**5. Summary and update of the best evidence of drug-delivering technology related to MACE in PAD**

The drug delivering device have been extensively investigated to inhibit arterial restenosis and ISR to improve clinical outcomes, patency, CD-TLR, amputation free survival rate after revascularization by ET. Because the positive results of drug delivering technology from several industry-sponsored studies which demonstrated the improvement in the primary patency and reduction of CD-TLR in CLTI patients FP arterial occlusive disease, the DCB and DES are widely used for ET in CLTI patients who indicate for revascularization [25, 58, 60, 65, 68]. Both FP and IP arterial occlusive disease are investigated the limb, morbidity and mortality outcome including MALE and MACE [3, 23–25, 27, 30, 31, 33, 54, 56, 57, 59, 61, 62, 74, 75]. Concerns about a long-term mortality in PAD patients who use the paclitaxel delivering device are first reported by a meta-analysis in 2018 that described the increasing of mortality rate in comparison to POBA or bare metal stent beginning at 2 years after ET [33]. In addition, the concerning of paclitaxel related MALE including major amputation rate and CD-TLR is raised after recent studies report the higher amputation rate in the paclitaxel coated balloon when compare with POBA under the particulate embolization hypothesis [27, 30, 61].

However, there are a lot of recent publication between 2020 and 2022 report the comparable result of MACE, mortality and amputation between paclitaxel delivering devices and non-drug device [82–86]. The 5-year follow-up of RCT for the safety and effectiveness of IP arterial occlusive disease report comparable risk of amputation and all-cause mortality rate between paclitaxel coated balloon and POBA in patients with CLTI [25, 85]. The independent patient-level meta-analysis revealed the safety of paclitaxel coated balloon without the relationship between level of paclitaxel exposure and mortality [84]. The recent study report no dose–response relationship between paclitaxel and mortality in drug delivering device [83]. In addition, the ET with drug delivering technology in patients with claudication are safety and effectiveness without increasing of mortality rate or MACE [86].

For the paclitaxel eluting stent, no difference in mortality between a DES and bare metal stent. Currently, ongoing study of polymer-coated DES had demonstrated the 1-year safety and efficacy with better patency when compare with bare metal stent [60]. As the United States Food and Drug Administration (FDA) and others have recommended follow patients to 5 years to collect safety and efficacy data, the result of long-term safety of DES is not completely concluded. The systematic review and meta-analysis report no significant difference in 12-month all-cause mortality between DES and DCB. Primary patency and freedom from CD-TLR are also comparable between the two groups [23].

For the local complications of drug delivering device, there are only few reports about aneurysmal degeneration, vascular fibrinoid necrosis, small vessel inflammation, and downstream skeletal muscle necrosis after paclitaxel agent device in ET. The risk of local complication for drug delivering technology in CLTI patients are not well identified. The further study is required to concluded about the local complication of DCB and DES in PAD [28–30, 78].

The limitation of meta-analysis and RCTs about the DCB and DES include: (1) most RCTs did not report the mortality rate, MACE or major amputations as the primary outcome or main outcome. So, the imprecision due to inadequate power of study can occurred and indued the error of the study result, (2) The heterogeneity of *Cardiovascular Complications Related to Lower Limb Revascularization and Drug-Delivering… DOI: http://dx.doi.org/10.5772/intechopen.107973*

patient's characteristic and demographic data such as ratio of CLTI and claudicants, (3) The different of the paclitaxel dose, paclitaxel crystallinity, balloon platforms and coating of agent technology. Low dose balloons may demonstrate the better outcome in safety with same efficacy due to the small number of events and lack of adequate statistical power to detect a true effect, (4) Lack of actual cause of death and the clinical indications to major amputation, (5) The chronology bias due to the long period to published of all RCTs. The improvements in MACE and co-morbidities management and the different in the design of newer paclitaxel coated balloon platforms over time, (6) Some RCT report the mortality outcome and analyzed under subgroup analysis and post-hoc analysis. The patient level time to event data should be extracted and analyzed with a one stage model to increase power and precision and there was also consistent size and direction of the summary effect in the various subgroups and sensitivity tests.

Due to the controversy result of the paclitaxel coated balloon related MACE and limitation of the previous studies, the additional patient-level, adequately powered meta-analyses with larger RCT data sets will be needed to confirm the correlation between paclitaxel and MACE. For the new drug coating balloon to avoid the possible adverse event and paclitaxel related MACE, sirolimus is promising the safety and efficacy of short-term period. However, to conclude the outcome of sirolimus coated device, the large RCT with long-term follow up is necessary.

## **6. Conclusion**

Cardiovascular disease is the life-threatening condition with high morbidity and mortality rate. The PAD is the vascular disease which has a strong relationship with the MACE. The revascularization is usually indicated in CLTI patients who have a high risk of perioperative MACE. The revascularization procedure in patients with CLTI to salvage a functional limb with aggressive best medical treatment can reduce MACE during the revascularization. Because of the physiologic changes and the autoregulation process after revascularization procedure by decreasing of the peripheral vascular resistance are the burden to the cardiovascular system. The cardiac reserve and response after lower limb revascularization, the anatomic distribution and severity of lower limb arterial occlusive disease as well as the type of revascularization are the important predictive factors of perioperative MACE.

The minimally invasive fashion of revascularization by endovascular-first strategy can reduce perioperative MACE by decreasing risk of anesthesia and operative risk. The drug-delivering technology including DCB, and DES can improve the long-term patency of ET in CLTI patients. However, the paclitaxel effect on the MACE and MALE are still debatable. The decision making of physicians under the individual patients-based approach and determine the strategies to offer the drug delivering technology in CLTI patients who undergo ET is a key to success in both short-term and long-term safety and efficacy of revascularization in PAD.

## **Acknowledgements**

We would like to thank the Research group in surgery, Faculty of Medicine, Thammasat University.
