• Information
  1. Overview of PCI
  2. Procedural Outlines
  3. Description
  4. Platelet Glycoprotein IIb/IIIa Inhibitors in PCI
  5. Coronary Stenting
  6. PCI for Stable Angina
  7. Restenosis

A. Overview of PCI

1. Types of Interventions
   1. PCI refers to any percutaneously accessed proceedure on the heart
   2. Includes percutaneous transluminal coronary angioplasty (PTCA)
   3. PTCA with stenting is now most common procedure [1]
   4. Thrombus aspiration [12]
   5. Atherectomy or laser revascularization (not commonly used)
2. Indications
   1. Treatment of angina: native vessels or bypass grafts
   2. Treatment (selectively) of acute coronary syndromes (ACS)
   3. Treatment of myocardial infarction (MI) [15]
   4. Drug-eluting stents can be used in small coronary arteries with good results [83]
   5. PCI is a common alternative to CABG with similar 10 year mortality, less stroke, but increased need for repeat revascularizations and poorer angina relief [76]
3. Treatment of Stable and Unstable Angina
   1. Native vessels with coronary artery disease (CAD)
   2. Occluded Coronary Artery Bypass Grafts (CABG)
   3. Superior to medical therapy for symptomatic (unstable) single vessel CAD
   4. PCI does not reduce cardiac events when added to medical therapy in stable CAD [104]
   5. Variable results for multivessel CAD versus CABG (see below)
   6. Stenting is used in majority of patients as it reduces restenosis (see below)
   7. PCI superior to medical therapy for refractory angina, including in elderly [84,104]
   8. Drug-eluting stents overall as good as CABG with slightly more revascularizations, superior to medications for left main disease [10,118]
   9. PCI provides benefits to persons >70 years old similar to younger patients
   10. In diabetes mellitus (DM), stenting may be as effective as CABG [40]
   11. In ACS (unstable angina or non-ST wave elevation MI, NSTEMI), routine PCI was superior to selective PCI on CV outcomes, but associated with higher early mortality [42]
   12. Whether PCI should be used routinely in ACS is not yet clear [17,42]
4. MI with ST Wave Elevation (STEMI) [3,4,15,47]
   1. Primary PCI ± stenting is superior to thrombolytic therapy and at least as safe when used within 12 hours of symptoms at experienced centers [4,8,70]
   2. Death, reinfarction or stroke occurred in 23.2% of alteplase (thrombolysis) versus
5. 5% of PTCA + stents + abciximab group at 6 months [5]
   1. Primary PCI ± stents (with gp2b/3a inhibitor) used >12 hours after symptom onset leads to reduced infarct size and CV events at 30 days versus medical therapy [31]
   2. Long term (1 year) followup showed PCI superior to thrombolysis for STEMI [6]
   3. Thrombolysis with GP2b/3a inhibitor is treatment of choice for STEMI when PCI cannot be done within 90 minutes of presentation [110]
   4. Preceding ("facilitating") PCI with either abciximab or retaplase thrombolysis did not improve STEMI outcomes and increased major and minor bleeding risks [119]
   5. Immediate transfer for PCI after thrombolysis with abciximab improves outcome in high-risk patients with STEMI [110]
   6. Post MI stenting+abciximab leads to more viable myocardium than alteplase plus abciximab [7]
   7. Tirofiban (another gp2b/3a inhibitor) is not inferior to abciximab in STEMI [116]
   8. Sirolimus-eluting stents are superior to uncoated stents in STEMI with 8 months' followup [116]
   9. Meta-analyses and long term follow up strongly support PCI+Stenting over thrombolysis for acute MI, particularly STEMI [70]
   10. Transfer for PCI preferred over on-site thrombolysis for transfer time <2 hours [13]
   11. Clopidogrel 300-600mg loading dose then 75mg po qd should be used in all STEMI patients prior to PCI, even those treated with thrombolytics [50,51,116]
   12. Thrombolytics should not be given prior to primary PCI for MI as they increase major adverse events [89,90,119]
   13. PCI after 3 days of persistent coronary occlusion is not beneficial; may be harmful [62]
   14. PCI post-MI in patients with asymptomatic ischemia and 1-2 vessel CAD superior to anti-ischemic drug therapy on all outcomes [106]
6. PCI Strategies in Non-ST segment elevation MI (NSTEMI) [17,18]
   1. Unclear whether PCI should be used routinely or selectively in USA or NSTEMI [19]
   2. In ACS (USA or non-ST wave elevation MI, NSTEMI), routine PCI was superior to selective PCI on CV outcomes, but associated with higher early mortality [19]
   3. In Non-ST elevation ACS, routine invasive strategy provided 5-year improved outcomes primarily in high risk patients [18]
   4. In NSETEMI, routine invasive strategy provided 5-year improved outcomes only in high risk male patients [32]
   5. Primary PCI showed similar results to complete medical therapy and elective revascularization for ACS, including "high risk" with elevated cardiac enzymes [17]
   6. Complete medical therapy includes enoxaparin, clopidogrel, gp2b/3a inhibitor, ASA
   7. Routine versus deferred selective use of glycprotein 2b/3a (gp2b/3a) inhibitors in ACS prior to PCI reduces ischemia somewhat but increases major bleeding [79]
7. Long Term Outcomes
   1. Aggressive statin therapy and use of ASA (and/or clopidogrel) recommended
   2. Fluvastatin after PCI in patients with average cholesterol reduced major cardiac events by >20% at 3.5 years [63]
   3. Abciximab reduces overall mortality ~20% in patients receiving PCI [64]
   4. High dose pretreatment with clopidogrel in elective PCI eliminates benefits of abciximab in mild to moderate risk patients [2]
   5. However, abciximab with clopidogrel and ASA are routinely given to patients undergoing stent placement [17]
   6. Elevated C-reactive protein (CRP) prior to angioplasty associated with increased risk for death or MI but not with restenosis [44]
   7. One-year clopidogrel (75mg qd) reduces risk of recurrent ischemic events [69]
8. Routine coronary artery revascularization before major vascular surgery does not affect long term outcomes and is not routinely recommended [39]

B. Procedural Outlines

1. Angioplasty
   1. Balloon angioplasty causes barotrauma induced plaque destruction
   2. Endothelial denudation - may precipitate acute thrombus formation
   3. Stretching ± taring of media and/or adventitia
   4. Dissection of arterial wall, aneurysmal dilatation of artery
   5. Extensive dissection may lead to lumen compromise and acute closure, infarction
   6. Aspirin (ASA), clopidogrel, heparin reduce incidence of platelet deposition and thrombosis
   7. Low molecular weight heparin (LMWH) may be preferred over standard heparin [71]
   8. Enoxaparin (a LMWH) reduced bleeding (0.5mg/kg, trend at 0.75mg/kg) and better target anticoagulation compared with standard heparin in elective PCI [14]
   9. Pre- and post-PTCA clopidogrel combined with ASA reduces cardiovascular events [9]
   10. Clopidogrel 600mg (high dose) po 2 hours before elective PCI eliminates benefits of abciximab (a gp2b/3a inhibitor) in mild to moderate risk patients [2]
   11. Clopidogrel 300-900mg loading dose followed by 75mg po qd is routine in PCI [50]
   12. Various platelet gp2b/3a inhibitors improve PCI outcomes
   13. Major problem is ~30-35% restenosis of non-stented sites within 6 months of procedure
   14. Stents reduce this rate substantially
   15. Pexelizumab, a monoclonal antibody which binds C5 complement, of no benefit in PCI [30]
   16. Ontracoronary streptokinase improves flow at 2 days but not 6 months after PCI [105]
2. Stenting [1]
   1. Placement of a coil in coronary artery at position of PTCA
   2. Increasingly used due to very low rate of restenosis compared with PTCA alone
   3. Anti-platelet therapy (clopidogrel±ASA) is critical to prevent reocclusion (see below) [103]
   4. Overall improvement in outcomes in MI setting versus PTCA alone
   5. Combination of metal stent + abciximab reduces post-PTCA death/MI by ~50%
   6. Drug coated stents have best 30-day and long term outcomes
3. Thrombus Aspiration [12]
   1. Usual PCI leads to distal microvascular obstruction due to fragmentation during angioplasty
   2. Thrombus aspiration has been developed to prevent distal embolization during PCI
   3. Aspiration is carried out after guide-wire is placed through target lesion
   4. Thrombus aspiration showed better complete ST segment elevation resolution (56%) versus standard PCI (44%) in patients with STEMI [12]
   5. Successful thrombus aspiration occurs in >73%
4. Laser angioplasty adds no benefit to standard balloon procedure
5. Post-Hospitalization Therapy [78]
   1. ASA 81-162mg/d po
   2. Clopidogrel 75mg po qd for at least 4 weeks; much longer therapy probably beneficial [103]
   3. In patients with PCI or medically treated ACS, discontinuation of Plavix associated with 1.8X increased risk of death and acute MI within the first 90 days versus the next 90 days [113]
   4. Warfarin generally not indicated
   5. Statins to reduce cholesterol to LDL <100mg/dL (perhaps for all patients)
   6. ß-adrenergic blockers reduce ischemia after MI
   7. ACE inhibitors (or angiotensin II receptor blockers) strongly recommended
6. Directional atherectomy is not recommended due to high rate of dissection

C. Description

1. Patient Management Overview [54,78]
   1. Assessment of contrast dye allergies and preventive management
   2. Good pre-procedure hydration to minimize risk of contrast nephropathy
   3. N-acetylcysteine (NAC) IV and/or oral reduces risk of nephropathy in high risk persons [55]
   4. Assessment for pre-procedure ischemia requiring aggressive intervention
   5. Post-procedure evaluation for signs and symptoms of retroperitoneal hematoma
   6. Post-procedure evaluation for femoral pseudoaneurysm or arteriovenous fistula
   7. For stented patients, combination ASA and clopidogrel antiplatelet therapy
   8. Typical anginal symptoms within 1-8 months likely due to restenosis
   9. Homocysteine lowering therapy with folate, vitamins B6 and B12 reduces major adverse events ~30% after PCI [67]
2. Preparation for PCI [78,85]
   1. ASA 75-325mg qd for all patients who can tolerate it (at least 1d prior and 1d after)
   2. Clopidogrel 300mg loading dose within 3 hours of PCI has minimal benefit [69]
   3. Clopidogrel 75mg po qd or bid is continued for >4 weeks after PTCA [9]
   4. Clopidogrel 75mg qd x 1 year reduces recurrent ischemic events [69]
   5. Heparin 10-15K U iv during procedure; continued for 6-24 hours post-procedure
   6. Nitroglycerin sublingual or IV given prior to or during the procedure as needed
   7. Calcium channel blockers may decrease vasospasm
   8. Glycoprotein IIb/IIIa inhibitors improve outcomes of PCI (see below)
3. Coronary Angiography Performed First
   1. Vascular access usually obtained through femoral artery
   2. Sheath is placed and catheter is inserted to the os of the coronary artery to be dilated
   3. Angiography is performed (both Left and Right sided)
   4. At experienced centers, stenting is routinely recommended over standard PTCA [27]
4. Procedure
   1. Wire is advanced through catheter
   2. Wire is fed across the lesion to be dilated
   3. The wire must be able to traverse the lesion to allow dilation (also for atherectomy)
   4. A deflated balloon catheter is advanced over the wire and positioned at the stenosis
   5. Balloon is then inflated for 1-2 minutes at 3-8 atmospheres
   6. Redilitation may be accomplished with special balloon catheters for up to 30 minutes
5. Effectiveness
   1. Efficacy >95% in opening non-occluded coronary arterry
   2. Failure <5%: stenosis not crossed by wire, inadequate dilation, abrupt closure of vessel
   3. Lower success rate: long, eccentric, calcified, or osteal lesions; intraluminal thrombus
   4. Chronically occluded arteries have poorer success rate (~75%)
   5. Restenosis over time is major long term complication (see below)
   6. Creatine kinase (CK) elevation after PTCA is associated with late cardiac mortality
   7. Chronic antianginals (but not ASA) are reduced or stopped after revascularization [60]
6. Complications [54]
   1. Older persons and those with complex lesions at high risk for ischemic complications
   2. Chest Pain - 50% of patient have mild pain; ~5% will have abrupt vessel closure
   3. Creatine kinase (CK) elevations - ~20% of patients; elevations >5 fold may be important
   4. Frank myocardial infarction occurs in ~10% of cases (based on CK elevations)
   5. Vascular access complication - hemorrhage, AV fistula, hematoma, retroperitoneal bleed
   6. Contrast induced nephropathy - mainly in patients with pre-existing renal disease
   7. Prophylactic hemodialysis after coronary angiography improves renal outcomes in patients with advanced renal failure (CRF or ARF) [115]
   8. Infection risk is very low
   9. Longer term problem is restenosis (greatly reduced with stenting)
   10. Mortality <1%
7. Abrupt Closure [78]
   1. Initially occured in ~5% of patients undergoing balloon angioplasty
   2. In ~75% of these, abrupt closure occurs within minutes after angioplasty
   3. About 25% of abrupt closures occur within 24 hours after angioplasty
   4. Stent use has reduced abrupt closure, but increased risk of acute thrombosis
   5. Risk factors for abrupt closure: unstable angina, ? female sex, multivessel disease, thrombus, calcified, >10mm long
   6. ASA and clopidogrel [9] reduce rate of acute closure and thrombosis
   7. Glycoprotein 2b/3a (gp2b/3a) inhibitors and/or bivalirudin (direct thrombin inhibitor) reduce closure
   8. Manage by redilitation (~50% success), or use perfusion catheter (30 minute inflation)
   9. Failed redilitation usually evaluated for stenting or emergent bypass surgery
   10. Early closure may be due to seretonin and thromboxane release
   11. Overall, about 1% of patients undergoing angioplasty have acute Q wave MI
8. Retroperitoneal Hematoma [54]
   1. Groin, flank, abdominal or back pain may be present
   2. Reduction in hematocrit always present
   3. Unexplained hypotehsion
   4. Evaluation with computed tomographic scan
   5. Reversal of anticoagulation usually sufficient
   6. Surgical evacuation in 10%, usually for vascular or neurological compression

D. Platelet Glycoprotein IIb/IIIa Inhibitors in PCI [85]

1. Eptifibatide (Integrilin®)
   1. Cyclic heptapeptide inhibitor of platelet gp IIb/IIIa given intravenously
   2. Reduces emergent events/complications in PTCA patients
   3. Improves short and long term outcomes in patients with elective stenting [20]
   4. Clear benefits when added to other antiplatelet agents in stenting procedures (see below)
   5. No effect on overall bleeding rates
2. Abciximab (ReoPro®) [21]
   1. c7E3 Fab monoclonal antibody against platelet glycoprotein IIb/IIIa
   2. ~30% reduction in 30 day death, MI or emergency procedure for ischemia in EPIC study
   3. Bleeding rates 2X higher in treated versus placebo group (with normal heparin)
   4. Approved for selected patients undergoing PTCA, other procedures
   5. Reduced rate of thrombotic complications in unstable angina PTCA patients
   6. Clearly synergistic with stent placement for reduction in post-PTCA MI/death
   7. Abciximab is superior to tirofiban (Aggrastat®) in elective or urgent PTCA [22]
   8. Reduced overall mortality in PCI patients ~20% [64]
   9. Abciximab is strongly recommended in setting of PTCA and/or stent placement
   10. In elective PCI, high dose clopidogrel pretreatment eliminates benefits of abciximab [2]
3. Tirofiban or abciximab with PCI in acute ST-segment MI, improves TIMI Grade III flow, possibly clinical outcomes [82]
4. Xemilofiban [23]
   1. Potent oral gp2b/3a inhibitor
   2. Reduces complications and death when used acutely in emergent PTCA
   3. Chronic therapy with xemilofiban for up to 6 months after PTCA adds no benefit
5. Bivalirudin (Angiomax®)
   1. Direct thrombin inhibitor
   2. Bivalirudin alone is safer and as effective as GP2b/3a inhibitor + heparin or enoxaparin [102,109]
   3. Moderate and hig-risk ACS can be given bivalirudin alone, deferring gp2b3a antagonists for only those patients undergoing PCI [109]

E. Coronary Stenting [1,24]

1. Placement of a coil in coronary artery at position of PCI
   1. For stable patients, the routine use of stents is recommended over angioplasty alone
   2. Drug eluting stents (DES) are usually standard of care over bare-metal stents but there are concerns about late stent thrombosis with DES [56,99]
   3. DES associated with 55-70% reduction on target vessel revascularization compared with bare metal stents, similar 2-4-year mortality, 1.5X-2X thrombosis risk [98,120]
   4. DES associated with 2.0% STEMI at 2 years versus 2.4% with bare metal stents [120]
   5. Late (>3 month) stent thrombosis occurs with DES, and prolonged (12 months or longer) dual anti-platelet therapy with ASA and clopidogrel is strongly recommended
   6. Consider bare-metal stents in patients who cannot comply with prolonged antiplatelet agents or in patients with low risk of restenosis [56,121]
   7. All individuals with DES should receive at least 12 months of dual antiplatelet treatment [121]
2. Stents in PCI
   1. Stents are first line in any patient undergoing PCI [27]
   2. At 12 months, stent angiographic restenosis rates is 19% versus 40% for angioplasty
   3. Stents reduced revascularization versus angioplasty at 6 months by >50% in acute MI
   4. DES have <15% risk of angiographic [25,49] and <10% clinical [75] restenosis
   5. Restenosis risk increased in patients with DD allele of ACE gene [80]
   6. Bivalirubin (Angiomax®) + provisional GP2b/3a inhibitor as effective as and safer than heparin + planned GP2b/3a inhibition in stenting [16] or high risk [48] PCI
   7. Bivalirudin alone or with GP2b/3a inhibition is as effective with less bleeding than heparin or enoxaparin [102]
   8. Bivalirudin alone is safer and as effective as GP2b/3a inhibitor + heparin or enoxaparin [102,109]
   9. Stent-based PCI compares favorably with CABG for multivessel CAD [41,68]
   10. Clinically overall, sirolimus-eluting stents appear to be superior to bare metal or paclitaxel- eluting stents [108]
3. Overview of Drug Eluting Stents (DES) [25,26,72,121]
   1. DES include sirolimus-eluting (S-stent, Cypher®) and paclitaxel-eluting (P-stent, Taxus®)
   2. DES have similar mortality to bare-metal stents at 3 and 4 years [56,97,98,99]
   3. DES may have increased risk of late thrombosis compared with bare-metal stents [99,100]
   4. S-stents have shown superiority to P-stents for target vessel revascularization, event rates, and restenosis [86,87]
   5. S-stents trended to reduced restensosis [91] and mortality [86,87] verus P-stents
   6. S-stents showed reduced late-luminal loss compared with P-stents in patients with diabetes and trends to lower target vessel revascularization [88]
   7. PCI with S-stents reduced rate of target-vessel revascularization in STEMI but did not affect overall mortality, reinfarction, or stent thrombosis [94]
   8. Drug eluting stents associated with reduced acute MI at 6- and 12-months versus bare metal stents [107]; overall, S-stents superior to P-stents [108]
   9. In routine clinical practice S- versus P-stents showed no significant differences in major cardiac events (9.3% vs. 11.2%) or stent thrombosis rates [112]
   10. Everolimus-eluting stents showed superior angiographic and clinical outcomes compared with P-stents at 9 months in patients with CAD [117]
4. S-Stents (Cypher®)
   1. Overall ~60% reduction in target vessel revascularization compared bare-metal stents, with no difference in death, MI, or stent thrombosis between groups [73,101]
   2. Associated with 8% restenosis and 20-30% reduced major cardiac events / MIs in small coronary arteries at 8 months versus 53% restenosis with bare-metal stents [83]
   3. S-stents are superior to uncoated stents in STEMI with 8 months' followup [116]
   4. Tirofiban with S-stent had 18% versus 32% for abciximab with bare-metal stent for composite death, reinfarction, stroke, or target vessel revascularization [36]
   5. Overall survival at 4 years similar with S-stent and bare-metal stent [97,98]
   6. In patients with diabetes, S-stent associated with lower survival than bare-metal stent [97]
   7. Rates of MI and stent thrombosis similar with bare-metal and S-stents [97]
5. P-Stents (Taxus®)
   1. At 9 months, P-stent had ischemia-driven target-vessel revascularization 4.7% versus 12.0% with bare-metal stent [49]
   2. PCI with P-stents reduced incidence of serious adverse cardiac events in STEMI but did not hit statistical significance [95]
   3. Paclitaxel-eluting stents are superior to bare-metal stents in complex CAD lesions [46]
6. Stent Thrombosis and Reocclusion
   1. Platelet reocclusion appears most common; antiplatelet agents required
   2. Acute and subacute thromboses occur in ~3% of patients undergoing stent placement
   3. Early occlusions within 14 days of stenting reduced by potent anti-platelet therapy
   4. Stent thrombosis can result in acute severe MI or death
   5. ASA is continued indefinitely
   6. Clopidogrel replaces ticlopidine and is continued for >6 (>12) months [103]
   7. Clopidogrel for at least 6 months associated with reduced mortality ± MI after drug eluting stents [58]
   8. ASA therapy is generally continued indefinitely
   9. Abciximab reduces incidence of death/MI post-PTCA + metal stent by ~50% at 1-6 months
   10. Abciximab was superior to tirofiban (Aggrastat®) at 30 days [22] but had similar outcomes at 6 months [65]
   11. Eptifibatide (Integrelin®) high dose double bolus with infusion reduces death+MI+early target vessel revascularization >30% when added to heparin, ASA, ticlopidine [34]
   12. Premature discontinuation of antiplatelet therapy associated with >80X increased risk for stent thrombosis which may be fatal [28]
   13. Renal failure, bifurcated lesions also associated with increased thrombosis risk [28]
7. Thrombosis and Drug Eluting Stents
   1. With P-stent and S-stent, overall ~3% incicdence of angiographic stent thrombosis at 3 years [96]
   2. ACS or diabetes at presentation associated with ~2X risks each of stent thrombosis [96]
   3. Late stent thrombos slightly higher with P-stent than with S-stent [96]
   4. Stopping clopidogrel associated with increased risk of late stent thrombosis [103]
8. In routine clinical practice S- and P-stents showed no significant differences in major cardiac events (9.3% vs. 11.2%) or stent thrombosis rates [112]

F. PCI for Stable Angina

1. Effective pain relief in patients with single and multi-vessel CAD
2. In general, culprit lesions should be identified first by functional (versus anatomic) study
   1. Exercise - Thallium perfusion scan
   2. Dobutamine Echocardiography
3. PTCA Versus Medical Therapy for Single Vessel CAD
   1. PTCA initial success rate ~80%
   2. Post-PTCA required less anti-anginals, better symptoms relief
   3. However, PTCA had increase in associated MI (4%) and emergent CABG (2%)
   4. In a meta-analysis, PTCA had less angina (53% versus 70%) but more CABG (7.6% versus 4.1%) compared with medical therapy [41]
4. Coronary artery bypass grafting (CABG) is superior to PTCA only for prevention of second MI in patients with DM who have had a first MI [43]
5. Stenting Versus CABG in Multivessel CAD [41,59,68]
   1. Several studies had similar outcomes for stroke, MI, and death 1 year after proceedure
   2. Subsequent revascularization is always higher with PCI±stent compared with CABG
   3. Post-procedure angina usually somewhat higher with PCI±stent compared with CABG
6. Stent placement in vessels with Recurrent CAD
   1. Less effective in diabetics, who have greater closure rate
   2. Stents more effective than PTCA overall and for multivessel disease
7. Minimally invasive CABG for left anterior decending (LAD) may be superior to standard stenting [66]
8. Conclusions
   1. PTCA ± stenting is very effective in single-vessel CAD
   2. PTCA ± stenting often preferred instead of (in addition to) medications
   3. PTCA is less effective in multivessel CAD and should be reserved for high risk CABG
   4. PTCA + stenting may be as effective as CABG for multivessel disease
   5. PTCA is effective in graft revascularization following CABG (2nd CABG is high risk)
   6. Stents are nearly always preferable to PTCA alone

G. Restenosis [77]

1. Major long term problem with PTCA
   1. PTCA induces increased collagen in extracellular matrix and vessel lumen reduction
   2. Restenosis rates are reduced with use of stents, particularly with drug-eluting stents
   3. Stent restenosis is distinct from that in PTCA, with neointimal hyperplasia
   4. Very low levels of restenosis (<5%) occur with drug eluting stents
2. Definition
   1. Angiographic restenosis: >50% narrowing of lumen at site of previously successful PTCA
   2. Clinical restenosis: symptomatic recurrence or cardiac event at PTCA site
3. Incidence
   1. Angiographic: 45-55% at 6 months with balloon angioplasty
   2. Usually occurs 1-3 months post-PTCA, ~95% have occurred within 6 months
   3. Rates are substantially lower with use of stents
   4. Drug-eluting stents have clinical restenosis rates <5%, angiographic rates ~20%
   5. Drugs such as rapamycin (sirolimus) or paclitaxel block neointimal hyperplasia
   6. Risk, even with stents, increased in patients with DD allele of ACE gene [37]
4. Mechanism of Restenosis
   1. Initiated by injury to the vessel wall with subsequent wound healing response
   2. Activation of platelets (thrombus), macrophages, and smooth muscle cells
   3. Oxidized LDL likely stimulate macrophage and endothelial cells, promote inflammation
   4. Cytokine and other growth factors are produced and also stimulate inflammation
   5. Integrins, Angiotensin II, myb, fibroblast growth factor are all implicated
   6. Various drug-coated stents can block inflammation and restenosis
5. Risk Factors
   1. Diabetes mellitus (DM) - probably strongest known risk factor
   2. Smoking Tobacco
   3. Male Sex
   4. Hypertension (HTN)
   5. Hypercholesterolemia
   6. Unstable Angina, Vasospastic Angina
   7. Endstage Renal Disease
   8. Proximal Stenosis, Vein Grafts, LAD Lesions, Chronic occlusion, >10mm long
   9. Residual Stenosis >30% post-PTCA
   10. Plaque composition - small lipid core and lack of macrophage (M_) infiltrates increase risk [114]
6. Plaque Composition and Restenosis [114]
   1. Large (>40%) lipid core odds ratio 0.4 of developing >50% restenosis versus <10% lipid core
   2. Marked M_ infiltration odds ratio of 0.43 of developing >50% restenosis compared with minor macrophage infiltration
7. Prevention of Restenosis [77]
   1. Coronary artery stenting reduces rate of clinical restenosis to ~20% (see above) [27]
   2. Drug eluting stents reduce clinical restenosis to <5-10% at 9 months [25,26]
   3. Drug eluting stents show angiographic restenosis of 14-21% at 6 months [11]
   4. Calcium channel blockers have shown some activity (possibly due to vasodilator effect)
   5. Eptifibatide (Integrilin®) improves outcomes in electively stented patients at 30 days and one year, suggesting reduction in restenosis (including in diabetics) [20]
   6. Abciximab (ReoPro®) may reduce 6 month clinical restenosis rate
   7. Statins reduce restenosis rates after PTCA and stenting
   8. Reducing serum homocysteine with folate (1mg), vitamin B12 (400µg) and vitamin B6 (pyridoxine, 10mg) daily reduced clinical restenosis rates 40-50% [60,67]
   9. Homocysteine reduction reduces overall severe major adverse events after PCI [67]
   10. In a later study, homocysteine reduction with vitamins increased the restenosis rate [81]
   11. Multivitamins, including high dose vitamin E, did not block stenosis [59]
   12. Endoluminal ß-radiation (18 Gy) reduces restenosis (15%) and 6-month revascularization rates (6%) without stenting or causing aneurysms [56]
   13. Endoluminal gamma-radiation (iridium-192, 14-15 Gy) after PTCA of blocked saphenous vein grafts reduced restenosis 70% and clinical events 49% [57]
   14. Celecoxib (Celebrex®) 200mg bid) added to ASA + clopidogrel reduced restenosis and target vessel revascularization at 6 months in patients with Taxus stents [111]
   15. Both atherosclerosis and restenosis have inflammatory components
8. Management of Restenosis
   1. Initial coronary stenting reduces risk of any restenosis
   2. Clinical restenosis usually treated with second PCI
   3. Irradiation (vascular brachytherapy) following PCI for stent restenosis can reduce further stent restenosis
   4. Paclitaxel-coated balloon catheter associated with signifcantly reduced restenosis in treatment of in-stent restenosis compared with uncoated balloon [33]
   5. Paclitaxel- [92] or sirolimus- [93] eluting stents are superior to angioplasty plus vascular brachytherapy for in-stent restenosis (within bare metal stents)
   6. Sirolimus-eluting stents are superior to uncoated stents in STEMI with 8 months' followup [116]
   7. CABG may be preferred or required over initial PCI for diabetics
   8. Vitamins to reduce homocysteine cannot be recommended at this time [81]

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