**4. Drug-delivering technology concept and their effect on the perioperative MACE**

The drug delivering technology of the paclitaxel, sirolimus, everolimus and other antiproliferative agent coated balloon and eluting stent to increase the patency of native artery and in-stent restenosis (ISR) through the aggressively inhibition of arterial damage induced neointimal hyperplasia are trending to increase for ET in patient with CLTI [21–26]. Due to the controversy of the MACE and potential complications related to DCB, and DES, the pharmacologic effect of drug-delivering technology and pathophysiology of MACE are very important to guide the individual patients-based approach and determine the strategies to offer the drug delivering technology in CLTI patients who undergo ET [30, 32, 33].

## **4.1 Strategies for drug-delivering technology and concept in endovascular treatment**

The management of LEAD included (1) the risk modification and medical treatment to prevent MACE and MALE, (2) Revascularization procedures to improve the quality of life and salvage a functional limb with maintaining ambulatory status for disabling intermittent claudication and CLTI, respectively [3, 13, 35, 39]. The ET is usually the first-line option in CLTI patients who are high risk for perioperative MACE [3, 46]. The fundamental steps of revascularization in ET include (1) percutaneous vascular access, (2) guidewire and catheter passage, (3) vessel preparation and, (4) definitive therapy of arterial occlusive lesion [37, 50–52]. After the vascular access approach and intraluminal passage of the wire across the stenotic or occlusive arterial lesion, the vessel preparation is the most important step to determine the definitive therapy of de novo arterial lesion which effect to the patency of the target arterial lesion in short- and long-term [51–53]. The aim of vessel preparation is modified local environment of the vessel prior to leaving something behind including stent or a nonstent anti-proliferative agent. The concept of vessel preparation included the altering residual mechanical forces in the vessel, improving luminal gain to deliver an implant and, debulking calcium or barriers to diffused of anti-proliferative agent. Thus, the vessel preparation allows an intraluminal maximal lumen diameter without thrombosis, early recoil, plaque-burden and, flow-limiting dissection is the ideal treatment for the best patency of target arterial lesion and limit the mechanism of late target vessel failure after intervention, namely, restenosis including negative vascular remodeling and intimal hyperplasia by definitive therapy [37, 50–55].

Plain balloon angioplasty (POBA) is used to dilate significant arterial stenotic or occlusive lesions with variable results. POBA can increase the luminal diameter of a target vessel by several mechanism including stretching or rupture of plaque and connective fibers in the intima and media, compression of plaque and thrombus, compression of the medial layers, redistribution of plaque or thrombus at the inner surface of an artery, and overstretching of the artery [51, 53]. The drug delivering technology which offer the best long-term patency and prevent restenosis in de novo arterial lesion which does not indicate to scaffolding or stenting after the vessel preparation process is DCB [22–25, 32, 55].

DCB is a balloon-mounted surround by an antiproliferative chemotherapeutic agent for delivering biologically active materials into the vessel wall. The paclitaxel is a majority of chemotherapeutic agent which is effects by binding to the beta subunit of tubulin, resulting in the cessation of microtubular function and the inhibition of cellular division [37, 55]. The technique of DCB in ET include (1) adequate vessel preparation by predilatation and gradually increasing diameter of the POBA to the optimal size of the target vessel diameter are achievable without the dissection or recoil, (2) transfer phase of DCB which needs to touch and press the vessel wall for agent release. The size of DCB need to be equal the last uncoated balloon or one by one ratio of the POBA:DCB diameter and, (3) The action phase of DCB, the agent should stay as long as possible as a reservoir for long-term antiproliferative effect on the vessel wall after the drug transfer [37, 55, 56]. The long-term effect on the vessel wall is needed the lipophilicity properties of the agent without any toxicity to the target arterial lesion and other vascular bed when the drug is released in the systemic circulation in minimal level. The paclitaxel is a highly lipophilic property which limits the ability to transfer into the vessel wall but long-term embedded in the vessel wall. So, the excipient co-drug is needed to facilitate absorption in transfer phase. The stable configuration during kept on the shelf, during transport and handling with minimal loss of the agents on the delivering device are very important factors which effect on the efficacy of the DCB. Several DCB for use in the peripheral vascular intervention on the market are developed currently. The main differences in each manufacturer including excipient molecules bound to the drug, nature of coating, and the concentration of drug lead to difference in the efficacy, effectiveness, and safety of DCB in real-world practice and their studies [53, 55, 56].

#### *Cardiovascular Complications Related to Lower Limb Revascularization and Drug-Delivering… DOI: http://dx.doi.org/10.5772/intechopen.107973*

For FP disease, there are a lot of the studies which are reporting the results in a common theme of a significantly better patency and freedom from CD-TLR when comparing DCB to POBA [24]. Therefore, the conclusion of DCB in FP arterial occlusive disease confirm the safety and effectiveness of in both simple and complex FP lesions [25, 53–55]. On the other hand, the IP arterial occlusive disease which are significant restenosis and progression of disease after POBA are still lack of the high evidence base and long-term data to conclude the result of DCB in IP disease. Currently, DCBs are ongoing evaluation for the treatment of IP target arterial lesions. Because of the downstream risk of embolization due to the increased paclitaxel dose and crystalline conferred by the early generation of DCB, the early study result of DCB in the IP patients who undergo ET is a trend toward higher 1-year major amputation rate as compared with POBA [57]. However, the next generation stage of DCB demonstrated the favorable result of freedom from CD-TLR and major amputations at 12 months. Thus, the long-term outcome data are needed to investigate in DCB of CLTI patients with IP arterial occlusive disease before implementation with the trend to early benefit in treatment of IP arterial occlusive disease by DCB [58, 59].

If flow-limiting dissection or recoil are present after POBA, the scaffolds are necessary to maintain the luminal diameter and prevent thrombosis by the closure of the dissection area [50, 51, 53]. Over recent years, the self-expanding nitinol stents has achieved the treatment of recoil, flow-limiting dissection. In addition, there are a lot of publications reported the significantly improved clinical results after nitinol stenting for the long arterial occlusive disease. However, the very long lesions are higher risk of ISR after bare metal stenting. Drug-eluting technology including DES has also limit ISR and increase freedom from clinical driven target lesion revascularization (CD-TLR) [51].

Drug delivering technology of the stents, namely, DES has demonstrated an aggressively inhibition the neointimal hyperplasia and improve patency rates. Initial clinical practice, paclitaxel, sirolimus, and everolimus have been attached to balloonexpandable stents (BES) for coronary arteries stenting in patients who undergo PCI which has a high technical success rate and reduction in restenosis rate [37, 53, 59]. Currently, DES loaded with chemotherapeutic agents such as paclitaxel, sirolimus, and everolimus usually using polymers. However, the chemotherapeutic agents which are inhibit the intimal response cause delay stent thrombosis as high as 4% after 1 year [37]. The stent thrombosis mechanism is the exposed raw surface of the stent to the blood circulation due to a minimal incorporation and a lack of endothelialization of the DES into the arterial wall. The latest generation of DES demonstrated the better patency freedom from CD-TLR when compare with bare metal stent in both FP and IP occlusive diseases [24, 26, 37, 60–62].

The FP disease which indicates for the stent deployment due to flow-limiting dissection or recoil, the first generation of DES, including sirolimus and everolimus coated self-expanding stent (SES) does not demonstrate the benefit for long-term patency and restenosis between DES and bare metal stents [63]. The next generation of DES which is a polymer-free paclitaxel coated SES demonstrates a sustained 2-year benefit for decreased target lesion revascularization and improve patency with 2% of stent thrombosis and less than 2% of stent fracture in FP occlusive disease. A polymer-free DESs release 95% of the antiproliferative within the first 24 hours. For long-term follow up, the relative risk reduction of 5-year reintervention or restenosis are greater than 40% in DES when compare with POBA and bare metal stent in FP occlusive disease [64–66]. The latest generation of DES in FP disease are elute the paclitaxel using a fluoropolymer coating which release 40% of the paclitaxel within

the first 30 days and continue to release a drug over time with an estimated 90% eluted at 12 months. So, the sustaining of paclitaxel levels in the arterial wall of the fluoropolymer coating DES are longer periods than the previous version polymer-free DES [26, 37, 53, 67, 68]. The latest ongoing clinical trial demonstrate the better initial 1-year outcome of the primary patency of latest DES when compare with bare metal stent [60]. In addition, the ongoing trial demonstrate the comparable result of the all-cause death and target-limb major amputation between the DES and bare metal stent at 12 months [60].

For IP disease, the POBA with bailout stenting is still the standard treatment for revascularization. Because of the similarity in size between the coronary and IP arteries, the IP arterial occlusive disease which needs to be stenting due to the significant dissection or recoil are treated by the coronary stent. The off-label use of fluoropolymer with everolimus eluting BES which use in the coronary artery system are reported in RCTs and the real-world practice studies [61, 62]. The DES in focal IP disease significantly inhibit vascular restenosis and improve primary patency, decrease reintervention, and improve wound healing in patients with CLTI [61]. In addition, DES of IP disease may decrease risk of CD-TLR, restenosis rate and, amputation rate without any impact on mortality [62].

Heavy calcifications of the vessel wall which are usually present in CLTI patients with DM, advance age and chronic kidney disease remain the risk of early restenosis, thrombosis, and high CD-TLR [51]. The mechanism of the poor patency of target arterial lesion in calcification of the vessel wall includes (1) The mechanical effect of the vessel wall calcification act as the barrier to optimal dilatation of POBA and stenting. The calcific arterial lesions are increased risk of flow limiting dissection, recoil, and other angiographic complications [51, 53]. In addition, an inadequate vessel preparation due to retain plaque burden lesion and calcified lesion are still limiting the maximal luminal gain, stent apposition and stent expansion which effect to the long-term patency and increased risk of ISR in both bare metal stent and DES. (2) The pharmacological effect, the drug absorption of drug delivering device including DCB and DES are decrease in high calcific lesions [53, 54]. So, the plaque modifying device such as focal pressure balloon, cutting balloon, scoring balloon, serranator balloon, and lithoplasty device are developed for achieving of the vessel preparation in plaque burden and calcified arterial lesion. For heavy and circumferential severe atherosclerotic plaque and calcification, there are several atherectomy devices on the market currently which can debulking the calcification to increase the drug uptake to the vessel wall by the DCB and DES [53, 55, 69, 70]. The atherectomy include directional atherectomy, rotational atherectomy, orbital atherectomy, and laser atherectomy. The best choice for plaque modifying device and atherectomy are still debate and beyond the scope of this article. The result of DCB combined techniques with the atherectomy trend toward better outcomes in severely calcified long segment lesions and chronic total occlusion (CTO). However, the recent randomized control trial (RCT) and real-world practice study result are a debate in the risk of dissection and bailout stenting result with limited 1-year patency benefit in the combination of DCB with atherectomy as compared to DCB alone [69, 70].

For the ISR lesion, the characteristic of the restenosis lesion is different from the de novo arterial lesion. The "sandwich" structure including (1) a cell-dense neointimal hyperplasia within the stent struts which has ingrain and elastic consistency and (2) a cell-poor layer with a fibrous matrix which is embedded in the intimal layer at the outer margin of the stent struts results in a rubbery consistency of the lesions which poor response to POBA. Therefore, the significant recurrent stenosis of the ISR *Cardiovascular Complications Related to Lower Limb Revascularization and Drug-Delivering… DOI: http://dx.doi.org/10.5772/intechopen.107973*

lesions usually presents after POBA without any specialty device [51, 53]. The DCB appears to be a significant benefit to treating ISR as opposed to POBA [21, 56, 71]. The combination of DCB with atherectomy devices is offered to increase the patency in patients with ISR. However, the results of these combinations for ISR have a little benefit when compare with DCB alone [53, 72].

## **4.2 Pharmacologic effect and pathophysiology of drug-delivering technology related to MACE**

The healing response of vascular endothelium after POBA and stent placement which induce vascular endothelial injury is the activation of a local inflammatory response and the proliferation of smooth muscle cells (SMC) as well as migration of SMC into the neointima leading to significant restenosis [73, 74]. Paclitaxel and sirolimus coating devices directly inhibit the proliferation and migration of SMC which cause neointimal hyperplasia inhibition [31].

The paclitaxel is a diterpenoid antineoplastic agent which inhibits the cell proliferation. The oncologist used the paclitaxel as the chemotherapy to treat cancers, including gastric, ovarian, endometrial, breast, non-small cell lung cancer, and other cancers. The antiproliferative effect of paclitaxel can prevent the restenosis of the LEAD by the inhibition of the intimal hyperplasia [31, 75]. In normal human body physiology, microtubules are maintained cell shape and intracellular transport function, signaling, protein secretion, and motility function. The antimicrotubule effect of paclitaxel causes the formation of stable dysfunctional microtubules by binding to intracellular tubulin and interfering with spindle formation. The mitotic cell division is inhibited by the prevention of tubulin depolymerization through the irreversible of paclitaxel-tubulin binding. The prevention of tubulin depolymerization led to a microtubular dynamics disruption and cell death. The inhibition of cytokine response, migration, and secretion of matrix metalloproteinases (MMP) are the main mechanism to prevent the intimal hyperplasia after ET [31]. Consequently, the SMC proliferation and migration are inhibited which prevent neointimal hyperplasia of the vessel wall [31, 73, 74]. After DCB treatment, the paclitaxel particles are localized in fibroblast and SMC layers to inhibit the neointimal hyperplasia [73, 74]. Following DCB inflation in post-vessel preparation artery, the tissue absorption of the paclitaxel is occurring. Because of the low solubility and solid state of the paclitaxel is lower than tissue metabolic clearance rate, the paclitaxel accumulated in the target arterial lesion and cause durable effect on intimal hyperplasia [30, 55]. Overall, the pharmacokinetics of paclitaxel which is multiphasic and non-linear cause long lasting tissue accumulation of paclitaxel. The prevention of intimal hyperplasia is effective in long-term period with unknown long-term biological side effects [76, 77].

The pathophysiology and mechanism of the cardiac side effect of paclitaxel is not well established. The current studies concluded that the paclitaxel is one of cardiotoxicity chemotherapeutic agents. Some studies report the severe reduction in EF and cardiac arrhythmia [77, 78]. Theoretically, paclitaxel-induced cardiotoxicity can be occurred by the two main mechanisms: (1) direct effect of the myocardial damage which reduce in EF and precipitate HF through a subcellular organelle disturbance, (2) indirect effect of the releasing of histamine and QT interval prolongation which disturbed the cardiac electrical conduction led to cardiac arrhythmia such as atrial fibrillation (AF) and bradycardia (**Figure 7**). There are a lot of literatures report the cardiac side effects which is the most serious adverse effects of chemotherapy in malignancy patients. The early cardiac side effect of paclitaxel in chemotherapeutic

**Figure 7.**

*Pathophysiology of paclitaxel-induced cardiotoxicity related to mortality risk. DCB, drug coated balloon; drug eluting balloon. DES; EF, ejection fraction; HF, heart failure; AF, atrial fibrillation.*

dose can occur in first month including ACS, myocardial dysfunction, reversible cardiac arrhythmias, ventricular repolarization abnormality, QT interval prolongation on electrocardiogram, and pericardial reaction. Long-term cardiac adverse events include cardiac dysfunction, which lead to HF and other MACE [77, 78]. However, most malignancy patients who have a paclitaxel-induced cardiotoxicity usually to be asymptomatic or mild severity. Under carefully monitoring of cardiac function, the safely use of paclitaxel as a chemotherapy in malignancy patients with cardiac co-morbidities including the UA, HF, and AF have been reported [76].

For the paclitaxel in ET, the dosage of paclitaxel in drug delivering technology including DCB and DES is less than 1% of chemotherapy in malignancy patients. Only asymptomatic bradycardia is seen in CLTI patients who perform ET with paclitaxel agent use [31, 55]. The other early cardiotoxicity of paclitaxel is unlikely to be from the direct effect of myocardial damage [77, 78]. However, the sustained retention of the drug in the vessel wall due to the crystalline form with a paclitaxel spacer may create the ongoing distal embolization of the paclitaxel in the systemic circulation which may relate to the increasing risk of MACE and MALE including the increasing of amputation rate [25, 27, 30]. In addition, the anti-neoplastic effect of paclitaxel causes the toxicity to the immune system (**Figure 7**). The human body immune system is inhibited by the paclitaxel which increased risk of non-cardiac deaths including systemic infection, pulmonary and gastrointestinal system failure.

The potential complications due to local toxicity of the paclitaxel which report in the literatures include aneurysmal degeneration, vascular fibrinoid necrosis, small vessel inflammation, and downstream muscle necrosis. The inhibition of intimal hyperplasia after balloon angioplasty causes the post-angioplasty injured artery dilatation and aneurysmal formation in long-term period. The paclitaxel particles which insoluble cause downstream embolization led to ischemia and repetitive inflammation of the small vessel. The primary hypothesis of downstream paclitaxel particulate showers is concordant to the higher amputation rate and MALE of the DCB when compare with POBA in CLTI patients with IP arterial occlusive disease [25, 27, 30, 62]. However, there are some studies report no significant adverse effects related to distal paclitaxel crystalline embolization. The early result of recent study demonstrated the promising safety and efficacy of paclitaxel coated balloon in CLTI patients with IP arterial occlusive disease [58, 62]. Thus, large well RCT and realworld registry are needed to investigate the long-term safety and efficacy of DCB for treatment of PAD.

#### *Cardiovascular Complications Related to Lower Limb Revascularization and Drug-Delivering… DOI: http://dx.doi.org/10.5772/intechopen.107973*

For the DES, the total dose of the paclitaxel is lower than DCB. The release kinetic of DCB via the transfer and action (releasing) phase of paclitaxel after balloon angioplasty are use the concept "the greater injury, the greater penetration of the drug" in injured vessel after balloon angioplasty. The large amount of paclitaxel on DCB which delivery to the vessel wall has a high rate of distal embolization. On the other hand, the release kinetic of DES is a polymer controlled sustained release process. Thus, the downstream paclitaxel showers are not occurred when the DES is used in CLTI patients with IP arterial occlusive disease. Previous studies report the non-significant distal embolization in coronary polymer coated paclitaxel eluting stents of IP arteries. Therefore, the DES is significant reducing of CD-TLR, MALE and major amputations in 5-year and 10-year period when compare with POBA and DCB. The DCB has no obvious advantage in the treatment of IP arterial occlusive disease [23, 57, 62].

Because of the pathophysiology of cardiotoxicity associated with paclitaxel used to not be well understood, the pathophysiology of the MACE related to drug delivering technology is not well determined [33, 77, 78]. However, previous study report high-risk features which associated with paclitaxel-induced cardiotoxicity including age >60 years, DM, hypertension, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) scale 2, and chest radiotherapy [76, 77]. The patients with CLTI usually have multiple co-morbidities including DM, hypertension, old age and poor ECOG PS scale [3, 35, 39]. Thus, closed monitoring of cardiac function after paclitaxel treatment is still required in CLTI patients who have high-risk features. Therefore, long-term result of paclitaxel related MACE and MALE needs to be more investigated [3, 22].

Because of the hypothesis of the paclitaxel delivering device related MACE in CLTI patients and some evidence of the paclitaxel related MALE through the particulate embolization induced slow flow or no-flow phenomenon especially in CLTI patients with the IP arterial occlusive disease [25, 27, 30, 62]. The sirolimus coated balloons to prevent the intimal hyperplasia are investigated. The sirolimus, also known as rapamycin, is a macrocyclic lactone antibiotic which produced by bacteria *Streptomyces hygroscopicus.* The sirolimus is isolated from the Easter Island soil which use as an antifungal medication especially in Candidiasis. The potent anti-neoplastic effect through the inhibition of the mammalian target of rapamycin (mTOR) of the sirolimus is investigated. Currently, the sirolimus is an immunosuppressive agent for prevention of organ transplant rejections and antineoplastic agent for treatment of lymphangioleiomyomatosis, and perivascular epithelioid cell tumors. The pathophysiology of the inhibition of neointimal hyperplasia has been less well studied. There are a lot of recent publications suggested excellent 6-month primary patency and encouraging 12-month freedom from CD-TLR, amputation-free survival rate, and limb salvage rates without early safety concerns [79]. In addition, particulate embolization due to downstream showers of drug particle and less found in the sirolimus coated balloon when compare with paclitaxel coated balloons. Comparing with paclitaxel coated balloon, the slow flow or no-flow phenomenon induced CD-TLR and MALE are less present in sirolimus coated balloon in patients with CLTI patients [80]. Thus, the sirolimus coated balloon may have a benefit to prevent restenosis of the target artery without significant MACE and MALE in ET in CLTI patients who candidate for revascularization. The further large randomized and real-world registry study in both short-term and long-term safety and efficacy is required to establish the result of sirolimus coated balloon in CLTI patients [81].
