Damian J Kelly
Clinical Research Fellow
Anthony H Gershlick
Consultant Cardiologist/Honorary Senior Lecturer
Clinical Sciences Department
Percutaneous coronary angioplasty (PCI) is now the dominant form of treatment for coronary artery disease, outstripping coronary bypass operations in the UK by three to one during 2005.(1) PCI involves placing a sheath in the femoral or radial artery and using a guide catheter to access the narrowed coronary artery. Dye injections show the site and severity of the narrowing. A small (0.35mm diameter) wire is used to cross the narrowing and a balloon inflated to “squash” it. There is no operation scar and the patient is frequently discharged the same day. However it soon became clear that re-narrowing (“re-stenosis”) following balloon alone necessitated repeat angioplasty in up to 40% of patients.
Bare-metal stents were introduced to “scaffold” the artery and reduce the incidence of re-stenosis and need for a repeat procedure. While an evident advance on balloon angioplasty alone, bare-metal stents did not, however, prevent scar tissue forming within the vessel, leading to a need for repeat treatment in approximately 15% of patients.
Drug-eluting stents and duration of dual antiplatelet therapy
Drug-eluting stents (DES) are increasingly used to reduce recurrence of symptoms. Antiproliferative agents loaded onto stents inhibit smooth-muscle cell proliferation and scar tissue formation – with the use of DES the need for a repeat procedure has fallen to about 5%. However, these agents also inhibit bystander endothelial cell recovery. Endothelial cells are the “Teflon” coating of arteries, and the presence of a functioning endothelial cell layer is essential in preventing clot formation within the stent. PCI by its action disrupts the endothelium. With bare- metal stents the endothelial cells recover within one month, and since within-stent thrombus is platelet initiated, this period can be covered with dual antiplatelet therapy (ATP) (aspirin and PY12 ADP receptor inhibitors – ticlopidine or, more recently, clopidogrel). The importance of prolonged APT has become evident with the advent of DES. The endothelial cell layer takes longer to recover because of the eluted drug, and during this time the patient is at risk of stent thrombosis. Up to 50% of patients (ie, those at higher risk of re-stenosis such as diabetics or those with longer, more severe coronary narrowings) are now treated with DES. By delaying regrowth of the protective endothelial cell layer, the struts of DES are exposed for longer and the risk of thrombus formation is present for longer than the one month with bare-metal stents (see Figure 1).
Stent thrombosis is not common, occurring in about 1.5% of all patients treated. However, it can have serious consequences. When stents thrombose, blood supply to the heart muscle may be blocked, potentially leading to a heart attack or death (see Figure 2). This may occur in up to 50% (of the 1.5%) of patients with stent thrombosis. With 70,000 PCIs in the UK in 2005, this means that there is a significant risk to a small but significant number of patients. To overcome the potential excess risk of stent thrombosis occurring in patients with DES, prolonged dual APT is required during the period of delayed endothelial recovery.
Currently, four DES are commercially available, using sirolimus (Cypher(R), Cordis Johnson & Johnson), zotarolimus (Endeavour(R), Medtronic Inc) or paclitaxel (Taxus(R), Boston Scientific; CoStar(R), Conor Medsystems Inc) as the active drug. Sirolimus and zotarolimus are cytostatic macrolide antibiotics that inhibit smooth muscle cell proliferation, while paclitaxel is a botanical cytotoxic agent that kills dividing cells. The drugs are bound to nonresorbable polymers that coat the stent struts.
Dual APT based on clopidogrel (Plavix(R), Sanofi-Aventis) is standard post-PCI treatment, with aspirin given indefinitely and clopidogrel for a predefined period.(2–4) Clopidogrel is given for one month following bare-metal stent implantation, but DES manufacturers stipulate clopidogrel use for at least three (Cypher) or six (Taxus) months. Recent concerns about a prolonged excess risk of stent thrombosis with DES have led to recommendations from the professional body (British Cardiovascular Intervention Society) that all DES patients be treated with dual APT for one year (see Resource). During this time, patients are at risk if they discontinue clopidogrel, be this for side-effects or if they need to undergo a noncardiac operative procedure.
The prime lesson of the DES era is clear: dual APT is vital throughout the “vulnerable period” of stent endothelialisation (see Box). Cohort studies report a nine-times-higher risk of stent thrombosis among patients discontinuing clopidogrel prematurely.(5,6) Moreover, stent thrombosis risk is highly individualised in each patient, consisting of procedural, anatomical and clinical factors, with renal failure, diabetes mellitus and heart failure being chief among the latter. Assessment of individual risk can only be made by the interventional cardiologist.
Safeguarding patients following coronary angioplasty
What role can the hospital pharmacist play in the prevention of potentially lethal stent thrombosis? Pharmacists provide an invaluable safeguard for hospital prescribing and are ideally placed to mitigate the risks of ill-advised clopidogrel discontinuation in patients with recent DES implants.
If an operative procedure needs to be performed within 12 months of PCI, DES are avoided so that a bare-metal stent can be used and a shorter (one-month) course of clopidogrel given.(7) Difficulties arise when urgent surgery is required. Here discussion with the interventional cardiologist is mandatory, and pharmacists who are aware of such conflicts should alert the interventional cardiologist. A decision must be made in conjunction with the surgical team as to whether surgery can be deferred or performed with clopidogrel. Prompt cardiology advice is also required in cases of major haemorrhage or trauma. Most cases of stent thrombosis in DES patients occur within seven days of clopidogrel withdrawal.(8)
Mild gastrointestinal upset may be alleviated by proton pump inhibition. True allergy to clopidogrel is uncommon (approximately 0.3%), but ticlopidine provides a reasonable alternative, allied with careful haematological monitoring to detect the 2-2.5% incidence of haematological toxicity. Bedside tests of platelet inhibition may soon have a role in tailoring treatment.(9,10) There is no evidence post-PCI for the use of cheaper but unproven agents such as dipyridamole.
Good communication between medical teams and pharmacists is vital. A degree of vigilance regarding early clopidogrel discontinuation in cardiac patients is required, but until a centralised database of DES procedures is accessible by pharmacy staff the onus for this vigilance must rest with the patient.
In collaboration with our pharmacy department, we have developed a clopidogrel warning card akin to streptokinase thrombolysis or long-term corticosteroid information cards.(11) We are currently auditing our success in educating the public and general practitioners alike to the pivotal role played by dual APT following PCI (see Figure 3).
With the support of pharmacists, the hospital can be made a safer place for thousands of cardiac patients.
- Ludman P. UK 2005 PCI Audit Data. British Cardiovascular Intervention Society. Presented to Autumn Meeting, September 2006. Available at: http://www.bcis.org.uk/resources/audit
- IMS Database. Worldwide drug sales 2005. IMS Group. Available at:http://www.imshealth.com
- Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting:the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624-9.
- Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-33.
- Iakovou I, Schmidt T, Bonizzoni E,et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.JAMA 2005;293:2126-30.
- Jeremias A, Sylvia B, Bridges J,et al. Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 2004;109:1930-2.
- Sharma AK, Ajani AE, Hamwi SM,et al. Major noncardiac surgery ï¿½following coronary stenting: when is it safe to operate? Catheter Cardiovasc Interv 2004;63:141-5.
- McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519-21.
- Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-13.
- Gurbel PA, Bliden KP, Samara W,et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study.J Am Coll Cardiol 2005;46:1827-32.
- Khambekar SK, Kovac J, Gershlick AH. Clopidogrel induced urticarial rash in a patient with left main stem percutaneous coronary intervention: management issues. Heart 2004;90:e14.
British Cardiovascular Intervention Society