Mark D. Iafrati • Joseph Zuniga
INTRAVASCULAR DELIVERY OF THERAPEUTIC AGENTS
Peripheral arterial disease (PAD) is a chronic condition that primarily arises from atherosclerosis and ultimately results in the occlusion of arteries to the limbs. It affects millions of Americans and is responsible for a significant burden of mortality, loss of limb, and decreased functional capacity and quality of life. Epidemiologic studies have estimated the prevalence to be at least 10% in the general population, with an almost twofold increase observed in people older than 70 years of age (approximately 15% to 20%).1,2
As PAD evolves, it causes progressive impedance in blood flow to distal tissues and subsequent ischemia. In severe cases, it causes critical limb ischemia (CLI), a condition characterized by rest pain, impaired wound healing, ulceration, and gangrene. CLI has classically been managed surgically via bypass procedures. Unfortunately, a large fraction of these procedures have proved unsuccessful due to the inadequacy of autologous veins for use as a bypass conduit, the occlusion of downstream arteries (poor “runoff”), or concurrent microvascular disease which impairs wound healing despite a successful bypass procedure. Ultimately, limb amputation remains the only option for several patients. Major limb amputation, however, is itself associated with significant (15% to 20%) perioperative mortality. For one-third of amputation survivors, amputation of the remaining limb will eventually be required.3
The need for safe and effective treatment cannot be overemphasized. The last 10 years have been witness to a dramatic shift to less invasive therapeutic approaches for PAD. In a study done by Goodney and associates4 in 2009, a threefold increase in endovascular procedures was documented alongside a 42% decrease in bypass surgery. This shift to less invasive therapy was accompanied by a 25% decrease in major lower extremity amputations and a decrease in overall mortality.4 Although other factors including improved medical management and wound care have undoubtedly played a role in this decline, the change appears to be at least partially driven by the successful use and safety of endovascular lower extremity revascularization.
Despite the tremendous progress made in the medical management and endovascular treatment of PAD, a significant number of patients referred to as no option critical limb ischemia (NO-CLI) patients have exhausted their conventional therapeutic options. Mechanical revascularization techniques, both bypass and endovascular, require an inflow source, an outflow target, and a conduit. For patients lacking any of these components, an alternative treatment approach using percutaneous or catheter-based delivery of pharmaceutical or biologic agents may offer the next best hope for symptom relief and limb salvage. This chapter will present a review of some of the more promising minimally invasive therapeutic options.
Angiogenesis is the formation and growth of new blood vessels from a previously existing vascular bed. This complex process entails disruption of vascular basement membranes, subsequent migration and proliferation of endothelial cells, and formation and maturation of blood vessels, all occurring under the strict regulation of growth and inhibitory factors.
Normally in adults, angiogenesis is a dormant process. The presence of angiogenesis in the setting of limb ischemia is of biologic interest as the ability to form new vessels to provide collateral arterial circulation may prove beneficial in the amelioration of ischemia caused by chronic arterial occlusion.
Multiple growth factors are involved in promoting formation of new blood vessels. Vascular endothelial growth factor (VEGF), in particular, plays a crucial role in angiogenesis mainly because its receptors are predominantly localized in the endothelial cells of blood vessels. Studies have also revealed lower levels of VEGF in the affected leg of CLI patients,5 hence supplementation with this growth factor has been hypothesized to assist in arterial collateralization.
Animal and clinical studies have shown that administration of VEGF either systemically or locally stimulates therapeutic angiogenesis.3,6,7 Its delivery, however, remains a big challenge. With a short half-life of about 1 hour, high dosages may be required to achieve desired effects.7 Systemic administration may also result in new vessel growth in undesired locations, such as in the retina, and raises the possibility of carcinogenesis.8
In 2008, the U.S. Food and Drug Administration reviewed the potential for carcinogenesis with prolonged use of the topical platelet-derived growth factor becaplermin. It was concluded that the increase in the risk of death from cancer in patients with prolonged exposure to topical becaplermin was five times higher than in those patients who did not use the product.9
Given the nonspecificity of delivering growth factors via infusion catheters, several delivery systems have been developed to limit systemic effects and improve target specificity. The introduction of a delivery vehicle made of cross-linked DNA–gelatin nanospheres greatly increased the stability of DNA, transfection efficiency, and target specificity.
Animal studies have shown the use of intra-arterial gene transfer via angioplasty using balloons coated with plasmid VEGF in improving blood supply to the ischemic limb.10–12 Isner et al.13 in 1996 reported that this method worked on a 71-year-old patient with limb ischemia and tissue loss. They administered human plasmid VEGF to the popliteal artery using a hydrogel-coated angioplasty balloon and reported increased collateral vessel formation on follow-up angiography at 4 weeks. Adverse events directly related to angiogenesis included the development of spider angiomas on the ankle and foot of the same extremity that was treated. Transient peripheral edema was also observed in the treated extremity likely due to the increased vascular permeability induced by VEGF. This was treated with diuretics and resolved by 4 weeks. Despite improvement in collateral flow, the gangrene could not be reversed and the patient eventually required a major amputation about 5 months after the procedure.8,13 Multiple randomized controlled trials (RCTs) using intra-arterial as well as intramuscular transfer of growth factor genes have been subsequently been reported.
Hammer and Steiner14 in 2013 analyzed 12 RCTs studying local administration of growth factors (VEGF, FGF, HGF, Del-1, HIF-1 alpha) using plasmid or viral gene transfer by intra-arterial or intramuscular injections. A total of 1,494 patients with the majority suffering from CLI (64 %) were included. This meta-analysis showed neither a significant benefit nor harm for gene therapy for all-cause mortality (odds ratio [OR] 0.88; 95% confidence interval [CI], 0.62 to 1.26), amputations (OR 0.64; 95% CI, 0.31 to 1.31), or ulcer healing (OR 1.79; 95% CI, 0.8 to 4.01). Despite the potential benefit seen from the individual clinical trials, no clear overall benefit was seen from gene therapy for PAD regardless of severity.14
Prostaglandins are lipid compounds known to exert significant vasoactive effects. Specific types of prostaglandins are known to produce vasodilation, motivating researchers to explore the application of this property in the management of CLI.
When used either alone or in conjunction with angioplasty, intravenous or direct intra-arterial administration of prostaglandin E1 (PGE1) has been reported to markedly improve microcirculation.15,16 This is evident through enhancement in efficacy parameters such as transcutaneous oxygen tension and ankle–brachial index (ABI). The effect of PGE1 is attributed not only to its vasodilatory property but also to several other factors such as inhibition of ischemia-induced neutrophil activation, reduction of platelet activation, improvement in hemorheologic properties and cellular metabolism, reduction in the number of circulating endothelial cells, and inhibition of adhesion molecule expression.15
Heider and associates16 discussed the role of PGE1 post percutaneous transluminal angioplasty (PTA). They demonstrated that angiography causes significant impairment of peripheral microcirculation in patients with intermittent claudication. Peripheral oxygen tension is significantly reduced after PTA and remains decreased for the next 4 weeks. This impairment can be addressed with PGE1 therapy by exploiting two of its pharmacologic effects: (1) the vasodilatory property, which diminishes angioplasty-caused vasoconstriction, and (2) its endothelial-protective effect, which has been shown to protect endothelial function after disturbance by nonionic contrast material.
In a recent meta-analysis by Ruffolo et al.17 in 2010, 20 publications describing RCTs on the use of prostanoids on CLI were reviewed. Prostanoids were found to be effective in relief of rest pain (risk ratio [RR] 1.32; 95% CI 1.10 to 1.57, P = .003) and ulcer healing (RR 1.54; 95% CI, 1.22 to 1.96). Iloprost in particular showed favorable results in terms of preventing major amputations (RR 0.69; 95% CI, 0.52 to 0.93). Despite these positive results, however, the authors of the meta-analysis believe that there is no conclusive evidence with regard to long-term effectiveness and safety of different prostanoids in patients with CLI.
The management of CLI from severe PAD is a challenge for the vascular medicine specialists. This is especially true for patients on whom conservative management has failed and who, at the same time, are not suitable for either surgical or endovascular revascularization due to existing comorbidities or anatomy.
A promising treatment strategy emerged about a decade ago for patients whose only other option in the past was to undergo limb amputation. The inspiration for this treatment arose from the observation that cells in the bone marrow or the peripheral blood that express CD34 surface markers have the capacity to transform into functional endothelial cells in vitro. 18,19 These stem cells have the capability of producing angiogenic factors and thus may play a potential role in the management of tissue ischemia by facilitating blood vessel development. Several studies done in the early 2000s reported remarkable outcomes when stem cell therapy was used to improve peripheral blood circulation in preclinical models. 20,21
The Therapeutic Angiogenesis using Cell Transplantation (TACT) study was the first clinical trial to ascertain the feasibility of this concept. It demonstrated that the intramuscular implantation of autologous bone marrow cells into critically ischemic legs significantly improved ABI, transcutaneous oxygen pressures, and rest pain.22 Multiple clinical trials have yielded similar encouraging results.23,24 Although most cellular therapy for CLI has been administered intramuscularly, a few studies have reported intra-arterial injection of bone marrow aspirate either alone or in combination with an intramuscular injection produced no significant difference in treatment result when compared to intramuscular implantation. These studies claim that intra-arterial administration ensured that the stem cells would reach all targeted vessels in an antegrade manner, allowing perfused ischemic muscle regions to receive a high concentration of stem cells. However, concern remains about the possibility of arterial puncture site complications, downstream arterial thrombosis, and the possibility that the cells will not reach the intended tissues of interest in patients with extremely poor baseline perfusion.25
Current knowledge supports intramuscular administration of bone marrow cells as a relatively safe, feasible, and potentially effective treatment for the patient with CLI which may reduce the need for major amputations. A recent systematic review of RCTs reporting intramuscular administration of bone marrow mononuclear cell concentrates in 291 NO-CLI patients (treatment group: 149, control: 142) reported a reduction in major limb amputation risk from 25.4% to 14.8% (P = .03).23 Furthermore, the treatment was found to be safe with few treatment-related complications. Pivotal studies are underway with the objective to verify the efficacy of this novel therapy.
The process of restenosis after vessel injury is mainly thought to involve inflammatory cells located in the vessel adventitia such as macrophages, dendritic cells, lymphocytes, neutrophils, and mast cells. Within hours after injury, these cells initiate the release of other inflammatory modulators such as cytokines, growth factors, and reactive oxygen species, which contribute to smooth muscle and adventitial cell proliferation. This same inflammatory response has also been noted to occur after vascular procedures.26,27
In line with the hypothesis, Owens et al.27 did a prospective, first-in-man study to determine the feasibility and safety of percutaneous perivascular delivery of dexamethasone after treatment of the femoral–popliteal segment. Using an over-the-wire microinfusion catheter, a microneedle was deployed into the vessel adventitia to deliver dexamethasone. Twenty patients with a mean age of 66 years with Rutherford category 2 to 5 were enrolled in this study. The range of lesion length treated was 8.9 ± 5.3 cm, half of which involved chronic total occlusions. Technical success of drug delivery was 100%, and no procedural or drug-related adverse events were noted. The preliminary results at 6 months suggest that perivascular dexamethasone treatment may improve outcomes following angioplasty to the femoral and popliteal arteries. The mean Rutherford score decreased from 3.1 ± 0.7 (median, 3.0) preoperatively to 0.5 ± 0.7 at the end of the study period (median, 0.0, P < .00001). The ABI index increased from 0.68 ± 0.15 to 0.89 ± .19 (P = .0003). Only two lesions reoccluded.28 These preliminary results are encouraging.
Another mechanism by which restenosis has been postulated to occur is through neointimal hyperplasia. In line with this, antiproliferative agents have been used to prevent restenosis after vascular procedures. Among these agents, paclitaxel, sirolimus, and everolimus have been well studied for this purpose. Their use was heightened with their incorporation into balloons and stents.28,29 Because the function of these antiproliferative agents is intimately tied to their delivery techniques, a more detailed description of these agents is presented in the following sections describing device considerations.
In the modern era of endovascular interventions for PAD, multiple devices have been developed to deliver therapeutic agents as close as possible to problematic regions with the goal of localizing treatment to prevent undesirable systemic effects.
The standard endovascular technique of using guidewire and catheter has undergone very minimal change throughout the years, and improvements were primarily centered on modifying the physical attributes of the devices being used.
Porous Balloon Catheters
A porous balloon catheter is a variation of the standard balloon catheter used in percutaneous angioplasty. With its reservoir and peripheral perforations, it is well suited for the administration of various therapeutic agents during or after balloon angioplasty.
The porous balloon catheter was developed with the intent to create an instrument that could deliver high concentrations of therapeutic agents locoregionally to the involved segment of the vasculature, thus allowing medications to work without exposing the entire circulation to the agent’s effects. Wolinsky and Thung,30 through their work with canine arteries in 1990, pioneered the use of porous balloon catheters in local drug delivery. This technique has been particularly significant in the prevention of restenosis. By itself, balloon angioplasty causes vessel damage, which may produce restenosis of the treated segment in the long term. It has been shown that the addition of therapeutic agents, such as reviparin, decreases the incidence of restenosis.31
Several factors such as the size of the particles within the infusate, infusion pressure, and infusate volume should be considered when using porous balloon catheters. Large particles cause more severe vascular damage, incite an inflammatory reaction, and promote intimal thickening. Similar detrimental effects are seen when trying to force a large volume of infusate through the porous balloon catheter. The use of infusates containing nanoparticles has been proven to cause less vascular damage than an infusate containing microparticles. Also with smaller particles, less infusion pressure is required to achieve deeper agent penetration with potentially greater treatment effect.
Porous balloon catheters are also used in thrombolysis. Specifically, the ClearWay (Atrium Medical, Hudson, New Hampshire) balloon catheter (Fig. 44.1) allows direct administration of thrombolytic agents within the thrombus. Benefits observed with the use of this catheter included a decreased lytic requirement and reduced duration of thrombolysis,32 thus reducing the potential for hemorrhagic complications related to prolonged exposure to the thrombolysis agent.
A more recent nonrandomized trial by Patrick Kelly (personal information) using the ClearWay infusion balloon catheter was done to determine if a single limited dose infusion of paclitaxel after standard endovascular revascularization would prevent recurrent stenosis due to intimal hyperplasia. A total of 42 limbs (16 limbs with 2 lesions, 2 limbs with 3 lesions) treated with angioplasty, stenting, and atherectomy individually or in combination with subsequent paclitaxel infusion were followed for 19 months. No adverse reaction was noted from paclitaxel administration. Six of the 42 (14%) limbs required additional revascularization (4 of 6 had total occlusion) during the study period. No amputations or bypass procedures were required. These early findings show favorable results. Long-term follow up studies are underway.
Iontophoresis Balloon Catheters
Another catheter-based system developed to deliver medications directly into the vessel wall involves manipulation of electric charges. Iontophoresis uses electric current to enhance the movement of charged molecules and thus facilitates the transfer of therapeutic agents from the source to surrounding tissues. It has proved valuable in a multitude of specialties, ranging from the delivery of chemotherapeutic agents to the transdermal administration of pain medications.
In PAD, iontophoresis is used for locoregional delivery of therapeutic agents. This technology has been incorporated into porous balloons. When the balloon is in the proper position during an endovascular procedure, it is expanded to occlude the vessel, thus allowing apposition of the porous membrane with the vessel wall. An electric field then drives the charged molecules of the agent into the arterial wall.
The first study to investigate the iontophoresis balloons in enhancing medication delivery involved hirudin administration in a porcine carotid model.33 Results showed that the concentration of hirudin was about 80-fold greater than would be anticipated when the same medication is administered via diffusion. Hirudin was also noted to have penetrated the entire circumference of the vessel wall. Predictably, the amount of hirudin within the vessel wall increased with the duration of administration. Increased duration of occlusion may be required to achieve desired effects with the balloon, thus raising the possibility of causing distal ischemia. A reperfusion lumen catheter may be required in this situation to reduce the ischemic risk. This study also showed that retention of the therapeutic agent is time-dependent, with approximately 80% of the drug eliminated from the arterial wall after 1 hour. A similar study demonstrated substantial intramural delivery of heparin using the same technology, and the results correlated with the observed therapeutic effects.34
Unfortunately, no further studies regarding the use of iontophoresis in PAD have been published since this report from 1997, as effort has been apparently been concentrated in other delivery techniques.
Drug-Eluting Balloons and Drug-Coated Balloons
Balloon angioplasty has been proven effective in the revascularization of extremities with stenosed or occluded arteries. However, prevention of restenosis due to neointimal hyperplasia remains a major challenge.
The drug-eluting balloon (DEB) (Fig. 44.2) platform has remained largely the same as that of standard PTA except for its drug-eluting component. The most frequently used agent is paclitaxel, a cytotoxic drug which halts the cell cycle in the M phase of the mitotic cycle. It is well studied and is known to have hydrophobic–lipophilic properties, facilitating drug delivery and uptake.
To achieve lasting antiproliferative effects on the vessel wall, a sufficient drug dose must be delivered to the target site during angioplasty. The amount of drug absorbed by the vessel wall depends on the chemical properties of the drug, the dose, the transfer system, inflation time, and release pattern.
The Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis (PACIFIER) trial by Werk et al.29 in 2012 randomized 91 limbs (44 to DEB and 47 to uncoated balloons) to evaluate the safety and efficacy of DEB versus standard balloons in the revascularization of infrainguinal arteries. This revealed that use of DEB for femoropopliteal PTA is feasible and safe. This trial also showed significant reduction in restenosis rates in comparison with current conventional balloons with fewer binary restenoses (3 [8.6%] vs. 11 [32.4%], P = .01). The reduced restenosis rate also translated to fewer target lesion revascularization (TLR) (3 [7.1%] vs. 12 [27.9%], P = .02) at up to 1-year follow-up.30
Drug-Eluting Balloon in Peripheral Intervention for Below-the-Knee Angioplasty Evaluation (DEBATE-BTK) is another randomized study designed to evaluate the advantage of DEBs over standard PTA balloons in terms of 12-month restenosis and TLR, specifically in diabetic patients with CLI undergoing revascularization of arteries, this time below the knee. A total of 158 infrapopliteal lesions were treated (DEB: 74, control: 74). The 12-month restenosis rate was significantly reduced using DEBs, with a relative reduction of 64% with results independent of the length of lesion or the technique of revascularization. Clinically driven TLRs were also reduced (12 [18%] vs. 29 [43%], P = .002).28
Another advantage noted with DEB is the absence of a foreign body being left inside the artery as occurs with stent placement. Although stents, either bare metal or drug eluting, have provided superior results to standard PTA for femoropopliteal disease, they permanently change the structure of the vessel, cause local inflammatory reaction, and potentially hasten restenosis. It is also known that in-stent restenosis is more difficult to treat than restenosis in nonstented segments.
The use of DEB has been tested using various inflation and drug-coating techniques. Cremers et al.35 found no difference in drug delivery when inflation times were varied (10 seconds, 60 seconds, and 2 × 60 seconds), suggesting that most of the drug was released on initial contact. Low inflation pressure (2 atm) was as effective as high pressure (12 atmospheres) in reducing late luminal loss (LLL) and intimal thickness.36 Further demonstrating that more is not always better, Kelsch et al.37 found 1 µg/mm2 doses of paclitaxel to be as efficacious as 3 µg/mm2, whereas 9 µg/mm2 lead to excess thrombotic complications. Despite the demonstrated biologic activity with relatively low doses of paclitaxel, it should be noted that only a small percentage of the drug applied to the balloon is taken up by the target tissues. During the process of guiding the balloon to the target lesion, approximately 10% of the initial drug is lost. During inflation, approximately 80% of the drug dose is released, with 20% of that delivered to the target vessel wall. The remaining 10% of the initial dose remains on the balloon and is removed from the patient.37,38 Although most of the drug is ultimately systemically circulated, the concentrations are low and by 24 hours have dropped to undetectable levels.39 In contrast to the quick systemic clearance, paclitaxel is known to remain in vascular smooth muscle cells for up to a week.40,41 Although the low circulating drug levels appear safe, there are ongoing efforts to improve the delivery kinetics. One promising approach is the use of “expedients,” which increase the contact area between paclitaxel molecules and the vessel wall, thus enhancing local bioavailability. Agents currently under investigation including urea, butyryl-trihexyl citrate, and iopromide have shown promising initial results.38,42
Drug-eluting stents (Fig. 44.3) are the most popular and widely studied of the local agent delivery devices. They are well-established tools in the field of coronary artery disease due to their lower rate of restenosis and TLR as compared with bare metal stents (BMS).43,44 This has prompted researchers to explore the possibility of using coronary balloon-expandable drug-eluting stents in other arterial beds such as the infrapopliteal region.
However, safety concerns surfaced with the new phenomena of late and very late stent thrombosis (ST) attributed to delayed endothelial healing, vessel wall inflammation, and impaired endothelial function.45
In 2011, the RCT by Rastan et al.46 looked at the 1-year primary patency rate of sirolimus-eluting stents compared with BMS for focal infrapopliteal lesions in patients with either claudication or CLI. Primary patency was 80.6% for drug-eluting stent versus 55.6% for BMS (P = .004), with respective 1-year secondary patency rates of 91.9% and 71.4%, respectively (P = .005).46
The Drug-Eluting Stents in the Critically Ischemic Lower Leg (DESTINY) trial in 2012 by Bosiers et al.47 showed in a randomized controlled study that for infrapopliteal disease in patients with CLI, everolimus-eluting stents had better primary patency compared to BMS. Seventy-four patients were treated with Xience V (Abbott, Santa Clara, California) everolimus-eluting stents, and 66 were treated with Vision BMS (Abbott, Santa Clara, California). At the end of 1 year, primary patency was 85% versus 54% (P < .0001) in favor of the Xience V stents. Freedom from TLR was also superior at 91% versus 66% (P < .001).47 More recently, a meta-analysis by Fusaro et al.,48 which included data from the two previous studies mentioned, revealed that in focal disease of infrapopliteal arteries, drug-eluting stent reduces the risk of reintervention and amputation compared with plain balloon angioplasty or BMS implantation at 1-year follow-up.
The use of metal implantable devices is not without limitations, however. Stent fractures or occlusions may occur, and patients need to be placed on long-term antiplatelet therapy, typically double antiplatelet therapy. Stent occlusions develop from neointimal formation and incomplete endothelialization brought on by the inflammatory response of the vessel wall to the continuous mechanical and chemical stimuli induced by the stent’s metal mesh and polymeric coating. These occlusions are especially problematic because the endovascular options are very limited for retreatment of the lesion. In addition, stent placement is not recommended in very small vessels, vessel bifurcations, and specific anatomical locations such as the popliteal artery and the distal third of the anterior tibial artery.
TIPS AND TRICKS
Porous balloon catheters
The size of the particles within the infusate, infusion pressure, and infusate volume should be considered when using porous balloon catheters. Large particles cause more severe vascular damage, incite an inflammatory reaction, and promote intimal thickening. Similar detrimental effects are seen when trying to force a large volume of infusate through the porous balloon catheter.
Iontophoresis balloon catheters
Great potential to increase drug delivery while minimizing hydrostatic pressure and local wall trauma, but no recent development reported
Ideally used for long lesions with high risk of recurrence
Ideally used for short lesions with high risk of recurrence
Stem cell therapy/bone marrow aspirate
Potentially ideal for patients lacking outflow targets
Injection pattern proposed; “biologic bypass” by linear injection patterns of stem cells onto the potential site of a bypass graft if revascularization was possible. Monitored anesthesia care preferred over general anesthesia.25
The world of peripheral vascular therapy has undergone a tremendous evolution during the last two decades resulting from improved awareness, medical therapies, smoking reduction, and endovascular techniques. This concentration of effort has resulted in a general decrease in cardiovascular morbidity, including amputation risk. The next decade promises to bring additional great strides as localized delivery of medications and cellular therapy further pushes back the frontiers in PAD, promising a truly transformative approach to this daunting problem. Although much remains to be discovered, this chapter has outlined some of the more promising approaches, one or more of which are likely to play a role in the development of the therapies of the future.
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