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Angina pectoris: interventional therapies and treatment of restenosis
The International Journal of Biochemistry & Cell Biology 35 (2003) 1399–1406
Medicine in focus
Angina pectoris: interventional therapies and treatment of restenosis Sunil V. Nair, Jean R. McEwan∗ Centre for Cardiovascular Biology and Medicine, BHF Laboratories, Rayne Building, 5 University Street, London WC1E 6JJ, UK
Abstract Angina pectoris is a clinical syndrome of symptoms caused by myocardial ischaemia due to oxygen demand exceeding supply. The most common cause is coronary artery stenosis due to progressive atherosclerotic disease. Angina has a prevalence of approximately 5% and increases with age. Despite improvements in treatment there remains a yearly mortality of 2–3%. A major advance in the treatment of symptomatic angina was the introduction of percutaneous transluminal coronary angioplasty (PTCA). This initial enthusiasm was dampened by significant numbers developing symptomatic restenosis from vascular elastic recoil and neointimal hyperplasia (NI). The widespread introduction of stent deployment following the initial angioplasty reduced the rates of elastic recoil but failed to prevent NI and may actually stimulate it. Currently, there is much interest in mechanisms that alter cell proliferation thereby decreasing NI. Techniques include brachytherapy, photodynamic therapy and drug-eluting stents. Provisional data for these new stents, which slowly release medication that inhibits cell turnover, are very good with few occurrences of restenosis. Results from larger randomised trials are awaited. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Angina; Restenosis; Sirolimus; Stent
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Percutaneous coronary intervention (PCI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Coronary angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Percutaneous transluminal coronary angioplasty (PTCA) . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Problems following PTCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Intracoronary stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Subacute thrombosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Antiplatelet and antithrombotic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Improving long term interventional outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Intracoronary brachytherapy and related techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Drug-eluting stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗
Corresponding author. E-mail addresses: [email protected] (S.V. Nair), [email protected] (J.R. McEwan).
1357-2725/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1357-2725(03)00135-3
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4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
2. Percutaneous coronary intervention (PCI)
Angina is a clinical syndrome consisting of pain, discomfort, and heaviness of the chest, arm or jaw. It is precipitated by exercise, emotional stress and anxiety and is relieved by rest and or administration of glyceryl trinitrate. The symptoms usually last for a few minutes and are caused by myocardial ischaemia of severity and duration insufficient to cause myocardial cell necrosis. The ischaemia occurs when myocardial blood flow is insufficient for myocardial oxygen demand. Most usually this is because of coronary artery narrowing due to atherosclerosis. Initial treatment for angina involves modification and treatment of underlying risk factors. Adequate time must be spent educating patients regarding their lifestyle and the effect it has on their disease. Additional medication may be required for optimum control of risk factors (diabetes, hypertension, hypercholesterolaemia). Treatment can then be divided into symptomatic including, beta blockers, nitrate preparations, calcium channel antagonists, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass grafting (CABG) and prognostic, including aspirin, lipid lowering agents such as statins, coronary artery bypass grafting and in recent studies, nicorandil (The IONA Study group, 2002), and angiotensin converting enzyme inhibitors (ACE inhibitors) (The Heart Outcomes Prevention Evaluation Study Investigators, 2000). The latter appear to have disease modifying effects which make them particularly beneficial in patients with hypertension or diabetes. Occlusive disease of coronary arteries, whether from atheroma or thrombosis, may be treated with percutaneous endovascular intervention, which restores patency without the need for major surgical reconstruction. In the UK in 1998/1999 there were more than 21,000 (Gray & Callum, 2002) such procedures and this figure has increased over time such that use of the technique has now exceeded that of coronary artery bypass grafting.
2.1. Coronary angiography This remains the gold standard for diagnosis of coronary artery disease. It involves insertion of a catheter into the heart via a cannula inserted in a distal artery. Under fluoroscopic guidance specific catheters are manipulated into the coronary ostia, where 5–10 ml of contrast is injected. Several images in different planes are taken of the left and right coronary arteries. The contrast delineates the coronary arteries and on X-ray screening demonstrates any occlusion or significant stenosis. 2.2. Percutaneous transluminal coronary angioplasty (PTCA) PTCA has been an effective treatment for patients with chronic severe angina unresponsive to medical therapy or in those unable to tolerate multiple medical therapies due to side effects. It has the potential to offer safe and cost effective patient management. Following standard coronary angiography; an angioplasty guide wire is advanced and manipulated across the stenosis to lie in the distal vessel. The wire acts as a guide for the passage of an elongated balloon which when inflated disrupts the wall of the blood vessel, displacing the atheroma laterally and improving the lumen diameter. Further injection of contrast enables assessment of the result (Fig. 1a–d). 2.3. Problems following PTCA Studies have shown the rates of restenosis following PTCA to be approximately 30%; this increases costs and decreases efficacy, dampening enthusiasm for this and related endovascular procedures (Greunzig, King, Schlumpf, & Seigenhaler, 1987; Serruys et al., 1988). PTCA causes increased vessel lumen diameter by different mechanisms. Firstly the vessel wall is stretched, and secondly the plaque is disrupted causing deep fissuring through the intima into the media,
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Fig. 1. (a) Right coronary artery (RCA) with mid segment stenosis. All images obtained during coronary angiography. (b) Distended balloon catheter at site of RCA stenosis. (c) Following removal of the balloon catheter the metal coronary artery stent can just be seen at the site of previous mid segment stenosis. (d) RCA post balloon angioplasty and stenting showing restoration of lumen diameter.
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2.4. Intracoronary stents
Fig. 1. (Continued )
dissection flaps and the displacement of plaque contents laterally. These mechanisms are also the cause of recurrent problems. Due to the inherent elasticity of the arterial wall, there is a degree of elastic recoil in the first 24 h post procedure. In addition dissection flaps and plaque disruption result in an unstable plaque, exposure of plaque contents to the bloodstream, platelet accumulation, activation, and adhesion, which can lead to thrombosis and plaque expansion at the treated site. Both of these can cause acute luminal occlusion in the first 24 h and this complicates approximately 5% of procedures (Ludman, 2002). A delayed response occurs during the first 6 months and relates to vessel healing. Ongoing reduction in external vessel diameter (negative remodelling) continues, and within the media, smooth muscle cells are activated, re-enter the cell cycle, proliferate and migrate into the intima to reline the damaged arterial lumen with a neointimal layer (neointimal hyperplasia (NI)) (Fig. 2a and b). Deposition and reorganisation of the extracellular matrix also contributes to the lesion (Isner, 1994; Waller et al., 1990). The pathogenesis of the restenotic lesion is complex and many different growth factors and cytokines have been implicated in the stimulation of vascular smooth muscle cell (VSMC) proliferation and synthetic activity (Ross, 1993). These processes cause a gradual reduction in arterial lumen and if the lumen narrows sufficiently to obstruct flow, recurrent symptoms will result, and further intervention may be necessary (Fig. 2a and c).
The widespread introduction of stent deployment following initial balloon angioplasty has greatly reduced rates of restenosis. Intracoronary stents are now used in greater than 70% of percutaneous coronary interventions. Following standard balloon angioplasty a second balloon catheter mounted with a steel mesh is inserted and guided to the problem area. Inflation of the balloon expands the stent and presses it into the arterial wall. On balloon deflation the catheter is withdrawn and the stent remains in place (Fig. 1d). Once expanded the rigid design of the stents prevents acute elastic recoil and limits negative remodelling. In addition, stents hold back dissection flaps. Stenting does not prevent neointimal hyperplasia and may actually stimulate it (Serruys et al., 1994). Following stent insertion a greater lumen diameter is achieved than with balloon alone, therefore although neointimal hyperplasia occurs, the overall effect on lumen diameter is proportionately reduced and the rates of restenosis are lower. Overall, stent insertion decreases the rate of acute luminal occlusion and 6-month restenosis rates are reduced to approximately 10–20%. Currently PTCA procedures have emergency CABG rates of ∼0.5% (de Belder, 1999), mortality rates of ∼0.9% (de Belder, 1999), and periprocedural MI rates of <1%. 2.5. Subacute thrombosis Subacute thrombosis complicates 1–2% of patients treated with intracoronary stents. Platelets aggregate on the stent struts and cause thrombus leading to reduction in myocardial blood flow. This usually occurs in the first 4 weeks post procedure. After this time duration the struts are covered by the growth of new endothelial cells. Rates of subacute thrombosis were previously higher but attention to technical aspects of stent implantation and the use of antithrombotic agents (intravenous heparin infusion) and antiplatelet agents (glycoprotein IIb/IIIa (GpIIb/IIIa) platelet receptor antagonists and clopidogrel) during the procedure have reduced rates to the above figure. In most centres an agent such as clopidogrel is continued for 4 weeks until new endothelial cells have grown. Longer term clopidogrel may have continuing advantages (Steinhubl et al., 2002), though cost/benefit considerations mean that this is not current UK practice.
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Fig. 2. (a) Coronary angiography of the same patient as in Fig. 1 representing with recurrent symptoms from the development of in-stent restenosis, due to neointimal hyperplasia. (b) RCA, after repeat balloon dilatation for in-stent restenosis, showing once more restoration of lumen diameter. (c) Rabbit iliac artery with coronary stent in situ (some stent struts visible). Established neointimal hyperplasia is present causing a reduction in vessel luminal diameter.
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2.6. Antiplatelet and antithrombotic agents Platelets play an important role in the complications of PCI, particularly the early acute vessel occlusion and sub acute thrombosis associated with stent insertion. For many years aspirin (an inhibitor of cyclo-oxygenase, required for the production of functioning platelets) and intravenous heparin (binds antithrombin 3 in the clotting cascade, resulting in inactive clotting factors) have been used to try and reduce complication rates due to thrombosis. Clopidogrel inhibits platelet activation by antagonising the adenosine diphosphate (ADP) receptor and is now widely used in addition to the above agents. All platelet aggregation is ultimately through the formation of fibrin bridges between the platelet glycoprotein IIb/IIIa receptors. GpIIb/IIIa antagonists are now recommended as adjuvants to PCI (The EPISTENT investigators, 1998). Abciximab is an intravenous preparation of a recombinant hybrid monoclonal antibody against the GpIIb/IIIa receptor. Alternatives are synthetic cyclical or simple peptide molecules (tirofiban and eptifibatide), which are of much shorter action. The benefit of these in reducing acute periprocedural occlusion, whether in elective or emergency cases has to be balanced against cost and increased bleeding complications (National Institute for Clinical Excellence, 2000).
3. Improving long term interventional outcomes No systemic pharmacological agent has resolved the problem of restenosis. There is currently much interest in mechanisms that alter cell proliferation thereby limiting NI. 3.1. Intracoronary brachytherapy and related techniques Intracoronary brachytherapy is now approved for use in the treatment of in-stent stenosis. A radioactive wire is inserted immediately after balloon angioplasty and left in place for around 40 min before removal. Both gamma and beta irradiation have been tested and shown to be effective (Teirstein et al., 1997; Verin et al., 1997). The radiation causes cell DNA damage, which manifests during mitosis, thus selectively
targeting rapidly proliferating cells, which die during abortive replication. VSMC are ablated in a dose dependent manner. Concerns exist regarding the late effects of brachytherapy and if stenosis recurs, it tends to be at the edges of the dilated areas, the candy wrapper effect, perhaps related to lower, ineffective, radiation doses at the edges of the treated segments (Salame et al., 2001; Seabra-Gomes, 2001). However, healing of the artery after the angioplasty and brachytherapy may be delayed, intimal dissections persist and stent struts remain unendothelialized for months to years. This potentially leaves a risk for vessel thrombosis at a very delayed stage (Ludman, 2002). Alternative arterial cell-ablative techniques include photodynamic therapy in which illumination of the artery through a modified balloon catheter activates a drug administered locally, or systemically. Reactive oxygen species are generated which kill the medial smooth muscle cells and responses to the angioplasty are modified. Potential advantages include that of rapid re-growth of the endothelium after PDT (Mansfield, Bown, & McEwan, 2001). However, such techniques are largely experimental at this time. 3.2. Drug-eluting stents The recent development of coated drug-eluting stents shows promise. The stent may be coated in an adsorbed drug that is slowly released over days to weeks. Sirolimus (rapamycin), a macrolide antifungal agent with a unique antiproliferative mode of action and powerful immunosuppressant properties, inhibits several regulators of cell cycle progression and the migration of vascular smooth muscle cells (Marx & Marks, 2001). These antiproliferative, antimigratory and anti-inflammatory properties are responsible for the efficacy of sirolimus therapy in preventing acute rejection of renal allografts and arteriopathy of cardiac allografts, as well as in-stent restenosis (Morrice et al., 2002). Sirolimus binds to an intracellular receptor protein FKBP12 and elevates p27 levels, which lead to the inhibition of cyclin/cyclin-dependent kinase complexes and ultimately induces cell-cycle arrest in the late G1 phase (Sousa et al., 2001) (Fig. 3). Animal studies and a small clinical study have shown sirolimus reduces neointimal proliferation (Gallo et al., 1999; Sousa et al., 2001). In the RAVEL trial, the first prospective randomised, double blind,
S.V. Nair, J.R. McEwan / The International Journal of Biochemistry & Cell Biology 35 (2003) 1399–1406
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Fig. 3. Effects of sirolimus (rapamycin) on cell proliferation mechanisms. Arterial injury induces growth factor expression and this in turn leads to increased activity of cyclin dependent kinases, decreased levels of their inhibitor p27 and inactivation of pRB by phosphorylation. The phosphorylation of the pRB is the stimulus to cell cycle progression from G1 to GS, the synthetic phase, S, in which DNA is replicated before cell division. Sirolimus (rapamycin) inhibits the fall in p27, which occurs after mitogen stimulation, and this, and reduced phosphorylation of pRB by cyclin-dependent kinases, contribute to its growth inhibitory effects. The effects of sirolimus are multiple. Sirolimus also binds to FKBP12 and the complex inactivates the mammalian target of rapamycin (mTOR), another enzyme involved in the regulation of protein synthesis and cell proliferation.
multicentre trial comparing sirolimus eluting stents with a standard uncoated stent in 238 patients, there were no significant restenosis at 6 months in the sirolimus eluting stent group compared with 26% in the standard stent group (Morrice et al., 2002). In addition there were no episodes of thrombosis, suggesting that re-endothelialisation occurs despite the immunosuppressive effects of sirolimus, and a low rate of cardiac events at 1 year. More recently, Sousa et al. report 2 years follow up results of 30 patients treated with sirolimus eluting stents. Their results are very promising showing in-stent lumen diameters remaining essentially unchanged after 2 years with no evidence of restenosis “catch up” (Sousa et al., 2003). Paclitaxel is a second agent being used in drugeluting stents. It is a microtubule inhibitor and therefore inhibits the microtubular function required for
cell division and replication. In a small study using paclitaxel coated stents there was minimal intimal hyperplasia and instent restenosis at 6 months, but the antiproliferative effect was not maintained at 12 months (Liistro et al., 2002). Larger randomised trials are underway to see if these excellent short term results continue in the longer term and also whether delayed healing may have longer term risks.
4. Summary Percutaneous interventions are now the mainstay of the treatment of symptomatic coronary narrowing, whether primarily due to atherosclerosis or secondary to previous procedures (restenosis). As demonstrated
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above, the current therapies to improve short and long term outcomes were designed on a background of scientific understanding of the disease processes. Further improvements in both the medical therapy and the application of this technology are dependent on further elucidation of the pathophysiology of vascular disease. References de Belder, M. A. (1999). Cardiac intervention procedures in the United Kingdom1997: Developments in data collection. Council of the British Cardiovascular Intervention Society (http://www.bcis.org.uk). Heart, 82(Suppl. 2), II2–9. Gallo, R., Padurean, A., Jayaraman, T., Marx, S., Raque, M., Adelma, S., Chesebro, J., Fallon, J., Fusber, V., Marks, A., & Badimon, J. J. (1999). Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation, 99(16), 2164–2170. Gray, H. H., & Callum, K. G. (2002). Death following coronary angioplasty. Heart, 87(3), 185–186. Greunzig, A. R., King, S. B., Schlumpf, M., & Seigenhaler, N. (1987). Long term follow up after coronary angioplasty. The early Zurich experience. The New England Journal of Medicine, 316(18), 1127–1132. Isner, J. M. (1994). Vascular remodelling. Honey, I think I shrunk the artery. Circulation, 89(6), 2937–2942. Liistro, F., Stankovic, G., Di Mario, C., Takagi, T., Chieffo, A., Moshiri, S., Montorfano, M., Carlino, M., Briguori, C., Pagnotta, P., Aubieno, R., Corvaja, N., & Colombo, A. (2002). First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for in-stent restenosis. Circulation, 105(16), 1883–1886. Ludman, P. F. (2002). Percutaneous coronary intervention. Medicine, 30(4), 81–84. Mansfield, R., Bown, S., & McEwan, J. (2001). Photodynamic therapy: Shedding light on restenosis. Heart, 86(6), 612–618. Marx, S. O., & Marks, A. R. (2001). Bench to bedside: The development of rapamycin and its application to stent restenosis. Circulation, 104(8), 852–855. Morrice, M. C., Serruys, P. W., Sousa, J. E., Fajadet, J., Ban Hayashi, E., Perrin, M., Columbo, A., Schuler, G., Barragan, P., Guogliumi, G., Molnar, F., & Falotico, R. (2002). The RAVEL Study Group. A randomised comparison of a sirolimus-eluting stent with a standard stent for coronary revascularisation. The New England Journal of Medicine, 346(23), 1773–1780. National Institute for Clinical Excellence (2000). Guidance on the use of glycoprotein 2b/3a inhibitors in the treatment of acute coronary syndromes. Technology Appraisal Guidance (No. 12) (http://www.nice.org.uk). Ross, R. (1993). The pathogenesis of atherosclerosis: A prospective for the 1990s. Nature, 362(6423), 801–809. Salame, M. Y., Verheye, S., Crocker, I. R., Chronos, M. A., Robinson, K. A., & King III, S. B. (2001). Intracoronary radiation therapy. European Heart Journal, 22(8), 629–647.
Seabra-Gomes, R. (2001). Radioactive stents to reduce restenosis: Time for an epitaph? European Heart Journal, 22(8), 621–623. Serruys, P. W., de Jaegere, P., Kiemeneij, F., Macaya, C., Rutsch, W., Heyndrickx, G., Emanuelsson, H., Marco, J., Legrand, V., & Materne, P. (1994). A comparison of balloon expandable stent implantation with balloon angioplasty in patients with coronary artery disease (the Benestent Study). The New England Journal of Medicine, 331(8), 489–495. Serruys, P. W., Luijten, H. E., Beatt, K. J., Geuskens, R., de Feyter, P. J., van der Brand, M., Reiber, J. H., ten Katen, H. J., van Es, G. A., & Hugenholtz, P. G. (1988). 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, 77, 361–371. Sousa, J. E., Costa, M. A., Abizaid, A. S., Feres, F., Pinto, I. M., Seixas, A. C., Staico, R., Mattos, L. A., Sousa, A. G., Falotico, R., Jaeger, J., Popma, J. J., & Serruys, P. W. (2001). Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: A quantitative coronary angiography and three dimensional intravascular ultrasound study. Circulation, 103(2), 192–195. Sousa, J. E., Costa, M. A., Sousa, A. G., Abizaid, A. C., Seixas, A. C., Abizaid, A. S., Feres, F., Mattos, L. A., Falotico, R., Jaeger, J., Popma, J. J., & Serruys, P. W. (2003). Two-year angiographic and intravascular ultrasound follow up after implantation of sirolimus-eluting stents in human coronary arteries. Circulation, 107(3), 381–383. Steinhubl, S. R., Berger, P. B., Mann III, J. T., Fry, E. T., DeLago, A., Wilmer, C., & Topol, E. J. (2002). CREDO investigators. Clopidogrel for the reduction of events during observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomised controlled trial. JAMA, 288(19), 2411–2420. Teirstein, P. S., Massullo, V., Jani, S., Popma, J. J., Muntz, G. S., Russo, R. J., Schatz, R. A., Guameri, E. M., Steiterman, S., Morris, N. B., Leon, M. B., & Tripuraneri, P. (1997). Catheter-based radiotherapy to inhibit restenosis after coronary stenting. The New England Journal of Medicine, 336(24), 1697– 1703. The EPISTENT investigators (1998). Evaluation of Platelet IIb/IIIa Inhibitor for stenting, Lancet, 352, 87–92. The Heart Outcomes Prevention Evaluation Study Investigators (2000). The Heart Outcomes Prevention Evaluation Study. The New England Journal of Medicine, 342, 145–153. The IONA Study group (2002). Effect of Nicorandil on coronary events in patients with stable angina: The impact of nicorandil in angina (IONA) randomised trial. Lancet, 359(9314), 1269–1275. Verin, V., Urban, P., Popowski, Y., Schwager, M., Novet, P., Dorsaz, P. A., Chatelain, P., Kurtz, J. M., & Rutishauser, W. (1997). Feasibility of intra-coronary beta-irradiation to reduce restenosis after balloon angioplasty: A clinical pilot study. Circulation, 95(5), 1138–1144. Waller, B. F., Orr, C. M., Pinkerton, C. A., VanTassel, J. W., & Pinto, R. P. (1990). Morphologic observations late after balloon angioplasty: Mechanisms of acute injury and relationship to restenosis. Radiology, 174(3142), 961–967.
Medicine in focus
Angina pectoris: interventional therapies and treatment of restenosis Sunil V. Nair, Jean R. McEwan∗ Centre for Cardiovascular Biology and Medicine, BHF Laboratories, Rayne Building, 5 University Street, London WC1E 6JJ, UK
Abstract Angina pectoris is a clinical syndrome of symptoms caused by myocardial ischaemia due to oxygen demand exceeding supply. The most common cause is coronary artery stenosis due to progressive atherosclerotic disease. Angina has a prevalence of approximately 5% and increases with age. Despite improvements in treatment there remains a yearly mortality of 2–3%. A major advance in the treatment of symptomatic angina was the introduction of percutaneous transluminal coronary angioplasty (PTCA). This initial enthusiasm was dampened by significant numbers developing symptomatic restenosis from vascular elastic recoil and neointimal hyperplasia (NI). The widespread introduction of stent deployment following the initial angioplasty reduced the rates of elastic recoil but failed to prevent NI and may actually stimulate it. Currently, there is much interest in mechanisms that alter cell proliferation thereby decreasing NI. Techniques include brachytherapy, photodynamic therapy and drug-eluting stents. Provisional data for these new stents, which slowly release medication that inhibits cell turnover, are very good with few occurrences of restenosis. Results from larger randomised trials are awaited. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Angina; Restenosis; Sirolimus; Stent
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Percutaneous coronary intervention (PCI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Coronary angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Percutaneous transluminal coronary angioplasty (PTCA) . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Problems following PTCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Intracoronary stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Subacute thrombosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Antiplatelet and antithrombotic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Improving long term interventional outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Intracoronary brachytherapy and related techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Drug-eluting stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗
Corresponding author. E-mail addresses: [email protected] (S.V. Nair), [email protected] (J.R. McEwan).
1357-2725/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1357-2725(03)00135-3
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4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1405 1406
1. Introduction
2. Percutaneous coronary intervention (PCI)
Angina is a clinical syndrome consisting of pain, discomfort, and heaviness of the chest, arm or jaw. It is precipitated by exercise, emotional stress and anxiety and is relieved by rest and or administration of glyceryl trinitrate. The symptoms usually last for a few minutes and are caused by myocardial ischaemia of severity and duration insufficient to cause myocardial cell necrosis. The ischaemia occurs when myocardial blood flow is insufficient for myocardial oxygen demand. Most usually this is because of coronary artery narrowing due to atherosclerosis. Initial treatment for angina involves modification and treatment of underlying risk factors. Adequate time must be spent educating patients regarding their lifestyle and the effect it has on their disease. Additional medication may be required for optimum control of risk factors (diabetes, hypertension, hypercholesterolaemia). Treatment can then be divided into symptomatic including, beta blockers, nitrate preparations, calcium channel antagonists, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass grafting (CABG) and prognostic, including aspirin, lipid lowering agents such as statins, coronary artery bypass grafting and in recent studies, nicorandil (The IONA Study group, 2002), and angiotensin converting enzyme inhibitors (ACE inhibitors) (The Heart Outcomes Prevention Evaluation Study Investigators, 2000). The latter appear to have disease modifying effects which make them particularly beneficial in patients with hypertension or diabetes. Occlusive disease of coronary arteries, whether from atheroma or thrombosis, may be treated with percutaneous endovascular intervention, which restores patency without the need for major surgical reconstruction. In the UK in 1998/1999 there were more than 21,000 (Gray & Callum, 2002) such procedures and this figure has increased over time such that use of the technique has now exceeded that of coronary artery bypass grafting.
2.1. Coronary angiography This remains the gold standard for diagnosis of coronary artery disease. It involves insertion of a catheter into the heart via a cannula inserted in a distal artery. Under fluoroscopic guidance specific catheters are manipulated into the coronary ostia, where 5–10 ml of contrast is injected. Several images in different planes are taken of the left and right coronary arteries. The contrast delineates the coronary arteries and on X-ray screening demonstrates any occlusion or significant stenosis. 2.2. Percutaneous transluminal coronary angioplasty (PTCA) PTCA has been an effective treatment for patients with chronic severe angina unresponsive to medical therapy or in those unable to tolerate multiple medical therapies due to side effects. It has the potential to offer safe and cost effective patient management. Following standard coronary angiography; an angioplasty guide wire is advanced and manipulated across the stenosis to lie in the distal vessel. The wire acts as a guide for the passage of an elongated balloon which when inflated disrupts the wall of the blood vessel, displacing the atheroma laterally and improving the lumen diameter. Further injection of contrast enables assessment of the result (Fig. 1a–d). 2.3. Problems following PTCA Studies have shown the rates of restenosis following PTCA to be approximately 30%; this increases costs and decreases efficacy, dampening enthusiasm for this and related endovascular procedures (Greunzig, King, Schlumpf, & Seigenhaler, 1987; Serruys et al., 1988). PTCA causes increased vessel lumen diameter by different mechanisms. Firstly the vessel wall is stretched, and secondly the plaque is disrupted causing deep fissuring through the intima into the media,
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Fig. 1. (a) Right coronary artery (RCA) with mid segment stenosis. All images obtained during coronary angiography. (b) Distended balloon catheter at site of RCA stenosis. (c) Following removal of the balloon catheter the metal coronary artery stent can just be seen at the site of previous mid segment stenosis. (d) RCA post balloon angioplasty and stenting showing restoration of lumen diameter.
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2.4. Intracoronary stents
Fig. 1. (Continued )
dissection flaps and the displacement of plaque contents laterally. These mechanisms are also the cause of recurrent problems. Due to the inherent elasticity of the arterial wall, there is a degree of elastic recoil in the first 24 h post procedure. In addition dissection flaps and plaque disruption result in an unstable plaque, exposure of plaque contents to the bloodstream, platelet accumulation, activation, and adhesion, which can lead to thrombosis and plaque expansion at the treated site. Both of these can cause acute luminal occlusion in the first 24 h and this complicates approximately 5% of procedures (Ludman, 2002). A delayed response occurs during the first 6 months and relates to vessel healing. Ongoing reduction in external vessel diameter (negative remodelling) continues, and within the media, smooth muscle cells are activated, re-enter the cell cycle, proliferate and migrate into the intima to reline the damaged arterial lumen with a neointimal layer (neointimal hyperplasia (NI)) (Fig. 2a and b). Deposition and reorganisation of the extracellular matrix also contributes to the lesion (Isner, 1994; Waller et al., 1990). The pathogenesis of the restenotic lesion is complex and many different growth factors and cytokines have been implicated in the stimulation of vascular smooth muscle cell (VSMC) proliferation and synthetic activity (Ross, 1993). These processes cause a gradual reduction in arterial lumen and if the lumen narrows sufficiently to obstruct flow, recurrent symptoms will result, and further intervention may be necessary (Fig. 2a and c).
The widespread introduction of stent deployment following initial balloon angioplasty has greatly reduced rates of restenosis. Intracoronary stents are now used in greater than 70% of percutaneous coronary interventions. Following standard balloon angioplasty a second balloon catheter mounted with a steel mesh is inserted and guided to the problem area. Inflation of the balloon expands the stent and presses it into the arterial wall. On balloon deflation the catheter is withdrawn and the stent remains in place (Fig. 1d). Once expanded the rigid design of the stents prevents acute elastic recoil and limits negative remodelling. In addition, stents hold back dissection flaps. Stenting does not prevent neointimal hyperplasia and may actually stimulate it (Serruys et al., 1994). Following stent insertion a greater lumen diameter is achieved than with balloon alone, therefore although neointimal hyperplasia occurs, the overall effect on lumen diameter is proportionately reduced and the rates of restenosis are lower. Overall, stent insertion decreases the rate of acute luminal occlusion and 6-month restenosis rates are reduced to approximately 10–20%. Currently PTCA procedures have emergency CABG rates of ∼0.5% (de Belder, 1999), mortality rates of ∼0.9% (de Belder, 1999), and periprocedural MI rates of <1%. 2.5. Subacute thrombosis Subacute thrombosis complicates 1–2% of patients treated with intracoronary stents. Platelets aggregate on the stent struts and cause thrombus leading to reduction in myocardial blood flow. This usually occurs in the first 4 weeks post procedure. After this time duration the struts are covered by the growth of new endothelial cells. Rates of subacute thrombosis were previously higher but attention to technical aspects of stent implantation and the use of antithrombotic agents (intravenous heparin infusion) and antiplatelet agents (glycoprotein IIb/IIIa (GpIIb/IIIa) platelet receptor antagonists and clopidogrel) during the procedure have reduced rates to the above figure. In most centres an agent such as clopidogrel is continued for 4 weeks until new endothelial cells have grown. Longer term clopidogrel may have continuing advantages (Steinhubl et al., 2002), though cost/benefit considerations mean that this is not current UK practice.
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Fig. 2. (a) Coronary angiography of the same patient as in Fig. 1 representing with recurrent symptoms from the development of in-stent restenosis, due to neointimal hyperplasia. (b) RCA, after repeat balloon dilatation for in-stent restenosis, showing once more restoration of lumen diameter. (c) Rabbit iliac artery with coronary stent in situ (some stent struts visible). Established neointimal hyperplasia is present causing a reduction in vessel luminal diameter.
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2.6. Antiplatelet and antithrombotic agents Platelets play an important role in the complications of PCI, particularly the early acute vessel occlusion and sub acute thrombosis associated with stent insertion. For many years aspirin (an inhibitor of cyclo-oxygenase, required for the production of functioning platelets) and intravenous heparin (binds antithrombin 3 in the clotting cascade, resulting in inactive clotting factors) have been used to try and reduce complication rates due to thrombosis. Clopidogrel inhibits platelet activation by antagonising the adenosine diphosphate (ADP) receptor and is now widely used in addition to the above agents. All platelet aggregation is ultimately through the formation of fibrin bridges between the platelet glycoprotein IIb/IIIa receptors. GpIIb/IIIa antagonists are now recommended as adjuvants to PCI (The EPISTENT investigators, 1998). Abciximab is an intravenous preparation of a recombinant hybrid monoclonal antibody against the GpIIb/IIIa receptor. Alternatives are synthetic cyclical or simple peptide molecules (tirofiban and eptifibatide), which are of much shorter action. The benefit of these in reducing acute periprocedural occlusion, whether in elective or emergency cases has to be balanced against cost and increased bleeding complications (National Institute for Clinical Excellence, 2000).
3. Improving long term interventional outcomes No systemic pharmacological agent has resolved the problem of restenosis. There is currently much interest in mechanisms that alter cell proliferation thereby limiting NI. 3.1. Intracoronary brachytherapy and related techniques Intracoronary brachytherapy is now approved for use in the treatment of in-stent stenosis. A radioactive wire is inserted immediately after balloon angioplasty and left in place for around 40 min before removal. Both gamma and beta irradiation have been tested and shown to be effective (Teirstein et al., 1997; Verin et al., 1997). The radiation causes cell DNA damage, which manifests during mitosis, thus selectively
targeting rapidly proliferating cells, which die during abortive replication. VSMC are ablated in a dose dependent manner. Concerns exist regarding the late effects of brachytherapy and if stenosis recurs, it tends to be at the edges of the dilated areas, the candy wrapper effect, perhaps related to lower, ineffective, radiation doses at the edges of the treated segments (Salame et al., 2001; Seabra-Gomes, 2001). However, healing of the artery after the angioplasty and brachytherapy may be delayed, intimal dissections persist and stent struts remain unendothelialized for months to years. This potentially leaves a risk for vessel thrombosis at a very delayed stage (Ludman, 2002). Alternative arterial cell-ablative techniques include photodynamic therapy in which illumination of the artery through a modified balloon catheter activates a drug administered locally, or systemically. Reactive oxygen species are generated which kill the medial smooth muscle cells and responses to the angioplasty are modified. Potential advantages include that of rapid re-growth of the endothelium after PDT (Mansfield, Bown, & McEwan, 2001). However, such techniques are largely experimental at this time. 3.2. Drug-eluting stents The recent development of coated drug-eluting stents shows promise. The stent may be coated in an adsorbed drug that is slowly released over days to weeks. Sirolimus (rapamycin), a macrolide antifungal agent with a unique antiproliferative mode of action and powerful immunosuppressant properties, inhibits several regulators of cell cycle progression and the migration of vascular smooth muscle cells (Marx & Marks, 2001). These antiproliferative, antimigratory and anti-inflammatory properties are responsible for the efficacy of sirolimus therapy in preventing acute rejection of renal allografts and arteriopathy of cardiac allografts, as well as in-stent restenosis (Morrice et al., 2002). Sirolimus binds to an intracellular receptor protein FKBP12 and elevates p27 levels, which lead to the inhibition of cyclin/cyclin-dependent kinase complexes and ultimately induces cell-cycle arrest in the late G1 phase (Sousa et al., 2001) (Fig. 3). Animal studies and a small clinical study have shown sirolimus reduces neointimal proliferation (Gallo et al., 1999; Sousa et al., 2001). In the RAVEL trial, the first prospective randomised, double blind,
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Fig. 3. Effects of sirolimus (rapamycin) on cell proliferation mechanisms. Arterial injury induces growth factor expression and this in turn leads to increased activity of cyclin dependent kinases, decreased levels of their inhibitor p27 and inactivation of pRB by phosphorylation. The phosphorylation of the pRB is the stimulus to cell cycle progression from G1 to GS, the synthetic phase, S, in which DNA is replicated before cell division. Sirolimus (rapamycin) inhibits the fall in p27, which occurs after mitogen stimulation, and this, and reduced phosphorylation of pRB by cyclin-dependent kinases, contribute to its growth inhibitory effects. The effects of sirolimus are multiple. Sirolimus also binds to FKBP12 and the complex inactivates the mammalian target of rapamycin (mTOR), another enzyme involved in the regulation of protein synthesis and cell proliferation.
multicentre trial comparing sirolimus eluting stents with a standard uncoated stent in 238 patients, there were no significant restenosis at 6 months in the sirolimus eluting stent group compared with 26% in the standard stent group (Morrice et al., 2002). In addition there were no episodes of thrombosis, suggesting that re-endothelialisation occurs despite the immunosuppressive effects of sirolimus, and a low rate of cardiac events at 1 year. More recently, Sousa et al. report 2 years follow up results of 30 patients treated with sirolimus eluting stents. Their results are very promising showing in-stent lumen diameters remaining essentially unchanged after 2 years with no evidence of restenosis “catch up” (Sousa et al., 2003). Paclitaxel is a second agent being used in drugeluting stents. It is a microtubule inhibitor and therefore inhibits the microtubular function required for
cell division and replication. In a small study using paclitaxel coated stents there was minimal intimal hyperplasia and instent restenosis at 6 months, but the antiproliferative effect was not maintained at 12 months (Liistro et al., 2002). Larger randomised trials are underway to see if these excellent short term results continue in the longer term and also whether delayed healing may have longer term risks.
4. Summary Percutaneous interventions are now the mainstay of the treatment of symptomatic coronary narrowing, whether primarily due to atherosclerosis or secondary to previous procedures (restenosis). As demonstrated
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above, the current therapies to improve short and long term outcomes were designed on a background of scientific understanding of the disease processes. Further improvements in both the medical therapy and the application of this technology are dependent on further elucidation of the pathophysiology of vascular disease. References de Belder, M. A. (1999). Cardiac intervention procedures in the United Kingdom1997: Developments in data collection. Council of the British Cardiovascular Intervention Society (http://www.bcis.org.uk). Heart, 82(Suppl. 2), II2–9. Gallo, R., Padurean, A., Jayaraman, T., Marx, S., Raque, M., Adelma, S., Chesebro, J., Fallon, J., Fusber, V., Marks, A., & Badimon, J. J. (1999). Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation, 99(16), 2164–2170. Gray, H. H., & Callum, K. G. (2002). Death following coronary angioplasty. Heart, 87(3), 185–186. Greunzig, A. R., King, S. B., Schlumpf, M., & Seigenhaler, N. (1987). Long term follow up after coronary angioplasty. The early Zurich experience. The New England Journal of Medicine, 316(18), 1127–1132. Isner, J. M. (1994). Vascular remodelling. Honey, I think I shrunk the artery. Circulation, 89(6), 2937–2942. Liistro, F., Stankovic, G., Di Mario, C., Takagi, T., Chieffo, A., Moshiri, S., Montorfano, M., Carlino, M., Briguori, C., Pagnotta, P., Aubieno, R., Corvaja, N., & Colombo, A. (2002). First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for in-stent restenosis. Circulation, 105(16), 1883–1886. Ludman, P. F. (2002). Percutaneous coronary intervention. Medicine, 30(4), 81–84. Mansfield, R., Bown, S., & McEwan, J. (2001). Photodynamic therapy: Shedding light on restenosis. Heart, 86(6), 612–618. Marx, S. O., & Marks, A. R. (2001). Bench to bedside: The development of rapamycin and its application to stent restenosis. Circulation, 104(8), 852–855. Morrice, M. C., Serruys, P. W., Sousa, J. E., Fajadet, J., Ban Hayashi, E., Perrin, M., Columbo, A., Schuler, G., Barragan, P., Guogliumi, G., Molnar, F., & Falotico, R. (2002). The RAVEL Study Group. A randomised comparison of a sirolimus-eluting stent with a standard stent for coronary revascularisation. The New England Journal of Medicine, 346(23), 1773–1780. National Institute for Clinical Excellence (2000). Guidance on the use of glycoprotein 2b/3a inhibitors in the treatment of acute coronary syndromes. Technology Appraisal Guidance (No. 12) (http://www.nice.org.uk). Ross, R. (1993). The pathogenesis of atherosclerosis: A prospective for the 1990s. Nature, 362(6423), 801–809. Salame, M. Y., Verheye, S., Crocker, I. R., Chronos, M. A., Robinson, K. A., & King III, S. B. (2001). Intracoronary radiation therapy. European Heart Journal, 22(8), 629–647.
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