Abstract
Background
The current revascularization treatment recommendation is different according to lesion location and a higher recommendation is given to surgery for proximal LAD (pLAD) lesions over PCI. This is based on previous studies and expert opinion. We aimed to investigate whether indeed there is a difference in outcome with respect to LAD lesion location while using a drug eluting stent (DES).
Methods
The NOBORI-2 trial, enrolled 3067 consecutive patients in 125 centers who were treated with DES for single and multivessel disease. We compared 834 [27.2%] patients who underwent PCI of the pLAD as part of their revascularization, to 2203 [71.8%] patients in which stenting to other lesion(s) but not the pLAD was performed.
Results
The pLAD group had lower incidence of hypertension, peripheral vascular disease, prior PCI and CABG, but had more lesions treated [1.55 ± 0.8 vs. 1.35 ± 0.6], more stents implanted [1.98 ± 1.2 vs. 1.66 ± 1.0] and longer overall stent length [31.8 ± 20.2 vs. 28.2 ± 17.8 mm].
There was no difference in the occurrence of the primary endpoint [cardiac death, myocardial infarction and target lesion revascularization] at 1 or 2 years of follow up between the pLAD and non pLAD [6.0% vs. 4.6%, p = 0.14 and 7.7% vs. 6.6%; p = 0.22, respectively]. The relief from anginal symptoms was similar. Multivariate analysis showed that pLAD location was not a variable that predicted MACE or TLF. Stent thrombosis rate was similar.
Conclusion
When considering PCI with DES, there is no difference in outcome between patients with and without proximal LAD lesions.
1
Introduction
The left anterior descending coronary artery (LAD) has long been a subject of debate concerning the most appropriate mode of revascularization therapy when indicated . In patients with significant proximal LAD lesion, there is a large amount of jeopardized myocardium. Failure of successful revascularization of this artery can cause significant ischemia, severe left ventricular impairment and clinically reduced functional capacity. The choice between different treatment strategies should take into account the invasiveness of the procedure, patients’ preferences, local expertise, initial efficacy and risks, short-term and long-term symptomatic improvement, and long-term survival. Whether management of patients with proximal LAD lesion should be different than non-proximal LAD and other coronary artery disease in the era of drug eluting stents (DES), is not well defined.
Once revascularization is chosen over optimal medical therapy, the choice between coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) depends on current knowledge about survival, myocardial infarction (MI), and rates of repeat revascularization . Generally the guidelines on myocardial revascularization give a higher level of recommendation for CABG over PCI for improving prognosis and symptoms in patients with coronary disease that involves the proximal LAD . However, there is an agreement that mortality and rates of MI are similar .
The basis for many of these recommendations is based on early comparative clinical trials, which may have limited usefulness in the current era of newer generations of DES and modern drug therapy. These recommendations cause constant debate in the catheterization laboratory. When an isolated proximal LAD lesion is diagnosed, both the European and American guidelines suggest stopping the procedure, and having a discussion regarding the most appropriate treatment with the patient and the heart team.
Yet, when a non-proximal lesion in the LAD is involved, the same guidelines recommend that both CABG and PCI treatments are equivalent. Thus, we aimed to examine whether indeed there is difference in outcomes when performing PCI with stenting to the proximal LAD as compared to non-proximal LAD lesions as part of single and multi-vessel PCI procedures. If PCI treatments with or without proximal LAD involvement are similar, this may add important information and may require re-evaluation of recommendations regarding the preferred revascularization method.
2
Methods
2.1
Study population
NOBORI-2 was a prospective, multi-center, observational single arm study of the Nobori™ drug eluting stent system which enrolled 3067 patients. Its primary objective was to validate, in a real life setting, the safety and effectiveness of the Nobori™ DES system previously observed in randomized trials . The secondary objectives were to assess the long term safety of the Nobori™ stent in a fully representative patient population with several patient/lesion subpopulations.
The Nobori™ coronary stent is coated with a bioabsorbable polymer and the anti-proliferative agent Biolimus A9.
The preset study included all patients from the NOBORI-2 trial and compared the group of patients in which stents were implanted in the proximal LAD to a control group of all those in which stents were implanted in other non-proximal LAD locations. In cases, where stents were implanted in the proximal LAD as well as another location as the RCA or LCx, they were grouped into the proximal LAD group.
2.2
Inclusion criteria
This was an all-comers trial of daily routine practice. Inclusion criteria were patients with coronary artery disease with reference vessel diameters between 2.5 and 3.5 mm, who according to hospital routine practice were eligible for PCI using DES and were treated using the Nobori™ stent only. Exclusion criteria were according to the instructions for the use of the device.
Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.
Proximal LAD was defined according to the CASS classification : End of Left Main to the first large septal or first diagonal, whichever is most proximal.
2.3
Coronary stent procedure
Stents were implanted according to standard local clinical practice. No predilatation was required per protocol. At least 75 mg of aspirin was administrated daily to all patients before the procedure and indefinitely thereafter. A loading dose of clopidogrel was recommended pre- and peri-procedurally and subsequently at 75 mg per day. The use of glycoprotein IIb/IIIa inhibitors was at the physician’s discretion. The stents were available in lengths of 8, 14, 18, 24 and 28 mm and in diameter of 2.5, 3.0 and 3.5 mm.
2.4
Success definition
Lesion and device success was defined as the attainment of less than 30% residual diameter stenosis (DS) by visual assessment. Procedure success was defined as achievement of a final DS of less than 30% by visual assessment, without the occurrence of death, MI, or repeat target lesion revascularization (TVR) during the hospital stay.
There was an independent angiographic core lab which analyzed all procedural angiograms and performed baseline and post stenting quantitative coronary angiographic (QCA) measurements.
2.5
Follow up
All routine hospital clinical and angiographic parameters were collected into a web based data management system coordinated and analyzed by an independent company [KIKA medical, Paris, France]. Clinical follow-up included documentation of adverse events, in particular death, MI, re-interventions, stent thrombosis, bleeding and documentation of cardiac medication regimen and angina status. Laboratory results were performed according to routine practice. Follow up was performed at 1, 6 and 12 months, and yearly up to 5 years.
All clinical end points were adjudicated by an independent clinical events committee blinded to treatment or lesion location. There was 100% monitoring on-line. In 30% of all patients on-site source data verification was achieved. The 12-month follow-up was 97%, and the 2-year follow up was 95%.
2.6
End points
The primary endpoint was target lesion failure (TLF) at 12 months. TLF was defined as composite of cardiac death, MI (Q-wave and non-Q-wave attributable to the target vessel) and clinically driven target lesion revascularization (TLR) at 12 months post-procedure.
MI was defined as creatine kinase (CK) greater than twice the upper limit of the normal range and an elevated level of CK-MB in the absence or presence of new pathological Q waves on the electrocardiogram for non-Q or Q-wave MI, respectively.
TLR was defined as any repeat PCI of the target lesion or bypass surgery of the target vessel performed for recurrent angina, ischemia, or DS ≥ 70% by QCA. TVR was defined as any clinically driven repeat PCI or bypass surgery of the entire target vessel.
2.7
Secondary outcome measures
The following endpoints were measured at 1, 6 and 12 months, 2, 3, 4 and 5 years: [1] patient oriented composite endpoint defined as any cause mortality, any MI or any coronary revascularization; [2] MACE, a composite of cardiac death, any MI and TVR; [3] death and MI; [4] stent thrombosis (definite and probable according to Academic Research Consortium [ARC] definitions); [5] duration of dual antiplatelet therapy; [6] clinically driven TLR; [7] clinically driven TVR; and [8] total revascularization rate (clinically and non-clinically driven).
2.8
Statistical analysis
Binary variables are presented as frequencies and compared using Cochran–Mantel–Haenszel test or the Fisher exact test. Continuous variables are expressed as mean ± standard deviation and compared using 2-sample t tests. All tests were 2-sided. Kaplan–Meier estimates were generated, and comparisons of MACE events were made using the log-rank test.
Multivariate analyses on the proximal LAD subgroups included a Cox Regression model to assess the hazard ratio for the time to MACE and time to TLF (composite endpoints). These analyses thus yield hazard ratios, with a 95% confidence interval and p-value of significance. For each event, the following 3 models were made: Univariate model, only using proximal LAD yes/no to assess whether there was a univariate effect of proximal LAD presence on the outcome. Full model: this model includes proximal. LAD and all the variables that were found to be different between the groups. Stepwise Selected Model: This algorithm enters all variables one by one if their p-value is < 0.25 (‘entry p-value’) and retains the variables in next steps when the p-value remains below 0.15 (‘stay p-value’). This gives a model with only a set of important, predictive variables and also avoiding multi-collinearity. Data analysis was performed by an independent statistical office (SBD Analytics, Bekkevoort, Belgium).
2
Methods
2.1
Study population
NOBORI-2 was a prospective, multi-center, observational single arm study of the Nobori™ drug eluting stent system which enrolled 3067 patients. Its primary objective was to validate, in a real life setting, the safety and effectiveness of the Nobori™ DES system previously observed in randomized trials . The secondary objectives were to assess the long term safety of the Nobori™ stent in a fully representative patient population with several patient/lesion subpopulations.
The Nobori™ coronary stent is coated with a bioabsorbable polymer and the anti-proliferative agent Biolimus A9.
The preset study included all patients from the NOBORI-2 trial and compared the group of patients in which stents were implanted in the proximal LAD to a control group of all those in which stents were implanted in other non-proximal LAD locations. In cases, where stents were implanted in the proximal LAD as well as another location as the RCA or LCx, they were grouped into the proximal LAD group.
2.2
Inclusion criteria
This was an all-comers trial of daily routine practice. Inclusion criteria were patients with coronary artery disease with reference vessel diameters between 2.5 and 3.5 mm, who according to hospital routine practice were eligible for PCI using DES and were treated using the Nobori™ stent only. Exclusion criteria were according to the instructions for the use of the device.
Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.
Proximal LAD was defined according to the CASS classification : End of Left Main to the first large septal or first diagonal, whichever is most proximal.
2.3
Coronary stent procedure
Stents were implanted according to standard local clinical practice. No predilatation was required per protocol. At least 75 mg of aspirin was administrated daily to all patients before the procedure and indefinitely thereafter. A loading dose of clopidogrel was recommended pre- and peri-procedurally and subsequently at 75 mg per day. The use of glycoprotein IIb/IIIa inhibitors was at the physician’s discretion. The stents were available in lengths of 8, 14, 18, 24 and 28 mm and in diameter of 2.5, 3.0 and 3.5 mm.
2.4
Success definition
Lesion and device success was defined as the attainment of less than 30% residual diameter stenosis (DS) by visual assessment. Procedure success was defined as achievement of a final DS of less than 30% by visual assessment, without the occurrence of death, MI, or repeat target lesion revascularization (TVR) during the hospital stay.
There was an independent angiographic core lab which analyzed all procedural angiograms and performed baseline and post stenting quantitative coronary angiographic (QCA) measurements.
2.5
Follow up
All routine hospital clinical and angiographic parameters were collected into a web based data management system coordinated and analyzed by an independent company [KIKA medical, Paris, France]. Clinical follow-up included documentation of adverse events, in particular death, MI, re-interventions, stent thrombosis, bleeding and documentation of cardiac medication regimen and angina status. Laboratory results were performed according to routine practice. Follow up was performed at 1, 6 and 12 months, and yearly up to 5 years.
All clinical end points were adjudicated by an independent clinical events committee blinded to treatment or lesion location. There was 100% monitoring on-line. In 30% of all patients on-site source data verification was achieved. The 12-month follow-up was 97%, and the 2-year follow up was 95%.
2.6
End points
The primary endpoint was target lesion failure (TLF) at 12 months. TLF was defined as composite of cardiac death, MI (Q-wave and non-Q-wave attributable to the target vessel) and clinically driven target lesion revascularization (TLR) at 12 months post-procedure.
MI was defined as creatine kinase (CK) greater than twice the upper limit of the normal range and an elevated level of CK-MB in the absence or presence of new pathological Q waves on the electrocardiogram for non-Q or Q-wave MI, respectively.
TLR was defined as any repeat PCI of the target lesion or bypass surgery of the target vessel performed for recurrent angina, ischemia, or DS ≥ 70% by QCA. TVR was defined as any clinically driven repeat PCI or bypass surgery of the entire target vessel.
2.7
Secondary outcome measures
The following endpoints were measured at 1, 6 and 12 months, 2, 3, 4 and 5 years: [1] patient oriented composite endpoint defined as any cause mortality, any MI or any coronary revascularization; [2] MACE, a composite of cardiac death, any MI and TVR; [3] death and MI; [4] stent thrombosis (definite and probable according to Academic Research Consortium [ARC] definitions); [5] duration of dual antiplatelet therapy; [6] clinically driven TLR; [7] clinically driven TVR; and [8] total revascularization rate (clinically and non-clinically driven).
2.8
Statistical analysis
Binary variables are presented as frequencies and compared using Cochran–Mantel–Haenszel test or the Fisher exact test. Continuous variables are expressed as mean ± standard deviation and compared using 2-sample t tests. All tests were 2-sided. Kaplan–Meier estimates were generated, and comparisons of MACE events were made using the log-rank test.
Multivariate analyses on the proximal LAD subgroups included a Cox Regression model to assess the hazard ratio for the time to MACE and time to TLF (composite endpoints). These analyses thus yield hazard ratios, with a 95% confidence interval and p-value of significance. For each event, the following 3 models were made: Univariate model, only using proximal LAD yes/no to assess whether there was a univariate effect of proximal LAD presence on the outcome. Full model: this model includes proximal. LAD and all the variables that were found to be different between the groups. Stepwise Selected Model: This algorithm enters all variables one by one if their p-value is < 0.25 (‘entry p-value’) and retains the variables in next steps when the p-value remains below 0.15 (‘stay p-value’). This gives a model with only a set of important, predictive variables and also avoiding multi-collinearity. Data analysis was performed by an independent statistical office (SBD Analytics, Bekkevoort, Belgium).
3
Result
3.1
Study patients
The NOBORI-2 trial enrolled 3067 consecutive patients in 125 centers from Europe, Asia, Africa and New Zealand. In the current study the population was compared according to location — proximal LAD stenting or non proximal LAD. There were 834 [27.2%] patients in the proximal LAD group and this group was compared to 2203 [71.8%] patients in which stenting of other lesion(s) but not the proximal LAD was performed.
Stable angina with symptoms or test suggestive of ischemia was the reason for PCI in 1427 [46.5%] of patients. In 1640 [53.5%] patients the reason for the procedure was acute coronary syndrome (ACS), 931 [57%] had troponin elevation. ST elevation MI occurred in 248 patients [15%] and non-ST elevation in 329 [20%]. There was no difference between groups in clinical presentation, 54.8% vs 52.9% (P = NS) of patients in the LAD and non LAD group respectively, presented with ACS.
3.1.1
Baseline demographics
There were 2371 [77.3%] men and 696 [22.7%] women. The demographics of the study population stratified by Proximal LAD location appear in Table 1 . The two populations were very similar except for a lower incidence of hypertension, PVD, prior PCI and CABG in the proximal LAD group.
| Variable | Prox. LAD | No Prox. LAD | P-value |
|---|---|---|---|
| Number of patients | 834 | 2203 | |
| Age [Mean ± SD] (years) | 64.32 ± 11.46 | 64.39 ± 10.73 | 0.8974 |
| Range (Min, Max) | (31.95, 95.28) | (27.48, 88.94) | |
| Male gender | 648 [77.7%] | 1723 [78.2%] | 0.7683 |
| Smoker, Current | 188 [25.3%] | 508 [25.5%] | 0.9606 |
| Past | 239 [32.2%] | 713 [35.8%] | 0.0787 |
| Hypercholesterolemia | 550 [68.9%] | 1523 [72.0%] | 0.1087 |
| Hypertension | 521 [63.9%] | 1523 [71.0%] | 0.0002 |
| Family History of CAD | 239 [34.9%] | 670 [36.9%] | 0.376 |
| Diabetes | 220 [27.0%] | 660 [30.4%] | 0.0715 |
| Insulin | 48 [5.9%] | 160 [7.4%] | 0.1703 |
| Oral Medication | 131 [16.1%] | 353 [16.3%] | 0.9114 |
| Diet Only | 23 [2.8%] | 91 [4.2%] | 0.0866 |
| Diabetes Mellitus with retinopathy, neuropathy or nephropathy | 17 [2.1%] | 70 [3.4%] | 0.0894 |
| Congestive heart failure | 31 [3.9%] | 80 [3.8%] | 0.914 |
| Peripheral vascular disease | 36 [4.5%] | 155 [7.4%] | 0.0044 |
| Previous PCI | 214 [26.1%] | 748 [34.4%] | < 0.0001 |
| Previous CABG | 27 [3.3%] | 233 [10.7%] | < 0.0001 |
| Cerebrovascular disease | 28 [3.5%] | 97 [4.6%] | 0.2194 |
| Renal Disease | 20 [2.5%] | 83 [4.0%] | 0.0718 |
| Previous MI | 239 [29.8%] | 739 [34.5%] | 0.0157 |
| Clinical Presentation | |||
| Stable Angina | 370 [44.4%] | 1019 [46.3%] | 0.3694 |
| Silent Ischemia | 120 [14.4%] | 340 [15.4%] | 0.4966 |
| Acute Coronary Syndrome (Unstable Angina or MI) | 457 [54.8%] | 1165 [52.9%] | 0.3489 |
| MI pre-procedure, ST elevated | 267 [32.0%] | 653 [29.6%] | 0.2155 |
| MI pre-procedure, non-ST elevated | 85 [10.2%] | 162 [7.4%] | 0.0139 |
| Evidence of MI (elevated enzymes) | 86 [10.3%] | 243 [11.0%] | 0.6011 |
3.1.2
Procedural and lesion characteristics
Radial approach was used in the same rate: 37% [ Table 2 ]. Patients in the proximal LAD group had on average more lesions treated [1.55 ± 0.8 vs. 1.35 ± 0.6] and more stents implanted [1.98 ± 1.2 vs. 1.66 ± 1] and a longer overall stent length [31.8 ± 20.2 vs. 28.2 ± 17.8]. Interestingly, the proximal LAD group had more stents implanted per lesion [1.67 ± 0.9 vs. 1.39 ± 0.7].
| Variable | Prox. LAD (06) | No Prox. LAD | |
|---|---|---|---|
| Arterial Access Site | |||
| Femoral Access | 515 [62.2%] | 1360 [62.4%] | 0.9329 |
| Radial Access | 311 [37.6%] | 807 [37.0%] | 0.8 |
| Number of Diseased Vessels, Mean ± SD | 1.76 ± 0.77 | 1.72 ± 0.77 | 0.151 |
| Vessel Disease | |||
| One Vessel Disease | 370 [44.4%] | 1046 [47.5%] | 0.1316 |
| Two Vessel Disease | 293 [35.1%] | 729 [33.1%] | 0.3019 |
| Three or more Vessel Disease | 171 [20.5%] | 427 [19.4%] | 0.5064 |
| Number of treated vessels | |||
| Mean ± SD (N) | 1.38 ± 0.59 | 1.20 ± 0.44 | < .0001 |
| Number of Vessels | |||
| One Vessel | 559 [67.0%] | 1799 [81.7%] | < .0001 |
| Two Vessels | 234 [28.1%] | 360 [16.3%] | < .0001 |
| Three or more Vessels Treated | 41 [4.9%] | 37 [1.7%] | < .0001 |
| Number of lesions treated | |||
| Mean ± SD (N) | 1.55 ± 0.81 | 1.35 ± 0.63 | < .0001 |
| 1 | 499 [59.8%] | 1595 [72.4%] | |
| 2 | 244 [29.3%] | 475 [21.6%] | |
| 3 | 67 [8.0%] | 108 [4.9%] | |
| 4 | 14 [1.7%] | 22 [1.0%] | |
| 5 | 10 [1.2%] | 2 [0.1%] | |
| Total Number of Implanted Stents per patient | |||
| Mean ± SD | 1.98 ± 1.24 | 1.66 ± 1.00 | < .0001 |
| 1 | 357 [42.8%] | 1250 [56.7%] | |
| 2 | 268 [32.1%] | 577 [26.2%] | |
| 3 | 104 [12.5%] | 232 [10.5%] | |
| 4 | 54 [6.5%] | 72 [3.3%] | |
| 5 | 26 [3.1%] | 34 [1.5%] | |
| 6 or more | 16 [1.9%] | 16 [0.7%] | |
| Total Implanted Stents per Lesion | |||
| Mean ± SD | 1.67 ± 0.92 | 1.39 ± 0.68 | < .0001 |
| Total Implanted Stents length | |||
| Mean ± SD (mm) | 31.81 ± 20.26 | 28.23 ± 17.81 | < .0001 |
| Range | (8.00, 146.00) | (8.00, 170.00) | |
| Target Vessel | |||
| LAD | 1012 [72.8%] | 815 [26.5%] | < .0001 |
| Proximal LAD | 837 | 0 | |
| RCA | 168 [12.1%] | 1160 [37.8%] | < .0001 |
| LCX | 194 [13.9%] | 966 [31.5%] | < .0001 |
| Left Main | 10 [0.7%] | 53 [1.7%] | 0.0085 |
| Saphenous Vein Graft | 7 [0.5%] | 79 [2.6%] | < .0001 |
| Dissection occurred | 50 [3.6%] | 144 [4.7%] | 0.1127 |
| Procedural info | |||
| Pre-dilatation performed | 972 [69.9%] | 2211 [72.0%] | 0.1526 |
| Post-dilatation performed | 544 [39.2%] | 977 [31.9%] | < .0001 |
| Maximum Stent Deployment pressure | |||
| Mean ± SD (N) | 14.47 ± 3.20 | 14.88 ± 3.34 | 0.0003 |
| Lesion Characteristics | |||
| Ostial lesion | 151 [12.8%] | 272 [10.1%] | 0.016 |
| Aorto-Ostial lesion | 19 [1.9%] | 105 [4.6%] | < .0001 |
| Eccentricity | 957 [81.1%] | 2197 [81.7%] | 0.6531 |
| Lesion Angulation | 90 [7.6%] | 273 [10.2%] | 0.014 |
| Bifurcation | 281 [23.8%] | 509 [18.9%] | 0.0006 |
| Lesion Ulceration | 95 [8.1%] | 229 [8.6%] | 0.6593 |
| Lesion Occlusion | 121 [10.5%] | 269 [10.1%] | 0.7276 |
| Moderate to Severe Tortuosity | 69 [5.9%] | 231 [8.6%] | 0.0032 |
| Moderate to Severe Calcification | 334 [28.3%] | 674 [25.1%] | 0.0351 |
| (Possible) Thrombus in Lesion | 109 [9.2%] | 265 [9.9%] | 0.595 |
| Lesion Type | |||
| Lesion Type A | 40 [3.4%] | 102 [3.8%] | 0.5783 |
| Lesion Type B1 | 257 [21.8%] | 656 [24.4%] | 0.0841 |
| Lesion Type B2 | 517 [43.9%] | 1104 [41.1%] | 0.1112 |
| Lesion Type C | 365 [31.0%] | 825 [30.7%] | 0.8797 |
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