**5. References**

148 Coronary Interventions

RISK and SAFE pathways. In a multicenter single-blinded controlled clinical trial, the effect of cyclosporine A was evaluated in 58 patients with acute ST-elevation myocardial infarction who received an intravenous bolus of 2.5mg/kg of cyclosporine immediately before undergoing PCI, significantly reduced the release of creatine kinase by 40% within the first 72 hours. (Piot *et al.* 2008) Infarct size, assessed on day 5 (by measuring the area of hyperenhancement on magnetic resonance imaging) was significantly reduced. Cyclosporine, routinely used as an immunosuppressive agent, is well known for its toxic side-effects, such as renal and hepatic toxicity and increased susceptibility to infections and cancers. A single bolus injection of cyclosporine did not show any of these side-effects, but larger and longer clinical trials are required to prove the safety and efficacy of cyclosporine

Two clinical trials have explored the effect of adenosine in patients with acute myocardial infarction (AMISTAD and AMISTAD II) but the results were mitigated by the haemodynamic effect of the drug. (Mahaffey *et al.* 1999, Ross *et al.* 2005) Although adenosine can successfully reduce the infarct size, it has a vasodilatory and negative chronotropic effect, causing hypotension and bradycardia, thus limiting its clinical application. However, recent experimental studies using polyethylene glycol liposomal adenosine in rats protected against ischemia-reperfusion and reduced the hemodynamic effect of adenosine. (Takahama *et al.* 2009) If this protocol can be applied in a clinical setting, it may limit the side effects of

Erythropoietin successfully reduced the infarct size in animal models but its clinical

At the present, little information is available in humans with regards to the success of ischemic postconditioning with different comorbidities and most of the clinical trials have excluded patients with diabetes/metabolic syndrome. Animal studies have shown that various comorbidities affect the protective effect of postconditioning. Rats with obesity, metabolic syndrome or diabetes become more resistant to the infarct limiting effect of ischemic postconditioning and additional cycles of ischemia-reperfusion are required to achieve a beneficial effect (Hausenloy *et al.* 2011). Similarly, hyperglycemia in rabbits abolishes the cardioprotective effect of ischemic postconditioning (Raphael *et al.*). More recently, depressed rats failed to be protected with ischemic postconditioning (Zhuo *et al.*

Ischemic postconditioning is a safe, simple and inexpensive therapy but several factors need to be taken into consideration for its efficacy. Remote ischemic postconditioning and pharmacological postconditioning present the advantage of being applied in AMI patients with or without PCI. However, the severity and duration of ischemia, the presence of collateral circulation and the algorithm of the postconditioning protocol may all affect the protective effect of ischemic postconditioning against lethal reperfusion injury (Hausenloy *et al.* 2010).

Although small clinical proof-of-concept studies suggest that ischemic postconditioning can protect the human heart against lethal reperfusion injuries, larger clinical trials testing

as a therapeutic agent following AMI.

application still needs to be confirmed. (Bullard *et al.* 2005)

**3.4 Ischemic postconditioning and comorbidities** 

adenosine.

2011).

**4. Conclusion** 


Cardiac Postconditioning:

No.5, pp.893-907

No.2, pp.179-94

An Additional Therapy to Limit Cell Death Following Myocardial Infarction 151

Hausenloy D. J., Maddock H. L., Baxter G. F., Yellon D. M.: Inhibiting mitochondrial

Hausenloy D. J., Mwamure P. K., Venugopal V., Harris J., Barnard M., Grundy E., Ashley E.,

Hausenloy D. J., Yellon D. M.: Cardioprotective growth factors 2009 *Cardiovasc Res* Vol.83,

Hausenloy D. J., Yellon D. M.: The mitochondrial permeability transition pore: its

Hoole S. P., Heck P. M., Sharples L., Khan S. N., Duehmke R., Densem C. G., Clarke S. C.,

Huffman L. C., Koch S. E., Butler K. L.: Coronary effluent from a preconditioned heart

Inserte J., Ruiz-Meana M., Rodriguez-Sinovas A., Barba I., Garcia-Dorado D.: Contribution

Jin Z. Q., Karliner J. S., Vessey D. A.: Ischaemic postconditioning protects isolated mouse

Jonassen A. K., Sack M. N., Mjos O. D., Yellon D. M.: Myocardial protection by insulin at

Juhaszova M., Zorov D. B., Kim S. H., Pepe S., Fu Q., Fishbein K. W., Ziman B. D., Wang S.,

permeability transition pore 2004 *J Clin Invest* Vol.113, No.11, pp.1535-49 Juhaszova M., Zorov D. B., Yaniv Y., Nuss H. B., Wang S., Sollott S. J.: Role of glycogen synthase kinase-3beta in cardioprotection 2009 *Circ Res* Vol.104, No.11, pp.1240-52 Kim J. S., Ohshima S., Pediaditakis P., Lemasters J. J.: Nitric oxide: a signaling molecule

Lacerda L., Smith R. M., Opie L., Lecour S.: TNFalpha-induced cytoprotection requires the

Lacerda L., Somers S., Opie L. H., Lecour S.: Ischaemic postconditioning protects against

Lecour S.: Activation of the protective Survivor Activating Factor Enhancement (SAFE)

randomized control trial 2009 *Circulation* Vol.119, No.6, pp.820-7

2008 *Am J Physiol Heart Circ Physiol* Vol.294, No.1, pp.H257-62

preconditioning? 2002 *Cardiovasc Res* Vol.55, No.3, pp.534-43

2007 *Lancet* Vol.370, No.9587, pp.575-9

*Mol Cell Cardiol* Vol.35, No.4, pp.339-41

*Antioxid Redox Signal* Vol.14, No.5, pp.923-39

*Mol Cell Cardiol* Vol.47, No.1, pp.32-40

activation 2008 *Cardiovasc Res* Vol.79, No.1, pp.134-40

cell-survival signaling 2001 *Circ Res* Vol.89, No.12, pp.1191-8

reperfusion 2004 *Free Radic Biol Med* Vol.37, No.12, pp.1943-50

postconditioning: two sides of the same coin 2011 *Antioxid Redox Signal* Vol.14,

permeability transition pore opening: a new paradigm for myocardial

Vichare S., Di Salvo C., Kolvekar S., Hayward M., Keogh B., Macallister R. J., Yellon D. M.: Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial

fundamental role in mediating cell death during ischaemia and reperfusion 2003 *J* 

Shapiro L. M., Schofield P. M., O'sullivan M., Dutka D. P.: Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective,

activates the JAK-STAT pathway and induces cardioprotection in a donor heart

of delayed intracellular pH recovery to ischemic postconditioning protection 2011

hearts against ischaemia/reperfusion injury via sphingosine kinase isoform-1

reperfusion requires early administration and is mediated via Akt and p70s6 kinase

Ytrehus K., Antos C. L., Olson E. N., Sollott S. J.: Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial

against mitochondrial permeability transition- and pH-dependent cell death after

production of free radicals within mitochondria in C(2)C(12) myotubes 2006 *Life Sci* 

reperfusion injury via the SAFE pathway 2009 *Cardiovasc Res* Vol.84, No.2, pp.201-8

pathway against reperfusion injury: Does it go beyond the RISK pathway? 2009a *J* 


Bolli R., Jeroudi M. O., Patel B. S., Dubose C. M., Lai E. K., Roberts R., Mccay P. B.: Direct

Bolli R., Li Q. H., Tang X. L., Guo Y., Xuan Y. T., Rokosh G., Dawn B.: The late phase of

Botker H. E., Kharbanda R., Schmidt M. R., Bottcher M., Kaltoft A. K., Terkelsen C. J., Munk

Bullard A. J., Govewalla P., Yellon D. M.: Erythropoietin protects the myocardium against

Cheung M. M., Kharbanda R. K., Konstantinov I. E., Shimizu M., Frndova H., Li J., Holtby

Darling C. E., Solari P. B., Smith C. S., Furman M. I., Przyklenk K.: 'Postconditioning' the

Deuchar G. A., Opie L. H., Lecour S.: TNFalpha is required to confer protection in an in vivo

Dong Z., Saikumar P., Weinberg J. M., Venkatachalam M. A.: Calcium in cell injury and

Garcia-Dorado D., Oliveras J.: Myocardial oedema: a preventable cause of reperfusion

Garcia S., Henry T. D., Wang Y. L., Chavez I. J., Pedersen W. R., Lesser J. R., Shroff G. R.,

Gho B. C., Schoemaker R. G., Van Den Doel M. A., Duncker D. J., Verdouw P. D.:

Halkos M. E., Kerendi F., Corvera J. S., Wang N. P., Kin H., Payne C. S., Sun H. Y., Guyton

Hausenloy D. J., Baxter G., Bell R., Botker H. E., Davidson S. M., Downey J., Heusch G.,

Hausenloy D. J., Lecour S., Yellon D. M.: Reperfusion injury salvage kinase and survivor

cardioprotection 2007 *Basic Res Cardiol* Vol.102, No.3, pp.274-8

*Rev* Vol.12, No.3-4, pp.189-99

*Cardiol* Vol.47, No.11, pp.2277-82

*Res* Vol.4, No.1, pp.92-8

Vol.94, No.9, pp.2193-200

pp.961-9; discussion 969

Vol.105, No.6, pp.677-86

death 2006 *Annu Rev Pathol* Vol.1, pp.405-34

injury? 1993 *Cardiovasc Res* Vol.27, No.9, pp.1555-63

No.9716, pp.727-34

evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog 1989 *Proc Natl Acad Sci U S A* Vol.86, No.12, pp.4695-9

preconditioning and its natural clinical application--gene therapy 2007 *Heart Fail* 

K., Andersen N. H., Hansen T. M., Trautner S., Lassen J. F., Christiansen E. H., Krusell L. R., Kristensen S. D., Thuesen L., Nielsen S. S., Rehling M., Sorensen H. T., Redington A. N., Nielsen T. T.: Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial *Lancet* Vol.375,

reperfusion injury in vitro and in vivo 2005 *Basic Res Cardiol* Vol.100, No.5, pp.397-403

H. M., Cox P. N., Smallhorn J. F., Van Arsdell G. S., Redington A. N.: Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans 2006 *J Am Coll* 

human heart: multiple balloon inflations during primary angioplasty may confer

model of classical ischaemic preconditioning 2007 *Life Sci* Vol.80, No.18, pp.1686-91

Moore L., Traverse J. H.: Long-term follow-up of patients undergoing postconditioning during ST-elevation myocardial infarction 2010 *J Cardiovasc Transl* 

Myocardial protection by brief ischemia in noncardiac tissue 1996 *Circulation* 

R. A., Vinten-Johansen J., Zhao Z. Q.: Myocardial protection with postconditioning is not enhanced by ischemic preconditioning 2004 *Ann Thorac Surg* Vol.78, No.3,

Kitakaze M., Lecour S., Mentzer R., Mocanu M. M., Ovize M., Schulz R., Shannon R., Walker M., Walkinshaw G., Yellon D. M.: Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations 2010 *Basic Res Cardiol* 

activating factor enhancement prosurvival signaling pathways in ischemic

postconditioning: two sides of the same coin 2011 *Antioxid Redox Signal* Vol.14, No.5, pp.893-907


Cardiac Postconditioning:

*Cardiol* Vol.91, No.3, pp.191-202

*Res* Vol.38, No.2, pp.291-300

Vol.55, No.4, pp.348-57

Vol.251, No.6 Pt 2, pp.H1306-15

*Am Coll Cardiol* Vol.45, No.11, pp.1775-80

*Heart Circ Physiol* Vol.283, No.4, pp.H1481-8

*Circulation* Vol.112, No.14, pp.2143-8

C2C12 2005 *J Mol Cell Cardiol* Vol.38, pp.1040-1041

An Additional Therapy to Limit Cell Death Following Myocardial Infarction 153

Piper H. M., Balser C., Ladilov Y. V., Schafer M., Siegmund B., Ruiz-Meana M., Garcia-

Piper H. M., Garcia-Dorado D., Ovize M.: A fresh look at reperfusion injury 1998 *Cardiovasc* 

Przyklenk K., Bauer B., Ovize M., Kloner R. A., Whittaker P.: Regional ischemic

Raphael J., Gozal Y., Navot N., Zuo Z.: Hyperglycemia inhibits anesthetic-induced

Reimer K. A., Murry C. E., Yamasawa I., Hill M. L., Jennings R. B.: Four brief periods of

Ross A. M., Gibbons R. J., Stone G. W., Kloner R. A., Alexander R. W.: A randomized,

Schulman D., Latchman D. S., Yellon D. M.: Urocortin protects the heart from reperfusion

Schulz R., Heusch G.: Tumor necrosis factor-alpha and its receptors 1 and 2: Yin and Yang in

Somers S., Lacerda L., Opie L., Lecour S.: NFkB triggers TNF induced cardioprotection in

Sorensson P., Saleh N., Bouvier F., Bohm F., Settergren M., Caidahl K., Tornvall P., Arheden

Staat P., Rioufol G., Piot C., Cottin Y., Cung T. T., L'huillier I., Aupetit J. F., Bonnefoy E.,

Suleman N., Opie L., Lecour S.: Ischemic postconditioning confers cardioprotection via phosphorylation of STAT-3 2006 *J Mol Cell Cardiol* Vol.40, No.6, pp.977 Takahama H., Minamino T., Asanuma H., Fujita M., Asai T., Wakeno M., Sasaki H., Kikuchi

cardioprotection in rats 2009 *J Am Coll Cardiol* Vol.53, No.8, pp.709-17 Tanno M., Gorog D. A., Bellahcene M., Cao X., Quinlan R. A., Marber M. S.: Tumor necrosis

Tarantini G., Favaretto E., Napodano M., Perazzolo Marra M., Cacciavillani L., Babuin L.,

activation 2003 *J Mol Cell Cardiol* Vol.35, No.12, pp.1523-7

myocardial infarction? 2009 *Circulation* Vol.119, No.10, pp.1355-7

ST elevation myocardial infarction *Heart* Vol.96, No.21, pp.1710-5

coronary occlusion 1993 *Circulation* Vol.87, No.3, pp.893-9

Dorado D.: The role of Na+/H+ exchange in ischemia-reperfusion 1996 *Basic Res* 

'preconditioning' protects remote virgin myocardium from subsequent sustained

postconditioning in the rabbit heart via modulation of phosphatidylinositol-3 kinase/Akt and endothelial nitric oxide synthase signaling *J Cardiovasc Pharmacol* 

myocardial ischemia cause no cumulative ATP loss or necrosis 1986 *Am J Physiol* 

double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II) 2005 *J* 

injury via upregulation of p42/p44 MAPK signaling pathway 2002 *Am J Physiol* 

H., Ryden L., Pernow J.: Effect of postconditioning on infarct size in patients with

Finet G., Andre-Fouet X., Ovize M.: Postconditioning the human heart 2005

H., Hashimoto K., Oku N., Asakura M., Kim J., Takashima S., Komamura K., Sugimachi M., Mochizuki N., Kitakaze M.: Prolonged targeting of ischemic/reperfused myocardium by liposomal adenosine augments

factor-induced protection of the murine heart is independent of p38-MAPK

Giovagnoni A., Renda P., De Biasio V., Plebani M., Mion M., Zaninotto M., Mistrorigo F., Panfili M., Isabella G., Bilato C., Iliceto S.: Design and methodologies


Lecour S.: Multiple protective pathways against reperfusion injury: a SAFE path without

Lecour S., Rochette L., Opie L.: Free radicals trigger TNFalpha-induced cardioprotection

Lecour S., Smith R. M., Woodward B., Opie L. H., Rochette L., Sack M. N.: Identification of a

mediated cardioprotection 2002 *J Mol Cell Cardiol* Vol.34, No.5, pp.509-18 Lecour S., Suleman N., Deuchar G. A., Somers S., Lacerda L., Huisamen B., Opie L. H.:

Limalanathan S., Andersen G. O., Hoffmann P., Klow N. E., Abdelnoor M., Eritsland J.:

Luo W., Li B., Chen R., Huang R., Lin G.: Effect of ischemic postconditioning in adult valve

Mahaffey K. W., Puma J. A., Barbagelata N. A., Dicarli M. F., Leesar M. A., Browne K. F.,

Morrison R. R., Tan X. L., Ledent C., Mustafa S. J., Hofmann P. A.: Targeted deletion of A2A

Murry C. E., Jennings R. B., Reimer K. A.: New insights into potential mechanisms of

Murry C. E., Jennings R. B., Reimer K. A.: Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium 1986 *Circulation* Vol.74, No.5, pp.1124-36 Nakagawa T., Shimizu S., Watanabe T., Yamaguchi O., Otsu K., Yamagata H., Inohara H.,

Ong S. B., Subrayan S., Lim S. Y., Yellon D. M., Davidson S. M., Hausenloy D. J.: Inhibiting

Pell T. J., Baxter G. F., Yellon D. M., Drew G. M.: Renal ischemia preconditions myocardium:

Piot C., Croisille P., Staat P., Thibault H., Rioufol G., Mewton N., Elbelghiti R., Cung T. T.,

myocardial infarction) study *Cardiology* Vol.116, No.2, pp.103-9

replacement 2008 *Eur J Cardiothorac Surg* Vol.33, No.2, pp.203-8

(AMISTAD) trial 1999 *J Am Coll Cardiol* Vol.34, No.6, pp.1711-20

ischemic preconditioning 1991 *Circulation* Vol.84, No.1, pp.442-5

1987 *Circulation* Vol.75, No.6 Pt 2, pp.V15-24

*Circulation* Vol.121, No.18, pp.2012-22

*Physiol* Vol.275, No.5 Pt 2, pp.H1542-7

*N Engl J Med* Vol.359, No.5, pp.473-81

No.7033, pp.652-8

novel role for sphingolipid signaling in TNF alpha and ischemic preconditioning

Pharmacological preconditioning with tumor necrosis factor-alpha activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal-regulated kinase) 2005b

Rationale and design of the POSTEMI (postconditioning in ST-elevation

Eisenberg P. R., Bolli R., Casas A. C., Molina-Viamonte V., Orlandi C., Blevins R., Gibbons R. J., Califf R. M., Granger C. B.: Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine

adenosine receptors attenuates the protective effects of myocardial postconditioning 2007 *Am J Physiol Heart Circ Physiol* Vol.293, No.4, pp.H2523-9 Murphy J. G., Marsh J. D., Smith T. W.: The role of calcium in ischemic myocardial injury

Kubo T., Tsujimoto Y.: Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death 2005 *Nature* Vol.434,

mitochondrial fission protects the heart against ischemia/reperfusion injury 2010

role of adenosine receptors and ATP-sensitive potassium channels 1998 *Am J* 

Bonnefoy E., Angoulvant D., Macia C., Raczka F., Sportouch C., Gahide G., Finet G., Andre-Fouet X., Revel D., Kirkorian G., Monassier J. P., Derumeaux G., Ovize M.: Effect of cyclosporine on reperfusion injury in acute myocardial infarction 2008

Aktion? 2009b *J Mol Cell Cardiol* Vol.46, No.5, pp.607-9

2005a *Cardiovasc Res* Vol.65, No.1, pp.239-43

*Circulation* Vol.112, No.25, pp.3911-8


**8** 

*USA* 

**DES Overview: A Historical and Current Review** 

The focus of this chapter is drug-eluting stents (DES) for the treatment of coronary artery disease (CAD). The clinical trial programs for the main DES approved by the Food and Drug Administration (FDA) for the treatment of CAD are presented. CAD is the leading cause of death in both men and women around the world. In the United States alone, there is a coronary event that occurs every 25 seconds and someone will die from a coronary event every minute (Roger et al., 2011). The current treatment options for ischemic CAD include medications, percutaneous interventions, and surgery to perform coronary artery bypass grafting (CABG). According to the American Heart Association (AHA) 2011 Statistics Update, the total number of percutaneous coronary interventions (PCI) procedures performed in 2007 was 1,178,000 compared to 408,000 CABG operations. With risk factors like obesity and diabetes prevalence increasing globally, the number of CAD interventions will likely continue to rise in the future and require more specialized treatment options for

In past decades, percutaneous angioplasty (PTCA) or plain old balloon angioplasty (POBA) was used to treat obstructive coronary lesions but had frequent incidence of abrupt closure and restenosis. The use of bare metal stents (BMS) helped to address the limitations of PTCA, as evident by reduced angiographic restenosis and target vessel revascularizations (TVR) in earlier clinical trials. The results of these trials led to the first FDA approved balloon-expandable BMS, the Palmaz-Schatz stent (Cordis Corp; a Johnson and Johnson Company) and the Gianturco-Roubin coil stent (Cook Inc, Bloomington, IN) (Fischman et al., 1994; Serruys et al., 1994). Compared to PTCA, the development of BMS reduced the need for urgent CABG associated with abrupt closures and restenosis, but the need for repeat procedures persisted (Doostzadeh et al., 2010). Although BMS provided the structural support to prevent abrupt closures, arterial wall recoil, and negative arterial wall remodeling, the problem of neointimal hyperplasia was not remedied by BMS. Some of the earlier trials evaluating BMS demonstrated that restenosis occurred in about 20% of cases by 6 months (Doostzadeh et al., 2009). The development of DES emerged and intended to

In order for DES to optimize therapeutic benefits with minimal risks, several factors must be considered. The stent cell design, strut thickness, polymer technology, mechanism of drug,

deliver localized pharmaceutical agents targeted to reduce restenosis.

**1. Introduction** 

more complex lesions and patient populations.

**of Pivotal Clinical Trial Programs** 

Susan Bezenek, Poornima Sood, Wes Pierson,

Chuck Simonton and Krishna Sudhir

*Abbott Vascular, Santa Clara, CA* 

of the POSTconditioning during coronary angioplasty in acute myocardial infarction (POST-AMI) trial 2010 *Cardiology* Vol.116, No.2, pp.110-6

