This analysis of pooled patient-level data, comparing EE-BRS with EES for treatment of CAD in patients with diabetes, showed similar event rates in both treatment groups for the device-oriented and the patient-oriented composite endpoint. Importantly, safety outcomes were also similar, including cardiac death and TV-MI. A multivariable analysis for the composite clinical endpoints TLF and MACE confirmed the absence of a significant difference between both groups.
Table 3. Safety and efficacy outcomes at follow-up
Endpoints and clinical events
|
EE-BRS
(n = 147)
|
EES
(n = 249)
|
p-value log rank
|
p-value PY event rate
|
|
% (n) KM
|
100 PY (95% CI)
|
% (n) KM
|
100 PY (95% CI)
|
|
|
TLF*
|
11.7 (16)
|
7.2 (4.1-11.7)
|
9.7 (24)
|
5.2 (3.3-7.7)
|
0.40
|
0.39
|
Cardiac death
|
3.4 (5)
|
2.1 (0.7-5.0)
|
4.4 (11)
|
2.3 (1.1-4.1)
|
0.84
|
>0.99
|
TV-MI
|
3.6 (5)
|
2.2 (0.7-5.1)
|
2.8 (7)
|
1.5 (0.6-3.1)
|
0.69
|
0.69
|
TLR
|
5.5 (7)
|
3.1 (1.2-6.3)
|
3.3 (8)
|
1.7 (0.7-3.3)
|
0.23
|
0.36
|
|
|
|
|
|
|
|
MACE**
|
15.2 (20)
|
9.1 (5.6-14.1)
|
15.3 (38)
|
8.3 (5.9-11.4)
|
0.75
|
0.83
|
All-cause death
|
3.4 (5)
|
2.1 (0.7-5.0)
|
6.8 (17)
|
3.5 (2.1-5.6)
|
0.35
|
0.45
|
Any MI
|
4.9 (7)
|
3.1 (1.3-6.4)
|
3.2 (8)
|
1.7 (0.7-3.3)
|
0.40
|
0.36
|
TVR
|
9.3 (11)
|
4.9 (2.5-8.8)
|
6.6 (16)
|
3.4 (2.0-5.5)
|
0.29
|
0.46
|
|
|
|
|
|
|
|
STʃ
|
1.4 (2)
|
0.9 (0.1-3.1)
|
1.2 (3)
|
0.6 (0.1-1.8)
|
0.90
|
>0.99
|
Early
|
(2)
|
|
(2)
|
|
|
|
Acute
|
(0)
|
|
(2)
|
|
|
|
Subacute
|
(2)
|
|
(0)
|
|
|
|
Late
|
(0)
|
|
(1)
|
|
|
|
Very late
|
(0)
|
|
(0)
|
|
|
|
Definite
|
(1)
|
|
(1)
|
|
|
|
Probable
|
(1)
|
|
(2)
|
|
|
|
Shown are the clinical outcomes represented as endpoints and clinical events. Three patients were lost to follow-up in the everolimus-eluting bioresorbable scaffolds group. The results are presented by 2-year Kaplan-Meier estimates and are also reported in event rates per 100 patient years with 95% confidence intervals to adjust for the variable time to follow-up between both groups. A p-value <0.05 was considered as statistically significant; no significant differences were found between both treatment groups at follow-up. * Target lesion failure was defined as a composite of cardiac death, target vessel myocardial infarction and clinically driven target lesion revascularization. ** Major adverse cardiac events were defined as a composite of all-cause death, any myocardial infarction and clinically driven target vessel revascularization. ʃ Device thrombosis was defined as early if observed between 0-30 days after index procedure, including a further distinction between acute ≤24 hours and subacute >1-30 days. Device thrombosis was defined as late if ≤1 year and as very late if >1 year. Abbreviations: EE-BRS = everolimus-eluting bioresorbable scaffolds, EES = everolimus-eluting stents, PY = patient years, KM = Kaplan-Meier, CI = confidence interval, TLF = target lesion failure, TV-MI = target vessel myocardial infarction, TLR = target lesion revascularization, MACE = major adverse cardiac events, MI = myocardial infarction, TVR = target vessel revascularization, ST = device thrombosis.
|
Table 4. Multivariate Cox regression models for target lesion failure and major adverse cardiac events
A. Variable for outcome TLF
|
Hazard ratio
|
95% CI
|
p-value
|
Age at device implantation
|
1.03
|
0.99-1.06
|
0.12
|
Insulin-treated diabetes
|
1.82
|
0.97-3.41
|
0.06
|
Number of treated vessels
|
1.17
|
0.47-2.91
|
0.74
|
Total treated length
|
1.00
|
0.99-1.02
|
0.84
|
EE-BRS vs. EES
|
1.48
|
0.77-2.87
|
0.24
|
B. Variable for outcome MACE
|
Hazard ratio
|
95% CI
|
p-value
|
Age at device implantation
|
1.03
|
1.00-1.05
|
0.06
|
Insulin-treated diabetes
|
1.40
|
0.82-2.37
|
0.22
|
Number of treated vessels
|
1.57
|
0.77-3.22
|
0.22
|
Total treated length
|
1.00
|
0.99-1.01
|
0.88
|
EE-BRS vs. EES
|
1.23
|
0.70-2.17
|
0.47
|
Section A. Multivariate Cox regression model for target lesion failure adjusted for age, insulin-treated diabetes, number of treated vessels, total treated length and destined treatment group. Section B. The same model calculated for major adverse cardiac events. Risk factors are given in hazard ratios with 95% confidence intervals with corresponding p-values. A p-value <0.05 was considered as statistically significant. No significant differences between both everolimus-eluting bioresorbable scaffolds and everolimus-eluting stents treatment groups were ascertained. Insulin-treatment for diabetes was the only variable that showed a trend as predictor for target lesion failure as was age for major adverse cardiac events.
Abbreviations: TLF = target lesion failure, CI = confidence interval, EE-BRS = everolimus-eluting bioresorbable scaffolds, EES = everolimus-eluting stents, MACE = major adverse cardiac events.
|
Comparing EE-BRS to EES in a wider perspective
Despite advances in interventional therapies and the implementation of new-generation DES, diabetic patients still have worse angiographic and clinical outcomes compared to nondiabetic patients undergoing PCI (21). Nevertheless, as shown in the EXCEL trial, the relative 30-day and 3-year outcomes of PCI with EES versus CABG were consistent in diabetic and nondiabetic patients with left main disease with low or intermediate SYNTAX score (22). Other factors like renal failure and hemodialysis as well as in-stent restenosis, both occurring more frequently in diabetic patients, might influence safety outcomes in this group (23).
In the present analysis, diabetic patients treated with EES showed clinical event rates similar to those of the EES-treated diabetic patients in a pooled analysis of the SPIRIT and COMPARE trials (6). Furthermore, in our patients with diabetes the efficacy and short- and long-term safety of EE-BRS treatment were favorable and comparable to previous studies (24-27). The performance of EE-BRS and EES have been compared in non-exclusive diabetes populations. Despite some promising early results, long-term assessment revealed no advantage for treating ‘all-comers’ with EE-BRS, but revealed a higher incidence of TV-MI and ST, and a greater angiographic late lumen loss (28-32). The findings of these trials led to the current withdrawal and utilization of EE-BRS and suggest a need for refined bioresorbable devices and a modified duration of DAPT (to correspond with scaffold resorption). Yet, it should be considered that in these previous trials operator experience with EE-BRS implantation was limited and that there was no requirement to follow a formal EE-BRS implantation protocol such as the pre-dilatation, sizing, and post-dilatation (PSP) approach, which in other studies improved safety outcomes (33-35). Interestingly, a 3-year landmark analysis of the ABSORB trials showed a significant improvement in composite safety outcomes beyond the resorption of the EE-BRS (36,37).
Nevertheless, previous trials did not focus exclusively on diabetic patients. Patients with diabetes represent a high-risk population that theoretically might show particular benefit from being treated with bioresorbable devices. This is because such devices ‘disappear’ over time, which allows for repeated PCI procedures in the same coronary segment without resulting in multiple metallic mesh layers. Furthermore, the EE-BRS does not cause an incessant stimulation of the diabetes-related vascular inflammation, which may be the case in the permanent presence of certain durable polymers. Therefore, it is conceivable that after PCI with EE-BRS long-term results might be more favorable in patients with diabetes (despite short and medium-term results similar to EES).
Revascularization in insulin-treated diabetic patients
In our current all-diabetic patient population, treatment with insulin showed an, albeit statistically non-significant, trend towards prediction of TLF. Such relation was observed in the diabetes subgroup analysis of the ABSORB trials and in a pooled analysis of the SPIRIT and COMPARE trials; both analyses found insulin-treatment to be a risk factor for TLF after PCI with either EE-BRS or EES (6,24). The increased event risk in insulin-treated patients may be attributable to the generally longer history of diabetes, during which the diabetes-induced chronic vascular inflammation stimulates the progression of atherosclerosis, alters plaque composition and promotes the development of advanced lesions. It is plausible that the severity and duration of diabetes is related to the risk of cardiovascular complications and it appears reasonable to consider this when choosing a coronary revascularization strategy.
Patient selection for EE-BRS treatment
Younger patients with non-insulin-treated diabetes and CAD of limited extent may be the most suitable candidates for treatment with EE-BRS (as an alternative to EES), as they might have the greatest benefit from the bioresorbable nature of the device. Furthermore, younger patients have a lower bleeding risk than elderly patients, which is beneficial considering that a prolonged DAPT regimen may be indicated following PCI with EE-BRS. Nevertheless, further dedicated research is required to assess the usefulness of EE-BRS in younger patients. Most likely, such studies will test novel thinner-strut bioresorbable scaffolds that recently became available for research purposes and these studies should include a long-term follow-up (38).
Limitations
The hypothesis-generating findings of the present post-hoc analysis should be interpreted carefully in the light of several limitations, including the intrinsic limitations of any comparison between multiple patient cohorts from different studies. Low cholesterol, and in particular values of remnant-like particle cholesterol below 0.5 mmol per liter have shown to be a predictor of freedom from in-stent restenosis in diabetic patients for all types of stents (39). In our study detailed patient specific cholesterol values were unobtainable, however a dichotomic hypercholesterolemia (treated) was available and similarly distributed between both groups. Profound data concerning the status of diabetes mellitus and medication prescription were unavailable for a substantial share of the included patients. Yet, all study participants were treated in the same geographical region and they received the same concomitant medication reflecting the international guidelines. Although most baseline clinical characteristics were fairly comparable, there were some differences in angiographic lesion characteristics. Hence, a multivariable analysis was performed, striving for adjustment of known confounders. Due to the population size, this study was not powered to detect significant differences in the composites of the endpoints, particularly low-incidence events like mortality and stent thrombosis, therefore these results should be interpreted with necessary caution. As we decided to share our results now as debate concerning the future of bioresorbable devices continues, this study does not provide sufficient information about differences between these devices in the phase beyond scaffold resorption in the majority of the EE-BRS patients. To correct for the variable time to follow-up, results were presented in PY which theoretically may obscure time-to-event related adverse outcomes. To minimize this limitation we also reported time-to-event analysis and the nominal incidence of ST. While the operators had considerable experience with implanting EE-BRS, the use of the PSP approach and intracoronary imaging were not mandatory according to the study protocol, while this might have improved clinical outcome. Finally, as the current EE-BRS generation has been withdrawn from daily practice due to the comprised safety outcomes, the clinical implication of our results should be interpreted in the light of newer bioresorbable devices which have been introduced recently.