Outcome after treatment of coronary in-stent restenosis

Results from a systematic review using meta-analysis techniques

P.W Radkea,b,*, A Kaisera,b, C Frostc and U Sigwarta

a Royal Brompton & Harefield NHS Trust, London, UK
b Department of Cardiology, RWTH University Hospital Aachen, Aachen, Germany
c London School of Hygiene and Tropical Medicine, Medical Statistics Unit, London, UK

Received December 19, 2001; accepted February 27, 2002 * Corresponding author. Department of Cardiology, RWTH University Hospital, Pauwelsstrasse 30. D-52057 Aachen, Germany

u.sigwart{at}rbh.nthames.nhs.uk


    Abstract
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims To evaluate the clinical outcome after treatment of coronary in-stent restenosis.

Methods and results For identification of the relevant literature a specific search strategy was conducted and explicit inclusion criteria were defined to avoid selection bias. Based on the selected literature, a systematic review using descriptive statistics and meta-analysis methods regarding the outcome after treatment of coronary in-stent restenosis was performed. The proportion of patients experiencing a major adverse cardiac event (MACE) as defined by death, myocardial infarction, and target lesion revascularization was the main outcome measure. A total of 1304 citations were identified. Among these, 28 studies (six different treatment modalities) including a total of 3012 patients met the inclusion criteria and were incorporated into this analysis. The estimated average probability of experiencing a major cardiac adverse event after treatment for in-stent restenosis with a follow-up period of 9±4 months was 30.0% (25.0–34.9%, 95% confidence interval) with strong evidence for heterogeneity between study specific results . The clinical outcome was not significantly different between treatment modalities. After adjustment for confounding factors (i.e. lesion length), however, patients undergoing intracoronary radiation showed an estimated advantage of 16.9% (–37.7±4.0%, 95% confidence interval) in MACE free survival, as compared to balloon angioplasty. The post-interventional diameter stenosis was the only independent predictor for the long-term outcome after treatment of in-stent restenosis.

Conclusions Treatment of in-stent restenosis is associated with an overall 30% rate of major adverse cardiac events. Currently, repeat angioplasty is the treatment option of choice, especially when a sufficient acute procedural result can be achieved. Intracoronary radiation should be considered in cases with therapy refractory forms of diffuse in-stent restenosis.

Key Words: Stent • Restenosis • Treatment • Outcome • Review • Meta-analysis


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The introduction of intracoronary stents intoclinical practice has dramatically changed treatment of obstructive coronary artery disease. Since having been shown to significantly reduce restenosis as compared to PTCA in selected lesions,1,2 the indication for stent implantation has been widened substantially. As a result of a dramatic increase in implantation numbers worldwide in less selected and more complex lesions (bypass grafts, restenostic lesions, unstable angina, myocardial infarction), in-stent restenosis has been disclosed as a new entity with significant clinical and socio-economic implications. Despite a variety of different therapeutic options (reviewed in3,4), the most effective treatment modality for ‘in-stent restenosis’ has as yet not been identified. This is, in part, due to a lack of randomized, controlled trials for most of the existing treatment modalities. At the moment, repeat balloon angioplasty is considered to be the first line treatment option, especially in focal lesions. First clinical data using intracoronary radiation therapy suggest beneficial effects inpatients with longer and more diffuse restenotic stents.5

With more than 1 000 000 stent implantations per year and an estimated overall clinical restenosis rate of 15–25%, between 150 000 and 250 000 patients will present with in-stent restenosis in the year 2002 and require treatment.3,4 At present, no clear recommendations are available for this important patient group. In an attempt to partially overcome this paucity of comparative data, we performed a systematic review using descriptive statistics and meta-analysis methods regardingthe outcome after treatment of coronary in-stent restenosis.


    2. Material and methods
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
For identification of the relevant literature aspecific search strategy was conducted and explicit inclusion criteria were defined to avoid selection bias. A MEDLINE search from January 1987 to March 2001 was performed with restrictions (type of study: human) using a combination of the terms ‘Coronary’, ‘Stent’, ‘Restenosis’, and ‘Treatment’. The reference lists of all retrieved articles were hand-searched for additional relevant articles. This analysis intended to include all clinical trialsconducted since 1987 (a) that described a study population treated for in-stent restenosis in a randomized or non-randomized fashion; (b) that used a specified technique to treat in-stent restenosis; (c) that enrolled ≥30 patients; (4) that included a follow-up period ≥3 months; (5) that provided information on the rate of major adverse cardiac events (MACE) as defined by death, myocardial infarction or target lesion (vessel) revascularization. These criteria were established in an attempt to control for a potential publication bias, to allow for an operator learning curve, and to define a clinically relevant and uniformly applicable outcomemeasure. Two investigators (P.W.R. and A.K.)independently assessed study eligibility.

The proportion of patients experiencing a major adverse cardiac event was defined as the main outcome measure. This proportion (and standard error) was obtained for each study. Where the event rate was zero the number of events was taken to be 0.5 in order to calculate the standard error. Random effect meta-analysis6 was used to combine results both for individual treatment modalities and overall. This random effects analysis was extended using meta-regression7 to evaluate and adjust for the effects of patient, lesion and procedural variables on the primary outcome measure. Analyses were also carried out using over-dispersed logistic regression models as a validation of the consistency of these findings.

To evaluate the quality of the studies identified, the selected literature was screened for validity by applying a series of weighted criteria.8 Thereby, quality assessment of the literature selected becomes a reproducible and quantitative process. The modified validity score used here had a maximal possible score of 25 points (Table 1).


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Table 1 Methodologic quality assessment

 
Analysis was performed with STATATM(StataCorporation, College Station, TX, USA) and SPSS (SPSS UK Ltd, Surrey, UK).


    3. Results
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The MEDLINE search revealed 1189 citations. After hand searching the reference lists, a total of 1304 citations were identified using our search strategy. Among these citations, 28 papers including a total of 3012 patients met the inclusion criteria and were therefore incorporated into this analysis. Within those papers, results from a total of six different treatment modalities have been reported (stent-in-stent therapy,9–11 rotational atherectomy,12–19 balloon angioplasty,9,12,17,19–28 excimer laser angioplasty,16,20,28–31 directional coronary atherectomy,27,32 and intracoronary radiation33–36). The baseline patient characteristics of the entire cohort are provided in Table 2 together with two historical patient populations (BENESTENT1 and ARTS study37). A separate comparison of baseline, procedural and outcome characteristics of thesix different treatment modalities is provided in Table 3.


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Table 2 Baseline characteristics of patients undergoing percutaneous treatment for in-stent restenosis included in the meta-analysis as compared to patients undergoing stent implantation in the BENESTENT and ARTS trial

 

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Table 3 Summary of baseline, procedural, and outcome characteristics of patients with in-stent restenosis undergoing percutaneous treatment using six different treatment modalities

 
The estimated average probability of experiencing a major cardiac adverse event (MACE) after treatment for in-stent restenosis with a follow-up period of 9±4 months was 30.0% (25.0–34.9%, 95% CI, Fig. 1) with strong evidence for heterogeneity between study specific results . The results of separate meta-analyses within thedifferent treatment groups are provided in Table 4 along with estimated differences in the probability of MACE for each treatment modality comparedto balloon angioplasty obtained from the meta-regression model.



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Fig. 1 Probability of major adverse cardiac events (MACE) after treatment of in-stent restenosis using different treatmentmodalities: overall meta-analysis including 3012 patients. The average probability of experiencing a major cardiac adverse event (MACE) 9±4 months after index procedure was 30.0% (25.0–34.9%, 95% CI) with strong evidence for heterogeneity between study specific results .

 

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Table 4 Results from a meta-analysis exploring the probability of major cardiac events (MACE) after treatment of in-stent restenosis using six different treatment modalities

 
Before adjustment for clinical confoundingfactors the differences between modalities were small (differences do not exactly equate to those calculable from the modality specific effects because the meta-regression model, unlike the separate meta-analyses, assumes a constant between study variance). After adjusting for clinical confounding factors (lesion length, pre-interventional diameter stenosis, prevalence of diabetes mellitus) the differences between modalities were largerbut still not statistically significant. In particular, intra-coronary radiation therapy showed a 16.9% advantage compared to balloon angioplasty in the probability of MACE.

Meta-regression analysis showed a significant and positive correlation between diameter stenosis post intervention and the probability of experiencing a major adverse cardiac event (Fig. 2(b)). For every 1.0% decrease in diameter stenosis post intervention, the rate of MACE was estimated to be reduced by 0.9%. All other tested variables were not significantly associated with the occurrence of MACE, however, there was a trend towards a better outcome with an increase in vessel size (Fig. 2(d)).



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Fig. 2 Meta regression analysis: effect of in-stent restenosis lesion length, vessel size, pre- and post-interventional diameter stenosis on the probability of major adverse cardiac events (MACE) in patients treated for in-stent restenosis. A significant and positive correlation was observed between diameter stenosis post intervention and the probability of experiencing a major adverse cardiac event (b). The remaining variables were not significantly associated with the occurrence of MACE.

 
The modified validity score used in this analysis including all 28 studies revealed an overall score of 18±3 (mean±SD). The values for the different treatment modalities are: (1) balloon angioplasty: 18±2; (2) stent-in-stent technique: 17±0; (3) rotational atherectomy: 17±3; (4) excimer laser angioplasty: 19±2; (5) directional coronary atherectomy: 20±1; (6) intracoronary radiation: 22±3.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Restenosis remains the major limitation of intracoronary stent implantation. The aim of this systematic review using meta-analysis techniques was to characterize the outcome after treatment of in-stent restenosis and to identify predictors of major adverse cardiac events after such treatment.

4.1. Clinical characteristics of patient undergoing treatment for in-stent restenosis
Overall, treatment of in-stent restenosis is characterized by a 30% rate of major cardiac events 9±4 month post procedure (Fig. 1, Table 2). In 90% of cases, the rate of MACE is driven by the need for target lesion revascularization (Table 2), mostoften as a result of recurrent restenosis. This unfavourable outcome is likely to reflect the baseline patient and lesion characteristics of the entire population. Patients with in-stent restenosis have already qualified as a ‘high-risk’ population for recurrent restenosis by developing in-stent restenosis in the first place. In addition, patients developing in-stent restenosis have a more significant co-morbidity (Table 2) as compared to patients undergoing primary stent implantation in highly selected lesions (BENESTENT population1) or even patients with multi-vessel disease undergoing stent implantation as studied in the ARTS trial.37 This includes longer lesions, smaller vessel diameters, higher pre-interventional diameter stenosis, and a higher proportion of diabetic and hypertensive patients. All those factors have been suggested to contribute to an unfavourable outcome after stent implantation.3 The lower rates for MACE (20 and 25% vs 30%), therefore, partially reflect those differences in baseline characteristics. Moreover, it is rather likely that the introduction of potent antiplatelet drugs and high-pressure stent implantation into clinical practice has resulted in even lower MACE rates in ‘BENESTENT’ patients currently undergoing primary stent implantation.38,39

4.2. Random effect meta-analysis and meta-regression analysis
An important finding of this meta-analysis is the comparable rate of major adverse cardiac events between the different treatment modalities. Baseline characteristics between studies, however, were not equally distributed. Patients undergoing intra-coronary radiation therapy (as compared to those treated by balloon angioplasty) were more often diabetic (29±8 vs 22±6%) and presented with a longer in-stent lesion length (20±6 vs 14±4mm). Adjustment for those confounding factors revealed an estimated reduction of 16.9% in the probability of MACE for patients undergoing intra-coronaryradiation therapy as compared to balloon angioplasty. This outcome, even though not statistically significant, supports first comparativedata suggesting an improved long-term outcomefor patients treated with gamma-radiation ascompared to placebo (balloon angioplasty).33,35 Randomized data for beta-radiation were notavailable for this analysis, however, effects are expected to be similar.34,36

Notably, intracoronary radiation still bearspotentially hazardous problems. The rate of MACE in patients undergoing intra-coronary radiation therapy is not entirely driven by the need for recurrent revascularization as a result of restenosis. Late thrombosis (>1 month) after intra-coronary radiation therapy, often leading to acute MI, is a threatening side effect with an incidence of up to 10%.33 As a result, the rates for MI in patients undergoing intra-coronary radiation therapy compare unfavourably. Potential risk factors for the development of late thrombosis like additional stent implantation at the time of radiation and absence of antiplatelet therapy have been identified;35 however, additional randomized trials are needed.

The meta-regression analysis revealed that the post-procedural diameter stenosis is the strongest, and only significant, predictor of the rate of MACE in patients undergoing treatment for in-stent restenosis (Fig. 2). The lower the final diameterstenosis, the lower the MACE rate, or ‘the bigger the better’. The importance of the acute procedural result in determining the outcome afterpercutaneous coronary interventions has initially been demonstrated for coronary atherectomy,conventional balloon angioplasty and stentimplantation.40

4.3. Differences in study validity
Despite the magnitude of the clinical and economic problem ‘in-stent restenosis’, only two randomized controlled clinical trials have been reported thus far33,35 and the majority of data originates from retrospectively analysed databases. Both trials evaluated the effects of intracoronary radiation therapy (gamma-radiation) and may well be considered as ‘evidence-based’. As a result, differences in the modified validity score between the group of studies using balloon angioplasty as compared to intracoronary radiation therapy study are statistically significant (18±2 vs 22±3, ). This finding and differences in baseline characteristics have to be taken into account when interpreting the similar long-term results between both groups regarding the primary outcome measure ‘MACE’. No alternative debulking technique has undergone a randomized comparison against intracoronary radiation or re-dilatation thus far. Two randomized, controlled clinical trials comparing rotational atherectomy with balloon angioplasty, however, have been conducted recently and preliminary results have been presented.41,42

4.4. How to treat in-stent restenosis?
This analysis clearly suggests that balloon angioplasty should be considered as the treatmentoption of choice, especially in short and focallesions, as long as a sufficient acute procedural result can be achieved. Re-dilatation is safe, provides high procedural success, and produces favourable long-term results in localized lesions. This is a cost-effective approach without further personal or infrastructural requirements. The value of debulking techniques is yet unclear, however, it is likely that these procedures do not provide an additional benefit when adequate final lumen dimensions can be achieved with balloon angioplasty alone. Intracoronary radiation, especially using gamma-radiation sources, is the only treatment modality that has convincingly shown a superiority above balloon angioplasty for the treatment of in-stent restenosis in more diffuse lesions. In addition, the results of our meta-analysis indicate a substantial advantage for intra-coronary radiation therapy as compared to balloon angioplasty. Therefore, inpatients with the therapy-refractory form of diffuse in-stent restenosis, intracoronary radiation should be considered. So far, however, no study has shown a superiority of intra-coronary radiation therapy when other treatment modalities have failed. The long-term adverse effects of intracoronary radiation like late thrombosis and egde stenosis, however, are still not fully understood even though prolonged antiplatelet combination therapies may overcome the limitation of late thrombosis.

As a result of the unsatisfying acute and long-term results when treating in-stent restenosis, prevention of this condition has become the major focus of pre-clinical and clinical research. Stent based drug delivery systems are very attractive and initial clinical data are most promising.43 Comparable to the success of combination-platelet-therapy to reduce the incidence of subacute stent thrombosis, it is very much hoped that in-stent restenosis can be effectively prevented in the near future by stent coating techniques.

4.5. Limitations
The data incorporated into this analysis are pooled from non-randomized studies in most cases. This analysis, therefore, does not have the power of a single randomized trial using different treatment modalities for in-stent restenosis. In addition, we were not able to compose our database from individual patient data. Some of the trials included are dealing with small patient populations potentially limiting the value of this analysis. Although asystematic literature search was performed, we may have missed publications leading to a potential publication bias. This may be a consequence of the rather rigorous study inclusion process. Further techniques, like the cutting balloon, could not be included into this review as they did not meet the inclusion criteria. Conclusions drawn from selected patient populations in clinical trials are not always generalizable to broader populations in dailyclinical practice.


    5. Conclusions
 Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Treatment of in-stent restenosis, the major limitation of percutaneous coronary interventions, isassociated with an overall 30% rate of major adverse cardiac events, irrespective of the treatment modality used. The acute procedural result is a major predictor for the long-term outcome after treatment of in-stent restenosis. Currently, the recommendation is to perform a repeat balloon angioplasty for focal lesions and to considerintracoronary radiation for cases with therapy-refractory forms of diffuse in-stent restenosis. Due to unsatisfying results after treatment of in-stent restenosis, the indication for stent implantation should be considered carefully, especially in certain risk populations (i.e. diabetics). Is very much hoped that in-stent restenosis can be effectively prevented in the near future, potentially by stent coating techniques.


    Footnotes
 
This work was supported in part by a fellowship of the German Cardiac Society and the RWTH University Aachen, Germany (P.W.R.).


    References
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 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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