New-generation drug-eluting stents in various patient populations
Due to the COVID-19 crisis the PhD defence Eline Ploumen will take place (partly) online.
The PhD defence can be followed by a live stream.
Eline Ploumen is a PhD student in the research group Health Technology & Services Research (HTSR). Her supervisors are prof.dr. C. von Birgelen and prof.dr. C.J.M. Doggen from the Faculty of Behavioural, Management and Social Sciences (BMS).
The prolonged efforts to develop superior drug-eluting stents (DES) for percutaneous coronary intervention (PCI) led to stents which, in clinical studies, were associated with diminishing adverse event rates in unselected patient populations (i.e., all-comers). Innovation and refinement of DES resulted in a constant supply of novel stents being introduced in clinical practice. Every novel DES comes with the promise of improved feasibility of PCI or improved clinical outcome, but whether this is actually the case will require assessment in large-scale randomized studies.
Although in all-comers there has been a general improvement in clinical outcome after coronary stenting, certain sub-populations still have an increased risk for repeat revascularization, myocardial infarction, and ultimately mortality. Further research in these patient groups is required to find out whether tailoring PCI with DES implantation to specific patient characteristics may result in more favorable outcomes.
This dissertation assessed the clinical outcome of all-comers as well as various subgroups of patients who were treated with new-generation DES for obstructive coronary artery disease.
Part I: All-comer patients
Chapter 1 provided a general introduction to this dissertation, discussed the development of new-generation DES, and highlighted various subgroups of patients.
Chapter 2 presented the 3-year clinical outcome of the BIO-RESORT trial participants who were randomized to treatment with one of two biodegradable polymer-coated DES (ultrathin cobalt-chromium strut Orsiro sirolimus-eluting stent; very thin cobalt-chromium strut Synergy everolimus-eluting stent) or the durable polymer-coated thin cobalt-chromium strut Resolute Integrity zotarolimus-eluting stent. Three-year follow-up was available in 3,393/3,514 patients (96.6%). Despite substantial differences in stent backbone and polymer coating, all 3 DES showed favorable 3-year safety and efficacy in all-comers, without significant between-stent differences (target vessel failure 8.5%, 8.8%, and 10.0%, respectively). Definite or probable stent thrombosis rates were low and similar in all 3 DES groups (1.1%, 1.1%, and 0.9%, respectively). The 3-year clinical results were favorable for all 3 DES. Nevertheless, further follow-up is required to definitely answer the question of whether one stent might improve long-term clinical outcomes.
Chapter 3 outlined the long-term follow-up of the BIO-RESORT trial, and discussed outcomes of all-comer patients as well as patients with diabetes. In all-comers, Orsiro, Synergy, and Resolute Integrity stents showed similar 5-year safety and efficacy; target vessel failure rates were 12.7%, 11.5%, and 14.1%, respectively. In patients with diabetes, there was also no between-stent difference in target vessel failure. Among patients with diabetes, cardiac mortality was lower in patients treated with Orsiro stents versus Resolute Integrity stents (3.0% vs. 8.3%), while there was no statistically significant difference between Synergy stents and Resolute Integrity stents (4.2% vs. 8.3%).
Chapter 4 assessed all-comer patients treated with novel Resolute Onyx stents versus patients treated with Orsiro stents in the randomized BIONYX trial. At 2-year follow-up, the novel thin composite-wire-strut durable polymer Resolute Onyx zotarolimus-eluting stent showed in all-comers similar safety and efficacy to the Orsiro sirolimus-eluting stent (target vessel failure: 7.6% vs. 7.1%). The analysis of patients who were stented in small vessels also suggested no advantage for either stent.
Chapter 5 reported the maintained safety and efficacy of treatment with the Resolute Onyx versus Orsiro stents at 3 years. Follow-up was available in 2,433/2,488 (97.8%) patients. This first 3-year randomized assessment of Resolute Onyx stents showed a favorable rate of target vessel failure (9.1%) that matched the outcome of patients treated with Orsiro stents (8.9%). We observed a lower rate of all-cause mortality in the Resolute Onyx group (3.7% vs. 5.4%), yet long-term clinical follow-up is required to gain more insights into the meaning of this finding.
Chapter 6 featured an interview study in cardiologists who perform coronary angiography, assessing their awareness of a potential issue regarding conflicting use of the radial artery. More than half of the interviewed cardiologists indicated that they had not realized that left transradial vascular access preceding coronary artery bypass grafting (CABG) may preclude later use of this artery as a conduit.
Chapter 7 commented on a study reporting 5-year follow-up of two new-generation DES and it suggested the use of a different statistical method to assess patient outcome. The I-LOVE-IT 2 trial reported no between-stent difference in the 5-year rates of ischemic and bleeding events in a broad patient population. The data collection and analysis of that study was performed according to current international standards. Yet, investigators of future DES trials may consider to change these standards by using more patient-centered methods that better reflect the severity and repeatability of the relevant adverse clinical events.
Part II. Various patient populations
Chapter 8 reported 2 separate analyses of the clinical outcome of all-comers with diabetes, treated with new-generation DES in the randomized BIO-RESORT and BIONYX trials. In BIO-RESORT, the 624 patients with diabetes showed no difference in 2-year clinical outcome following treatment with Orsiro or Synergy versus Resolute Integrity stents. In BIONYX, the 510 patients with diabetes showed no difference in clinical outcome following treatment with Orsiro versus Resolute Onyx stents. These findings may be considered as a signal of safety and efficacy of the studied DES in patients with diabetes.
Chapter 9 assessed the impact of prediabetes and diabetes on 3-year outcome of patients treated with new-generation DES in the BIO-RESORT and BIONYX trials. Not only patients with diabetes but also patients with prediabetes represent a high-risk population. After treatment with new-generation DES, both patient groups had higher risks of ischemic and bleeding events. Between-group differences in major bleeding were mainly attributable to dissimilarities in baseline patient characteristics. Routine assessment of glycemic state may help to identify patients with prediabetes for intensified management of cardiovascular risk factors.
Chapter 10 described the clinical outcome after new-generation DES implantation in patients without known diabetes, in whom oral glucose tolerance testing was performed, and HbA1c and fasting plasma glucose levels were assessed. Based on the results of these laboratory analyses, patients were classified as having a normal glycemic state, or an abnormal glucose metabolism (i.e., prediabetes or silent diabetes). Patients with silent diabetes, assessed by HbA1c and fasting glucose, showed higher rates of target vessel myocardial infarction. Furthermore, prediabetes and silent diabetes, assessed by oral glucose tolerance testing were independently associated with higher 3-year target vessel failure rates; this difference was driven by periprocedural myocardial infarction (i.e., within the first 48 hours) and cardiac death. However, after the first 48 hours, the rates of target vessel failure, target vessel myocardial infarction, and target vessel revascularization were low and did not differ significantly between the metabolic groups.
Chapter 11 reported an analysis of patient-level pooled data from 4 large-scale randomized trials (TWENTE, DUTCH PEERS, BIO-RESORT, and BIONYX), to evaluate the treatment of octogenarians with new-generation DES. Octogenarian participants in these randomized DES trials had more comorbidities and a higher incidence of the main endpoint target vessel failure than younger patients (7.3% vs. 5.3%). In octogenarians, cardiac mortality was higher, as may be expected based on their advanced age. Nevertheless, myocardial infarction and target vessel revascularization rates were not increased, and treatment of octogenarian patients with new-generation DES appears to be safe and effective.
Chapter 12 evaluated the 2-year outcome of patients who presented with an acute myocardial infarction and were treated with Resolute Onyx or Orsiro stents in the BIONYX trial. Two years after stenting, patients treated for acute myocardial infarction had lower adverse event rates than patients treated for other coronary syndromes. However, these findings were mainly attributable to between-group differences in the baseline characteristics of patients and target lesions. Furthermore, in patients with acute myocardial infarction there was no between-stent difference in target vessel failure (6.2% vs. 6.1%), and definite stent thrombosis rates were low and similar in both DES groups (0.2% vs. 0.9%). Hence, it is fair to state that in patients who underwent percutaneous coronary intervention for acute myocardial infarction, both Resolute Onyx and Orsiro stents showed favorable and similar 2-year outcomes.
Chapter 13 describes the general discussion of the findings in this dissertation.
Conclusions
Following decades of stent innovation and assessment in randomized clinical trials, new-generation DES are currently the primary choice for percutaneous treatment of patients with obstructive coronary artery disease. In this dissertation, the favorable initial clinical outcomes with new-generation DES were confirmed at long-term follow-up.
Percutaneous treatment with the new-generation Resolute Integrity, Synergy, and Orsiro stents was shown to be safe and efficacious in all-comer patients up to 5-year follow-up. The longest available follow-up of the novel Resolute Onyx, the next iteration of Resolute Integrity stent, showed favorable and similar 3-year outcome as compared to the Orsiro stent. Subgroup analyses in patients with small target vessels, acute myocardial infarction, or diabetes also showed no between-stent differences in safety and efficacy. Novel statistical methods which incorporate the patients’ perspective and both severity and repeatability of adverse events might reveal different outcomes than the outcomes found with the current standard approach. This should be considered when designing future DES trials in order to perform more patient-centered and cost-effective clinical research. Furthermore, updates of international practice guidelines may sometimes result in conflicting recommendations, as was the case with the radial artery that is recommended to be used for both percutaneous vascular access (for coronary angiography and PCI) and as an arterial conduit for CABG. Awareness of this issue is highly desirable, as cardiologists may consider using alternative vascular access sites in particular patients to preserve the radial artery for future use as a bypass conduit.
The excellent clinical outcomes in all-comer patients are promising, and encourage the use of new-generation DES even in high-risk subgroups. While no between-stent differences were found in various subgroups, patients with prediabetes, silent diabetes, or known diabetes treated with new-generation DES were still at a higher risk of adverse events than patients with normoglycemia. Furthermore, percutaneous treatment with new-generation DES showed in octogenarian patients a higher cardiac mortality than in younger patients, as may be expected based on the advanced age. Nevertheless, myocardial infarction, stent thrombosis, and repeat revascularization rates were similar between groups, suggesting treatment of octogenarians with new-generation DES to be safe and effective. Lastly, randomized trial participants presenting with an acute myocardial infarction had a lower adverse event risk than patients presenting with stable coronary syndromes or unstable angina, which was most likely related to the lower age and fewer comorbidities of patients with an acute myocardial infarction. These findings can be considered reassuring, as they suggest that being treated with PCI and new-generation DES for an acute myocardial infarction does not necessarily lead to inferior clinical outcomes.
