) cardiac death, and (3) arrhythmia morbidity, defined as sudden death, resuscitation from documented From Medizinische Klinik I, University of Giessen, Giessen, Germany. Dr. Schwab’s address is: Mediz. Klinik I, Justus-Liebig University Giessen, Klinikstr. 36, 35385 Giessen, Germany. E-mail: joerg.o.schwab @med.uni-giessen.de. Manuscript received May 22, 2000; revised manuscript received and accepted August 29, 2000.
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ventricular fibrillation, or development of sustained VT. Diagnosis of AMI required the presence of typical chest pain and diagnostic ST-segment elevation in patients with supraventricular arrrhythmias and no left bundle branch block. The clinical presentation was decisive in patients with other arrhythmias or conduction defects. Diagnosis of AMI currently prompts treatment with intravenous heparin, acetylsalicylic acid (500 mg), and  blockers, if not contraindicated. Thereafter, all patients routinely undergo angiography at our institution and direct PTCA (if Thrombolysis In Myocardial Infarction [TIMI] grade flow is ⬍39 in the infarct-related artery). Direct PTCA is considered successful if the occluded vessel can be reopened and the residual stenosis is reduced to ⱕ50%. All 400 patients or the closest relatives gave informed consent to this invasive approach. Hospital care followed recent guidelines until discharge.10 Left ventricular function was assessed 10 to 30 days after the index AMI. It was determined angiographically in 176 patients and echocardiographically in 193 patients. Beta-blocker medication was given to 296 of 400 patients (74%) and angiotensin-converting enzyme inhibitors to 225 of 400 patients (56%) at the time of discharge. Antiarrhythmic medication was used in 4 patients: amiodarone to control recurrent atrial fibrillation (2 patients) and sotalol to suppress inducible VT (2 patients). The Reynolds Pathfinder (Nuernberg, Germany) as well as the Oxford Excel 2 systems (Wiesbaden, Germany) were used to record ventricular ectopy over 24 hours between days 10 and 30 after the index AMI. The patient‘s arrhythmia status during Holter monitoring was classified according to Lown’s classification.11 Patients who had long runs (⬎10 cycles) of nonsustained VT at a rate ⬎140 beats/min underwent invasive electrophysiologic testing (17 patients). If no sustained monomorphic VT was inducible, these patients (n ⫽ 13), along with all other patients, were discharged without specific antiarrhythmic drugs. Otherwise, antiarrhythmic therapy was individually tailored: an implantable cardioverter defibrillator was 0002-9149/01/$–see front matter PII S0002-9149(00)01407-7