Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting.

Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, Wong SC, Fish D, Ellis S, Holmes DR, Kerieakes D, Kuntz RE

Cardiovascular Research Foundation, Lenox Hill Hospital, New York, NY

We report on a multicenter, double-blind, randomized trial of intracoronary radiation therapy for the treatment of in-stent restenosis. METHODS: Of 252 eligible patients in whom in-stent restenosis had developed, 131 were randomly assigned to receive an indwelling intracoronary ribbon containing a sealed source of iridium-192, and 121 were assigned to receive a similar-appearing nonradioactive ribbon (placebo). RESULTS: The primary end point, a composite of death, myocardial infarction, and the need for repeated revascularization of the target lesion during nine months of follow-up, occurred in 53 patients assigned to placebo (43.8 percent) and 37 patients assigned to iridium-192 (28.2 percent, P=0.02). However, the reduction in the incidence of major adverse cardiac events was determined solely by a diminished need for revascularization of the target lesion, not by reductions in the incidence of death or myocardial infarction. Late thrombosis occurred in 5.3 percent of the iridium-192 group, as compared with 0.8 percent of the placebo group (P=0.07), resulting in more late myocardial infarctions in the iridium-192 group (9.9 percent vs. 4.1 percent, P=0.09). Late thrombosis occurred in irradiated patients only after the discontinuation of oral antiplatelet therapy (with ticlopidine or clopidogrel) and only in patients who had received new stents at the time of radiation treatment. CONCLUSIONS: Intracoronary irradiation with iridium-192 resulted in lower rates of clinical and angiographic restenosis, although it was also associated with a higher rate of late thrombosis, resulting in an increased risk of myocardial infarction.

Circulation 2000 Aug 29;102(9):951-8

Inhibition of restenosis with beta-emitting radiotherapy: Report of the Proliferation Reduction with Vascular Energy Trial (PREVENT).

Raizner AE, Oesterle SN, Waksman R, Serruys PW, Colombo A, Lim YL, Yeung AC, van der Giessen WJ, Vandertie L, Chiu JK, White LR, Fitzgerald PJ, Kaluza GL, Ali NM

Baylor College of Medicine, Houston, TX, USA. araizner@tmh.tmc.edu

A prospective, randomized, sham-controlled study of intracoronary radiotherapy with the beta-emitting (32)P source wire, using a centering catheter and automated source delivery unit, was conducted. A total of 105 patients with de novo (70%) or restenotic (30%) lesions who were treated by stenting (61%) or balloon angioplasty (39%) received 0 (control), 16, 20, or 24 Gy to a depth of 1 mm in the artery wall. Angiography at 6 months showed a target site late loss index of 11+/-36% in radiotherapy patients versus 55+/-30% in controls (P:<0.0001). A low late loss index was seen in stented and balloon-treated patients and was similar across the 16, 20, and 24 Gy radiotherapy groups. Restenosis (>/=50%) rates were significantly lower in radiotherapy patients at the target site (8% versus 39%; P:=0.012) and at target site plus adjacent segments (22% versus 50%; P:=0.018). Target lesion revascularization was needed in 5 radiotherapy patients (6%) and 6 controls (24%; P:<0.05). Stenosis adjacent to the target site and late thrombotic events reduced the overall clinical benefit of radiotherapy. CONCLUSIONS: beta-radiotherapy with a centered (32)P source is safe and highly effective in inhibiting restenosis at the target site after stent or balloon angioplasty. However, minimizing edge narrowing and late thrombotic events must be accomplished to maximize the clinical benefit of this modality.

J Invasive Cardiol 2000 Jun;12(6):330-2
The SCRIPPS trial--catheter-based radiotherapy to inhibit coronary restenosis.

Malhotra S, Teirstein PS

Interventional Cardiology, Green Hospital of Scripps Clinic, 10666 North Torrey Pines Road, La Jolla, CA, 92037, USA.

The SCRIPPS trial is a randomized, double-blind, placebo-controlled trial evaluating the impact of gamma radiation to inhibit in-stent restenosis. Fifty-five patients were enrolled; twenty-six were assigned to receive catheter-based radiation with Ir-192 and 29 were treated with placebo. Angiographic restenosis in the Ir-192-treated patients was significantly reduced at six months (17% vs. 54%; p = 0.01), with the results sustained at 3-year follow-up (33.3% vs. 63. 6%; p<0.05). Likewise, the composite clinical endpoint of death, myocardial infarction or target lesion revascularization was also commensurately lower in the treated group as compared to the placebo group (23.1% vs. 55.2%; p = 0.01). Late angiography revealed no perforation, aneurysm or pseudoaneurysm or special safety issues unique to radiotherapy.

Circulation 2000 Apr 25;101(16):1895-8

Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis.

Waksman R, Bhargava B, White L, Chan RC, Mehran R, Lansky AJ, Mintz GS, Satler LF, Pichard AD, Leon MB, Kent KK

Vascular Brachytherapy Institute, Washington Hospital Center, Washington, DC 20010, USA. rxw8@mhg.edu

BACKGROUND: Intracoronary gamma-radiation therapy reduces recurrent in-stent restenosis (ISR). This study, BETA WRIST (Washington Radiation for In-Stent restenosis Trial) was designed to examine the efficacy and safety of the beta-emitter 90-yttrium for the prevention of recurrent ISR. METHODS AND RESULTS: A total of 50 consecutive patients with ISR in native coronaries underwent percutaneous transluminal coronary angioplasty, laser angioplasty, rotational atherectomy, and/or stent implantation. Afterward, a segmented balloon catheter was positioned and automatically loaded with a 90-yttrium, 0.014-inch source wire that was 29 mm in length to deliver a dose of 20.6 Gy at 1.0 mm from the balloon surface. In 17 patients, manual stepping of the radiation catheter was necessary for lesions >25 mm in length. The radiation was delivered successfully to all patients, with a mean dwell time of 3.0+/-0.4 minutes. Fractionation of the dose due to ischemia was required in 11 patients. At 6 months, the binary angiographic restenosis rate was 22%, the target lesion revascularization rate was 26%, and the target vessel revascularization rate was 34%; all rates were significantly lower than those of the placebo group of gamma-WRIST. CONCLUSIONS: beta-Radiation with a 90-yttrium source used as adjunct therapy for patients with ISR results in a lower-than-expected rate of angiographic and clinical restenosis

Circulation 2000 May 9;101(18):2165-71
Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis.

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

Cardiology Research Foundation, Division of Cardiology, Washington Hospital Center, Washington DC 20010, USA.

BACKGROUND: Treatment of in-stent restenosis presents a critical limitation of intracoronary stent implantation. Ionizing radiation has been shown to decrease neointimal formation within stents in animal models and in initial clinical trials. We studied the effects of intracoronary gamma-radiation therapy versus placebo on the clinical and angiographic outcomes of patients with in-stent restenosis. METHODS AND RESULTS: One hundred thirty patients with in-stent restenosis underwent successful coronary intervention and were then blindly randomized to receive either intracoronary gamma-radiation with (192)Ir (15 Gy) or placebo. Four independent core laboratories blinded to the treatment protocol analyzed the angiographic and intravascular ultrasound end points of restenosis. Procedural success and in-hospital and 30-day complications were similar among the groups. At 6 months, patients assigned to radiation therapy required less target lesion revascularization and target vessel revascularization (9 [13.8%] and 17 [26.2%], respectively) compared with patients assigned to placebo (41 [63.1%, P=0.0001] and 44 [67.7%, P=0.0001], respectively). Binary angiographic restenosis was lower in the irradiated group (19% versus 58% for placebo, P=0.001). Freedom from major cardiac events was lower in the radiation group (29.2% versus 67.7% for placebo, P<0.001). CONCLUSIONS: Intracoronary gamma-radiation used as adjunct therapy for patients with in-stent restenosis significantly reduces both angiographic and clinical restenosis.

Current interventional cardiology reports. 2000 Nov;2(4):326-331
Anti-restenosis Trials.

de Feyter PJ, Vos J, Rensing BJ

Thoraxcenter, University Hospital Rotterdam, Bd 410, PO Box 2040, Rotterdam 3000 CA, The Netherlands. defeyter@card.azr.nl

The high frequency of restenosis after percutaneous coronary angioplasty is still a major clinical problem. It occurs in 30% to 60% of patients and limits the long-term success of angioplasty. Many clinical trials have been conducted to resolve this problem, using a wide range of pharmacologic agents such as antiplatelet agents, anticoagulation drugs, lipid-lowering drugs, angiotensin-converting enzyme inhibitors, anti-inflammatory drugs, and antiproliferative drugs. Thus far, no effective drug has been reported, with the exception of probucol, which unfortunately is not approved by the US Food and Drug Administration because it prolongs the QT time, and possibly trapidil and cilostazol, two agents that are currently being tested in larger trials. Stent implantation has significantly reduced the frequency of restenosis in patients with 1) short lesions in large coronary arteries, (> 3.0 mm), 2) native coronary restenosis lesions, 3) venous bypass graft obstructions, 4) chronic total occlusions, and 5) acute myocardial infarction in patients referred for primary percutaneous intervention. A significant problem is the occurrence of in-stent restenosis because it is associated with a high recurrence of restenosis, after repeat coronary intervention irrespective of the technique or device used. Brachytherapy may limit this problem. The high restenosis rate occurring in long lesions and in small vessels still remains an unresolved issue.

Ann Med 2000 Dec;32(9):622-31

Intracoronary radiotherapy for prevention of restenosis after percutaneous coronary interventions.

Kaluza GL, Ali NM, Raizner AE

The Methodist Hospital and Baylor College of Medicine, Houston, TX 77030, USA.

More than 50 different pharmacological and mechanical interventions have been tested to date for prevention of vascular restenosis without success. Intracoronary radiotherapy is the first one showing promise of significantly attenuating neointimal proliferation, causing positive vascular remodelling and thus inhibiting restenosis. This promising modality has moved from animal experiments via safety and feasibility testing into the phase of clinical trials of efficacy in large numbers of patients. While ongoing research continues to search for new sources and delivery techniques, currently available technology is being optimized. The randomized clinical trials conducted to date have shown consistently a reduction of target site restenosis rates by 55-79%. Lower incidence of major adverse cardiac events after radiotherapy has also been demonstrated, primarily as a result of reduction in target site and target vessel revascularization rates. However, experimental and clinical research has identified two major complications of this approach: stenosis at the ends of the radiation zone ('edge effect' or 'candywrapper') as well as late thrombosis (beyond 30 days after intervention) of the angioplasty or stent site. If these two adverse effects can be minimized, intracoronary radiotherapy may prove to be a major breakthrough in percutaneous coronary interventions.