Author + information
- Received August 25, 2014
- Accepted August 28, 2014
- Published online January 1, 2015.
- Stephan Blazek, MD∗,
- Cornelius Rossbach, BSc∗,
- Michael A. Borger, MD†,
- Georg Fuernau, MD∗,
- Steffen Desch, MD∗,‡,
- Ingo Eitel, MD∗,‡,
- Thomas Stiermaier, MD∗,
- Philipp Lurz, MD∗,
- David Holzhey, MD†,
- Gerhard Schuler, MD∗,
- Friedrich-Wilhelm Mohr, MD† and
- Holger Thiele, MD∗,‡∗ ()
- ∗Department of Internal Medicine/Cardiology, University of Leipzig—Heart Center, Leipzig, Germany
- †Department of Cardiac Surgery, University of Leipzig—Heart Center, Leipzig, Germany
- ‡Medical Clinic II, University of Lübeck, Lübeck, Germany
- ↵∗Reprint requests and correspondence:
Dr. Holger Thiele, University of Lübeck and University Hospital Schleswig-Holstein–Campus Lübeck, Medical Clinic II, Internal Medicine/Cardiology/Angiology/Intensive Care Medicine, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Objectives The aim of this analysis was to assess the 7-year long-term safety and effectiveness of a randomized comparison of percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SES) versus minimally invasive direct coronary artery bypass (MIDCAB) surgery for the treatment of isolated proximal left anterior descending lesions.
Background Long-term follow-up data comparing PCI by SES and MIDCAB surgery for isolated proximal left anterior descending lesions are sparse.
Methods Patients were randomized either to PCI with SES (n = 65) or MIDCAB (n = 65). Follow-up data were obtained after 7 years with respect to the primary composite endpoint of death, myocardial infarction, and target vessel revascularization. Angina was assessed by the Canadian Cardiovascular Society classification and quality of life with Short Form 36 and MacNew quality of life questionnaires.
Results Follow-up was conducted in 129 patients at a median time of 7.3 years (interquartile range: 5.7, 8.3). There were no significant differences in the incidence of the primary composite endpoint between groups (22% PCI vs. 12% MIDCAB; p = 0.17) or the endpoints death (14% vs. 17%; p = 0.81) and myocardial infarction (6% vs. 9%, p = 0.74). However, the target vessel revascularization rate was higher in the PCI group (20% vs. 1.5%; p < 0.001). Clinical symptoms and quality of life improved significantly from baseline with both interventions and were similar in magnitude between groups.
Conclusions At 7-year follow-up, PCI by SES and MIDCAB in isolated proximal left anterior descending lesions yielded similar long-term outcomes regarding the primary composite clinical endpoint and quality of life. Target vessel revascularization was more frequent in the PCI group. (MIDCAB Versus DES in Proximal LAD Lesions; NCT00299429)
- bypass surgery
- drug-eluting stent
- left anterior descending artery
- long-term follow-up
- percutaneous coronary intervention
Clinical prognosis in patients with untreated high-grade proximal stenosis of the left anterior descending (LAD) artery is poor due to the large territory of myocardium at risk (1,2). Established treatment options in isolated severe stenosis of the proximal LAD comprise bypass grafting by minimally invasive direct coronary artery bypass (MIDCAB) surgery and percutaneous coronary intervention (PCI) either with bare-metal (BMS) or drug-eluting stents (DES) (3–5). At long-term follow-up, BMS in proximal LAD disease had a higher target vessel revascularization (TVR) rate in comparison to MIDCAB surgery, whereas the incidence of more critical endpoints such as myocardial infarction and death was similar (6,7). The risk of in-stent restenosis and TVR could be reduced with the use of DES instead of BMS (8). We previously presented 12 month results of the only randomized comparison of PCI with sirolimus-eluting stents (SES) to MIDCAB surgery for isolated proximal lesions of the LAD showing noninferiority of the percutaneous approach (9). To further elucidate long-term advantages or disadvantages of PCI with SES in comparison to MIDCAB surgery, we hereby present the 7-year follow-up of this randomized, prospective trial (9).
The detailed design of this trial has been described previously (9). In summary, symptomatic patients with compatible symptoms and/or documented myocardial ischemia and isolated high-grade lesions (>50% diameter stenosis) of the proximal LAD were included. A consensus on patient eligibility had to be obtained from both the cardiac surgeon and the cardiologist before randomization. After written informed consent, balanced randomization via sealed envelopes was performed, assigning patients to PCI by SES (Cypher, Cordis, Langenfeld, Germany) or MIDCAB surgery.
Exclusion criteria were acute coronary syndromes requiring immediate intervention, additional valvular heart disease requiring treatment, previous interventional or surgical treatment for coronary artery or valvular disease, severe peripheral arterial disease, significant carotid stenosis requiring treatment, renal dysfunction requiring dialysis, any diseases with limited life expectancy, overt congestive heart failure, upper gastrointestinal bleeding <4 weeks, contraindication to antiplatelet therapy, and extreme obesity (due to MIDCAB surgery preclusion).
Angiographic exclusion criteria were total occlusions, involvement of the left main stem, stenosis of the first diagonal branch, intramyocardial course of the LAD, stenosis extending over a major diagonal branch (>1.5 mm), and stenosis at any other location requiring treatment. The study was approved by the institutional ethics committee and all patients gave written informed consent.
Stenting with SES was performed according to standard practice (9). Patients received aspirin 100 mg/d indefinitely and clopidogrel 75 mg/d for 12 months following a loading dose of 600 mg before the procedure.
Minimally invasive direct coronary artery bypass surgery
Standard MIDCAB surgery was performed through a left anterolateral minithoracotomy on the beating heart without cardiopulmonary bypass under general anesthesia (9). The left internal thoracic artery was used as bypass graft. Aspirin (100 mg/d) treatment was recommended indefinitely.
At 7 years, data were collected by a structured patient interview including assessment of clinical endpoints, anginal symptoms, and quality of life. Reported clinical events were confirmed by contact with the general practitioner, referring cardiologist, and/or the treating hospital. Death was defined as death from any cause. Death was regarded as cardiac in origin unless obvious noncardiac causes could be identified. In case of any doubt, death was counted as cardiac. For myocardial infarction, the universal definition of myocardial infarction criteria was applied (10).
The initial study protocol mandated a complete clinical work-up, including symptom-limited exercise stress test and invasive coronary angiography at 12-month follow-up. During the subsequent course, further noninvasive or invasive studies were only performed if clinically indicated due to symptoms or objective ischemia. Repeated interventions were therefore clinically driven and performed only in case of recurrence of angina and/or a positive stress test. For survival analysis, data until their last known status were used.
All events were adjudicated by a blinded event committee consisting of an experienced cardiologist and cardiovascular surgeon.
The primary composite endpoint was freedom from major adverse cardiovascular events (MACE), defined as death from any cause, myocardial infarction, and the need for repeated TVR. Secondary endpoints were each individual component of the primary endpoint. For the combined MACE rate, to avoid double counting of patients with more than 1 event, each patient contributed only once to the composite MACE endpoint and the first occurring event was counted regardless of severity.
Quality of life
Quality of life was assessed by 2 standard questionnaires. The Short Form 36 (SF-36) is a 36-item test evaluating 8 dimensions of health including: limitations in physical functioning; usual role activities; social functioning related to health problems; and vitality. Furthermore, it provides a global evaluation of health. Each dimension is scored on a scale from 0 to 100 (11).
Additionally, health-related quality of life was assessed using the MacNew Quality of Life Questionnaire, which is specifically designed for patients with heart disease. It involves 27 items with 3 subscales (emotional, physical, and social) and a global scale (12). In both tests, higher scores indicate higher quality of life.
Anginal symptoms were assessed by the Canadian Cardiovascular Society classification and the use of antianginal drugs such as nitrates, ranolazine, or ivabradine was recorded.
All analyses were performed according to the intention-to-treat principle. Patients lost to follow-up were excluded in the analysis. Categorical variables are expressed as number and percent of patients. Continuous variables are reported as mean ± SD or median and interquartile range (IQR) according to their distribution. Values between groups were compared by unpaired Student t-test after testing for normal distribution; otherwise, nonparametric Mann-Whitney U tests were used. Fisher exact or chi-square tests were used for categorical variables with nominal scales. Values across time were compared by paired t-tests or nonparametric Wilcoxon tests.
For clinical endpoints, the Kaplan-Meier method was applied, and differences were assessed by the log-rank test. Hazard ratios and their 95% confidence intervals (CIs) were calculated according to Klein (13). For quality of life endpoints, a mixed model for repeated measures was used to compare sirolimus-eluting stenting and MIDCAB surgery at 12-month to 7-year follow-up on SF-36 and MacNew domains. For intragroup comparison, paired t-tests or nonparametric Wilcoxon rank sum tests were used.
Additionally, exploratory landmark analyses using the Kaplan-Meier method were performed for the primary composite endpoint and TVR. The landmark was chosen at 12 months and therefore the first analysis covers the period from 0 to 12 months and the second the period from 12 months to 7 years. Detailed results in the time frame 0 to 12 months have been published previously (9). Any patient with an event prior to the 12-month landmark was excluded from further analysis for the second period regarding the composite endpoint. For the TVR landmark analysis, those patients with previous TVR or death where excluded.
The statistical analyses were conducted with the use of SPSS (version 17.0, SPSS Inc., Chicago, Illinois). A 2-tailed probability value of p < 0.05 was considered statistically significant.
Between January 1, 2003 and October 31, 2007, 213 patients with isolated proximal LAD stenosis were screened for inclusion into the trial. Of these, 130 patients met the inclusion and exclusion criteria and were randomized to revascularization either by MIDCAB surgery (n = 65) or stenting (n = 65). All patients received the assigned treatment. The long-term follow-up was completed for 129 patients (99.3%) with a median follow-up of 7.3 years (IQR: 5.7 to 8.3 years). One patient in the PCI group was lost to follow-up; despite intensive efforts, no information could be obtained (Figure 1).
Baseline characteristics and angiographic characteristics were not significantly different between the treatment groups and have been published previously (9).
Primary composite endpoint
In both the binary event and the time-to-event analysis at 7 years, there were no significant differences with regard to the combined primary endpoint between PCI with SES and MIDCAB surgery (hazard ratio [HR]: 1.70, 95% CI: 0.71 to 4.05; p = 0.23) (Table 1, Figure 2A).
Landmark analyses showed no statistically significant differences between groups with regard to the primary endpoint during the first 12 months (HR: 1.23, 95% CI: 0.33 to 4.57; p = 0.75) and the time frame from 12 months to 7 years (HR: 2.26, 95% CI 0.71 to 7.24; p = 0.16) (Figure 2B).
The binary incidence of the individual endpoints at 7-year follow-up are shown in Table 1.
Landmark analyses revealed a higher rate of TVR in the PCI group in the time frame 12 months to 7 years (HR: 8.2, 95% CI: 1.03 to 66.37; p = 0.02) (Figure 3B).
Overall, in the interventional group, a total of 17 TVR were performed in 13 patients with the following methods: 2 drug-eluting balloons; 3 BMS; 8 DES; 2 MIDCAB in single vessel disease; and 2 coronary artery bypass grafts in multivessel disease.
In the surgical group, 1 patient required TVR via PCI with 1 DES at long-term 7-year follow-up.
Death and myocardial infarction
All-cause mortality did not differ between the 2 treatment groups at 7-year follow-up (PCI 14% vs. MIDCAB 17%; p = 0.81) (Table 1). In addition, cardiac death rates were similar (Table 1). Cardiac deaths in the stenting group included 1 death due to congestive heart failure and 1 death due to myocardial infarction. One patient in the surgery group died of sudden cardiac death.
The rate of myocardial infarctions was not statistically different between stenting and surgery at 7-year follow-up (time-to-event analysis: HR: 0.56, 95% CI: 0.16 to 2.03; p = 0.38). Landmark analysis showed no statistically significant differences between groups for the period 12 months to 7 years (HR: 1.08, 95% CI: 0.18 to 6.57; p = 0.93).
No acute, subacute, or late stent thromboses were observed at long-term follow-up in the PCI group.
Anginal symptoms and antianginal medication
One patient in each group passed away shortly after completing the 7-year follow-up questionnaire. These patients were included in the analysis of anginal symptoms, medication, and quality of life.
After PCI, the Canadian Cardiovascular Society classification score at 12 months was 0 (IQR: 0 to 1) and at 7 years was 0 (IQR: 0 to 2) (p = 0.07 for the comparison with 12-months follow-up). Overall, 75% of the patients were completely free from angina at 7-year follow-up.
In the MIDCAB group, the median angina class was 0 (IQR: 0 to 1) at 12-month and 0 (IQR: 0 to 1) at 7-year follow-up (p = 0.92 for the comparison with 12-months follow-up), with 86% of patients free of anginal symptoms (p = 0.24 for the intergroup comparison).
There were no significant differences between groups at 7-year follow-up with regard to cardiovascular medications including antianginal agents (Table 2).
Quality of life
One patient in each group passed away 1 2 months, respectively, after completing the 7-year follow-up quality of life questionnaire resulting in 56 completed questionnaires (86%) in the PCI group and 55 (85%) in the MIDCAB group.
The treatment effect of stenting and surgery on changes in the perceived quality of life from the 12-month to 7-year follow-up is displayed in Table 3. There were no significant differences in SF-36 and MacNew domains between groups.
However, patients after both stenting and surgery showed a significant improvement from short-term to long-term follow-up in nearly all domains. Only the physical functioning domain in the SF-36 questionnaire declined in comparison to the 12-month follow-up.
To the best of our knowledge, this is the only prospective, randomized study with long-term results at 7 years in patients with isolated lesions of the proximal LAD treated by either PCI with SES or MIDCAB surgery. There were no significant differences in the composite primary endpoint and individual “hard” endpoints such as cardiac death and myocardial infarction between PCI with SES and MIDCAB. However, TVR was more frequent with PCI.
Current guidelines for revascularization of stable coronary artery disease recommend a stop of the procedure and discussion of further therapy with the patient and the heart team, after the discovery of an isolated proximal LAD stenosis. In American guidelines, revascularization in patients with single-vessel disease and an isolated proximal LAD stenosis PCI has a Class IIb Level of Evidence: B recommendation and surgery with left internal mammary artery a Class IIa B recommendation, whereas in European guidelines PCI has a Class IIa Level of Evidence: B recommendation and surgery a Class I Level of Evidence: A recommendation (14,15).
The lack of a significant difference in mortality or myocardial infarction rates between PCI and surgery observed in the present study is in line with another registry trial with propensity scoring comparing DES with MIDCAB in patients with isolated proximal LAD coronary artery lesions (16). Furthermore, the rate of MACE in the PCI group was similar to a retrospective study comparing different types of DES to BMS in proximal LAD lesions. Of note, no differences in MACE rates could be detected between first- and second-generation DES (8).
A large prospective, multicenter, observational study with 3,067 patients using a biolimus-coated stent compared those patients with a proximal LAD stenosis (n = 834, 27.2%) with patients who received stenting at a nonproximal LAD location (n = 2,203, 71.8%). After 2 years of follow-up, event rates in both groups were similar (proximal LAD vs. other location: MACE 7.67% vs. 6.45%, p = 0.23; TVR 5.28% vs. 4.72%, p = 0.51) (17).
Recently published data of the Swedish Coronary Angiography and Angioplasty Registry (7,840 patients with a proximal single-vessel coronary artery disease with a follow-up of roughly 2 years) demonstrated that proximal LAD lesions (n = 4,476) had a higher restenosis rate than did proximal left circumflex lesions (n = 1,294; HR: 2.28, 95% CI: 1.56 to 3.34; p < 0.001) but not right coronary artery lesions (2,070 patients; HR: 0.94, 95% CI: 0.73 to 1.22; p = 0.658). In comparison to BMS, the use of DES resulted in lower restenosis rates (HR: 0.39, 95% CI: 0.27 to 0.55; p < 0.001) and mortality (HR: 0.58, 95% CI: 0.41 to 0.82; p = 0.002) solely in proximal LAD stenosis (18).
Long-term patency of internal mammary arterial grafting and its superiority compared to vein grafts anastomosed to the LAD in terms of survival, freedom from infarction, angina, and repeated revascularization could be observed in various trials (19–21).
Relief of angina was preserved at 7-year long-term follow-up, in comparison to 12-month follow-up, in both groups. In the SES group, 75% of the patients were free from angina and 86% in the MIDCAB group. Other studies described similar relief of angina in the range of 67% to 96% for PCI and 83% to 85% for MIDCAB (7,22,23). For PCI in general, several studies described a steady decline in quality of life at mid-term follow-up in elderly patients after initial major improvements (24–26). For MIDCAB studies, data on quality of life at mid- to long-term follow-up are scarce; 75 patients had similar quality of life compared to an age-matched group after 1 year of follow-up (27). The observed decline in physical functioning in both groups is in line with another study reflecting the reduction of general health due to the advancement of age (28). However, the general subjective quality of life has increased.
As a result of the trial design, blinding was not possible. The use of a first-generation DES may have led to a higher event rate in the PCI group in comparison to a more contemporary setting using second-generation DES. Due to the relatively small sample size, the confidence intervals for the study endpoints, especially MACE and TVR are wide, potentially masking any small but meaningful differences in the endpoints. Another caveat is that results are from a single high-volume tertiary care center and may not be generalizable.
At 7-year follow-up, stenting with SES or MIDCAB surgery for isolated proximal LAD lesions was associated with similar long-term outcomes regarding hard endpoints (all-cause and cardiac death as well as myocardial infarction) and the combined composite endpoint. However, a higher rate of TVR could be observed. Quality of life and angina-free survival were similar in both groups.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- confidence interval(s)
- drug-eluting stent(s)
- hazard ratio(s)
- interquartile range
- left anterior descending
- major adverse cardiac events
- minimally invasive direct coronary artery bypass
- percutaneous coronary intervention
- sirolimus-eluting stent(s)
- Short Form 36
- target vessel revascularization
- Received August 25, 2014.
- Accepted August 28, 2014.
- American College of Cardiology Foundation
- Kishi K.,
- Kimura T.,
- Morimoto T.,
- et al.,
- for the j-Cypher Registry Investigators
- Blazek S.,
- Holzhey D.,
- Jungert C.,
- et al.
- Drenth D.J.,
- Veeger N.J.,
- Grandjean J.G.,
- Mariani M.A.,
- van Boven A.J.,
- Boonstra P.W.
- Jones D.A.,
- Rathod K.S.,
- Gallagher S.,
- et al.
- Thiele H.,
- Neumann-Schniedewind P.,
- Jacobs S.,
- et al.
- Thygesen K.,
- Alpert J.S.,
- Jaffe A.S.,
- et al.
- Klein J.P.,
- Moeschberger M.L.
- Fihn S.D.,
- Gardin J.M.,
- Abrams J.,
- et al.
- Task Force Members,
- Montalescot G.,
- Sechtem U.,
- et al.
- Etienne P.Y.,
- D'Hoore W.,
- Papadatos S.,
- et al.
- Goy J.J.,
- Kaufmann U.,
- Hurni M.,
- et al.,
- for the SIMA Investigators
- Diehr P.H.,
- Thielke S.M.,
- Newman A.B.,
- Hirsch C.,
- Tracy R.