BIOABSORBABLE VASCULAR SCAFFOLD AND ITS APPLICATIONOLD.pptx

BIOVASCULAR SCAFFOLD FOE CORONARY AND PAD DISEASE

1. BIOABSORBABLE VASCULAR SCAFFOLD History & evolution of BVS Advantages Types of BVS Physiology of BVS Clinical trials of BVS Future perspectives of BVS

2. History of angioplasty First revolution- balloon angioplasty The invention of balloon angioplasty as a percutaneous treatment for obstructive coronary disease by Andreas Gruntzig in 1977 was a huge leap forward in cardiovascular medicine and undoubtedly will always be remembered as a revolution in the field of revascularization

3. Plain Old Balloon Angioplasty(POBA) In 1964, Charles Theodore Dotter and Melvin P. Judkins described the first angioplasty 1977, Andreas Grüntzig performed the first balloon coronary angioplasty Dissections – Focal to threatened dissection Acute recoil Chronic constrictive remodeling

4. DISADVANTAGES Although late luminal enlargement and vascular remodeling could take place, more often restenosis would occur instead. The restenosis would essentially be caused by constrictive remodeling and, to a lesser extent, by elastic recoil or the neointimal hyperplastic healing response.

5. second revolution -BMS The advent of BMS and the landmark Belgian-Netherlands Stent Study (BENESTENT ) and Stent Restenosis Study (STRESS) trials have established BMS as the second revolution in interventional cardiology. A solution to acute vessel occlusion by sealing the dissection flaps and preventing recoil & making emergency bypass surgery a rare occurrence .

6. In 1986, first coronary stent by Sigwart et al Gianturco-Roubin first FDA – BES – 1993 Palmaz- schartz first STENT VS POBA Plain Old Balloon Angioplasty(POBA) Bare Metal Stent(BMS) STENT IMPLANTATION PENETRATION OF LIPID CORE & REACTION TO STRUTS EXPOSURE OF SUBINTIMAL COMPONENTS THROMBOGENIC METAL ACTIVATION AND PROLIFERATION OF SMCs PLATELET ACTIVATION Instent restenosis Stent thrombosis

7. Restenosis rates were further reduced from 32% to 22% at 7 months, but this rate was still high, and neointimal hyperplasia inside the stent was even more prominent than with angioplasty. Disadvantages (Because the vessel was now caged with metal) late luminal enlargement and advantageous vascular remodeling could no longer occur. late stent thrombosis (ST), was also first described . Serruys PW, Daemen J. Late stent thrombosis: a nuisance in both bare metal and drug-eluting stents Circulation. 2007;

8. Third revolution-DES The first 45 patients implanted with the sirolimus eluting Bx velocity stent (Cordis, Johnson & Johnson, Warren, NJ) were found to have negligible neointimal hyperplasia at follow-up. This was confirmed in the randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization (RAVEL) study. Morice MC, Serruys PW A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:

9. The RAVEL Study A RAndomised (double blind) study with the Sirolimus coated BX™ VElocity balloon expandable stent (CYPHER™) in the treatment of patients with De Novo native coronary artery Lesions M.C. Morice , P.W Serruys , J.E. Sousa, J. Fajadet , M. Perin , E. Ban Hayashi, A. Colombo, G. Schuler, P. Barragan, C. Bode The treatment of a de novo lesion with CYPHER™ appears feasible and safe : no acute, subacute (30 days) or late occlusion occurred although clopidogrel / ticlopidine was administered for only 2 months Virtual elimination of neo-intimal in-stent proliferation: MLD post deployment (2.43 mm) remains essentially unchanged at 6 months (2.42 mm) with no measurable late loss (-0.05 mm) Restenosis (0%) and no evidence of edge effect

10. Plain Old Balloon Angioplasty(POBA) Bare Metal Stent(BMS) Drug Eluting Stent(DES) 1 st Generation QuaDS-1 st DES in human coronaries(taxane) Most important – CYPHER , TAXUS. STENT THROMBOSIS INSTENT RESTENOSIS

11. Disadvantages Increased risk of late and very late ST. late ST rates of 0.53%/y, with a continued increase to 3% over 4 years. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet. 2004 In the (ARTS II) trial,with complex multivessel disease, the rate of combined definite, probable, and possible ST was as high as 9.4% at 5 years, accounting for 32% of major adverse cardiovascular events (MACEs). J Am Coll Cardiol . 2009 Postmortem specimens of DES revealed significant numbers of uncovered struts with persistent inflammation around the stent struts. Vasomotion testing demonstrated vasoconstriction to Ach. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol. 2007

12. BALLON ANGIOPLASTY ENLARGES NARROW ARTERY SYMPTOMS REDUCES ELASTIC RECOIL OF ARTERY EARLY RESTENOSIS BARE METAL STENTS LESS ELASTIC RECOIL RISK LOWER EARLY RESTENOSIS METAL SCARS ENDOTHELIAL TISSUE NEOINTIMAL GROWTH RESPONSE LEAD TO LATE RESTENOSIS DRUG ELUTING STENTS ANTIPROLIFEARATIVE RESPONSE LEADS TO ↓RESTENOSIS RISK OF THROMBOSIS+

13. POTENTIAL ADVANTAGE OF BRS Baloon angiplasty bms Metallic DES Biovascular scaffold acute occlusion + + + - Acute scaffold thrombosis NA _ _ - Sub acute scaffold thrombosis NA _ _ - acute recoil + + + - Constrictive remodelling _ + + - Neointimal hyperplasia _ _ + - Expansive remodelling + _ _ - Late luminal enlargement + _ _ - Late scaffold thrombosis NA _ _ -

14. STENT FEATURES BARE METAL STENT DRUG ELUTING STENT BIOABSORBABLE DRUG ELUTING STENT REDUCED DUAL ANTIPLATELET THERAPY +++ +++ + NEO INTIMAL HYPERPLASIA ++ + RESTORATION OF VASOMOTION +++ TISSUE COMPATIBLE +++

15. ADVANTAGES of BVS 1. A reduction in adverse events such as ST. Because drug elution and scaffolding are temporary and are provided by the device only until the vessel has healed, no foreign material such as nonendothelialized struts and drug polymers (potential triggers for ST) can persist long term.

16. 2.The removal,through bioabsorption of the rigid caging of the stented vessel. This can facilitate the return of vessel vasomotion, adaptive shear stress, late luminal enlargement, and late expansive remodeling. Furthermore, this might reduce the problems of jailing of the ostium of side branches as seen with permanent metallic stent struts.

17. 3.A reduction in bleeding complications. No requirement for long-term dual antiplatelet therapy. This is particularly pertinent given that the elderly, who are at the greatest risk of bleeding. Furthermore, early discontinuation of dual antiplatelet therapy with current metallic DES,for whatever indication, has consistently been shown to be an independent predictor of ST. Development and validation of a prognostic risk score for major bleeding in patients undergoing percutaneous coronary intervention via the femoral approach. Eur Heart J. 2007;

18. 4.An improvement in future treatment options. The treatment of complex multivessel disease frequently results in the use of multiple long DES; for example, in the synergy between percutaneous coronary intervention with TAXUS and cardiac surgery (SYNTAX) trial, the average number of stents was 4, and one third of patients had 100 mm of stent implanted. In such cases, repeat revascularization is potentially challenging. The use of a BRS would mean that there would potentially be no restriction on any future percutaneous or surgical revascularization should they be needed.

19. 5.Allowing noninvasive imaging (CT/MR angio .) Metallic stents can cause a blooming effect with these imaging modalities, making interpretation more difficult. The (PLLA) scaffold should not restrict the use of CT or MRI because it is nonmetallic; once bioabsorption has been completed with a BRS, it should also not restrict the use of CT or MRI Noninvasive imaging follow-up could therefore become an alternative to invasive imaging followup . Artifact-free coronary magnetic resonance angiography and coronary vessel wall imaging in the presence of a new, metallic, coronary magnetic resonance imaging stent. Circulation. 2005

20. 6.Reservoir for the local delivery of drugs and genes. Because the duration of bioresorption is modifiable, according to the type of polymers/copolymers, a tuned elution of multiple drugs can potentially be achievable ( eg , early elution of antiproliferative agent from a coated polymer and long-term elution of an antiinflammatory or other agent from the backbone polymer).

21. 7.Elimination of the concern that some patients have at the thought of having an implant in their bodies for the rest of their lives.(esp. in young individuals) Ormiston JA, Serruys PW. Bioabsorbable coronary stents. Circ Cardiovasc Interv . 2009;2:255–260 .

22. 8.VASCULAR REPARATIVE THERAPY On Premise that scaffolding & drug are only required on a temporary basis following coronary interventions. Several studies support this concept and indicate that there is no incremental clinical benefit of a permanent implant over time. The use of Absorb eliminates the presence of a mechanical restraint and offers the potential of restoring natural vessel reactivity. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation, 1988 .

23. While stent performance is characterized by a single phase (Revascularization), the performance of Absorb is governed by three distinct phases: Revascularization Restoration Resorption. Together, these phases of Absorb performance deliver VRT

24. 1 RESCULARISATION The rescularisation phase is when absorb resvascularizes the vessel like a best in class DES Absorb achieves this goal by offering good deliverability ,a minimum of acute recoil ,high radial strength and controlled release of the anti prolifferative drug everolimus to minimize neointimal growth The late lumen loss is comparable to those observed in best in class DES 2 RESTORATION During the restoration phase,absorb gradually ceases providing luminal support and evolves from an intact scaffold to a discontinuous structure embedded within neointimal tissue Absorb no longer mechanically restrains the vessel allowing it to return to a more natural ,uncaged state without the presence of a permanent metallic stent Vasomotion is possible as early as 12months post procedure 3 RESORPTION The resorption phase is the final process in which the discontinuous scaffold structure disappears,because there is no longer a structure that mechanically restrains the vessel,a more natural vascular response to physiological stimuli is possible Absorb is now an inert implant designed to benignly resorb into the vessel wall.it degrades to lactic acid and ultimately the benign by products of carbon dioxide and water over time.lactic acid is readily converted to lactate ,which is found naturally in the blood stream and participates in human metallic processes

25. What is Required of a Fully Bioresorbable Scaffold to Fulfill the Desire for ‘Vascular Restoration Therapy’? Revascularisation Restoration Resorption 3MONTHS 3 TO 6 MONTHS 12MONTHS Performance should mimic that of a standard DES Good deliverability Minimum of acute recoil High acute radial strength Controlled delivery of drug to luminal tissue Excellent conformability Transition from scaffolding to discontinuous structure Gradually lose radial strength Struts must be incorporated into the vessel wall (strut coverage) Become structurally discontinuous Allow the vessel to respond naturally to physiological stimuli Implant is discontinuous and inert Resorb in a benign fashion

26. What is Required of a Fully Bioresorbable Scaffold to Fulfill the Desire for ‘Vascular Restoration Therapy’? Revascularization Restoration Resorption FULL MASS loss & bioresorption 1 6 2yrs 3 Everolimus elution support Mass loss Platelet deposition Vascular function

27. 9.Vessel Remodeling Through the use of the imaging modality intravascular ultrasound (IVUS), data from the ABSORB Cohort B trial, reveals an increase in lumen area between 6 months and 2 years. As Absorb resorbs, the vessel segment becomes unconstrained and there is the potential for lumen gain.

28. 10.Vasomotion As Absorb resorbs, the treated vessel segment is able to react to changes in blood flow and physiological stimuli that may occur with exercise or certain drugs. By no longer supporting or caging the vessel, there is the potential for allowing the vessel to respond naturally to physiological stimuli, which could provide unique benefits.

29. Restoration to a More Natural State with Absorb Another appealing long-term benefit of Absorb is the possibility of progressive restoration of Absorb-treated vessel segments to a more natural state as the polymeric scaffold undergoes degradation. Restore vasomotor tone for regulation of coronary blood flow Restore vessel compliance and cyclic strain in response to pulsatile flow Enable adaptive shear stress, allowing the vessel to regain its ability to maintain quiescent homeostasis Permit accommodative, beneficial remodeling.

30. Importance of Respecting Natural Vessel Curvature 91° 88 Long-term flow disturbances and chronic irritation can contribute to adverse events Pre BVS Post BVS

31. Potential for Mechanical Conditioning Design Goals Support Vascular Function Mechanical conditioning may lead to improved cellular organization and vascular function Vascular Restoration Therapy Shear stress & pulsatility Tissue adaptation Structure and functionality

32. MECHANICAL CONDITIONING IN PRE-CLINICAL MODEL (PORCINE) Transmission Electron Microscopy (TEM) Smooth Muscle -Actin Dense bodies At 36 months, SMCs are well organized and have undergone transformation to a functional, contractile phenotype

33. An occlusive vessel segment that is first implanted with Absorb has the potential to restore to a more natural state. In the event of restenosis (tissue regrowth) at the treated site, more treatment options are available – another Absorb, a DES or even balloon angioplasty. Furthermore, the more natural state can make re-treatment easier, given the recognized difficulties involved in treatment of in-stent restenosis

34. Fourth revolution All these problems promise to be solved with the advent of fully biodegradable scaffolds. Offers the possibility of Transient scaffolding of the vessel to prevent acute vessel closure and recoil & Transiently eluting an antiproliferative drug to counteract the constrictive remodeling and excessive neointimal hyperplasia

35. Development of BRS The efforts to create BRS started 32years ago . The first experimental studies using a nonbiodegradable polyethylene-terephthalate braided mesh stents in porcine animal models were published in 1992. In 1996, it was reported in porcine coronary arteries negative consequences after implantation of the Wiktor stent coated with 5 different types of biodegradable polymers ,all resulting in marked inflammation leading to neointimal hyperplasia and/or thrombus formation. Development of a polymer endovascular prosthesis and its implantation in porcine arteries. J Interv Cardiol. 1992;5:175–185.

36. Lincoff et al -- high-molecular-weight (321 kDa ) PLLA was well tolerated and effective, where as a stent coated with low-molecular-weight (80 kDa ) PLLA was associated with an intense inflammatory neointimal response. They also proved the feasibility of drug elution from the PLLA, although no suppression of neointimal hyperplasia was reported. - Lincoff AM, Schwartz RS, van Beusekom HM . Circulation. 1996;94:1690 –1697. In 1998, Yamawaki et al reported that in the porcine model the fully biodegradable PLLA stent with tyrosine kinase inhibitor efficiently suppressed proliferative stimuli caused by balloon injury. Yamawaki T, Shimokawa H, Kozai T. J Am Coll Cardiol . 1998;32:780 –786. The technology failed to develop an ideal polymer that could limit inflammation and restenosis and secondarily because of the growing interest in metallic DES.

37. The key mechanical traits for ideal material : High -elastic moduli to impart radial stiffness, Large -break strains to impart the ability to withstand deformations from the crimped to expanded states, and Low -yield strains to reduce the amount of recoil and overinflation necessary to achieve a target deployment.

38. Numerous polymers are available, each with different chemical compositions, mechanical properties, and subsequently bioabsorption times Material Stent Status Polymers PLA Thermal balloon expandable,ring ( igaki-tamai ) 4-year clinical data Tamai et CCT 2004 PLA balloon expandable,Abott Vascular , inc Phase1 clinical trial Stock RS tct 2005 Ormiston J.TCT 2006 Tyrosine polycarbonate balloon expandable,REVA Medical Preclinical Kaliza G.TCT 2006 PAE salicylate balloon expandable,tubular preclinical Robinston KA TCT 2006 Metallic magnesium balloon expandable,biotronik Phase 1 clinical Heublein B et al.Heart 2003 Iron balloon expandable,tubular Pre-clinical Pauster M et Heart 2001

39. TYPES OF BVS Polymer based metal based - BVS (abbot) DREAMS 1, 2 - igaki tamai iron - REVA stent - ART - IDEAL

40. IGAKI-TAMAI BIOABSORBABLE STENT First absorbable stent implanted in humans,is constructed from poly-L-lactic acid (PLLA). In the absorption process, hydrolysis of bonds between repeating lactide units produces lactic acid that enters the Krebs cycle First-in-man prospective, nonrandomized clinical trial that enrolled 50 patients a 4yr follow-up of all the patients (100%) revealed a low complication rate. Loss index (late loss/acute gain) was 0.48 mm, which was comparable to BMS, and demonstrated for the first time that BRS did not induce an excess of intimal hyperplasia .Focus is now on a peripheral application Tamai H, Igaki K, Kyo E. Initial and 6-month results of biodegradable poly-L-lactic acid coronary stents in humans. Circulation. 2000

41. Despite these impressive results, the failure of the stent to progress was related primarily to the use of heat to induce self-expansion. There were concerns that this could cause necrosis of the arterial wall, leading to excessive intimal hyperplasia or increased platelet adhesion, leading to ST. Biodegradable peripheral Igaki -Tamai stents PERSEUS study,the stent became available in Europe for peripheral use; Biamino G, Schmidt A, Scheinert D. Treatment of SFA lesions with PLLA biodegradable stents: results of the PERSEUS Study. J Endovasc Ther . 2005;12:5.

42. BIOABSORBABLE MAGNESIUM STENT The degradation of Mg produces an electronegative charge that results in the stent being hypothrombogenic . Although the stent was completely absorbed within 2 months, radial support was lost much earlier so that, perhaps within days, there was an insufficient radial strength to counter the early negative remodeling forces after PCI. In addition, it did not release an antiproliferative drug to counter the intimal hyperplastic response to stenting. Consequently, there was a high restenosis rate at 4 months of almost 50% and target vessel revascularization at 1 year was 45% PROGRESS AMS trial: Lancet. 2007;369:1869 –1875.

43. It provides prolonged mechanical stability, which has been achieved by using a different magnesium alloy that has not only a higher collapse pressure of 1.5 bar compared with 0.8 bar for AMS-1 but also a slower degradation time. In addition, the stent surface has been modified; the stent strut thickness has been reduced And the shape of the strut in cross section has been altered from rectangular to square (improving radial strength). These changes have prolonged scaffolding and stent integrity, improved radial strength, and reduced neointima proliferation in animal models.

44. AMS-3 stent The AMS-3 stent (drug-eluting AMS) is designed to reduce neointimal hyperplasia by incorporating a bioresorbable matrix for controlled release of an antiproliferative drug onto the AMS-2 stent. Research is currently focused on establishing the ideal drug kinetics; initial animal trials have demonstrated a sustained antiproliferative effect at 1 month. A new clinical program resumed in July 2010.

45. BIOTRONIK DREAMS Pimecrolimus-Eluting Stent System Drug: Pimecrolimus Stent: Bioabsorbable Magnesium Alloy Discrete Drug Delivery Reservoirs Carrier: Bioresorbable Matrix Modifications

46. Next generation coronary AMS Current coronary AMS is currently improved by ... Prolonged mechanical Stability Reduction of neointima hyperplasia Surface passivation Improved stent design Improved stent design Modified Alloy Animal feasibility trial ongoing Next steps of AMS improvement in preparation Goal: Continue human trials with improved AMS early

47. REVA Endovascular Study of a Bioresorbable Coronary Stent (RESORB) study

48. The REVA Endovascular Study Of a bioresorbable coronary stent End points -end points -primary -30day MACE -secondary -6month QCA & IVUS derived paramaters (restenosis) Clinical Follow Up -Discharge ,2 weeks,1,6,12,24,36,48 and 60 months

49. ReZolve stent. More robust polymer, a spiral slide-and-lock mechanism to improve clinical performance, and a coating of sirolimus (80% is eluted by 30 days and 95% by 90 days.) The RESTORE Trial (Pilot Study of the ReZolve Sirolimus-Eluting Bioresorbable Coronary Scaffold) is evaluating the safety and performance of the first-generation ReZolve scaffold in 26 patients that were enrolled 2011 & 2012-F/u-5yrs. The ReZolve2 scaffold , a lower profile and sheathless version of the original ReZolve scaffold, is being evaluated clinically in the RESTORE II TriaL (IN 2013)

50. Poly (Anhydride Ester) Salicylic Acid: The IDEAL Stent both antiinflammatory and antiproliferative properties

51. Whisper trial , a stent with strut thickness of 200 m and a crossing profile of 2.0 mm with a stent-to artery coverage of 65% was implanted in 8 patients. Because of higher-than-expected intimal hyperplasia, a subsequent design iteration will have thinner struts, a higher dose of sirolimus, and a lower percent wall coverage.

52. Everolimus -Eluting PLLA Stent: BVS Scaffold The BVS stent design is characterized by a crossing profile of 1.4 mm with circumferential hoops of PLLA. The struts are 150 m thick and are either directly joined or linked by straight bridges. Both ends of the stent have 2 adjacent radiopaque platinum markers. The radial strength = BMS. The backbone of the BVS device is made of semicrystalline polymer called PLLA. The coating consists of poly D,L-lactide acid (PDLLA), which is a random copolymer of D and L-lactic acid with lower crystallinity than the BVS backbone. The coating contains and controls the release of the antiproliferative drug everolimus .

53. Polymer backbone Drug/polymer matrix Everolimus /PDLLA Matrix Coating Thin coating layer Amorphous (non-crystalline) 1:1 ratio of Everolimus /PLA matrix Conformal Coating, 2-4 m thick Controlled drug release PLLA Scaffold Highly crystalline Provides device integrity Processed for increased radial strength

54. Absorb Design Elements

55. Two versions of the stent have been developed. The design of the BVS stent Revision 1.0 consists of circumferential out-of-phase zigzag hoops of PLLA with a strut thickness of 150 μm , linked either directly or by straight bridges, with two radiopaque markers at each end which enable a good visualization on angiography.

56. The BVS Revision 1.1 consists of the same polymer , but different process refinements allow the stent to increase its radial force, provide radial support for a longer time, and, consequently, avoid the slightly higher, but nonsignificant, recoil shown by QCA. MCUSA- This stent version has a different strut distribution, reducing the maximum circular unsupported cross-sectional area, in contrast to BVS Revision 1.0. It is currently under evaluation in the Cohort B of the non-randomized ABSORB trial (NCT00856856) in 80 patients.

57. Bioresorption Process of PLLA In the PLA family of polymers, molecular-weight degradation occurs in vivo predominantly through hydrolysis , which is a bimolecular nucleophilic substitution reaction that can be catalyzed by the presence of either acids or bases. The hydrolysis reaction in which water catalyzes a chain scission event at an ester bond.

58. From chemical standpoint, resorbable implants undergo 5 stages First stage is hydration of polymer.Starting at Hydrophilic (carboxylic acid )end . second phase is depolymerization by hydrolysis. reduction in molecular weight. Third stage- loss of mass (starts to fragment into segments of low-weight polymer (radial strength reduces) . The fourth phase is assimilation or dissolution of the monomer by Phagocytes Fifth -L-lactate is changed into pyruvate, which eventually enters the Krebs cycle and is further converted into carbon dioxide and water. Handbook of Biodegradable Polymers. Boca Raton, FL: CRC Press; 1998

59. REACTION PATHWAY FOR HYDROLYTIC DEGRADATION OF THE PLA FAMILY OF POLYMERS.

60. Poly-L-lactide is a semicrystalline polymer. The ordered polymer chains constitute the crystalline component of the semicrystalline polymer, and the random polymer chains form the amorphous segment In other words, the semicrystalline PLLA polymer is made of crystal lamella (regions with high concentrations of polymer with crystalline structure) interconnected by amorphous tie chains binding the crystallites Because the amorphous regions are less packed and therefore are more accessible to water, more susceptible to hydration.

61. Vascular Response to BVS at 2, 3 & 4 years: Arterial Integration and Accommodation 4 years The shape,Mass loss data suggests 100% of material mass has been lost at 2 years The shape of struts is still apparent at 2 years, although the device is fully resorbed No inflammation around the pre-existing strut regions 3 years: struts fully replaced by tissue is still apparent at 2 years, although the device is fully resorbe 4 years: sites of pre-existing struts are indiscernible No inflammation around the pre-existing strut regions

62. Echogenicity analysis of BVS 1.0 after the procedure (BL) and at the 6-month follow-up (FU). The polymeric strut was highly echogenic at baseline and thus colored green by the dedicated echogenicity software. At 6 months, most struts are no longer hyperechogenic (absence of green spots and prevalence of red background), suggesting that the bioresorption has already occurred

63. IVUS virtual histology (IVUS-VH) images after the procedure and at 6 and 24 months after implantation of BVS 1.0, respectively. With IVUS-VH, the struts were misclassified as dense calcium after the procedure and at 6 months, whereas at 24 months, they were no longer visible

64. Absorb Drug Dosing and Release Clinical data from the ABSORB Cohort A and Cohort B trials have demonstrated that Absorb is able to revascularize the vessel similar to a XIENCE V stent. In part, this success is due to the similar drug release profile between the two devices. • Absorb uses the same drug dose density (100 μg /cm2) • Similar to XIENCE V, Absorb releases approximately 80% of the total everolimus in the first 90 days after implantation21 • The controlled release of everolimus in both XIENCE V and Absorb contributes to the decrease in vessel tissue re-growth that can lead to restenosis

65. Regulatory Status Absorb received CE Mark on December 14, 2010 for a limited number of sizes. Additional sizes have received CE Mark on August 13, 2012

66. Indications for Use Absorb is a temporary scaffold indicated for improving coronary luminal diameter that will eventually resorb and potentially facilitate normalization of vessel function in patients with ischemic heart disease due to de novo native coronary artery lesions. The treated lesion length should be less than the nominal scaffolding length (12 mm, 18 mm, 28 mm) with reference vessel diameters ≥ 2.0 mm and ≤ 3.8 mm.

67. Implantation of Absorb Absorb is implanted into the patient’s coronary arteries via a percutaneous intervention. The procedure of implanting an Absorb should only be performed by physicians who have received appropriate training. The implantation procedure of an Absorb is similar to a metallic stent; however, additional attention is needed to ensure: • Careful selection of the scaffold diameter for the target lesion reference vessel diameter • Thorough lesion preparation prior to scaffold implantation to optimize scaffold deployment • Safe advancement of Absorb across the lesion.