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Original Contribution
Temporal Trends in Target Vessel Revascularization in Clinical Practice: Long-Term Outcomes following Coronary Stenting
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September 2006
Randomized clinical trials evaluating coronary stents versus balloon angioplasty have demonstrated marked improvements in the short- and long-term safety and efficacy of percutaneous coronary intervention (PCI) by reducing restenosis and the need for repeat revascularization.1–5 However, since the introduction of coronary stents, whether advances in stent design, balloon delivery catheter and adjunctive pharmacologic therapies have improved clinical outcomes among patients undergoing percutaneous revascularization remains uncertain.
The Duke Database for Cardiovascular Disease is the largest observational study of patients with cardiovascular disease, providing insight to early and late clinical outcomes that are not systematically acquired in the context of routine clinical practice. Although patients enrolled in the database may be included in other clinical trials, this longitudinal study overall represents a broad, unselected patient population with varying cardiovascular risk and disease severity. Among 5,765 patients in this study who underwent percutaneous coronary revascularization with stent placement between 1994 and 2002, we examined temporal trends in long-term outcomes to characterize rates of death and clinical restenosis in a general PCI population and compared these results with recent clinical trials involving compulsory follow-up angiography.
Methods
To characterize the effectiveness of coronary stenting and define patterns of clinical events in routine practice, we examined 1-year clinical outcomes of death and target vessel revascularization (TVR) among 5,765 patients with complete clinical, demographic and angiographic data who were enrolled in the Duke Database for Cardiovascular Disease and underwent stent placement between 1994 and 2002. Patients included in this analysis represented a broad population of patients with coronary artery disease and varied clinical presentation, including those with stable angina and acute coronary syndromes. Patients in the database are routinely followed at 6 months and annually thereafter using mailed questionnaires, telephone interviews or via a search in the National Death Index for patients whose vital status is unknown. Clinical events are verified using source documentation. Data collection and archiving of clinical variables in the database were performed according to methods previously described.6,7 Except for those patients with prior bypass surgery, valvular heart disease and congenital heart disease, all patients undergoing percutaneous revascularization of a de novo native coronary lesion with stent placement were included. Decisions regarding additional device selection and use of adjunctive pharmacological therapies during the revascularization procedure were not assessed. Following informed consent, patients were evaluated for outcomes of death and TVR at 3-month intervals over a 1-year period. To assess for temporal trends in outcomes, patients were further divided into tertiles according to the year of initial revascularization.
The primary objective of this analysis was to determine rates of death and TVR in an unselected patient population and identify whether differences in clinical outcome existed over an 8-year period that paralleled substantial advances in stent design, balloon delivery catheter and adjunctive pharmacologic therapies. Further, we intended to compare these outcomes with those from contemporary stent trials that require compulsory angiographic follow up.
Baseline characteristics and event rates were summarized for all patient groups as percentages for categorical variables and medians with interquartile ranges (25th, 75th) for continuous variables. Cumulative event-free survival was determined for clinical outcomes of death and TVR using the Kaplan-Meier method. Adjusted analyses were performed using Cox proportional hazards multivariable modeling techniques. Adjustment was made for patient demographics, angiographic characteristics (particularly stent diameter and length), underlying comorbidities and other clinical factors (Appendix A). P-values reported are from the year-tertile variables inserted in the respective Cox models.
Results
Between 1994 and 2002, 5,675 patients with ischemic heart disease who underwent coronary stenting and were enrolled in the Duke Database for Cardiovascular Disease were included in this analysis. One-year follow up for event-free survival of death and repeat revascularization was complete for 98% of the study population. Depending upon the date of initial revascularization, patients were further divided into 3 tertiles, 1994 to 1996 (Group 1: 1,101 patients), 1997 to 1999 (Group 2: 2,500 patients) and 2000 to 2002 (Group 3: 2,164 patients).
Table 1 describes the patient clinical and demographic characteristics. Patients underwent PCI for a variety of clinical presentations including recent myocardial infarction (MI) (43.3%), acute MI (i.e., infarction during index hospitalization, 26.8%), unstable angina (23.1%), and heart failure (9.7%). Most patients had single-vessel disease (>/=75% stenosis), and elective PCI was performed in 87.7% of patients.
Comparing patient tertiles over the 8-year period, risk factors such as hypertension, hyperlipidemia, smoking and prior MI or peripheral vascular disease significantly declined (Table 1). Conversely, characteristics related to the acuity of patient presentation and illness severity increased, such as acute MI, advanced heart failure, unstable angina and the presence of multivessel disease. Further, a significant decline in the number of revascularization procedures performed on larger-caliber vessels (e.g., >/=3.0 mm) was balanced by a considerable increase in revascularization involving smaller-diameter vessels.
Over 1 year, survival free of repeat TVR incrementally decreased, with most events occurring within the initial 9 months following the index procedure (Figure 1). In the entire cohort, unadjusted 1-year rates of death and TVR were 4.9% and 11.4%, respectively. Among the patient tertiles divided according to the year of revascularization, rates of TVR tended to decrease with more recent years in unadjusted analysis (p = 0.01 for 1 year TVR across the groups). However, survival did not statistically differ across patient groups (p = 0.23 for 1-year mortality across the groups). Similarly, following adjustment for differences in baseline clinical and angiographic risk, 1-year survival did not significantly differ between patients undergoing coronary stenting over time (p = 0.95) (Figure 2), although rates of repeat TVR significantly decreased (11.1% for patients treated in 1994–1996, 11.5% for 1997–1999, 9.3% for 2000–2002; p = 0.003) (Figure 3).
Conclusions
Although long-term survival has not changed since the advent of coronary stenting, we identified a modest but significant decline in the rate of repeat revascularization over an 8-year period of consecutive patients undergoing catheter-based revascularization. Most events occur within the initial months following revascularization, yet late clinical restenosis persists. Nevertheless, in a broad, unselected population of patients in whom repeat angiography is not protocol-specified, rates of repeat TVR following percutaneous revascularization with coronary stents are substantially lower than those observed in recent clinical trials. These findings have important implications when considering clinical trial outcomes in the context of real-world clinical practice.
Although binary restenosis appears to correlate with target lesion revascularization (TLR), a common observation in contemporary stent trials is the substantially higher rate of repeat revascularization among patients in the angiographic cohorts compared with those in the non-angiographic cohorts within the same studies.8–12 In general, the rate of clinical restenosis is one-half that of angiographic restenosis1–3,13 and is predicted by the same variables associated with an increased risk of angiographic restenosis.13 From previous studies of coronary stenting that included both angiographic and clinical restenosis outcomes, most of the difference in this ratio has been attributed to less frequent TLR in lesions with less severe (e.g., 13 However, there are additional factors that may strongly influence this relationship; for example, the reluctance to treat side branch restenosis in a bifurcation when the parent vessel is patent, or a higher threshold for treating restenosis in smaller diameter vessels that supply a small myocardial territory.
Because rates of repeat TVR in clinical practice vary considerably compared with those enrolled in trials that include routine follow-up angiography (Table 2), these results highlight the discordance between angiographic and clinical restenosis, suggesting either that many patients with angiographically-defined luminal narrowing do not actually have hemodynamically significant disease, or instead that many patients with restenosis may remain clinically asymptomatic. This marked disparity in repeat TVR indicates that trial protocol angiography is likely to have a considerable impact on the rates of repeat TVR, such that some adjustment for protocol-specified re-look angiography rates should be considered when applying trial findings to clinical practice. The difference in repeat TVR is even further remarkable given that patients in the present analysis were not excluded based on angiographic lesion complexity (e.g., long lesions, bifurcations, total occlusions) or comorbidity. In fact, despite relatively lower rates of repeat revascularization, 1-year mortality was considerably higher in the unselected database patients compared indirectly with clinical trial populations.
It is also noteworthy that the event rates in TVR between 9 months and 1 year continue to diverge between trial and general patient populations (Table 2),8–12 also suggesting that participation in a clinical trial may influence outcomes beyond the period of follow-up angiography. Although a gradual decrement in repeat TVR is observed over the initial year following revascularization, most events related to TVR do occur within the initial 6 to 9 months. However, clinical restenosis persists beyond 6 months, with an observed relative 30% and 10% increase every 3 months in repeat TVR at 9 and 12 months, respectively, implying that abbreviated follow up of clinical outcomes in clinical trials may fail to capture many events.
Perhaps due to refinements in catheter-based technologies and advances in adjunctive pharmacologic therapies, rates of repeat TVR in clinical practice have significantly declined in a modern era of PCI yet without significant improvement in survival. The temporal reduction in TVR in an era of bare metal stents is remarkable given that advances in stent technology have enabled treatment of more complex disease, including smaller vessels and longer lesions that might instead predict a higher likelihood for restenosis. However, despite the advancement of therapies and technique, the absence of improved survival over time with PCI underscores the ongoing need for adherence to therapeutic interventions associated with improvements in long-term survival (e.g., smoking cessation, exercise and diet modification, aspirin and pharmacologic therapies for hypercholesterolemia, hypertension or heart failure). In addition, compared with lower-risk patients in clinical trials, the higher mortality observed in a real-world PCI population emphasizes the need for evaluation of novel stent technologies in off-label use and higher-risk groups.
Given that most TVR events in contemporary practice are clinically driven, the impact of drug-eluting stents (DES) on the avoidance of long-term repeat TVR is likely to be substantial, with event rates following treatment with DES in clinical practice expected to parallel the observations with bare metal stents and be lower than those observed in DES trials involving compulsory follow-up angiography. Compared with clinical trials, however, the relative reduction in long-term repeat TVR with DES versus bare metal stents is likely to be lessened in a broad, unselected population than in clinical trials. Importantly, such differences should not imply reducing efficacy in avoiding restenosis and TVR, but rather reflect considerable practice variation in the threshold to perform repeat revascularization.
Study limitations. As an observational study, an important limitation to this study is that clinical events in the Duke Cardiovascular Database are verified with source documentation, but not centrally adjudicated, an issue which may be particularly relevant for the confirmation of nonfatal events like repeat revascularization. Results from this report also represent those from a single institution and may therefore not be generalizable to broader clinical practice. Further, our analysis examined rates of TVR rather than TLR, with this latter endpoint more closely representing clinical restenosis associated with the index procedure. However, previous studies that have assessed both TVR and TLR events demonstrate that the two outcomes are highly correlated with only a 13 It is therefore likely that evaluation of TLR in the Duke database would parallel the discordance observed with TVR between a general patient population and those enrolled in contemporary clinical trials. Finally, any comparisons of outcomes between patients in routine practice with those enrolled in clinical trials are indirect and limited by the likelihood for unmeasured, confounding differences between study populations. However, it was in part because of this likelihood for differences in clinical, demographic and angiographic characteristics that this analysis was performed to describe the disparity in clinical restenosis between clinical trial and real world patient populations.
Appendix A
Patient demographic, clinical and treatment characteristics for the multivariable model for target vessel revascularization included: age, history of diabetes, left ventricular ejection fraction, renal insufficiency, Charlson comorbidity index, New York Heart Failure classification, body mass index, elective versus urgent PCI, history of myocardial infarction, vessel diameter (
References
1. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease: BENESTENT study group. N Engl J Med 1994;331:489-495.
2. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis study investigators. N Engl J Med 1994;331:496–501.
3. Serruys PW, van Hout B, Bonnier H, et al. Randomized comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (BENESTENT II). Lancet 1998;352:673–681.
4. Weaver WD, Reisman MA, Griffin JJ, et al. Optimum percutaneous transluminal coronary angioplasty compared with routine stent strategy trial (OPUS-1): A randomized trial. Lancet 2000;355:2199–2203.
5. Rodriguez A, Ayala F, Bernardi V, et al. Optimal coronary balloon angioplasty with provisional stenting versus primary stent (OCBAS): Immediate and long-term follow-up results. J Am Coll Cardiol 1998;32:1351–1357.
6. Harris PJ, Lee KL, Harrell FE, et al. Outcome in medically treated coronary artery disease: Nonfatal infarction and death. Circulation 1980;62:718–726.
7. Mark DB, Nelson CL, Califf RM, et al. Continuing evolution of therapy for coronary artery disease. Initial results from the era of coronary angioplasty. Circulation 1994;89:2015–2025.
8. Morice MC, Serruys PW, Sousa EJ, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1173–1780.
9. Moses JW, Leon MB, Popma JJ, et al. for the SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
10. Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. The TAXUS II study group. Circulation 2003;108:788–794.
11. Stone GW, Ellis SG, Cox DA, et al. for the TAXUS IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231.
12. Wijns W. A randomized trial to evaluate the safety and efficacy of the Medtronic AVE ABT-578 eluting Driver stent in de novo native coronary artery lesions. Presented at: 2005 Scientific Session of the American College of Cardiology; March 6, 2005; Orlando, Florida.
13. Cutlip DE, Chauhan MS, Baim DS, et al. Clinical restenosis after coronary stenting: Perspectives from multicenter clinical trials. J Am Coll Cardiol 2002;40:2082–2089.
14. Holmes DR, Leon MB, Moses JW, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial: A randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation 2004;109:634–640.
15. Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: The TAXUS-IV Trial. Circulation 2004;109:1942–1947.
16. Wijns W. A randomized trial to evaluate the safety and efficacy of the Medtronic AVE ABT-578 eluting Driver stent in de novo native coronary artery lesions: 1-year clinical outcomes. Presented at: 2005 European Society of Cardiology Scientific Sessions; September 4, 2005; Stockholm, Sweden.
