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Drug and Innovation Review

Intracoronary Brachytherapy

KW Tim Park, MD
Beth Israel Deaconess Medical Center Boston, MA

Percutaneous coronary intervention (PCI) was introduced in the 1970s and its use has increased dramatically, being performed in about 650,000 patients in 1999¹. A continuing challenge with PCI has been the problem of restenosis of the target coronary artery². Immediate periprocedural myocardial injury or infarction is estimated to occur in 1 - 10 %. Periprocedural ischemic complications have been reduced by use of platelet glycoprotein IIb/IIIa receptor inhibitors such as abciximab, eptifibatide, and tirofiban. Immediate elastic recoil of the angioplastied vessel has been reduced by use of a stent, in use since the early 1990s and now used in about 80 % of all PCIs. Subacutely within the first 30 days, there may be thrombotic occlusion of the coronary stent. Patients are treated with a platelet ADP receptor antagonist such as clopidogrel for 4 weeks as well as aspirin indefinitely and, with appropriate antiplatelet therapy, the incidence of subacute thrombosis may be kept < 1 %. Long-term restenosis rate remains at about 20 % even with use of a stent (vs. 30-60 % without a stent) and may be higher with small stent diameters (< 2.5 mm), long stent lengths, multiple stents, and in patients with diabetes. Long-term restenosis occurs as a result of gradual formation of a neointima composed of smooth muscle cells and macrophages within the stent and inward remodeling of external elastic lamina (EEL) in response to injury and peaks between 6 - 8 months after stent placement.

Various mechanical measures have been introduced in an attempt to reduce periprocedural and long-term restenosis of the intervention site. Directional coronary atherectomy, used since the late 1980s, physically removes plaque from the arterial wall and facilitates angioplasty and stenting in ostial or bifurcation lesions, but has not been shown to reduce the need for repeat target lesion revascularization (TLR)³. Rotational atherectomy pulverizes the plaque into particles 20-50 mm in diameter, which then pass through the coronary microcirculation and are removed by the reticuloendothelial system. This technique is an adjunct tool to facilitate angioplasty and stenting in calcified lesions, but has not been shown to reduce target lesion revascularization⁴. Rheolytic thrombectomy is used to remove coronary thrombi by Venturi effect before coronary stenting, but has not been shown to reduce restenosis⁵. Current treatment modalities that may reduce in-stent restenosis include intracoronary brachytherapy and use of stents eluting antineoproliferative agents such as rapamycin, paclitaxel, and antisense DNA.

Intracoronary brachytherapy takes advantage of (a) the powerful but nonselective inhibition of cell proliferation, especially during mitotic and G2 phase of the cell cycle, (b) an increase in the rate of apoptosis or programmed cell death, and (c) damaging effect on the macrophages and monocytes, which play a crucial role in in-stent restenosis⁶. Radiation may be provided by a high-energy g source such as iridium-192 (¹⁹²Ir) or a b source such as phosphorus-32 (32P) (GalileoTM, Guidant; IsostentTM) or yttrium-90/strontium-90 (⁹⁰Sr/⁹⁰Y) (Beta-CathTM, Novoste). Both g and b radiation appear effective; however, g radiation, which penetrates deeper and requires greater radiation protection and shielding, may be less practical.

There have been > 20 randomized trials of brachytherapy, involving more than 5,000 patients collectively⁷. These trials show an overall trend in reduction of restenosis and need for further intervention by about 50 %, but there is no long-term follow-up data of a large series of patients beyond 9-12 months. In the SCRIPPS trial of 55 patients receiving either placebo or ¹⁹²Ir, TLR was reduced by 74 % and angiographic restenosis by 69 % at 6 months⁸. In the Gamma-One trial of 252 patients randomized to ¹⁹²Ir or placebo, TLR was reduced by 33 % in the radiation group, but there was a 5.3 % incidence of late thrombosis in the irradiated patients, occurring after antiplatelet medications were discontinued⁹. In the largest (476 patients) randomized placebo-controlled trial of radiation in restenotic arteries, START (STents And Radiation Therapy) investigators showed that the composite of death, myocardial infarction, and TLR was significantly reduced by ⁹⁰Sr/⁹⁰Y radiation (19.1 % vs. 28.7 % at 8 months, P=0.024)¹⁰. Radioactive stents, initially touted for the dual benefits of stenting and radiation, have turned out to be disappointing. Whereas in-stent restenosis may indeed be prevented, stenosis may occur at the stent edges, producing the "candy wrapper" effect¹¹.

As hinted above, several major complications of brachytherapy have already been identified and will require resolution. First is the problem of edge restenosis. Plaque volume increases in the irradiated area, but does not decrease luminal volume because the EEL undergoes a compensatory outward remodeling. However, in areas at the edge of the radiation field, there is an increase in plaque volume without a compensatory change in EEL¹². One solution to this problem may be to use a source length longer than the lesion⁷. Second, radiation induces thrombosis in a dose-dependent manner. Radiation may also delay complete re-endothelialization, thus promoting thrombus formation. A multivariate analysis of 473 patients with in-stent restenosis in various radiation protocols showed that new stenting is the main predictor of late thrombotic occlusion¹³. The WRIST PLUS investigators used a prolonged antiplatelet therapy (aspirin and clopidogrel for 6 months) and a policy to avoid stenting when using radiation to treat in-stent restenosis and were able to bring down the late thrombosis rate to 2.5 % - comparable to those without radiation¹⁴. A recent editorial recommends using aspirin and clopidogrel for a minimum of 12 months after brachytherapy for chronic coronary occlusions¹⁵. Finally, the late effects of radiation on the vasculature remain to be defined.

References

1. Shah PB, Lilly CM. Interventional therapy for coronary artery disease. Am J Respir Crit Care Med 2002; 166:791-6

2. Bailey SR. Coronary restenosis: a review of current insights and therapies. Catheter Cardiovasc Interv 2002; 55:265-71

3. Baim DS, Cutlip DE, Sharma SK, et al. Final results of the Balloon vs. Optimal Atherectomy Trial (BOAT). Circulation 1998; 97:322-3

4. Reifart N, Vandormael M, Krajcar M, et al. Randomized comparison of angioplasty of complex coronary lesions at a single center: excimer laser, rotational atherectomy, and balloon angioplasty comparison (ERBAC) study. Circulation 1997; 96:91-8

5. Kuntz RE, Baim DS, Cohen DJ, et al . A trial comparing rheolytic thrombectomy with intracoronary urokinase for coronary and vein graft thrombus (the Vein Graft AngioJet Study [VeGAS]). Am J Cardiol 2002; 89:326-30

6. Finkelstein A, Makkar R, Doherty T, et al. Increased expression of macrophage colony-stimulating factor after coronary artery balloon injury is inhibited by intracoronary brachytherapy. Circulation 2002; 105:2411-5

7. Sims EC, Rothman MT, Warner TD, Powell MEB. Coronary artery brachytherapy. Clin Oncol 2002; 14:313-26

8. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336:1697-1703

9. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001; 344:250-6

10. Popma JJ, Suntharalingam M, Lansky AJ, et al. Randomized trial of ⁹⁰Sr/⁹⁰Y b-radiation versus placebo control for treatment of in-stent restenosis. Circulation 2002; 106:1090-6

11. Albiero R, Adamanian M, Kobayashi N, et al. Short and intermediate term results of 32P radioactive beta emitting stent implantation in patients with coronary artery disease. The Milan dose response study. Circulation 2000; 101:18-26

12. Sabate M, Serruys PW, van der Giessen WJ, et al. Geometric vascular remodeling after balloon angioplasty and beta radiation therapy. A three dimensional intravascular ultrasound study. Circulation 1999; 100:1182-8

13. Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000; 36:65-8

14. Waksman R, Ajani AE, White RL, et al. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma radiation in patients with in-stent restenosis. Circulation 2001; 103:2332-5

15. Hehrlein C. Brachytherapy in total coronary occlusions: quidquid agis, prudenter agas, et respice finem. Catheter Cardiovasc Interv 2003; 58:330

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Table of Contents:

• President's Message
  
  
• Letters to the Editor
  
  
• Drug and Innovation Review
• Intracoronary Brachytherapy
• An Update on Lung Volume Reduction Surgery
• Stem Cell Therapy


• Literature Reviews
• Prevalence of Left Ventricular Diastolic Dysfunction by Doppler Echocardiography: Clinical applications of the Canadian Consensus Guidelines
• Intermittent antegrade warm myocardial protection compared to intermittent cold blood cardioplegia in elective coronary surgery - do we have to change?
• Combined steroid treatment for congenital heart surgery improves oxygen delivery and reduces postbypass inflammatory mediator expression.
• A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema.
• Nitroprusside in Critically Ill Patients with Left Ventricular Dysfunction and Aortic Stenosis


• Update on American Heart Association
  
  
• Call for Nominations
  
  
• Breakfast Panel at ASA: Hemostatic Balance in Non-Cardiac and Cardiac Surgery Patients
  
  
• Fellow/Faculty Recruitment Reception
  
  
• SCA Research Starter and MidCareer Grants Winners
  
  
• Calendar of Future Meetings

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