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J Am Coll Cardiol, 2001; 38:1049-1053
© 2001 by the American College of Cardiology Foundation
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CLINICAL STUDY

The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with chronic renal failure

Luis Gruberg, MD*, Ron Waksman, MD, FACC*, Andrew E. Ajani, MD*, Han-Soo Kim, MD*, R. Larry White, MD{dagger}, Ellen Pinnow, MS*, Regina Deible, RN*, Lowell F. Satler, MD, FACC*, Augusto D. Pichard, MD, FACC*, Kenneth K. Kent, MD, PhD, FACC* and Joseph Lindsay, Jr, MD, FACC*

* Washington Hospital Center, Washington, D.C., USA
{dagger} Washington Cancer Institute at the Washington Hospital Center, Washington, D.C., USA

Manuscript received March 9, 2001; revised manuscript received June 4, 2001, accepted June 25, 2001.

Reprint requests and correspondence: Dr. Ron Waksman, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, D.C. 20010
rxw8{at}mhg.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

This study was designed to analyze the in-hospital and six-month clinical and angiographic outcomes of patients with chronic renal failure (CRF) treated with intracoronary radiation for the prevention of recurrence of in-stent restenosis.

BACKGROUND

Patients with CRF are at a higher risk than the general population for accelerated atherosclerotic cardiovascular disease and for restenosis after percutaneous coronary intervention. Previous studies have shown the effectiveness of both beta and gamma radiation in preventing recurrent restenosis in patients with in-stent restenosis.

METHODS

We studied the in-hospital and six-month clinical and angiographic outcomes of 118 patients with CRF and 481 consecutive patients without CRF who were treated with intracoronary radiation for the prevention of recurrence of in-stent restenosis in native coronaries and saphenous vein grafts.

RESULTS

Patients with CRF were usually older, women, hypertensive and diabetic, with multivessel disease and with reduced left ventricular function. In-hospital outcome for patients with CRF was marred by a higher incidence of death, non–Q-wave myocardial infarction and major vascular and bleeding complications. At six-month follow-up, the mortality rate was higher in patients with CRF, 7.6% compared with 1.9% in non-CRF patients (p = 0.003). Restenosis, target lesion revascularization (TLR) and target vessel revascularization (TVR) rates were similar in the two groups. In patients with CRF, radiation therapy compared to placebo reduced restenosis (53.8% vs. 22.6%, p = 0.04), TLR (71.4% vs. 15.3%, p < 0.0001) and TVR (78.6% vs. 23.7%, p = 0.0002).

CONCLUSIONS

Intracoronary radiation for the prevention of recurrence of in-stent restenosis achieved similar rates of restenosis and revascularization procedures in patients with and without CRF. Despite this benefit, patients with renal dysfunction continued to have significantly higher in-hospital and six-month adverse outcomes.

Abbreviations and Acronyms
  CABG = coronary artery bypass graft
  CRF = chronic renal failure
  CrCl = creatinine clearance
  MI = myocardial infarction
  PCI = percutaneous coronary intervention
  TLR = target lesion revascularization
  TVR = target vessel revascularization
  WRIST = Washington Radiation for In-Stent Restenosis Trial

Patients with chronic renal failure (CRF) are at a higher risk for cardiovascular complications, as they account for ~50% of deaths among this patient population, with an annual mortality rate of 18% to 20% (1–6). Recent data from our experience and from other groups have shown that patients with CRF are at a higher risk than the general population for accelerated atherosclerotic cardiovascular disease and for restenosis after percutaneous coronary intervention (PCI) (7–10). Intracoronary radiation therapy with gamma- and beta-emitting sources is a novel catheter-based procedure that has demonstrated, in a series of prospective, randomized, double-blind trials, a reduction in the need for revascularization procedures as well as in binary angiographic restenosis rates in a broad range of patients with prior in-stent restenosis (11–13). The objective of this report is to analyze the efficacy of intracoronary radiation for the prevention of recurrence of stenosis in patients with in-stent restenosis and CRF and to compare their outcome to patients with normal renal function who underwent intracoronary radiation for the prevention of in-stent restenosis.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
The WRIST Trials (Washington Radiation for In-stent Restenosis Trial) are a series of different studies conceived at the Washington Hospital Center. They were designed to assess the benefit of intracoronary radiation (gamma and beta) for the treatment of in-stent restenosis in both native coronary arteries and in saphenous vein grafts. Details of these trials (WRIST, LONG WRIST, BETA WRIST, WRIST PLUS and COMPASSIONATE USE) have been published previously (11,12,14,15). Briefly, all these trials were sponsored by an Investigational Device Exemption granted by the Food and Drug Administration and approved by the Institutional Review Board and Radiation Safety Committee at the Washington Hospital Center. These studies were monitored by an external data and safety monitoring board, and an independent clinical event committee that adjudicated all clinical events. Informed consent was obtained from each patient before enrollment in any of the trials. All patients underwent coronary intervention via the transfemoral approach with conventional catheter-based systems according to current guidelines (16). Weight-adjusted heparin dosage was administered during the procedure in order to maintain an activated clotting time 250 to 300 s and routinely discontinued at the end of the procedure. Patients received aspirin 325 mg at least 24 h before the procedure and continued indefinitely afterwards. Patients were treated concomitantly with either ticlopidine 250 mg bid or clopidogrel 75 mg qd for four weeks per the routine protocol. Clinical follow-up was performed at one, three and six months. Angiographic follow-up was performed at six months in 85.3% of patients. The occurrence of major late clinical events was recorded, including death, Q-wave myocardial infarction (MI) and revascularization procedures, whether percutaneous or surgical. All events were source documented and adjudicated by an independent committee.

Study population.   From the records of patients with in-stent restenosis enrolled in these trials, we identified 118 patients with CRF and 481 patients without CRF who were treated with intracoronary radiation for the prevention of recurrence of in-stent restenosis. Angiographic entry criteria included a diameter stenosis ≥50% within the stented area in vessels 2.5 to 5.0 mm in diameter in patients who underwent successful angioplasty (<30% residual diameter stenosis in the absence of complications). Device selection, including atheroablative devices (rotational and directional atherectomy or excimer laser angioplasty), or additional stents, were left at the discretion of the operator. Patients with a recent MI (<72 h), left ventricular ejection fraction <20%, prior irradiation to the chest, angiographic evidence of thrombus or multiple lesions in the target vessel were excluded from the studies. Quantitative coronary angiographic analysis was performed by two independent core laboratories blinded to the treatment protocols, and has been described previously (11,14).

Definitions.   Chronic renal failure was defined as the presence of previously documented renal insufficiency and/or a baseline serum creatinine above the normal range (≥1.4 mg/dl in women or ≥1.5 mg/dl in men) or a creatinine clearance (CrCl) <50 ml/min (17,18). Creatinine clearance was calculated by applying the Cockcroft-Gault formula (19) using the baseline serum creatinine: CrCl = [(140 – age) x weight/serum creatinine x 72] with female gender adjustment (CrClfemale = CrCl x 0.85). Procedural success was defined as the absence of death, emergency coronary artery bypass graft (CABG) or Q-wave MI. Q-wave MI was defined by the presence of new pathological Q waves in the electrocardiogram associated with an elevation of cardiac enzyme at least two times the upper normal values. Non–Q-wave MI after the PCI was defined as a creatine kinase-MB enzyme elevation ≥5 times the upper normal value without new Q waves. Major bleeding was defined as a reduction in hemoglobin >5 g/dl (or ≥15% in hematocrit) or any intracranial bleeding. Major vascular complications were defined as any retroperitoneal bleed, pseudoaneurysm or fistula. Major adverse cardiac events were defined as death, MI or target vessel revascularization (TVR). Angiographic binary restenosis at follow-up was defined as ≥50% diameter narrowing within the stent and in the segment that included the stent plus its edges (within 5 mm). Late loss was defined as the minimal lumen diameter immediately after the procedure minus the minimal lumen diameter at the six-month angiographic follow-up.

Radiation delivery and dosimetry.   For the gamma radiation, a 192-iridium source train was delivered into a noncentering end-lumen catheter. The prescribed dose was 15 Gy to a distance of 2.0 mm from the surface of the source for vessels between 2.5 and 4.0 mm or 15 Gy to a distance of 2.4 mm for vessels >4.0 mm in diameter. Maximal dose to the near wall was ≤45 Gy, whereas the minimum dose to the far wall was ≤7.3 Gy. For the beta radiation, a 90-yttrium pure beta-emitter source was delivered into a centering balloon end-lumen catheter. The prescribed dose was 20.6 Gy to a distance 1.0 mm from the surface of the inflated balloon. The dose rate varied from 16.0 to 5.6 Gy/min.

Statistical analysis.   Data are presented as mean ± standard deviation. For continuous variables, comparisons between the two groups were made with the Student t test and for categorical values by the chi-square or Fisher exact test. Target lesion revascularization (TLR) and TVR rates were analyzed by Kaplan-Meier survival curves, with differences between the two groups compared by the log-rank test. Statistical analysis was performed with SAS software (SAS Institute, Cary, North Carolina). A p value <0.05 was considered statistically significant.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Between February 1997 and January 2000, 719 patients were enrolled in various in-stent restenosis radiation trials at our institution. A total of 599 patients (118 with CRF and 481 with normal renal function) were assigned to radiation therapy and 120 patients were assigned to the placebo arm (14 with CRF and 106 without CRF). All patients presented with angina and had >50% in-stent restenosis either in native coronaries or vein grafts. The baseline clinical characteristics are shown in Table 1. Patients with CRF were older and had more risk factors for coronary artery disease than patients with normal renal function; they had higher rates of female gender, hypertension, insulin-treated diabetes and decreased left ventricular function. Angiographic characteristics are shown in Table 2. There was a higher percentage of multivessel disease and a trend towards more diffuse disease in patients with CRF. Device use was similar between the two groups; 50% of patients with CRF underwent stenting, compared to 43% in the non-CRF group, rotational atherectomy was performed in 43% versus 48% and 33% versus 26% underwent excimer laser angioplasty, respectively (p = NS).


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  		Table 1 Clinical Characteristics

 

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  		Table 2 Angiographic Characteristics

 
Despite similar procedural success rates, in-hospital outcome was significantly worse for patients with CRF, who had higher vascular and bleeding complications, MI rates and mortality, as shown in Table 3. Clinical events at six-month follow-up are depicted in Table 4. Overall mortality rates and cardiac death rates were significantly higher in patients with CRF. Restenosis, TLR and TVR rates by either coronary angioplasty or CABG were similar between the two groups, although there was a trend towards a higher rate of TLR and TVR by CABG in patients without CRF. Late thrombosis rates were similar between the two groups (0.8% in patients with CRF vs. 2.1% in non-CRF patients, p = 0.70).


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  		Table 3 In-Hospital Clinical Outcome

 

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  		Table 4 Clinical Outcome at Six Months

 
Radiation versus placebo.   During the performance of the radiation trials, 120 patients were assigned to the placebo arm; 14 (12%) of these patients had CRF. Comparison between the radiated group and the control group in patients with CRF detected similar baseline clinical, angiographic and procedural characteristics and similar in-hospital outcome. At six-months follow-up, the overall mortality in the CRF group was high in both the irradiated and the placebo-treated patients (7.6% and 7.1% respectively, p = NS). In contrast, there was a 58% reduction in binary restenosis in patients with CRF treated with radiation compared with control, as shown in Figure 1. Rates of TLR and TVR were also significantly lower in comparison with the placebo arm. Patients with CRF treated with placebo had a trend towards higher TLR rates (71.4% vs. 58.6%, p = 0.34) and TVR rates (78.6% vs. 60.4%, p = 0.18) compared with non-CRF patients treated with placebo, respectively. Restenosis rates were similar in both groups (53.8% vs. 54.6%, p = 0.83). Non-TVR rates were similar in the radiation and the placebo arms (12.7% vs. 7.1%, p = 0.98). Event-free survival (freedom from death, MI and repeat revascularization) was significantly higher in patients treated with intracoronary radiation, 72.9% versus 21.4% in the placebo group (p = 0.0003).



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  		Figure 1 Binary restenosis rates, target lesion revascularization rates (TLR) and target vessel revascularization rates (TVR) at six-month angiographic follow-up in chronic renal failure patients treated with either intracoronary radiation (white bar) or placebo (black bar).

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The present study demonstrates that in patients with CRF with in-stent restenosis, intracoronary radiation therapy reduced the recurrence of in-stent restenosis and revascularization procedures, but did not have an impact on the incidence of MI, major vascular and bleeding complications and short- and long-term mortality rates seen in these patients. Despite the increased burden of risk factors in patients with CRF compared with patients having normal renal function, restenosis, TLR and TVR rates were similar between both groups at six-months clinical and angiographic follow-up.

Treatment of in-stent restenosis without radiation therapy is associated with recurrence rates between 30% and 70%, regardless of the technique or device used. In the present study, patients with CRF who had been randomized to placebo had a trend towards higher revascularization rates compared with non-CRF patients who had been randomized to placebo. These findings substantiate previous data that have shown that patients with CRF have a higher incidence of restenosis and cardiac events. In contrast, when intracoronary radiation adjunctive therapy was delivered to the treated lesion, the overall TVR and restenosis rates were low, with no differences between CRF and non-CRF patients. Thus, patients with CRF and in-stent restenosis treated with intracoronary radiation for prevention of restenosis achieved the same rates of restenosis, revascularization procedures and event-free survival as non-CRF patients treated with intracoronary radiation, equalizing their outcome. Unfortunately, the robust reduction for the need of revascularization procedures with intracoronary radiation therapy did not affect the high mortality rates seen in patients with CRF. Therefore, our study corroborates previous observations that reduction in restenosis rates and the need for repeat revascularization procedures do not have an effect on mortality, which is probably related to the nature of the disease and obviously is not influenced by radiation therapy.

Previous studies.   The presence of CRF has been associated in previous studies with an increased risk for cardiovascular disease, generally attributed to the combination of "traditional" atherogenic risk factors that are present in the general population such as age, diabetes mellitus, hypertension, smoking and dyslipidemia with additional hemodynamic and metabolic factors specifically related to the uremic state, i.e., anemia, dyslipoproteinemia, hyperfibrinogenemia and hyperhomocysteinemia, which develop in the early stages of CRF (9,20,21). As shown in previous trials and in our study (8,9,17,22), patients with CRF had a higher prevalence of established risk factors for cardiovascular disease, including older age, hypertension, insulin-treated diabetes and reduced left ventricular function.

Study limitations.   The present study was a retrospective analysis and, therefore, the results and conclusions are subject to the limitations inherent in all such reports. The current analysis was not prespecified at the time of protocol design and, thus, the absence of significant differences between the groups can be attributed to beta-type statistical error. Although clinical follow-up was obtained in all patients, angiographic follow-up was completed in a smaller percentage of patients. Although trial data support the use of glycoprotein IIb/IIIa inhibitors in patients undergoing PCI, <10% of patients received this treatment. In view of the higher incidence of non–Q-wave MI in patients with CRF, maybe these patients would have benefited from such a therapy. Finally, the relatively small number of patients in the CRF arm, especially in the placebo arm, may also lead us to incur a type II statistical error.

Clinical implications.   Despite the high degree of procedural success that may be achieved in the present interventional era, patients with CRF with in-stent restenosis represent one of the most demanding patient populations to treat. The increased number of risk factors seen in these patients, combined with severe and diffuse disease and a high incidence of in-hospital and long-term complications, make PCI in these patients particularly challenging. The use of intracoronary radiation in patients with CRF with in-stent restenosis provides hope for reducing the need of revascularization procedures, and should be considered the treatment of choice. Despite this benefit, patients with renal dysfunction continued to have significantly higher in-hospital and six-month adverse events.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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