- Email: [email protected]
Serial volumetric intravascular ultrasound analysis of the efficacy of beta irradiation in preventing recurrent in-stent restenosis
Serial Volumetric Intravascular Ultrasound Analysis of the Efficacy of Beta Irradiation in Preventing Recurrent In-Stent Restenosis Balram Bhargava, MD, DM, Gary S. Mintz, MD, Roxana Mehran, MD, Alexandra J. Lansky, MD, Neil J. Weissman, MD, Carol Walsh, RCVT, Rosanna C. Chan, PhD, and Ron Waksman, MD tents have been shown to reduce restenosis; however, in-stent restenosis has become a major clinS ical problem. Intracoronary irradiation (brachyther1,2
apy) is a promising approach to prevent or treat restenosis.3–5 Animal studies have shown reduction in neointima formation both with ␥ and  radiation.6 –10 In randomized clinical trials, ␥ radiation has been shown to reduce recurrent in-stent restenosis,4,11,12 but the safety, handling, and prolonged dwell times with ␥ sources are considered practical limitations. On the other hand,  emitters are less penetrating, have shorter dwell times, cause less exposure to patients and personnel, and require less shielding. Although limited preclinical studies found  emitters to be efficacious,9,10 the preliminary clinical results were not conclusive.13,14 The rapid falloff of the radial dose, low penetration, and potential problem of shielding of  radiation by stents are concerns, especially for the treatment for in-stent restenosis.15 The present study uses serial (postintervention and follow-up) volumetric intravascular ultrasound (IVUS) analysis to assess the efficacy of  irradiation in preventing recurrent in-stent restenosis. •••
The study population consisted of 3 groups of patients (1 group treated with  irradiation, 1 treated with ␥ irradiation, and 1 group of controls) who presented with native coronary artery in-stent restenosis and who, after giving informed consent, were enrolled into 1 of 2 institutional review board-approved brachytherapy trials at the Washington Hospital Center. Twenty-five patients from the -Washington Radiation for InStent restenosis Trial (with  emitters), an open-label registry in which all patients received radiation, were compared with 75 patients from the Washington Radiation for InStent restenosis Trial, in which patients were randomized to ␥ irradiation (n ⫽ 36) versus placebo (n ⫽ 39). This represents all of the patients in these 2 trials who had complete postintervention and follow-up IVUS. The Washington Radiation for InStent restenosis Trial with  emitters enrolled 50 patients, and there were 100 patients in the From the Intravascular Ultrasound Imaging and Cardiac Catheterization Laboratories, Washington Hospital Center, Washington, DC. This study was supported by a grant from the Cardiovascular Research Foundation, Washington, DC. Dr. Mintz’s address is: 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010. E-mail: [email protected]. Manuscript received September 17, 1999; revised manuscript received and accepted October 1, 1999. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 March 1, 2000
Washington Radiation for InStent restenosis Trial with native artery in-stent restenosis. Primary treatment strategy was at the discretion of the operator: percutaneous transluminal coronary angioplasty, rotational atherectomy (SCIMED/Boston Scientific Corporation, Nattick, Massachusetts), excimer laser coronary angioplasty (Spectranetics, Colorado Springs, Colorado), implantation of additional stents, or any combination of these. After obtaining a good primary result, patients received either openlabel  irradiation or were randomized to ␥ irradiation versus placebo. In the  registry the source was a yttrium-90 (90Y) wire that was inserted automatically by the BETAMED Intracoronary Radiation System (Boston Scientific Corporation) afterloader into a segmented-centering balloon delivery catheter positioned at the treatment site. The prescribed dose was 20.6 Gy at 1 mm from the surface of the balloon. In the ␥ study, patients were randomized to either placebo or ribbon with active iridium-192 (192Ir) seeds (Best Industries, Springfield, Virginia). The ribbon was handdelivered into a noncentered closed-end lumen catheter (Medtronic Corporation, Minneapolis, Minnesota) that was positioned at the treatment site. The prescribed dose was 15 Gy at 2 mm from the center of the source. Cine fluoroscopy was used to verify catheter and source position to cover the angioplasty site for both systems. All IVUS studies were performed after administration of 200 g of intracoronary nitroglycerin. The actual interval between the postintervention and 6-month follow-up IVUS studies was 184 ⫾ 24 days for the 90Y group, 188 ⫾ 59 days for the 192Ir group, and 151 ⫾ 71 days for the placebo group. Studies were performed using a single-element 30-MHz transducer rotating at 1,800 rpm and withdrawn automatically at 0.5 mm/s within a 3.2Fr short monorail stationary imaging catheter (Boston Scientific Corporation, San Jose, California). The IVUS catheter was advanced 10 mm distal to the lesion, the motorized transducer pullback started, and a complete imaging run performed to the aorto-ostial junction. Studies were recorded on 0.5-inch high-resolution s-VHS tapes for off-line analysis. Using computerized planimetry (Tape Measure or Echoplaque, Indec Systems, Mountain View, California) and previously reported methods, planar and volumetric IVUS analysis was performed by those blinded to the treatment arms. The uses of automatic transducer pullback to measure lesion length, reproducibility of IVUS in studying stented lesions, and IVUS measurement of in-stent 0002-9149/00/$–see front matter PII S0002-9149(99)00827-9
651
192
Yttrium-90
Placebo
Iridium-192
p Value
Ir groups, but was greater in 90Y versus placebo (p ⫽ 0.0008) and 192 Ir versus placebo (p ⬍0.0001).
26 ⫾ 8
29 ⫾ 11
28 ⫾ 12
0.52
•••
TABLE I Intravascular Ultrasound Analysis
In-stent restenosis length (mm) After intervention Minimum lumen area (mm2) Stent volume (mm3) Lumen volume (mm3) Intimal hyperplasia volume (mm3) 6-month follow-up Minimum lumen area (mm2) Stent volume (mm3) Lumen volume (mm3) Intimal hyperplasia volume (mm3) ⌬ Minimum lumen area (mm2) Stent volume (mm3) Lumen volume (mm3) Intimal hyperplasia volume (mm3)
Volumetric IVUS analysis in the 5.5 ⫾ 1.3 4.5 ⫾ 2.1 4.9 ⫾ 1.8 0.084 present study indicates that  radia291 ⫾ 127 277 ⫾ 166 284 ⫾ 168 0.94 tion at appropriate doses has a simi189 ⫾ 83 174 ⫾ 135 186 ⫾ 100 0.85 lar efficacy as ␥ radiation for pre102 ⫾ 53 103 ⫾ 72 97 ⫾ 82 0.94 venting recurrent in-stent neointimal tissue accumulation. In 3 previously 4.5 ⫾ 2.2 2.5 ⫾ 1.4 4.1 ⫾ 2.1 ⬍0.0001 published or presented randomized 283 ⫾ 126 275 ⫾ 165 279 ⫾ 168 0.98 studies, ␥ radiation (using 192Ir) has 165 ⫾ 105 117 ⫾ 105 173 ⫾ 106 0.0447 been shown to reduce recurrent in118 ⫾ 61 158 ⫾ 91 106 ⫾ 84 0.0193 stent restenosis.5,11,12 All 3 had serial volumetric IVUS analysis. The mag⫺1.0 ⫾ 1.4 ⫺2.0 ⫾ 1.8 ⫺0.8 ⫾ 1.7 0.0066 nitude of reduction in intimal hyper⫺8 ⫾ 15 ⫺2 ⫾ 18 ⫺5 ⫾ 14 0.31 plasia volume increase after  radia⫺24 ⫾ 25 ⫺57 ⫾ 54 ⫺14 ⫾ 41 0.0001 tion in the present study is similar to 16 ⫾ 30 55 ⫾ 55 9 ⫾ 38 ⬍0.0001 these previous reports. Stenting induces more neointima ⌬ ⫽ change. than balloon angioplasty. In porcine coronary artery models, 192Ir and 90Y radiation causes a significant (and neointimal hyperplasia volumes have all been report- similar) reduction in neointima after balloon injury or ed.16 –19 The in-stent restenosis lesion was the length stent implantation.6 –10 The present study extends of the stent where intimal hyperplasia occupied ⬎75% these studies to in-stent restenosis in humans. Beta of the stent area or was packed around the IVUS particles have limited penetration in tissue and deliver catheter on the preintervention IVUS study. a significantly lower dose beyond the prescription Statistical analysis was performed using StatView point (compared with ␥ emitters); thus, dosing and 4.5 (SAS Institute, Cary, North Carolina). Data are centering become more important. Absorption and presented as mean ⫾ 1SD. Continuous variables were scattering by stent struts (shielding effect) were recompared using paired t test or factorial analysis of ported with up to 15% attenuation by stent struts.19 variance with post hoc comparisons using Fisher’s The prescription dose in the  registry was chosen to protected least-significant difference. A p value ⬍0.05 be about 20% higher than the one used in the ␥ study was considered significant. based on the different properties of the  emitter IVUS results are listed in Table I. In-stent resteno- including the shielding effects of the stent. This dose sis length and postintervention stent, lumen, and inti- selection was supported by preclinical studies in the mal hyperplasia volumes and the postintervention porcine model, which showed complete inhibition of minimum lumen area were similar in the 3 groups. neointima formation whether Y90 was administered During the follow-up period, there was a decrease in before or after stenting.20 lumen dimensions in all 3 groups—90Y, 192Ir, and This study is a post hoc comparison of patients placebo: p ⬍0.0001, p ⬍0.0001, and p ⫽ 0.0534 for from 2 separate brachytherapy trials; patients were not lumen volumes and p ⫽ 0.0022, p ⬍0.0001, and p ⫽ randomized to  versus ␥ radiation versus placebo. 0.0105 for minimum lumen area, respectively. Thus, there was not a true control for the -irradiation At follow-up, minimum lumen area was similar in group. The statistical comparison should be interboth the 90Y versus 192Ir groups, but larger in 90Y preted in this light. The current analysis does not versus placebo (p ⬍0.0001) and 192Ir versus placebo include all of the patients in these 2 trials, only those (p ⫽ 0.0003). Lumen volume was similar in both the 90Y with complete (postintervention and follow-up) IVUS. versus 192Ir groups, but larger in 90Y versus placebo This is not a true comparison of  versus ␥ because of (p ⫽ 0.0712) and 192Ir versus placebo (p ⫽ 0.0195). differences in dose, centering, and length of the The intimal hyperplasia volume was similar in source; the shorter length of the  source required both the 90Y versus 192Ir groups, but smaller in 90Y stepping and resulted in small regions of overlap. The versus placebo (p ⫽ 0.0608) and 192Ir versus placebo present study did not assess plaque composition (i.e., calcium), stent overlap, and different stent designs that (p ⫽ 0.0069). The decrease in minimum lumen area was similar might attenuate the -irradiation dose delivered to the in both the 90Y versus 192Ir groups, but smaller in 90Y adventitia. The current IVUS analysis was confined to versus placebo (p ⫽ 0.0222) and 192Ir versus placebo the axial length of the stent. Therefore, it did not (p ⫽ 0.0029). The decrease in lumen volume was assess the edge effect of either  or ␥ irradiation; this similar in both the 90Y versus 192Ir groups, but was is an important concern during  irradiation. less in 90Y versus placebo (p ⫽ 0.0041) and 192Ir In summary, IVUS analysis shows that  irraversus placebo (p ⬍0.0001). The increase in intimal hyperplasia volume was similar in both the 90Y versus diation (90Y, 20.6 Gy at 1 mm from the source) 652 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 85
MARCH 1, 2000
appears to be as efficacious as ␥ irradiation (192Ir, 15 Gy at 2 mm from the source) in preventing reaccumulation of neointimal tissue within the stented segment. 1. Mintz GS, Mehran R, Waksman R, Pichard AD, Kent KM, Satler LF, Leon MB. Treatment of in-stent restenosis. Semin Interv Cardiol 1998 3;2:117–121 2. Mehran R, Mintz GS, Satler LF, Pichard AD, Kent KM, Bucher TA, Popma JJ, Leon MB. Treatment of in-stent restenosis with excimer laser coronary angioplasty. Mechanisms and results compared to PTCA alone. Circulation 1997;96:2183–2189. 3. Liermann DD, Boettcher HD, Kollatch J, Schopol B, Strassman G, Strecker EP, Breddin KH. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoro-popliteal arteries. Cardiovasc Intervent Rad 1994;17:12–16. 4. 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. 5. 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. 6. Wiedermann JG, Marboe C, Amols H, Schwartz A, Weinberger J. Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol 1994;23:1491–1498. 7. Waksman R, Robinson KA, Crocker IR, Gravanis MB, Cipolla GD, King SB III. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. A possible role for radiation therapy in restenosis prevention. Circulation 1995;91:1533–1539. 8. Waksman R, Robinson KA, Crocker IR, Gravanis MB, Palmer SJ, Wang C, Cipolla GD, King SB III. Intracoronary radiation before stent implantation inhibits neointima formation in stented porcine coronary arteries. Circulation 1995;92:1383–1386. 9. Waksman R, Robinson KA, Crocker IR, Wang C, Gravanis MB, Cipolla GD, Hillstead RA, King SB III. Intracoronary low-dose beta-irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation 1995;92:3025–3031.
10. Verin V, Popowski Y, Urban P, Belenger J, Redard M, Costa M, Widmer MC, Rouzaud M, Nouet P, Grob E, et al. Intra-arterial beta irradiation prevents neointimal hyperplasia in a hypercholesterolemic rabbit restenosis model. Circulation 1995;92:2284 –2290. 11. Waksman R, White L, Chan R, Porrazo MS, Bass BG, Satler LF, Kent KM, Geirlach LM, Mehran R, Murphy M, Mintz GS, Leon MB. Intracoronary radiation therapy for patients with in-stent restenosis: 6 month follow-up of a randomized clinical study. Circulation. 1998;98(suppl I):I-651. 12. Leon MB, Teirstein PS, Lansky AJ, Moses JW, Wong SC, Willerson JT, Ellis SG, Nawaz DM, Kereikas DJ, Hermiller JB, Holmes DR, George BS, Kluck BW, Kuntz RE. Intracoronary gamma radiation to reduce instent restenosis: the multicenter Gamma-I randomized clinical trial (abstr). J Am Coll Cardiol 1999;33: 19A. 13. Verin V, Urban P, Popowski Y, Schwager M, Nouet P, Dorsaz PA, Chatelain P, Kurtz JM, Rutishauser W. Feasibility of intracoronary beta-irradiation to reduce restenosis after balloon angioplasty. A clinical pilot study. Circulation 1997;95:1138 –1144. 14. King SB, Williams DO, Chougule P, Klein JL, Waksman R, Hilstead R, MacDonald J, Andergerg 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. 15. Amols HI, Trichter F, Weinberger J. Intracoronary radiation for prevention of restenosis: dose perturbations caused by stents. Circulation 1998;98:2024 –2029. 16. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis: a serial intravascular ultrasound study. Circulation 1996;94:1247–1254. 17. Fuessl RT, Mintz GS, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. In vivo validation of intravascular ultrasound length measurements using a motorized transducer pullback device. Am J Cardiol 1996;77:1115–1118. 18. Mintz GS, Griffin J, Chuang YC, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. Reproducibility of the intravascular ultrasound assessment of stent implantation in saphenous vein grafts. Am J Cardiol 1995;75:1267–1270. 19. Mehran R, Mintz GS, Hong MK, Tio FO, Bramwell O, Brahimi A, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Validation of the in vivo intravascular ultrasound measurement of instent neointimal hyperplasia volumes. J Am Coll Cardiol 1998;32:794 –799. 20. Waksman R, Bhargava B, Saucedo JF, Chan R, Tio FO, Vodovotz Y, Verin V. Yttrium-90 delivered via a centering catheter and afterloader, given both before and after stent implantation, completely inhibits neointima formation in swine coronary arteries (abstr). J Am Coll Cardiol 1999;33:20A.
Effects of Transcendental Meditation on Symptoms and Electrocardiographic Changes in Patients With Cardiac Syndrome X Charles Cunningham,
MSc,
Sue Brown,
he term cardiac syndrome X is applied to patients with anginal chest pain, positive response to exerT cise stress testing, and normal coronary angiograms. Such patients have a good prognosis regarding survival and acute coronary events but often remain symptomatic despite conventional antianginal medications and the reassurance provided by the cardiologist.1 The chest pain that they experience is often exertional but frequently also occurs at rest. Such symptoms may mimic unstable angina and lead to readmission to the hospital and repeat investigations. Cardiac syndrome X is costly to the health service and also has considerable adverse effects on the patient’s From the University of Westminster, London; and St. George’s Hospital, London, United Kingdom. This study was supported in part by The Mason Medical Moores Rowland Foundation, Brighton, United Kingdom. Dr. Kaski’s address is: Coronary Artery Disease Research Unit, Cardiological Sciences, St. George’s Hospital Medical School, London SW17 0RE, United Kingdom. Manuscript received July 15, 1999; revised manuscript received and accepted October 6, 1999. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 March 1, 2000
RGN, BSc,
and Juan Carlos Kaski,
MD
quality of life, self-esteem, interpersonal relations, and employment.1 Cardiac syndrome X probably encompasses multiple pathogenic mechanisms. Among these, psychological abnormalities, particularly anxiety disorders, have been identified.2 These abnormalities are not a transient reaction to the medical condition but are persistent, increase over time, and predict chest pain many years later. Anxiety may contribute to the evolution of chest pain through different mechanisms.2 There is evidence that autonomic imbalance with persisting sympathetic stimulation is present in many patients with cardiac syndrome X. Increased sympathetic drive may be responsible for the “ischemia-like” ST-segment depression observed during exercise. This hypothesis is supported by the observation of improved responses with  blockade, improved coronary flow reserve with ␣ blockade, and abnormal reactivity to vasoconstrictor mediators in arteriolar resistance vessels.3 Because of these responses, we hypothesized that transcendental medita0002-9149/00/$–see front matter PII S0002-9149(99)00828-0
653
apy) is a promising approach to prevent or treat restenosis.3–5 Animal studies have shown reduction in neointima formation both with ␥ and  radiation.6 –10 In randomized clinical trials, ␥ radiation has been shown to reduce recurrent in-stent restenosis,4,11,12 but the safety, handling, and prolonged dwell times with ␥ sources are considered practical limitations. On the other hand,  emitters are less penetrating, have shorter dwell times, cause less exposure to patients and personnel, and require less shielding. Although limited preclinical studies found  emitters to be efficacious,9,10 the preliminary clinical results were not conclusive.13,14 The rapid falloff of the radial dose, low penetration, and potential problem of shielding of  radiation by stents are concerns, especially for the treatment for in-stent restenosis.15 The present study uses serial (postintervention and follow-up) volumetric intravascular ultrasound (IVUS) analysis to assess the efficacy of  irradiation in preventing recurrent in-stent restenosis. •••
The study population consisted of 3 groups of patients (1 group treated with  irradiation, 1 treated with ␥ irradiation, and 1 group of controls) who presented with native coronary artery in-stent restenosis and who, after giving informed consent, were enrolled into 1 of 2 institutional review board-approved brachytherapy trials at the Washington Hospital Center. Twenty-five patients from the -Washington Radiation for InStent restenosis Trial (with  emitters), an open-label registry in which all patients received radiation, were compared with 75 patients from the Washington Radiation for InStent restenosis Trial, in which patients were randomized to ␥ irradiation (n ⫽ 36) versus placebo (n ⫽ 39). This represents all of the patients in these 2 trials who had complete postintervention and follow-up IVUS. The Washington Radiation for InStent restenosis Trial with  emitters enrolled 50 patients, and there were 100 patients in the From the Intravascular Ultrasound Imaging and Cardiac Catheterization Laboratories, Washington Hospital Center, Washington, DC. This study was supported by a grant from the Cardiovascular Research Foundation, Washington, DC. Dr. Mintz’s address is: 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010. E-mail: [email protected]. Manuscript received September 17, 1999; revised manuscript received and accepted October 1, 1999. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 March 1, 2000
Washington Radiation for InStent restenosis Trial with native artery in-stent restenosis. Primary treatment strategy was at the discretion of the operator: percutaneous transluminal coronary angioplasty, rotational atherectomy (SCIMED/Boston Scientific Corporation, Nattick, Massachusetts), excimer laser coronary angioplasty (Spectranetics, Colorado Springs, Colorado), implantation of additional stents, or any combination of these. After obtaining a good primary result, patients received either openlabel  irradiation or were randomized to ␥ irradiation versus placebo. In the  registry the source was a yttrium-90 (90Y) wire that was inserted automatically by the BETAMED Intracoronary Radiation System (Boston Scientific Corporation) afterloader into a segmented-centering balloon delivery catheter positioned at the treatment site. The prescribed dose was 20.6 Gy at 1 mm from the surface of the balloon. In the ␥ study, patients were randomized to either placebo or ribbon with active iridium-192 (192Ir) seeds (Best Industries, Springfield, Virginia). The ribbon was handdelivered into a noncentered closed-end lumen catheter (Medtronic Corporation, Minneapolis, Minnesota) that was positioned at the treatment site. The prescribed dose was 15 Gy at 2 mm from the center of the source. Cine fluoroscopy was used to verify catheter and source position to cover the angioplasty site for both systems. All IVUS studies were performed after administration of 200 g of intracoronary nitroglycerin. The actual interval between the postintervention and 6-month follow-up IVUS studies was 184 ⫾ 24 days for the 90Y group, 188 ⫾ 59 days for the 192Ir group, and 151 ⫾ 71 days for the placebo group. Studies were performed using a single-element 30-MHz transducer rotating at 1,800 rpm and withdrawn automatically at 0.5 mm/s within a 3.2Fr short monorail stationary imaging catheter (Boston Scientific Corporation, San Jose, California). The IVUS catheter was advanced 10 mm distal to the lesion, the motorized transducer pullback started, and a complete imaging run performed to the aorto-ostial junction. Studies were recorded on 0.5-inch high-resolution s-VHS tapes for off-line analysis. Using computerized planimetry (Tape Measure or Echoplaque, Indec Systems, Mountain View, California) and previously reported methods, planar and volumetric IVUS analysis was performed by those blinded to the treatment arms. The uses of automatic transducer pullback to measure lesion length, reproducibility of IVUS in studying stented lesions, and IVUS measurement of in-stent 0002-9149/00/$–see front matter PII S0002-9149(99)00827-9
651
192
Yttrium-90
Placebo
Iridium-192
p Value
Ir groups, but was greater in 90Y versus placebo (p ⫽ 0.0008) and 192 Ir versus placebo (p ⬍0.0001).
26 ⫾ 8
29 ⫾ 11
28 ⫾ 12
0.52
•••
TABLE I Intravascular Ultrasound Analysis
In-stent restenosis length (mm) After intervention Minimum lumen area (mm2) Stent volume (mm3) Lumen volume (mm3) Intimal hyperplasia volume (mm3) 6-month follow-up Minimum lumen area (mm2) Stent volume (mm3) Lumen volume (mm3) Intimal hyperplasia volume (mm3) ⌬ Minimum lumen area (mm2) Stent volume (mm3) Lumen volume (mm3) Intimal hyperplasia volume (mm3)
Volumetric IVUS analysis in the 5.5 ⫾ 1.3 4.5 ⫾ 2.1 4.9 ⫾ 1.8 0.084 present study indicates that  radia291 ⫾ 127 277 ⫾ 166 284 ⫾ 168 0.94 tion at appropriate doses has a simi189 ⫾ 83 174 ⫾ 135 186 ⫾ 100 0.85 lar efficacy as ␥ radiation for pre102 ⫾ 53 103 ⫾ 72 97 ⫾ 82 0.94 venting recurrent in-stent neointimal tissue accumulation. In 3 previously 4.5 ⫾ 2.2 2.5 ⫾ 1.4 4.1 ⫾ 2.1 ⬍0.0001 published or presented randomized 283 ⫾ 126 275 ⫾ 165 279 ⫾ 168 0.98 studies, ␥ radiation (using 192Ir) has 165 ⫾ 105 117 ⫾ 105 173 ⫾ 106 0.0447 been shown to reduce recurrent in118 ⫾ 61 158 ⫾ 91 106 ⫾ 84 0.0193 stent restenosis.5,11,12 All 3 had serial volumetric IVUS analysis. The mag⫺1.0 ⫾ 1.4 ⫺2.0 ⫾ 1.8 ⫺0.8 ⫾ 1.7 0.0066 nitude of reduction in intimal hyper⫺8 ⫾ 15 ⫺2 ⫾ 18 ⫺5 ⫾ 14 0.31 plasia volume increase after  radia⫺24 ⫾ 25 ⫺57 ⫾ 54 ⫺14 ⫾ 41 0.0001 tion in the present study is similar to 16 ⫾ 30 55 ⫾ 55 9 ⫾ 38 ⬍0.0001 these previous reports. Stenting induces more neointima ⌬ ⫽ change. than balloon angioplasty. In porcine coronary artery models, 192Ir and 90Y radiation causes a significant (and neointimal hyperplasia volumes have all been report- similar) reduction in neointima after balloon injury or ed.16 –19 The in-stent restenosis lesion was the length stent implantation.6 –10 The present study extends of the stent where intimal hyperplasia occupied ⬎75% these studies to in-stent restenosis in humans. Beta of the stent area or was packed around the IVUS particles have limited penetration in tissue and deliver catheter on the preintervention IVUS study. a significantly lower dose beyond the prescription Statistical analysis was performed using StatView point (compared with ␥ emitters); thus, dosing and 4.5 (SAS Institute, Cary, North Carolina). Data are centering become more important. Absorption and presented as mean ⫾ 1SD. Continuous variables were scattering by stent struts (shielding effect) were recompared using paired t test or factorial analysis of ported with up to 15% attenuation by stent struts.19 variance with post hoc comparisons using Fisher’s The prescription dose in the  registry was chosen to protected least-significant difference. A p value ⬍0.05 be about 20% higher than the one used in the ␥ study was considered significant. based on the different properties of the  emitter IVUS results are listed in Table I. In-stent resteno- including the shielding effects of the stent. This dose sis length and postintervention stent, lumen, and inti- selection was supported by preclinical studies in the mal hyperplasia volumes and the postintervention porcine model, which showed complete inhibition of minimum lumen area were similar in the 3 groups. neointima formation whether Y90 was administered During the follow-up period, there was a decrease in before or after stenting.20 lumen dimensions in all 3 groups—90Y, 192Ir, and This study is a post hoc comparison of patients placebo: p ⬍0.0001, p ⬍0.0001, and p ⫽ 0.0534 for from 2 separate brachytherapy trials; patients were not lumen volumes and p ⫽ 0.0022, p ⬍0.0001, and p ⫽ randomized to  versus ␥ radiation versus placebo. 0.0105 for minimum lumen area, respectively. Thus, there was not a true control for the -irradiation At follow-up, minimum lumen area was similar in group. The statistical comparison should be interboth the 90Y versus 192Ir groups, but larger in 90Y preted in this light. The current analysis does not versus placebo (p ⬍0.0001) and 192Ir versus placebo include all of the patients in these 2 trials, only those (p ⫽ 0.0003). Lumen volume was similar in both the 90Y with complete (postintervention and follow-up) IVUS. versus 192Ir groups, but larger in 90Y versus placebo This is not a true comparison of  versus ␥ because of (p ⫽ 0.0712) and 192Ir versus placebo (p ⫽ 0.0195). differences in dose, centering, and length of the The intimal hyperplasia volume was similar in source; the shorter length of the  source required both the 90Y versus 192Ir groups, but smaller in 90Y stepping and resulted in small regions of overlap. The versus placebo (p ⫽ 0.0608) and 192Ir versus placebo present study did not assess plaque composition (i.e., calcium), stent overlap, and different stent designs that (p ⫽ 0.0069). The decrease in minimum lumen area was similar might attenuate the -irradiation dose delivered to the in both the 90Y versus 192Ir groups, but smaller in 90Y adventitia. The current IVUS analysis was confined to versus placebo (p ⫽ 0.0222) and 192Ir versus placebo the axial length of the stent. Therefore, it did not (p ⫽ 0.0029). The decrease in lumen volume was assess the edge effect of either  or ␥ irradiation; this similar in both the 90Y versus 192Ir groups, but was is an important concern during  irradiation. less in 90Y versus placebo (p ⫽ 0.0041) and 192Ir In summary, IVUS analysis shows that  irraversus placebo (p ⬍0.0001). The increase in intimal hyperplasia volume was similar in both the 90Y versus diation (90Y, 20.6 Gy at 1 mm from the source) 652 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 85
MARCH 1, 2000
appears to be as efficacious as ␥ irradiation (192Ir, 15 Gy at 2 mm from the source) in preventing reaccumulation of neointimal tissue within the stented segment. 1. Mintz GS, Mehran R, Waksman R, Pichard AD, Kent KM, Satler LF, Leon MB. Treatment of in-stent restenosis. Semin Interv Cardiol 1998 3;2:117–121 2. Mehran R, Mintz GS, Satler LF, Pichard AD, Kent KM, Bucher TA, Popma JJ, Leon MB. Treatment of in-stent restenosis with excimer laser coronary angioplasty. Mechanisms and results compared to PTCA alone. Circulation 1997;96:2183–2189. 3. Liermann DD, Boettcher HD, Kollatch J, Schopol B, Strassman G, Strecker EP, Breddin KH. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoro-popliteal arteries. Cardiovasc Intervent Rad 1994;17:12–16. 4. 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. 5. 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. 6. Wiedermann JG, Marboe C, Amols H, Schwartz A, Weinberger J. Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol 1994;23:1491–1498. 7. Waksman R, Robinson KA, Crocker IR, Gravanis MB, Cipolla GD, King SB III. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. A possible role for radiation therapy in restenosis prevention. Circulation 1995;91:1533–1539. 8. Waksman R, Robinson KA, Crocker IR, Gravanis MB, Palmer SJ, Wang C, Cipolla GD, King SB III. Intracoronary radiation before stent implantation inhibits neointima formation in stented porcine coronary arteries. Circulation 1995;92:1383–1386. 9. Waksman R, Robinson KA, Crocker IR, Wang C, Gravanis MB, Cipolla GD, Hillstead RA, King SB III. Intracoronary low-dose beta-irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation 1995;92:3025–3031.
10. Verin V, Popowski Y, Urban P, Belenger J, Redard M, Costa M, Widmer MC, Rouzaud M, Nouet P, Grob E, et al. Intra-arterial beta irradiation prevents neointimal hyperplasia in a hypercholesterolemic rabbit restenosis model. Circulation 1995;92:2284 –2290. 11. Waksman R, White L, Chan R, Porrazo MS, Bass BG, Satler LF, Kent KM, Geirlach LM, Mehran R, Murphy M, Mintz GS, Leon MB. Intracoronary radiation therapy for patients with in-stent restenosis: 6 month follow-up of a randomized clinical study. Circulation. 1998;98(suppl I):I-651. 12. Leon MB, Teirstein PS, Lansky AJ, Moses JW, Wong SC, Willerson JT, Ellis SG, Nawaz DM, Kereikas DJ, Hermiller JB, Holmes DR, George BS, Kluck BW, Kuntz RE. Intracoronary gamma radiation to reduce instent restenosis: the multicenter Gamma-I randomized clinical trial (abstr). J Am Coll Cardiol 1999;33: 19A. 13. Verin V, Urban P, Popowski Y, Schwager M, Nouet P, Dorsaz PA, Chatelain P, Kurtz JM, Rutishauser W. Feasibility of intracoronary beta-irradiation to reduce restenosis after balloon angioplasty. A clinical pilot study. Circulation 1997;95:1138 –1144. 14. King SB, Williams DO, Chougule P, Klein JL, Waksman R, Hilstead R, MacDonald J, Andergerg 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. 15. Amols HI, Trichter F, Weinberger J. Intracoronary radiation for prevention of restenosis: dose perturbations caused by stents. Circulation 1998;98:2024 –2029. 16. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis: a serial intravascular ultrasound study. Circulation 1996;94:1247–1254. 17. Fuessl RT, Mintz GS, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. In vivo validation of intravascular ultrasound length measurements using a motorized transducer pullback device. Am J Cardiol 1996;77:1115–1118. 18. Mintz GS, Griffin J, Chuang YC, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. Reproducibility of the intravascular ultrasound assessment of stent implantation in saphenous vein grafts. Am J Cardiol 1995;75:1267–1270. 19. Mehran R, Mintz GS, Hong MK, Tio FO, Bramwell O, Brahimi A, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Validation of the in vivo intravascular ultrasound measurement of instent neointimal hyperplasia volumes. J Am Coll Cardiol 1998;32:794 –799. 20. Waksman R, Bhargava B, Saucedo JF, Chan R, Tio FO, Vodovotz Y, Verin V. Yttrium-90 delivered via a centering catheter and afterloader, given both before and after stent implantation, completely inhibits neointima formation in swine coronary arteries (abstr). J Am Coll Cardiol 1999;33:20A.
Effects of Transcendental Meditation on Symptoms and Electrocardiographic Changes in Patients With Cardiac Syndrome X Charles Cunningham,
MSc,
Sue Brown,
he term cardiac syndrome X is applied to patients with anginal chest pain, positive response to exerT cise stress testing, and normal coronary angiograms. Such patients have a good prognosis regarding survival and acute coronary events but often remain symptomatic despite conventional antianginal medications and the reassurance provided by the cardiologist.1 The chest pain that they experience is often exertional but frequently also occurs at rest. Such symptoms may mimic unstable angina and lead to readmission to the hospital and repeat investigations. Cardiac syndrome X is costly to the health service and also has considerable adverse effects on the patient’s From the University of Westminster, London; and St. George’s Hospital, London, United Kingdom. This study was supported in part by The Mason Medical Moores Rowland Foundation, Brighton, United Kingdom. Dr. Kaski’s address is: Coronary Artery Disease Research Unit, Cardiological Sciences, St. George’s Hospital Medical School, London SW17 0RE, United Kingdom. Manuscript received July 15, 1999; revised manuscript received and accepted October 6, 1999. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 March 1, 2000
RGN, BSc,
and Juan Carlos Kaski,
MD
quality of life, self-esteem, interpersonal relations, and employment.1 Cardiac syndrome X probably encompasses multiple pathogenic mechanisms. Among these, psychological abnormalities, particularly anxiety disorders, have been identified.2 These abnormalities are not a transient reaction to the medical condition but are persistent, increase over time, and predict chest pain many years later. Anxiety may contribute to the evolution of chest pain through different mechanisms.2 There is evidence that autonomic imbalance with persisting sympathetic stimulation is present in many patients with cardiac syndrome X. Increased sympathetic drive may be responsible for the “ischemia-like” ST-segment depression observed during exercise. This hypothesis is supported by the observation of improved responses with  blockade, improved coronary flow reserve with ␣ blockade, and abnormal reactivity to vasoconstrictor mediators in arteriolar resistance vessels.3 Because of these responses, we hypothesized that transcendental medita0002-9149/00/$–see front matter PII S0002-9149(99)00828-0
653