a Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 Leiden, The Netherlands
b Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands
c Department of Medical Statistics, Academic Medical Center, Amsterdam, The Netherlands
d Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands
e Department of Cardiology, Academic Hospital Groningen, The Netherlands
f Department of Cardiology, University Medical Center Utrecht, The Netherlands
g Department of Cardiology, Academic Hospital Maastricht, The Netherlands
h Gaubius Laboratory, TNO PG, Leiden, The Netherlands
i Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
* Corresponding author. Tel.: +31-71-526-20-20; fax: +31-71-526-68-85
E-mail address: j.w.jukema{at}lumc.nl
Received 23 December 2003; revised 23 April 2004; accepted 5 May 2004
Abstract
Aims To document the practice of interventional cardiology and the clinical restenosis rate, as well as the risk factors for clinical restenosis in an unselected population of patients in daily practice and to provide a perspective for the need of new devices such as drug-eluting stents.
Methods and results A total of 3177 consecutive patients, who underwent successful percutaneous transluminal coronary angioplasty (PTCA) in the Netherlands, were included. Patients with acute myocardial infarction were excluded. The pre-defined end-point of clinical restenosis was defined as cardiac death, myocardial infarction and revascularisation of the target vessel. Follow-up (9.6 months, IQR 3.9) was complete in 3146 (99.3%) patients with a mean age of 62.1±10.7 years. Of them 896 (28.5%) were female, 459 (14.6%) had diabetes and 1459 (46.4%) had multi-vessel disease. Most patients (2105, 66.9%) were treated for stable angina. Of all patients, 819 (26.0%) were treated for multiple lesions, 2340 (74.4%) underwent stenting and 820 (26.1%) received glycoprotein IIb/IIIa inhibitors. All stented patients received life-long aspirin and ticlopidin/clopidogrel during at least 1 month after the procedure. Target vessel revascularisation during follow-up by either coronary artery by-pass grafting (CABG) or PTCA was necessary in 304 patients (9.7%). Thirty-three (1.1%) patients died of cardiac disease and 22 (0.7%) patients suffered from myocardial infarction (MI) attributable to the originally treated vessel. Overall, the need for revascularisation, or the incidence of cardiac death or MI occurred in 346 patients (11.0%), at 9 and 12 months these event-rates were 10.2% and 12.0%, respectively. Diabetes, hypertension, peripheral vessel disease, multi-vessel disease and treatment of type C lesions prevailed as independent risk factors for clinical restenosis. Longer stents and smaller minimal stent diameter were risk factors for in-stent stenosis.
Conclusion In this unselected series of consecutive patients treated for stable and unstable angina in everyday clinical practice in the pre-drug-eluting stent era, clinical restenosis after 9 and 12 months follow-up of the patients occurred in 10.2% and 12.0%, respectively. The risk varies from 8.3% to 17.6% depending on the number of risk factors. A proper selection of patients that benefit from new devices warranted, since the vast majority are well-treated with standard techniques and proper assignment of expensive new devices is obviously of importance for overall health care.
Key Words: Percutaneous transluminal coronary angioplasty Restenosis Risk factors
Introduction
Restenosis has been the main drawback to percutaneous transluminal coronary angioplasty (PTCA) since its introduction. Despite lowering the restenosis rate with the implantation of coronary stents, restenosis occurs in approximately 1260% of the patients within 6 months after intervention, depending on the patients' and procedural characteristics.1,2 The recently introduced drug-eluting stents give an additional reduction of the restenosis rate.3 However, long-term follow up for most drug-eluting stents is still lacking and only selected populations were studied.
Identifying patients at increased risk for restenosis is important, because these patients might benefit from additional or alternative treatment such as the novel drug-eluting stents or other therapeutic modalities, such as coronary artery by-pass surgery (CABG).4 Thus far however, it has proven difficult to stratify patients with regard to risk for coronary restenosis,5,6 and most of the standard risk factors for atherosclerosis have no relation with restenosis.7 Only diabetes is consistently reported to be associated with restenosis.8
The aim of this study was to evaluate the incidence of clinical restenosis in an unselected sample of patients treated with contemporary intervention techniques in the pre-drug-eluting stent era and to develop a statistical model to identify patients with an increased risk of restenosis-related clinical events in order to provide a clinically relevant perspective for the use of drug-eluting stents.
Methods
Study design
The GENetic DEterminants of Restenosis project (GENDER) was designed as a prospective multi-centre follow-up study to evaluate various gene polymorphisms in association with clinically important restenosis. Patients were eligible for inclusion if they were successfully treated for stable angina, non-ST-elevation acute coronary syndromes or silent ischaemia with PTCA. Patients treated for acute ST-elevation myocardial infarction (MI) were excluded. All patients were treated in four of the 13 referral centres for interventional cardiology in the Netherlands (Academic Medical Centre Amsterdam, Academic Hospital Groningen, Leiden University Medical Centre and Academic Hospital Maastricht). The overall inclusion period lasted from March 1999 until June 2001, with inclusion intervals varying between the centres in order to include equal numbers of patients per centre. In total, 3177 consecutive patients were included in this prospective multi-centre cohort study.
The study protocol conforms to the Declaration of Helsinki and was approved by the ethics committees of each participating institution. Written informed consent was obtained from each participant before the PTCA procedure.
Angioplasty and stenting procedure
Balloon angioplasty and intra-coronary stenting was performed with standard techniques using the radial or femoral approach. Before the procedure patients received 300 mg of aspirin and 7500 IU of heparin. The use of intra-coronary stents and additional medication, such as glycoprotein IIb/IIIa inhibitors was at the discretion of the operator. In case a stent was implanted, patients received either ticlopidin or clopidigrel for at least one month following the procedure depending on local practice. In general, routine re-angiography was not performed.
Follow-up and study endpoints
Patients were followed for at least nine months. They were either seen in the outpatient clinic of the centre for interventional cardiology or contacted by telephone. Primary endpoint of this analysis was the incidence of clinical restenosis, which is nowadays considered to be the most important endpoint by regulatory agencies. Clinical restenosis was defined as death presumably from cardiac causes, MI not attributable to another coronary artery than the target vessel, and target vessel revascularisation (TVR) either by repeat PTCA or CABG. An independent clinical events committee of experienced cardiologists (J.J. Schipperheyn, MD PhD; J.W. Viersma, MD PhD; D. Düren, MD PhD; Y. Vainer, MD) adjudicated the clinical events. The committee members did not review patients treated in their own centre.
Events occurring within one month were classified and analysed separately, since these events are more likely attributable to sub-acute stent thrombosis or occluding dissections and not to restenosis. Data were collected with standardised case-report forms that were completed by the research co-ordinator at each site. Representatives from the data co-ordinating centre monitored the sites carefully.
Definitions
A PTCA procedure was considered successful if, upon visual inspection, the luminal stenosis of at least one lesion was reduced to less than 50% of the luminal diameter. Hypertension was defined as a blood pressure of either above 160 mmHg systolic or 90 mmHg diastolic. Hypercholesterolaemia was defined as total cholesterol concentrations of above 5 mmol/L. Current smokers were individuals who smoked within the month preceding the index intervention. Past smokers were those individuals who gave up smoking in the preceding year. Individuals who stopped smoking for more than one year were classified as non-smokers. A positive family history was noted if the patient had a first degree relative with history of coronary artery disease before the age of 60. Renal failure was defined as a serum creatinine concentration 150 µmol/L or patients treated with dialysis. Patients using anti-diabetic medication or insulin at study entry were considered to be diabetics. Patients with a history of surgical treatment for non-cardiac vascular disease such as aortic aneurysm or by-pass surgery of the peripheral arteries were considered to have peripheral vessel disease. The pre-procedural lesions were classified according to the modified American College of Cardiology and American Heart Association Task Force classification.9
Statistical methods
All data are expressed as means±standard deviation, unless stated otherwise. Time to first clinical event was compared between (sub) groups of patients with the log-rank test. Prognostic value of clinical and procedural variables was assessed with Cox proportional hazards model. We univariately evaluated all known clinical risk factors of restenosis and risk factors related to the PTCA procedure. The proportional hazards assumption of the model, and the assumed linear relation between the log-hazard and quantitative variables were checked graphically by inspection of the martingale residuals.10 Age and univariate predictors of clinical restenosis or TVR with a p-value0.1 were entered into a multivariable Cox model. A backward selection algorithm was used to select independent predictors. In case of multi-vessel PTCA, the worst lesion characteristics were evaluated as factors in the univariate and multivariable model. In stented patients, the total length of the stented segment and the minimal diameter of the stents were calculated per patient. A two-sided p-value of 0.05 or less was considered statistically significant in the univariate analysis and a two-sided p-value of 0.1 or less was considered statistically significant in the multivariable analysis. The predictive accuracy was quantified by calculating the percentage variance of the clinical restenosis rate and of TVR that is explained by the Cox proportional hazards model; for this purpose we used Schemper's R2 measure, which uses a bootstrap method to validate the Cox model.11 Analyses were performed with SPSS for Windows version 10.0 and SAS version 8.
Results
Demographic and clinical characteristics
A total of 3509 patients were eligible for the study, of them 3177 patients were included in the study. Of the 3509 eligible patients, 223 (6.4%) underwent an unsuccessful procedure, or during the procedure the operator decided to refer the patient for alternative treatment options (CABG). One hundred and forty patients (4%) refused informed consent for DNA analysis and 510% of the patients, who were already included in the cohort, were re-admitted for restenosis or PTCA of a lesion in another vessel. These individuals were not included a second time in the registry. Of the included 3177 patients, 23 were lost to follow-up and 8 withdrew their consent after inclusion. Follow-up was complete in 3146 patients (99.3%) with a median duration of 9.6 months (interquartile range (IQR) 3.9). The baseline characteristics of the study population are presented in Table 1. Most patients were men (2250, 71.5%), 459 (14.6%) were diabetics and 1272 (40.4%) had hypertension. Patients had a history of MI, PTCA or CABG in 1264 (40.2%), 567 (18.0%), 383 (12.2%), respectively. Most patients (2105, 66.9%) were treated for stable angina and 1459 (46.4%) patients had multi-vessel disease. Only 1706 (54.2%) of the patients used cholesterol-lowering therapy at the time of the procedure.
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Clinical follow-up
Clinical restenosis occurred in 371 patients during the complete follow-up period (Table 3). In 42 patients, the event occurred within one month of the index intervention. Of them 31 (73.8%) were initially stented. These events all resulted from acute stent thrombosis, except for the death of whom this is unknown. The remaining 11 patients had occluding dissections. Excluding the events that occurred in the first month, clinical restenosis occurred in 346 (11%) of the patients: KaplanMeier restenosis event-rates at 9 and 12 months were 10.2% and 12.0%, respectively.
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In the multivariable Cox proportional hazards model analysis, diabetes and the treatment of total occlusions prevailed as independent risk factors for TVR after backward restriction algorithm. In contrast, current smokers were at a lower risk of TVR than non-smokers (Table 7). The percentage variance explained by the five selected risk factors was 2.1% and the percentage variance explained by all 14 factors in Table 7 was 2.7%.
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The mean total stent length in patients with restenosis was 24.6±17.0 mm compared to 21.5±13.4 mm in controls (RR 1.01, 95% CI 1.011.02). The mean minimal stent diameter was 3.2±0.4 mm and 3.3±0.4 mm (RR 0.67, 95% CI 0.451.00), respectively. In the stented group diabetes, renal failure, peripheral vessel disease, multi-vessel disease, type C lesion, left main intervention, total stent length and minimal stent diameter emerged as univariate predictors of clinical restenosis. Additionally, previous MI was associated with TVR. In the multivariable model peripheral vessel disease (RR 2.24, 95% CI 1.313.82), stent length (1.02, 95% CI 1.011.03), larger minimal stent diameter (RR 0.65, 95% CI 0.440.96) and multi-vessel disease (RR 1.53, 95% 1.102.12) were independently associated with clinical restenosis. Furthermore, diabetes (RR 1.52, 95% CI 0.992.32), previous MI (RR 0.68, 95% CI 0.470.98), total stent length (RR 1.01, 95% CI 1.011.02), larger minimal stent diameter (RR 0.50, 95% CI 0.320.78) and multi-vessel disease (RR 1.37, 95% CI 0.961.95) were independently associated with TVR.
Discussion
Event rate
In this unselected series of patients, treated with contemporary intervention techniques in four Dutch university centres, we observed that the incidence of clinical restenosis after 9 and 12 months follow-up of the patients was 10.2% and 12.0%, respectively, considering that events within the first month are more likely to be attributable to sub-acute stent thrombosis and occluding dissections. These data are consistent with, for example, the recent ISAR-STEREO-2 trial, in which TVR rate was 12.3% in the favourable stent-diameter group in selected patients.2 In a single centre, an observational study carried out between 1996 and 1999 (thus just preceding our observation period) a clinical restenosis rate of 14.8% in women and 17.5% in men was reported.12 In the CART-1 trial evaluating anti-oxidant drugs in a selected population, a clinical restenosis rate of 18.3% was found in the control group.13 Clinical trials with drug-eluting stents report more favourable results with clinical restenosis rates from 0% to 5% in favourable lesions.3,14 In contrast, the results of the SIRIUS trial, which randomised 1058 patients to either bare metal stents or sirolimus-eluting stents and included more complex lesions, reported an overall rate of target-lesion revascularisation of 4.1% and any major adverse cardiac event occurred in 7.1%. This is still low, however restenosis is not yet totally eradicated.15 Thus, although the results of drug-eluting stent trials are promising, the present study demonstrates that in daily practice, including patients with complex lesions, restenosis rates have decreased significantly compared to initial experiences.16,17
Risk factors
Previous studies in both the pre-stent and stent era have reported associations between different clinical variables and primarily angiographic restenosis. Diabetes is the most frequently reported factor that is consistently associated with an increased risk of restenosis.7,12,18 Other frequently reported risk factors for restenosis include unstable angina,8 hypertension,6,8,12 multilesion PTCA,7 sub-optimal procedural result18 and total occlusions7. In this study, we focused on clinically relevant restenosis and our model included exclusively clinical and morphological factors. Diabetes, hypertension, peripheral artery disease, multi-vessel disease and type C lesions were independently associated with clinical restenosis. When we restricted the analysis to TVR, diabetes and treatment of total occlusions were associated with an adverse prognosis. Furthermore, a sub-optimal result increased the risk of TVR with 34%. The successful placement of an intra-coronary stent was associated with a reduced risk of clinical restenosis and TVR. Thus, the patient characteristics that evolved as factors independently associated with clinical restenosis are largely in concordance with the experiences from previous studies. To our knowledge, the association of peripheral artery disease with clinical restenosis has not been reported before.
Diabetes
Diabetes has been shown to be an independent risk factor for restenosis in several studies.7,18 The clinical follow-up of diabetics is characterised by a higher incidence of death, MI and re-interventions.19 Furthermore, in five stent studies, including over 4800 patients, the angiographic in-stent stenosis rate was consistently higher among diabetics than non-diabetics. Despite using a variety of stents over a broad range of patients, the overall 6-month angiographic restenosis rates were 36.8% and 26.3% for patients with and without diabetes, respectively (odds ratio 1.6, 95% CI, 1.41.9, ).19 These findings are in concert with the presently reported adjusted relative risk of clinical restenosis of 1.4 (95% CI 1.071.82) and 1.6 (95% CI 1.192.07) for TVR.
Since diabetes is a consistent risk factor for restenosis, diabetics in particular would benefit from the drug-eluting stents. In the previously mentioned SIRIUS trial 26% of the patients were diabetics. The rate of in-segment stenosis was reduced from 50.5% to 17.6%, ; and the rate of target lesion revascularisation was reduced from 22.3% to 6.9%,
. This represents an important advance in the management of patients with symptomatic ischaemic heart disease. However, long-term safety and efficacy data are needed.15
Stenting
Stenting reduced both clinical restenosis and TVR (RR 0.75, 95% CI 0.600.94 and RR 0.78, 95% CI 0.601.02, respectively). Previously, several clinical trials have demonstrated that stenting reduces rates of clinical and angiographic restenosis; this reduction is clinically important.1618 Although our observation is in concert with previous observations, it should be kept in mind that this registry was not designed to evaluate the efficacy of intra-coronary stenting. The use of stents was at the discretion of the operator and the reason to refrain from stenting was not evaluated. Therefore, in this observation selection bias cannot be excluded.
In stented patients increasing length of the stents and smaller vessel diameter have been reported to increase the risk of in-stent stenosis.12 In this cohort these factors, i.e., total stent length and minimal stent diameter, were independently associated with both clinical restenosis and TVR.
Merits and limitations of the risk model
In this study, we constructed a multivariable risk model to predict the likelihood of clinical restenosis likelihood. As can be derived from Fig. 1, individuals with a risk factor of zero or one had a clinical restenosis rate at one year of only 8.3%, whereas those with four or five factors had a clinical restenosis rate of 17.6%. Therefore, the group of patients with the highest number of risk factors has twice the risk of clinical restenosis compared to those in the lowest category. These data suggest that individuals in the high-risk group might benefit most from new technology such as the drug-eluting stent.
Study limitations
Although nowadays clinical restenosis is considered the most important endpoint by patients as well as by regulatory agencies, a limitation of our study is the absence of angiographic data for all patients. We were not able to perform follow-up angiography and quantitative coronary angiography systematically, because of restriction by the ethical committee and limited funds.
Our prognostic model for clinical restenosis was developed using about 25 variables. In the univariate analysis, we did not use a multiple testing correction method, which possibly inflated type-I error, in order to preserve power for the multivariable analysis.
Conclusions
This large, unselected, observational study shows that at present it is feasible to treat lesions that were previously considered to bare a high risk of long-term complications. In fact, in this series of daily clinical practice, including complex lesions, clinical restenosis occurred in only 10.2% and 12.0% of the patients after 9 and 12 months follow-up, respectively. This event rate should be considered in the interpretation of the studies on new devices such as drug-eluting stents. Although drug-eluting stents are very promising, long-term follow-up is missing. Furthermore, with the present costs of drug-eluting stents, using these stents in every suitable patient is impossible as funds are limited. In order to tailor therapy to the individual patient and reduce costs, risk stratification can be very useful. Specific sub-groups have a higher risk of restenosis. These sub-groups may benefit most from new technologies. Although the risk increases with the number of clinical risk factors, it remains difficult to predict events solely based upon clinical risk factors, because the relative risks of the known clinical risk factors for restenosis are quite modest (in our study the highest RR was 1.7). Therefore, we expect that additional factors can be useful to stratify individuals further to tailored therapy. In this perspective, the quest for genetic risk factors has a potentially important role.
In conclusion, clinical restenosis rate in an unselected patient population with complex lesions, is low, however not negligible. Individualising therapy to provide the patient with an optimal intervention strategy seems useful, in order to improve the (cost) efficacy and avoid side-effects of PTCA as much as possible.
Acknowledgments
The contribution of the members of the clinical event committee, J.J. Schipperheyn, MD PhD, J.W. Viersma, MD PhD, D. Düren, MD PhD and Y. Vainer, MD, is greatly acknowledged. W.R.P.A. is supported by Grant 99.210 from the Netherlands Heart Foundation and a grant from the Interuniversity Cardiology Institute of the Netherlands (ICIN). J.W.J. is an Established Clinical Investigator of The Netherlands Heart Foundation (2001 D 032).
Footnotes
1 These authors contributed equally to the drafting of the manuscript.
References