- Email: [email protected]
Restenosis detected by routine angiographic follow-up and late mortality after coronary stent placement
Interventional Cardiology
Restenosis detected by routine angiographic follow-up and late mortality after coronary stent placement Helmut Schu ¨ hlen, MD, FESC, FACC,a Adnan Kastrati, MD, FESC,a Julinda Mehilli, MD,a Jo ¨ rg Hausleiter, MD,a b b a Ju ¨ rgen Pache, MD, Josef Dirschinger, MD, and Albert Scho ¨ mig, MD, FESC Munich, Germany
Background
Routine 6-month follow-up angiography (FU angio) is the most sensitive tool to detect restenosis. Thus, FU angio protocols have been a pivotal part of trials on long-term efficacy of stents. However, it is unclear if such protocols supply data relevant for the prognosis of individual patients. The purpose of this study was to assess the impact of angiographic restenosis detected by FU angio on late mortality after coronary stent placement.
Methods and Results We analyzed 2272 consecutive patients with successful stent placement performed from May 1992 through December 1996. All patients were scheduled for 6-month FU angio and contacted again after 4 years. FU angio was performed in 1958 patients. Of those, 557 patients (28.4%) had restenosis. After 4 years, 8.8% of patients with restenosis died, compared to 6.0% without (P ⫽ .02). There were several significant differences in clinical and angiographic characteristics between the 2 groups. In a multivariate analysis including those characteristics plus restenosis, only older age and restenosis were independent risk factors for late mortality. In patients with severe restenosis (⬎75% of lumen diameter; n ⫽ 231), late mortality was 7.6% in those with target vascular revascularization, compared to 14.9% without (P ⫽ not significant). Conclusions
In this analysis, mortality 4 years after stent placement was higher in patients with angiographic restenosis. Restenosis was an independent risk factor for late mortality, with a potential benefit after target vessel revascularization in severe restenoses. These data suggest that routine FU angio after stenting provides data relevant for long-term prognosis of patients. (Am Heart J 2004;147:317–22.)
See related Editorial on page 197.
Stent placement during percutaneous transluminal coronary angioplasty (PTCA) has been widely adopted for the treatment of coronary artery disease. The principal drawback of stent placement has been in-stent restenosis, which develops during the first few months after the procedure.1 Typically, restenosis is viewed as a binary figure, defined by ⱖ50% lumen diameter stenosis at 6-month follow-up angiography (FU angio). This definition was based on early experimental
From the aDeutsches Herzzentrum Mu¨nchen, Technische Universita ¨ t, Munich, and b 1. Medizinische Klinik rechts der Isar, Technische Universita ¨ t, Munich, Germany. Partially supported by funds from the Technische Universita ¨ t Munich and the State of Bavaria. Submitted March 27, 2003; accepted October 6, 2003. Reprint requests: Helmut Schu¨hlen, MD, FESC, FACC, Deutsches Herzzentrum, Mu¨nchen, Lazarettstr. 36, 80636 Mu¨nchen, Germany. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.10.002
animal data indicating that coronary flow reserve is diminished in ⱖ50% diameter stenoses.2 Since then, many trials evaluating new developments in coronary interventions have included 6-month FU angio as an integral part of the protocol. This allowed for detail quantitative assessment of the lesions and vessels treated, yielding the primary end point of many trials. However, doubts have been raised with respect to the validity and clinical relevance of FU angio.3 Concerns about risks to the patient and cost of the catheterization procedures, as well as additional risks and costs due to a greater number of consecutive target vessel revascularization procedures (TVR) in patients with FU angio,4 have led to the perception that individual patients obtain no clinically relevant information or personal benefit from FU angio. More distinct data on this issue, however, might be valuable evidence for physicians caring for patients after coronary interventions. Therefore, this study sought to assess the association of angiographic results obtained by 6-month FU
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318 Schu¨hlen et al
Statistical analysis
Table I. Baseline patient characteristics Without With restenosis restenosis
P
Number of patients 1401 557 – Female (%) 22.6 24.1 .50 Age (y) 62.3 ⫾ 10.9 64.0 ⫾ 10.1 ⬍.001 Cardiovascular risk factors (%) Arterial hypertension 66.0 70.7 .042 Hypercholesterolemia 44.1 37.9 .012 Diabetes mellitus 16.3 28.2 ⬍.001 Smoker 44.4 38.4 .016 Acute coronary syndromes (%) 46.1 46.9 .80 Previous myocardial infarction (%) 40.9 35.5 .029 Previous bypass surgery (%) 11.6 12.7 .47 Multivessel disease (%) 68.0 70.6 .26 LV ejection fraction 59% ⫾ 12% 60% ⫾ 13% .45 P values as calculated by univariate analysis.
angio with mortality 4 years after successful PTCA with stent placement. This analysis is based on a large unselected study population with a routine FU angio protocol.
Methods Patient population During the study period from May 1992 throughout December 1996, 2362 consecutive patients underwent PTCA with successful stent placement at our institutions. Procedural success was defined by a residual stenosis ⬍30% and distal Thrombolysis in Myocardial Infarction flow grade ⱖ2. All patients were routinely scheduled for 6-month FU angio. Ninety patients died before FU angio. The present analysis is based on the remaining 2272 patients who were eligible for FU angio.
Procedure and follow-up management The protocol for stent placement and postprocedural management during that time period is described elsewhere.5,6 Several slotted-tube stent types were used, predominantly Palmaz-Schatz (Johnson & Johnson Interventional Systems, Warren, NJ) or Pura-A (Devon Medical, Hamburg, Germany). Patients received either an anticoagulant regimen with aspirin plus warfarin or a combined antiplatelet therapy with aspirin plus ticlopidine, both given for 4 weeks.6 Upon discharge, all patients were given a scheduled appointment for routine FU angio, typically 6 months after the procedure. Patients who did not show up were contacted by phone and offered another appointment. After 1 year and again after 4 years, patients were systematically seen or contacted by telephone. Otherwise, information was obtained from their primary care physician. Additional information on mortality was obtained from German municipal registries or inquiries were sent to foreign consulates if patients came from abroad. With this effort, mortality data at 4 years was available for 96.2% of all patients with successful stent placement.
Quantitative angiographic analysis was performed off-line on a commercially available system with edge detection algorithms (CMS, Medis Medical Imaging Systems, Nuenen, The Netherlands) by trained technicians not involved in the procedures. Data were continuously assessed and entered into a relational database. Clinical data were recorded to define procedures; angiographic data were assessed for individual lesions treated during a procedure. Analyses were performed with S-Plus software (MathSoft, Seattle, Wash), expanded by a function library by Harrell.7 Statistical significance was assumed at P ⬍ .05. For discrete variables, comparisons of 2 groups were performed using the 2 test or Fisher exact test, if appropriate. Continuous variables were analyzed with an unpaired, 2-tailed t test if normally distributed, otherwise by a Mann-Whitney U test. For interventions in ⬎1 lesion, angiographic variables of 1 randomly assigned lesion were entered into the analysis. Survival analysis was performed by the Kaplan-Meier method, and differences were assessed with log-rank tests. Logistic regression analysis was used to assess the independent role of angiographic restenosis in determining the risk for death at 4 years postprocedure, after adjusting for potential confounding variables. All clinical, angiographic or procedural factors that differed with a P value ⬍.10 in the univariate comparison of patients with and without restenosis (as specified in Tables I and II) were entered into this analysis. Adjusted risks and their 95% CIs were computed for the identified significant correlates.
Results All 2272 patients with successful coronary stent placement during the study period were scheduled for FU angio, which was performed in 1958 patients (86.2%). Overall, 181 the patients eligible for FU angio died during long-term follow-up (8.0%). Mortality was significantly lower in patients with FU angio in comparison to those without (6.8 vs 15.3%; P ⬍ .0001). In the study cohort of 1958 patients in whom FU angio had been performed, angiographic restenosis (⬎50% lumen diameter stenosis) was detected in 557 patients (28.4%). Baseline clinical and angiographic characteristics of patients with and without restenosis are illustrated in Table I; lesion characteristics and procedural data are given in Table II. The 2 patient groups differed in several respects: patients with restenosis were significantly older and more often had arterial hypertension and diabetes mellitus, but less frequently had hypercholesterolemia or were smokers. A history of previous myocardial infarction was significantly more frequent in patients with restenosis. Lesions of patients with restenosis had been more complex before PTCA (according to the American College of Cardiology/ American Heart Association classification),8 and more often consisted of restenotic lesions or chronic occlusions. Before PTCA, vessel size in these patients had been significantly smaller, stenoses had been tighter,
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Table II. Lesion characteristics and procedural data Without restenosis ACC/AHA lesion type B2 or C (%) Restenotic lesion (%) Chronic occlusion (%) Target lesion (%) LAD CX Left main RCA Venous bypass graft Vessel size (mm) Percent stenosis before PTCA Lesion length (mm) Total length of stents placed (mm) Balloon/vessel-size ratio Percent stenosis after stenting Abciximab therapy (%)
With restenosis
71.9 22.7 5.1
80.3 28.2 7.7
41.0 17.2 1.8 34.2 5.8 3.14 ⫾ 0.53 74.5 ⫾ 15.8 10.9 ⫾ 6.1 17.9 ⫾ 10.3 1.07 ⫾ 0.12 6.0 ⫾ 9.7 8.0
45.2 18.7 0.9 30.7 4.5 2.96 ⫾ 0.52 76.3 ⫾ 14.9 11.9 ⫾ 6.6 19.8 ⫾ 11.2 1.08 ⫾ 0.13 5.8 ⫾ 10.4 9.7
P ⬍.001 .011 .028 .14
⬍.001 .018 .002 ⬍.001 .051 .67 .22
ACC/AHA lesion type according to the classification described elsewhere.8 P values as calculated by univariate analysis.
Figure 1
Cumulative mortality curves for all patients with FU angio, differentiating patients with and without angiographic restenosis.
and lesions had been longer. These were treated with a longer total length of all implanted stents, and with a slightly higher balloon-to-vessel ratio. Figure 1 illustrates the Kaplan-Meier curves for mortality for all patients who underwent FU angio. Late mortality after FU angio was significantly higher in patients with restenosis in comparison to those without (8.8 vs 6.0%; P ⫽ .021). The graph illustrates that the absolute difference in mortality of almost 3% develops within the first year and is maintained thereafter. Mortality increased with severity of restenosis, as illustrated in Figure 2: it was 6.0% in patients without re-
Figure 2
Late mortality for patients with FU angio, discriminating 3 groups of different severity of restenosis according to the results of quantitative angiography: patients without restenosis (⬍50% lumen diameter stenosis), patients with moderate restenosis (50%–75% stenosis), and patients with severe restenosis (⬎75% stenosis); P value as determined by analysis for linear trend in proportions.
stenosis, 8.0% in patients with moderate restenosis (ie, 50%–75% lumen diameter stenosis), and 10% in those with severe restenosis (⬎75% lumen diameter stenosis; P ⫽ .016). Overall, TVR was performed in 59.4% of patients with restenosis during the first year after the procedure. The operator made the decision for such a procedure based on the clinical evaluation of recurrent symptoms and/or a positive stress test. Figure 3 illustrates mortality rates separately for patients with and without TVR. For patients with moderate restenosis
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320 Schu¨hlen et al
Figure 3
Figure 4
Independent factors for late mortality of patients with FU angio as identified by multivariate analysis. The graph illustrates the adjusted risk ⫾ 95% CI associated with the 2 identified independent factors (the adjusted risk was calculated per 10-year increment for the continuous variable age).
Association of late mortality with TVR for patients with angiographic restenosis. Mortality rates are illustrated separately for patients with moderate and severe restenosis, and if TVR was performed within the first year (all P ⫽ NS).
(50%–75% lumen diameter stenosis), rates were similar (8.6% for patients with TVR and 7.2% for patients without); in patients with severe restenosis (⬎75% lumen diameter stenosis), mortality was 7.6% in patients with TVR, compared to 14.9% without (P not significant for all). Overall, 49 deaths occurred in this group of patients with angiographic restenosis. Five were of definitive noncardiac cause: 2 in each group of patients with moderate restenosis, and 1 in the group of patients with severe restenosis and TVR. In a multivariate analysis comprising all patients with FU angio, the factors angiographic restenosis and TVR were entered together with all the factors with a P value ⬍ .1 by univariate analysis listed in Tables I and II. Figure 4 illustrates the only 2 identified independent factors; older age and a restenosis detected by FU angio were both significantly associated with a higher risk for mortality.
Discussion This study analyzes in detail the relationship of angiographic restenosis detected by routine FU angio and long-term mortality 4 or more years after successful stent placement, based on an unselected study population in which a routine 6-month FU angio had been planned in all patients. In this analysis, a higher mortality was seen in patients with angiographic restenosis, and mortality increased with the severity of lumen nar-
rowing. A consecutive multivariate analysis suggests that angiographic restenosis is an independent risk factor for long-term mortality, along with older age. Routine FU angio has been an integral part of follow-up protocols of the majority of trials evaluating coronary interventions. Coupled with computer-assisted quantitative analysis systems, angiographic FU provides important insights into the renarrowing process, yielding several important continuous variables of late lumen loss and comprehensive restenosis analyses.9 Together with data on the clinical course and adverse events, angiographic data provide the means to evaluate long-term efficacy of new technologies for coronary interventions. In this context, however, the value of routine FU angio has been questioned, mainly because functional status, not angiographic restenosis, was considered to be the relevant factor for long-term clinical outcome and future major adverse events.3 Outside the setting of clinical trials, FU angio has been mostly restricted to patients with recurrent symptoms or positive functional testing. Only few interventional centers have installed a routine FU angio protocol for their patients, despite a restenosis rate of approximately 30% after stent placement in an unselected study population. In addition, concerns about costs of routine FU angio and potential complications due to routine catheterization have been raised.3 Furthermore, routine FU angio leads to a significantly higher TVR rate.4,10 –12 with a further increase in costs and potential complications. Consequently, it has been questioned whether individual patients obtain any relevant data for their individual prognosis and therefore a personal benefit from a routine FU angio. These concerns have led to a general perception that there is no rationale for a routine FU angio protocol in daily practice. For an analysis of the relationship of results of FU angio with consecutive
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adverse events, however, a patient cohort in which FU angio was performed only in patients with recurrent symptoms or positive functional testing might be less suitable, as this would create a bias. At our institutions, we have maintained a FU angio protocol during the past years. The present analysis comprises our patients from May 1992 throughout December 1996, allowing long-term follow-up with data on mortality after 4 years. This was significantly lower in patients without FU angio. However, inferences from this particular observation are limited as a patient’s decision to take on a set appointment for FU angio is influenced by several variables of morbidity, noncardiac comorbidity, and patient compliance. Comprehensive data on these factors were not available for this analysis. Previous studies have investigated the long-term impact of routine FU angio. Rupprecht et al found that FU angio after PTCA was correlated with a significantly lower mortality rate during a 10-year follow-up period for 400 patients in whom a control angiography had been scheduled and performed in 79%.11 In a randomized trial of 527 patients, ten Berg at al found no difference in mortality after 2 years between a clinical and an angiographic FU.10 Both trials found a significantly higher TVR rate in the groups of patients with FU angio. Therefore it is clear that the results and potential therapeutic implications of FU angio have to be studied in more detail, as FU angio is solely a diagnostic procedure. In our study, 28.4% of patients with FU angio had ⱖ50% lumen diameter stenosis, and TVR was performed due to recurrent symptoms or signs of ischemia in 16.9% of patients. These figures are comparable to those obtained in unselected study populations after coronary stent placement in whom an FU angio protocol was carried out.13 In our study, mortality increased significantly with an increasing percentage of lumen diameter stenosis (Figure 2). In patients with severe restenosis, mortality was approximately 50% lower in patients with TVR compared to those without (Figure 3). Furthermore, restenosis along with older age were independent risk factors for late mortality in the multivariate analysis. Weintraub et al have found that restenosis is a determinant of a higher rate of myocardial infarction, but not of survival, 6 years after successful PTCA.12 However, overall mortality was very low in this study population (⬍3% after 4 years) in which patients with acute coronary syndromes had been excluded. Therefore, the present analysis is the first study to suggest a significant impact of angiographic restenosis detected by FU angio on long-term survival, based on a large and unselected study population with a general routine FU angio protocol.
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Limitations This is a retrospective analysis of an interventional database of a consecutive series of patients who had all been scheduled for FU angio. Data on noncardiac comorbidity of the study population are limited, and comprehensive data on symptoms of patients with FU angio as well as on medical therapy during the follow-up period are not available. This study does not comprise a control group of patients with repeat angiography only for recurrent symptoms. Furthermore, patients with FU angio and restenosis were not randomized to TVR versus no TVR. In particular, data on TVR have to be interpreted with caution, as it was the operator’s decision to perform TVR, based either on recurrent symptoms or signs of ischemia. The so-called “oculostenotic reflex” cannot be ruled out for individual decisions.14 Therefore, the data on TVR have to be interpreted with caution, and final conclusions should be made only after dedicated randomized trials.
Conclusions This study in a large unselected study population with a routine FU angio protocol suggests that longterm mortality is significantly higher in patients with angiographic restenosis, and increases with the grade of angiographic stenosis. In patients with severe restenosis, TVR was associated with a reduction in mortality of approximately 50%. Therefore, this analysis suggests that the individual result obtained by routine FU angio may have a significant impact on a patient’s long-term prognosis. As these data may influence daily practice and lead to important implications for physicians in charge of patients after coronary interventions, they warrant a randomized trial on routine FU angio protocol after coronary stent placement.
References 1. Lowe HC, Oesterle SN, Khachigian LM. Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol 2002; 39:183–93. 2. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis: instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974;33:87–94. 3. Litvack F, Eigler NL, Hartzler GO, et al. Universal angiographic follow-up in trials of new interventional devices: a concept whose time has passed. Circulation 1994;90:2529 –33. 4. Ruygrok PN, Melkert R, Morel MA, et al. Does angiography six months after coronary intervention influence management and outcome? Benestent II Investigators. J Am Coll Cardiol 1999;34: 1507–11. 5. Scho ¨ mig A, Kastrati A, Mudra H, et al. Four-year experience with Palmaz-Schatz stenting in coronary angioplasty complicated by dissection with threatened or present vessel closure. Circulation 1994;90:2716 –24. 6. Scho ¨ mig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the
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placement of coronary-artery stents. N Engl J Med 1996;334: 1084 –9. Harrell FE. Predicting outcomes: applied survival analysis and logistic regression. Charlottesville (Va): University of Virginia; 1997. Ellis SG, Vandormael MG, Cowley MJ, et al. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease: implications for patient selection: Multivessel Angioplasty Prognosis Study Group. Circulation 1990;82:1193–202. Baim DS, Kuntz RE. Appropriate uses of angiographic follow-up in the evaluation of new technologies for coronary intervention. Circulation 1994;90:2560 –3. ten Berg JM, Kelder JC, Suttorp MJ, et al. Influence of planned six-month follow-up angiography on late outcome after percutane-
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13. 14.
ous coronary intervention: a randomized study. J Am Coll Cardiol 2001;38:1061–9. Rupprecht HJ, Espinola-Klein C, Erbel R, et al. Impact of routine angiographic follow-up after angioplasty. Am Heart J 1998;136: 613–9. Weintraub WS, Ghazzal ZM, Douglas JS Jr, et al. Long-term clinical follow-up in patients with angiographic restudy after successful angioplasty. Circulation 1993;87:831– 40. Al Suwaidi J, Berger PB, Holmes DR Jr. Coronary artery stents. JAMA 2000;284:1828 –36. Deshpande NV, Serruys PW. Asymptomatic restenosis: should we (re)intervene? An unresolved dilemma. Am Heart J 1998;136: 576 –7.
Restenosis detected by routine angiographic follow-up and late mortality after coronary stent placement Helmut Schu ¨ hlen, MD, FESC, FACC,a Adnan Kastrati, MD, FESC,a Julinda Mehilli, MD,a Jo ¨ rg Hausleiter, MD,a b b a Ju ¨ rgen Pache, MD, Josef Dirschinger, MD, and Albert Scho ¨ mig, MD, FESC Munich, Germany
Background
Routine 6-month follow-up angiography (FU angio) is the most sensitive tool to detect restenosis. Thus, FU angio protocols have been a pivotal part of trials on long-term efficacy of stents. However, it is unclear if such protocols supply data relevant for the prognosis of individual patients. The purpose of this study was to assess the impact of angiographic restenosis detected by FU angio on late mortality after coronary stent placement.
Methods and Results We analyzed 2272 consecutive patients with successful stent placement performed from May 1992 through December 1996. All patients were scheduled for 6-month FU angio and contacted again after 4 years. FU angio was performed in 1958 patients. Of those, 557 patients (28.4%) had restenosis. After 4 years, 8.8% of patients with restenosis died, compared to 6.0% without (P ⫽ .02). There were several significant differences in clinical and angiographic characteristics between the 2 groups. In a multivariate analysis including those characteristics plus restenosis, only older age and restenosis were independent risk factors for late mortality. In patients with severe restenosis (⬎75% of lumen diameter; n ⫽ 231), late mortality was 7.6% in those with target vascular revascularization, compared to 14.9% without (P ⫽ not significant). Conclusions
In this analysis, mortality 4 years after stent placement was higher in patients with angiographic restenosis. Restenosis was an independent risk factor for late mortality, with a potential benefit after target vessel revascularization in severe restenoses. These data suggest that routine FU angio after stenting provides data relevant for long-term prognosis of patients. (Am Heart J 2004;147:317–22.)
See related Editorial on page 197.
Stent placement during percutaneous transluminal coronary angioplasty (PTCA) has been widely adopted for the treatment of coronary artery disease. The principal drawback of stent placement has been in-stent restenosis, which develops during the first few months after the procedure.1 Typically, restenosis is viewed as a binary figure, defined by ⱖ50% lumen diameter stenosis at 6-month follow-up angiography (FU angio). This definition was based on early experimental
From the aDeutsches Herzzentrum Mu¨nchen, Technische Universita ¨ t, Munich, and b 1. Medizinische Klinik rechts der Isar, Technische Universita ¨ t, Munich, Germany. Partially supported by funds from the Technische Universita ¨ t Munich and the State of Bavaria. Submitted March 27, 2003; accepted October 6, 2003. Reprint requests: Helmut Schu¨hlen, MD, FESC, FACC, Deutsches Herzzentrum, Mu¨nchen, Lazarettstr. 36, 80636 Mu¨nchen, Germany. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.10.002
animal data indicating that coronary flow reserve is diminished in ⱖ50% diameter stenoses.2 Since then, many trials evaluating new developments in coronary interventions have included 6-month FU angio as an integral part of the protocol. This allowed for detail quantitative assessment of the lesions and vessels treated, yielding the primary end point of many trials. However, doubts have been raised with respect to the validity and clinical relevance of FU angio.3 Concerns about risks to the patient and cost of the catheterization procedures, as well as additional risks and costs due to a greater number of consecutive target vessel revascularization procedures (TVR) in patients with FU angio,4 have led to the perception that individual patients obtain no clinically relevant information or personal benefit from FU angio. More distinct data on this issue, however, might be valuable evidence for physicians caring for patients after coronary interventions. Therefore, this study sought to assess the association of angiographic results obtained by 6-month FU
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318 Schu¨hlen et al
Statistical analysis
Table I. Baseline patient characteristics Without With restenosis restenosis
P
Number of patients 1401 557 – Female (%) 22.6 24.1 .50 Age (y) 62.3 ⫾ 10.9 64.0 ⫾ 10.1 ⬍.001 Cardiovascular risk factors (%) Arterial hypertension 66.0 70.7 .042 Hypercholesterolemia 44.1 37.9 .012 Diabetes mellitus 16.3 28.2 ⬍.001 Smoker 44.4 38.4 .016 Acute coronary syndromes (%) 46.1 46.9 .80 Previous myocardial infarction (%) 40.9 35.5 .029 Previous bypass surgery (%) 11.6 12.7 .47 Multivessel disease (%) 68.0 70.6 .26 LV ejection fraction 59% ⫾ 12% 60% ⫾ 13% .45 P values as calculated by univariate analysis.
angio with mortality 4 years after successful PTCA with stent placement. This analysis is based on a large unselected study population with a routine FU angio protocol.
Methods Patient population During the study period from May 1992 throughout December 1996, 2362 consecutive patients underwent PTCA with successful stent placement at our institutions. Procedural success was defined by a residual stenosis ⬍30% and distal Thrombolysis in Myocardial Infarction flow grade ⱖ2. All patients were routinely scheduled for 6-month FU angio. Ninety patients died before FU angio. The present analysis is based on the remaining 2272 patients who were eligible for FU angio.
Procedure and follow-up management The protocol for stent placement and postprocedural management during that time period is described elsewhere.5,6 Several slotted-tube stent types were used, predominantly Palmaz-Schatz (Johnson & Johnson Interventional Systems, Warren, NJ) or Pura-A (Devon Medical, Hamburg, Germany). Patients received either an anticoagulant regimen with aspirin plus warfarin or a combined antiplatelet therapy with aspirin plus ticlopidine, both given for 4 weeks.6 Upon discharge, all patients were given a scheduled appointment for routine FU angio, typically 6 months after the procedure. Patients who did not show up were contacted by phone and offered another appointment. After 1 year and again after 4 years, patients were systematically seen or contacted by telephone. Otherwise, information was obtained from their primary care physician. Additional information on mortality was obtained from German municipal registries or inquiries were sent to foreign consulates if patients came from abroad. With this effort, mortality data at 4 years was available for 96.2% of all patients with successful stent placement.
Quantitative angiographic analysis was performed off-line on a commercially available system with edge detection algorithms (CMS, Medis Medical Imaging Systems, Nuenen, The Netherlands) by trained technicians not involved in the procedures. Data were continuously assessed and entered into a relational database. Clinical data were recorded to define procedures; angiographic data were assessed for individual lesions treated during a procedure. Analyses were performed with S-Plus software (MathSoft, Seattle, Wash), expanded by a function library by Harrell.7 Statistical significance was assumed at P ⬍ .05. For discrete variables, comparisons of 2 groups were performed using the 2 test or Fisher exact test, if appropriate. Continuous variables were analyzed with an unpaired, 2-tailed t test if normally distributed, otherwise by a Mann-Whitney U test. For interventions in ⬎1 lesion, angiographic variables of 1 randomly assigned lesion were entered into the analysis. Survival analysis was performed by the Kaplan-Meier method, and differences were assessed with log-rank tests. Logistic regression analysis was used to assess the independent role of angiographic restenosis in determining the risk for death at 4 years postprocedure, after adjusting for potential confounding variables. All clinical, angiographic or procedural factors that differed with a P value ⬍.10 in the univariate comparison of patients with and without restenosis (as specified in Tables I and II) were entered into this analysis. Adjusted risks and their 95% CIs were computed for the identified significant correlates.
Results All 2272 patients with successful coronary stent placement during the study period were scheduled for FU angio, which was performed in 1958 patients (86.2%). Overall, 181 the patients eligible for FU angio died during long-term follow-up (8.0%). Mortality was significantly lower in patients with FU angio in comparison to those without (6.8 vs 15.3%; P ⬍ .0001). In the study cohort of 1958 patients in whom FU angio had been performed, angiographic restenosis (⬎50% lumen diameter stenosis) was detected in 557 patients (28.4%). Baseline clinical and angiographic characteristics of patients with and without restenosis are illustrated in Table I; lesion characteristics and procedural data are given in Table II. The 2 patient groups differed in several respects: patients with restenosis were significantly older and more often had arterial hypertension and diabetes mellitus, but less frequently had hypercholesterolemia or were smokers. A history of previous myocardial infarction was significantly more frequent in patients with restenosis. Lesions of patients with restenosis had been more complex before PTCA (according to the American College of Cardiology/ American Heart Association classification),8 and more often consisted of restenotic lesions or chronic occlusions. Before PTCA, vessel size in these patients had been significantly smaller, stenoses had been tighter,
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Table II. Lesion characteristics and procedural data Without restenosis ACC/AHA lesion type B2 or C (%) Restenotic lesion (%) Chronic occlusion (%) Target lesion (%) LAD CX Left main RCA Venous bypass graft Vessel size (mm) Percent stenosis before PTCA Lesion length (mm) Total length of stents placed (mm) Balloon/vessel-size ratio Percent stenosis after stenting Abciximab therapy (%)
With restenosis
71.9 22.7 5.1
80.3 28.2 7.7
41.0 17.2 1.8 34.2 5.8 3.14 ⫾ 0.53 74.5 ⫾ 15.8 10.9 ⫾ 6.1 17.9 ⫾ 10.3 1.07 ⫾ 0.12 6.0 ⫾ 9.7 8.0
45.2 18.7 0.9 30.7 4.5 2.96 ⫾ 0.52 76.3 ⫾ 14.9 11.9 ⫾ 6.6 19.8 ⫾ 11.2 1.08 ⫾ 0.13 5.8 ⫾ 10.4 9.7
P ⬍.001 .011 .028 .14
⬍.001 .018 .002 ⬍.001 .051 .67 .22
ACC/AHA lesion type according to the classification described elsewhere.8 P values as calculated by univariate analysis.
Figure 1
Cumulative mortality curves for all patients with FU angio, differentiating patients with and without angiographic restenosis.
and lesions had been longer. These were treated with a longer total length of all implanted stents, and with a slightly higher balloon-to-vessel ratio. Figure 1 illustrates the Kaplan-Meier curves for mortality for all patients who underwent FU angio. Late mortality after FU angio was significantly higher in patients with restenosis in comparison to those without (8.8 vs 6.0%; P ⫽ .021). The graph illustrates that the absolute difference in mortality of almost 3% develops within the first year and is maintained thereafter. Mortality increased with severity of restenosis, as illustrated in Figure 2: it was 6.0% in patients without re-
Figure 2
Late mortality for patients with FU angio, discriminating 3 groups of different severity of restenosis according to the results of quantitative angiography: patients without restenosis (⬍50% lumen diameter stenosis), patients with moderate restenosis (50%–75% stenosis), and patients with severe restenosis (⬎75% stenosis); P value as determined by analysis for linear trend in proportions.
stenosis, 8.0% in patients with moderate restenosis (ie, 50%–75% lumen diameter stenosis), and 10% in those with severe restenosis (⬎75% lumen diameter stenosis; P ⫽ .016). Overall, TVR was performed in 59.4% of patients with restenosis during the first year after the procedure. The operator made the decision for such a procedure based on the clinical evaluation of recurrent symptoms and/or a positive stress test. Figure 3 illustrates mortality rates separately for patients with and without TVR. For patients with moderate restenosis
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Figure 3
Figure 4
Independent factors for late mortality of patients with FU angio as identified by multivariate analysis. The graph illustrates the adjusted risk ⫾ 95% CI associated with the 2 identified independent factors (the adjusted risk was calculated per 10-year increment for the continuous variable age).
Association of late mortality with TVR for patients with angiographic restenosis. Mortality rates are illustrated separately for patients with moderate and severe restenosis, and if TVR was performed within the first year (all P ⫽ NS).
(50%–75% lumen diameter stenosis), rates were similar (8.6% for patients with TVR and 7.2% for patients without); in patients with severe restenosis (⬎75% lumen diameter stenosis), mortality was 7.6% in patients with TVR, compared to 14.9% without (P not significant for all). Overall, 49 deaths occurred in this group of patients with angiographic restenosis. Five were of definitive noncardiac cause: 2 in each group of patients with moderate restenosis, and 1 in the group of patients with severe restenosis and TVR. In a multivariate analysis comprising all patients with FU angio, the factors angiographic restenosis and TVR were entered together with all the factors with a P value ⬍ .1 by univariate analysis listed in Tables I and II. Figure 4 illustrates the only 2 identified independent factors; older age and a restenosis detected by FU angio were both significantly associated with a higher risk for mortality.
Discussion This study analyzes in detail the relationship of angiographic restenosis detected by routine FU angio and long-term mortality 4 or more years after successful stent placement, based on an unselected study population in which a routine 6-month FU angio had been planned in all patients. In this analysis, a higher mortality was seen in patients with angiographic restenosis, and mortality increased with the severity of lumen nar-
rowing. A consecutive multivariate analysis suggests that angiographic restenosis is an independent risk factor for long-term mortality, along with older age. Routine FU angio has been an integral part of follow-up protocols of the majority of trials evaluating coronary interventions. Coupled with computer-assisted quantitative analysis systems, angiographic FU provides important insights into the renarrowing process, yielding several important continuous variables of late lumen loss and comprehensive restenosis analyses.9 Together with data on the clinical course and adverse events, angiographic data provide the means to evaluate long-term efficacy of new technologies for coronary interventions. In this context, however, the value of routine FU angio has been questioned, mainly because functional status, not angiographic restenosis, was considered to be the relevant factor for long-term clinical outcome and future major adverse events.3 Outside the setting of clinical trials, FU angio has been mostly restricted to patients with recurrent symptoms or positive functional testing. Only few interventional centers have installed a routine FU angio protocol for their patients, despite a restenosis rate of approximately 30% after stent placement in an unselected study population. In addition, concerns about costs of routine FU angio and potential complications due to routine catheterization have been raised.3 Furthermore, routine FU angio leads to a significantly higher TVR rate.4,10 –12 with a further increase in costs and potential complications. Consequently, it has been questioned whether individual patients obtain any relevant data for their individual prognosis and therefore a personal benefit from a routine FU angio. These concerns have led to a general perception that there is no rationale for a routine FU angio protocol in daily practice. For an analysis of the relationship of results of FU angio with consecutive
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adverse events, however, a patient cohort in which FU angio was performed only in patients with recurrent symptoms or positive functional testing might be less suitable, as this would create a bias. At our institutions, we have maintained a FU angio protocol during the past years. The present analysis comprises our patients from May 1992 throughout December 1996, allowing long-term follow-up with data on mortality after 4 years. This was significantly lower in patients without FU angio. However, inferences from this particular observation are limited as a patient’s decision to take on a set appointment for FU angio is influenced by several variables of morbidity, noncardiac comorbidity, and patient compliance. Comprehensive data on these factors were not available for this analysis. Previous studies have investigated the long-term impact of routine FU angio. Rupprecht et al found that FU angio after PTCA was correlated with a significantly lower mortality rate during a 10-year follow-up period for 400 patients in whom a control angiography had been scheduled and performed in 79%.11 In a randomized trial of 527 patients, ten Berg at al found no difference in mortality after 2 years between a clinical and an angiographic FU.10 Both trials found a significantly higher TVR rate in the groups of patients with FU angio. Therefore it is clear that the results and potential therapeutic implications of FU angio have to be studied in more detail, as FU angio is solely a diagnostic procedure. In our study, 28.4% of patients with FU angio had ⱖ50% lumen diameter stenosis, and TVR was performed due to recurrent symptoms or signs of ischemia in 16.9% of patients. These figures are comparable to those obtained in unselected study populations after coronary stent placement in whom an FU angio protocol was carried out.13 In our study, mortality increased significantly with an increasing percentage of lumen diameter stenosis (Figure 2). In patients with severe restenosis, mortality was approximately 50% lower in patients with TVR compared to those without (Figure 3). Furthermore, restenosis along with older age were independent risk factors for late mortality in the multivariate analysis. Weintraub et al have found that restenosis is a determinant of a higher rate of myocardial infarction, but not of survival, 6 years after successful PTCA.12 However, overall mortality was very low in this study population (⬍3% after 4 years) in which patients with acute coronary syndromes had been excluded. Therefore, the present analysis is the first study to suggest a significant impact of angiographic restenosis detected by FU angio on long-term survival, based on a large and unselected study population with a general routine FU angio protocol.
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Limitations This is a retrospective analysis of an interventional database of a consecutive series of patients who had all been scheduled for FU angio. Data on noncardiac comorbidity of the study population are limited, and comprehensive data on symptoms of patients with FU angio as well as on medical therapy during the follow-up period are not available. This study does not comprise a control group of patients with repeat angiography only for recurrent symptoms. Furthermore, patients with FU angio and restenosis were not randomized to TVR versus no TVR. In particular, data on TVR have to be interpreted with caution, as it was the operator’s decision to perform TVR, based either on recurrent symptoms or signs of ischemia. The so-called “oculostenotic reflex” cannot be ruled out for individual decisions.14 Therefore, the data on TVR have to be interpreted with caution, and final conclusions should be made only after dedicated randomized trials.
Conclusions This study in a large unselected study population with a routine FU angio protocol suggests that longterm mortality is significantly higher in patients with angiographic restenosis, and increases with the grade of angiographic stenosis. In patients with severe restenosis, TVR was associated with a reduction in mortality of approximately 50%. Therefore, this analysis suggests that the individual result obtained by routine FU angio may have a significant impact on a patient’s long-term prognosis. As these data may influence daily practice and lead to important implications for physicians in charge of patients after coronary interventions, they warrant a randomized trial on routine FU angio protocol after coronary stent placement.
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