Abstract
Background
We examined the long term clinical outcomes after administration of intravascular brachytherapy (IVBT) for instent restenosis (ISR) and de novo coronary artery lesions in percutaneous coronary intervention (PCI).
Methods and Materials
From May 2000 to August 2004, 129 symptomatic patients with ISR and de novo coronary artery lesions were treated with intravascular beta radiation after successful PCI. The primary end-point was major adverse cardiac event (MACE), i.e., a composite of all-cause death, myocardial infarction and target lesion revascularization (TLR) within 5 years of follow-up.
Results
The mean age of patients was 64+10 years with a male predominance (78%). The majority of patients had diffuse bare metal instent restenotic lesions and 19 patients (15%) had de novo coronary artery lesions. From hospital discharge to follow-up at 5 years (mean follow-up period 75.3 + 17.7 months), the annual consecutive MACE rates were 16.3%, 13.4%, 8%, 12.2% and 6.6% respectively and were mainly driven by the need for TLR. Left anterior descending artery (LAD) as target vessel of PCI was an independent predictor of long term MACE (OR: 3.5; 95% confidence interval:1.2–10.6; P =.03). There were six cases of stent thrombosis (cumulative incidence of 4.7%) with case fatality rate of 33% (2/6).
Conclusion
MACE rates remained high post IVBT at 5 years of follow-up and were mainly driven by the need for TLR. LAD as target vessel of PCI was an independent predictor of long term MACE.
1
Introduction
Intravascular brachytherapy (IVBT) with the use of gamma and beta radiation was previously considered the gold standard for the treatment of bare metal instent restenosis (ISR) in native coronary arteries following the results of randomized, controlled studies that showed catheter-based IVBT reduced rates of restenosis and repeat revascularization when compared with placebo. Its clinical use was subsequently expanded to percutaneous coronary intervention (PCI) of de novo coronary artery lesions and saphenous venous graft ISR lesions . In recent years, the clinical use of IVBT for ISR lesions has been mostly superseded by drug-eluting stents (DES) which have been shown to be superior for this lesion subset in several studies and also partly due to physician and patients’ concern of radiation exposure . Nevertheless, many questions on the long term clinical effects of IVBT remain unanswered as most studies only reported short and intermediate term results. One study had shown that adverse effects of radiation could occur in coronary arteries years or decades after patients had received external-beam radiotherapy for treatment of malignancy. It is currently unknown whether such adverse effect can also occur after irradiation of a small volume of coronary artery. We therefore examined the long term clinical outcomes in our cohort of patients who had received IVBT for ISR and de novo coronary artery lesions during PCI.
2
Methods
2.1
Study population
From May 2000 to August 2004, a total of 129 symptomatic patients with ISR (in native coronary arteries and saphenous venous grafts) and de novo coronary artery lesions were treated with intravascular beta radiation after successful PCI at our institution.
2.2
Interventional procedure
All PCIs were performed using standard techniques and according to current practice guidelines. PCI was performed with the use of balloon dilatation (majority using cutting balloon), rotational atherectomy, new or additional stenting or a combination of the above methods. Intravascular ultrasound studies (IVUS) were also performed to determine the length of the lesion and the size of the target vessel. No glycoprotein IIb/IIIa inhibitors was administered during PCI. Irradiation was performed after the completion of PCI. The system used for IVBT was the Guidant Galileo system (Guidant, Houston, TX, USA) which consists of the beta ray-emitting, solid isotope P-32 source wire, a centering balloon and an automated delivery device. The prescribed dose, delivered at a distance of 2 mm from the radiation source, was 20 Gy. The source delivery unit performed automated stepping of the source with an active source length of 40 or 60 mm.
All the procedures were performed by a team composed of a cardiologist, an oncologist and a medical physicist who collaborated according to local practices and regulations. All patients were treated with aspirin (80–300 mg daily) prior to the procedure and indefinitely thereafter. Patients also received clopidogrel (an oral loading dose of 300 mg followed by 75 mg daily) prior to the procedure, followed by a minimum of 6 months in patients with ISR (who mostly received cutting balloon angioplasty) and a minimum of 12 months in patients with de novo coronary artery lesions who received new stents. All patients also received concomitant medical therapy such as statin, beta-blockers and angiotensin converting enzyme inhibitors.
2.3
Study design
Upon hospital discharge for the index procedure, demographic characteristics, and procedural data were entered into the Grantham Hospital Cardiovascular Interventional Services Database. All patients were followed up in our cardiac clinic at 4 weeks, 12 weeks, and then every 3 months. The study was given approval by the local institutional review committee and all patients gave informed consent for participation in the study. For the present study, clinical data concerning major adverse cardiovascular events during any subsequent hospitalization within the 5-year follow-up period after the index procedure were retrieved from the medical records and discharge summaries from our hospital as well as other institutions. Patients who were lost to follow-up within the 5-year follow-up period were contacted by phone.
2.4
End-points and definitions
The primary end point was major adverse cardiac event (MACE), i.e., a composite of all-cause death, myocardial infarction and target lesion revascularization (TLR) within 5 years of follow-up. Secondary end-points include all cause death, myocardial infarction, TLR, and stent thrombosis. Myocardial infarction was defined as the presence of new Q waves in at least two contiguous leads with elevation in cardiac troponins or in creatine kinase/creatine kinase-MB above the upper limit of the normal range, or in the absence of pathologic Q waves, myocardial infarction was diagnosed in the presence of an elevation in cardiac troponins or in creatine kinase >2 times the upper limit of normal. TLR was defined as any repeat revascularization (percutaneous or surgical)secondary to a stenosis >50% within the stent or within 5 mm proximal or distal to the stented segment. Stent thrombosis was defined according to the Academic Research Consortium criteria. Stent thrombosis was classified as acute if it occurred within 24 h after index PCI, subacute if it occurred between 1 and 30 days, late if it occurred between 31 days and 1 year, and very late if it occurred more than 1 year after the procedure. Furthermore, definite stent thrombosis was defined as the occurrence of acute coronary syndrome together with angiographic or pathologic evidence of stent thrombosis. Probable stent thrombosis was defined as any unexplained death within 30 days after the index procedure or myocardial infarction at any time after the procedure, documented in the area supplied by the stented vessel without angiographic confirmation. Possible stent thrombosis was defined as any unexplained death after 30 days of the index procedure.
2.5
Statistical analysis
Continuous variables were expressed as mean±S.E.M. Dichotomous variables were expressed as counts and percentage. Statistical comparisons were performed using Student’s t test or Fisher’s Exact test, as appropriate. Cox regression analysis was used to evaluate clinical and procedural variables related to occurrence of MACE within 5 years of follow-up. Univariate logistic regression analysis was initially performed; variables <0.2 were entered into the Cox model. Kaplan-Meier curve for freedom from MACE at 5 years of follow-up was constructed when predictor (s) of MACE was identified with the difference compared with log-rank test. Calculations were performed using SPSS software (version 12.0; SPSS, Chicago, IL, USA). All P values were two sided, and P <.05 was considered statistically significant.
2
Methods
2.1
Study population
From May 2000 to August 2004, a total of 129 symptomatic patients with ISR (in native coronary arteries and saphenous venous grafts) and de novo coronary artery lesions were treated with intravascular beta radiation after successful PCI at our institution.
2.2
Interventional procedure
All PCIs were performed using standard techniques and according to current practice guidelines. PCI was performed with the use of balloon dilatation (majority using cutting balloon), rotational atherectomy, new or additional stenting or a combination of the above methods. Intravascular ultrasound studies (IVUS) were also performed to determine the length of the lesion and the size of the target vessel. No glycoprotein IIb/IIIa inhibitors was administered during PCI. Irradiation was performed after the completion of PCI. The system used for IVBT was the Guidant Galileo system (Guidant, Houston, TX, USA) which consists of the beta ray-emitting, solid isotope P-32 source wire, a centering balloon and an automated delivery device. The prescribed dose, delivered at a distance of 2 mm from the radiation source, was 20 Gy. The source delivery unit performed automated stepping of the source with an active source length of 40 or 60 mm.
All the procedures were performed by a team composed of a cardiologist, an oncologist and a medical physicist who collaborated according to local practices and regulations. All patients were treated with aspirin (80–300 mg daily) prior to the procedure and indefinitely thereafter. Patients also received clopidogrel (an oral loading dose of 300 mg followed by 75 mg daily) prior to the procedure, followed by a minimum of 6 months in patients with ISR (who mostly received cutting balloon angioplasty) and a minimum of 12 months in patients with de novo coronary artery lesions who received new stents. All patients also received concomitant medical therapy such as statin, beta-blockers and angiotensin converting enzyme inhibitors.
2.3
Study design
Upon hospital discharge for the index procedure, demographic characteristics, and procedural data were entered into the Grantham Hospital Cardiovascular Interventional Services Database. All patients were followed up in our cardiac clinic at 4 weeks, 12 weeks, and then every 3 months. The study was given approval by the local institutional review committee and all patients gave informed consent for participation in the study. For the present study, clinical data concerning major adverse cardiovascular events during any subsequent hospitalization within the 5-year follow-up period after the index procedure were retrieved from the medical records and discharge summaries from our hospital as well as other institutions. Patients who were lost to follow-up within the 5-year follow-up period were contacted by phone.
2.4
End-points and definitions
The primary end point was major adverse cardiac event (MACE), i.e., a composite of all-cause death, myocardial infarction and target lesion revascularization (TLR) within 5 years of follow-up. Secondary end-points include all cause death, myocardial infarction, TLR, and stent thrombosis. Myocardial infarction was defined as the presence of new Q waves in at least two contiguous leads with elevation in cardiac troponins or in creatine kinase/creatine kinase-MB above the upper limit of the normal range, or in the absence of pathologic Q waves, myocardial infarction was diagnosed in the presence of an elevation in cardiac troponins or in creatine kinase >2 times the upper limit of normal. TLR was defined as any repeat revascularization (percutaneous or surgical)secondary to a stenosis >50% within the stent or within 5 mm proximal or distal to the stented segment. Stent thrombosis was defined according to the Academic Research Consortium criteria. Stent thrombosis was classified as acute if it occurred within 24 h after index PCI, subacute if it occurred between 1 and 30 days, late if it occurred between 31 days and 1 year, and very late if it occurred more than 1 year after the procedure. Furthermore, definite stent thrombosis was defined as the occurrence of acute coronary syndrome together with angiographic or pathologic evidence of stent thrombosis. Probable stent thrombosis was defined as any unexplained death within 30 days after the index procedure or myocardial infarction at any time after the procedure, documented in the area supplied by the stented vessel without angiographic confirmation. Possible stent thrombosis was defined as any unexplained death after 30 days of the index procedure.
2.5
Statistical analysis
Continuous variables were expressed as mean±S.E.M. Dichotomous variables were expressed as counts and percentage. Statistical comparisons were performed using Student’s t test or Fisher’s Exact test, as appropriate. Cox regression analysis was used to evaluate clinical and procedural variables related to occurrence of MACE within 5 years of follow-up. Univariate logistic regression analysis was initially performed; variables <0.2 were entered into the Cox model. Kaplan-Meier curve for freedom from MACE at 5 years of follow-up was constructed when predictor (s) of MACE was identified with the difference compared with log-rank test. Calculations were performed using SPSS software (version 12.0; SPSS, Chicago, IL, USA). All P values were two sided, and P <.05 was considered statistically significant.
3
Results
The baseline clinical characteristics of the study patients are summarized in Table 1 . The mean age of the patients was 64.0+10.3 years with male preponderance (78%). Diabetes mellitus was present in 63 patients (49%). The mean left ventricular function was 53.4+12.8%. Stable angina pectoris was the most common indication for PCI (82%). The mean duration of clopidogrel therapy was 8.0+2.8 months. Table 2 summarized the angiographic findings and procedural data for the study patients. The majority of patients (66%) had multivessel disease on coronary angiography. Left anterior descending (LAD) artery was the most common target vessel for PCI. The majority of the lesions (85%) were bare metal stent ISR followed by 19 de novo coronary artery lesions (15%). There was only one case of DES ISR that was treated with IVBT. The majority of patients had a diffuse pattern of ISR. Table 3 shows the annual consecutive MACE rates from the first year to fifth year of follow-up along with the secondary end points. Data on clinical follow-up was available for all 129 patients with mean follow-up period of 75.3+17.7 months. There was no in-hospital MACE. Overall, 80 patients (62%) remained completely MACE-free during the 5-year follow-up period. From hospital discharge to follow-up at 5 years, the annual consecutive MACE rates were 16.3%, 13.4%, 8%, 12.2% and 6.6%, respectively. There were two deaths each year with six of the deaths being related to cardiovascular cause. The incidence of myocardial infarction was low throughout the 5 years of follow-up. Annual MACE rates were mainly driven by the need for TLR with the highest rates occurring within the first 2 years after IVBT. The majority of patients required repeat revascularization with PCI and 5 patients required coronary artery bypass grafting (CABG). Cox regression analysis showed that LAD as target vessel of PCI was an independent predictor of long term MACE (hazard ratio: 3.5; CI: 1.2–10.6; P =.03). Fig. 1 showed the Kaplan-Meier curve for freedom from MACE events over the period of 5 years for LAD and non-LAD lesions (log rank test; P =.04). Finally, there were six cases of stent thrombosis (cumulative incidence of 4.7%) with two cases of late stent thrombosis and four cases of very late stent thrombosis. There was one case of definite, three cases of probable and two cases of possible stent thrombosis. All six cases were patients that had undergone PCI and IVBT of LAD artery with three cases of de novo LAD lesions and the remaining three, LAD ISR lesions. Two cases presented as death, three as anterior myocardial infarction and 1 as non-ST-elevation myocardial infarction. The case fatality rate for stent thrombosis including death at presentation was 33% (2/6). The mean number of days to stent thrombosis was 801+647 days (range: 116–1527 days). The two patients with late stent thrombosis were still taking dual anti-platelet therapy when the adverse events occurred at the fourth and fifth month post PCI, respectively. As for the remaining four patients who developed very late stent thrombosis, only one patient was taking both aspirin and clopidogrel and the rest were taking only aspirin when the adverse events happened.
