Disclosures. Update on Interventional Cardiology. Overview. In-stent restenosis (ISR) versus stent thrombosis (ST) No financial conflict of interest

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Disclosures No financial conflict of interest Update on Interventional Cardiology Primary Care Medicine: Principles and Practice October 2008 Andrew Boyle MBBS, PhD Assistant Clinical

Evolving Therapies In-stent restenosis (ISR) versus stent thrombosis (ST) ISR is a cellular proliferative response of the vessel wall to trauma of PCI Largely composed of smooth muscle

1 Disclosures No financial conflict of interest Update on Interventional Cardiology Primary Care Medicine: Principles and Practice October 2008 Andrew Boyle MBBS, PhD Assistant Clinical Professor of Medicine UCSF Division of Cardiology Overview Stent thrombosis and clopidogrel duration Peri-operative management of patients with PCI COURAGE trial Case studies New and Evolving Therapies In-stent restenosis (ISR) versus stent thrombosis (ST) ISR is a cellular proliferative response of the vessel wall to trauma of PCI Largely composed of smooth muscle cells and extra-cellular matrix. Gradual reduction in lumen size (cf acute occlusion in ST) Can completely occlude, causing MI. Angiographic ISR in 20-30% of BMS, clinical ISR in 10-15%. DES reduce ISR. 1

Stent Thrombosis risk for in-stent restenosis risk for stent thrombosis Stent thrombosis is rare (0.4 1.

Lancet 2007; Cutlip et al Circulation 2001 1) Procedural factors Long stents, overlapping stents Bifurcation lesions Inadequate procedural

Bifurcation lesions Inadequate procedural results 2) Patient factors Are DES Small vessels Elderly really Diabetes Renal failure Low EF

ACS 3) Definition ARC versus protocol Bare metal stents long term Mayo clinic registry of 4,503 pts receiving bare-metal stents 10 year

2 Stent Thrombosis risk for in-stent restenosis risk for stent thrombosis Stent thrombosis is rare ( %), Mauri et al NEJM 2007; but is a catastrophe: % have MI, 11-45% death Deamen et al. Lancet 2007; Cutlip et al Circulation ) Procedural factors Long stents, overlapping stents Bifurcation lesions Inadequate procedural results 2) Patient factors Small vessels Elderly Diabetes Renal failure Low EF ACS 1) Procedural factors Long stents, overlapping stents Bifurcation lesions Inadequate procedural results 2) Patient factors Are DES Small vessels Elderly really Diabetes Renal failure Low EF dangerous? ACS 3) Definition ARC versus protocol Bare metal stents long term Mayo clinic registry of 4,503 pts receiving bare-metal stents 10 year follow-up Percent of patients Stent Thrombosis ISR presenting with MI 1 year 5 year 10years Doyle et al. Circulation. 2007;116: Pooled Data from Pivotal Trials of Sirolimus- and Paclitaxel-Eluting Stents* Late 2006: Registry data from real-world practice suggested increased rates of late and very late stent thrombosis Jeremias et. al. Ann Intern Med 2008;148:

Delayed endothelial coverage of DES Finn, A. V. et al. Arterioscler Thromb Vasc Biol 2007;27:1500-1510 FDA CDSAP Recommendations 1.

3 Delayed endothelial coverage of DES Finn, A. V. et al. Arterioscler Thromb Vasc Biol 2007;27: FDA CDSAP Recommendations 1. On-label DES use compared to BMS use is not associated with an increased incidence of death or MI. 2. On-label DES use compared to BMS use is associated with an increased incidence of very late ST that is of uncertain magnitude and clinical significance. 3. Benefits of on-label DES use (reduced restenosis) appear to outweigh the risks (ST). 4. Off-label DES use compared to on-label DES use is associated with an increased incidence of death and MI. Whether this is because of increased complexity in off-label use, increased risk of ST, or a combination of these two factors is unknown. 5. Dual antiplatelet therapy should be continued for at least 12 months following DES PCI, especially in the off-label setting, for patients at low risk for bleeding. Use of DES in a patient who may not be able to adhere to extended thienopyridine therapy is not recommended. Pinto Slottow et al Cath Cardiovasc Interven 2007:69; How Can We Balance the Risk? Current Approach to PCI (1) Evidence based medicine Rare Potentially catastrophic ST More common Rarely catastrophic ISR PCI has mortality benefit in STEMI and in highrisk ACS PCI has symptomatic benefit in stable angina. Many of our patients fall outside clinical trial populations eg multivessel disease, very elderly, heart failure, renal failure etc Many lesions fall outside clinical trial inclusion criteria/on-label device usage eg bifurcations, long lesions, bypass graft lesions etc. Where there is no data: use best clinical judgement. 3

4 Current Approach to PCI (2) Clopidogrel duration Bare metal stents: 1 month Drug-eluting stents: 12 months at least. Acute Coronary Syndromes: 12 months Where there is no data: use best clinical judgement. Multiple overlapping drug-eluting stents: Lifelong Complex interventions: at least 12 months, preferably lifelong Left main stent: Lifelong Current Approach to PCI (3) Minimize risk All patients screened prior to cardiac cath for compliance, need for elective surgery Discuss issue of prolonged dual anti-platelet therapy with patient Try to avoid long, multiple stents and bifurcation lesions. Meticulous procedural technique. Consider CABG instead of PCI if unable or unwilling to comply with prolonged dual antiplatelet therapy Current Approach to PCI (4) BMS versus DES Try to use BMS if risk of ISR is acceptably low. If patient is agreeable, use DES if risk versus benefit profile is acceptable Remember DES is an excellent treatment with beneficial sustained results in vast majority of patients. Complex decision making process, there is no one-size-fits-all option! Stent thrombosis and clopidogrel duration Peri-operative management of patients with PCI COURAGE trial Case studies New and Evolving Therapies 4

Minimum Duration of Dual Anti-Platelet Therapy with Aspirin and Plavix Bare Metal Stent --- 4 weeks Sirolimus Eluting Stent (CYPHER) --- 3 months Paclitaxel Eluting Stent (TAXUS) --- 6 months Is this

5 Minimum Duration of Dual Anti-Platelet Therapy with Aspirin and Plavix Bare Metal Stent weeks Sirolimus Eluting Stent (CYPHER) months Paclitaxel Eluting Stent (TAXUS) months Is this enough for all patients? NO! What to do with Patients Awaiting Surgery after PCI? Is there an optimal delay after coronary stenting prior to non-cardiac surgery? Analysis of the Mayo Clinic PCI and Surgical databases ( ) 207 patients identified who underwent surgery after a successful PCI with Bare Metal Stent How did they do? Wilson SH et al JACC 2003;42: Complications of Non-cardiac Surgery after Coronary PCI It is suggested that post PCI with a BMS, surgery be delayed by 6 weeks What to do with DES?? Wilson SH et al JACC 2003;42: What is the Risk of Early Surgery (or within the timeframe when Clopidogrel is required) Poststenting? Single center study, 192 patients Successful PCI (either BMS or DES) BMS treated with asa/plavix for at least 1 month Cypher treated at least 3 months Taxus treated at least 6 months Early surgery vs. late surgery outcomes (within 30 days post-op): Death or MI: 13.3% early vs. 0.6% late (if on asa/plavix) Early surgery: 30.7% death or MI if NOT TAKING plavix!! Transfusions 24% vs. 20% (with vs. without antiplatelet Rx) Schouten O et al JACC 2007;49:

6 How to Avoid Peri-op Stent Thrombosis? Avoid pre-op revascularization Revascularize without stent (balloon only) Delay surgery PTCA only delay surgery at least 1 week (ideally, days 14-29) BMS delay surgery at least 6 weeks DES (any type) delay surgery 12 months Optimize anti-platelet therapy (i.e. operate on aspirin and Clopidogrel) Education and team-approach of everyone involved Stent thrombosis and clopidogrel duration Peri-operative management of patients with PCI COURAGE trial Case studies New and Evolving Therapies Grines at al. Circulation 2007;115; Brilakis ES et al. JACC 2007;49: COURAGE trial 2287 patients in US and Canada Coronary artery disease documented by coronary angiography + ischemia Randomized to optimal medical therapy (OMT) or PCI +OMT (PCI) Boden et al NEJM 2007 Boden et al NEJM

7 Inclusion criteria: one 70% stenosis + abnormal ECG /positive stress test OR one 80% stenosis + angina Exclusion criteria CCS class IV angina Markedly positive stress test Refractory heart failure LVEF < 30% Revasculariaztion w/in 6 months Cardiogenic shock Unsuitable coronary anatomy Boden et al NEJM 2007 COURAGE - Results Boden et al NEJM COURAGE - Results p=ns % Patients with angina p<0.001 p=0.02 p=ns 0 Baseline 1 year 3 year 5 year OMT PCI COURAGE - Results Excellent lipid management Boden et al NEJM 2007 Boden et al NEJM

8 COURAGE - Limitations COURAGE Nuclear Substudy Few drug-eluting stents ~3% 33% of OMT group had PCI or CABG 42% of patients had class 0 or 1 angina at baseline Residual Ischemia and Outcome Ischemia Reduction and Outcome Shaw, L. J. et al. Circulation 2008;117: COURAGE Nuclear Substudy COURAGE - Summary Total stress perfusion defect p=ns Baseline p=0.018 Follow-up PCI OMT Authors conclusions: PCI results in greater reduction in ischemia than OMT alone Findings suggest a treatment target of 5% ischemia reduction In stable coronary artery disease: PCI does not reduce MI or death over optimal medical therapy PCI improves angina better than optimal medical therapy alone PCI reduces ischemia and reduced ischemia is associated with reduced events All patients had cardiac catheterization at baseline - COURAGE does NOT mean keep patients out of the cath lab! Optimal medical therapy for all, PCI if symptomatic Shaw, L. J. et al. Circulation 2008;117:

9 Case 1 Stent thrombosis and clopidogrel duration Peri-operative management of patients with PCI COURAGE trial Case studies New and Evolving Therapies 58F presenting with shortness of breath 3 weeks earlier had several hours of bilateral anterior chest tightness. Worsening SOB since then Previous workup: normal CXR and VQ scan, granulomatous mediastinal disease on CT chest Past History Type 2 diabetes X 10 years Hypertension X 6 years Obesity 5 1, 245 lbs Benazepril HCTZ Glyburide Metformin Inhaled insulin Medications Vitals: HR 93bpm; 134/68; Wt 243 lbs; afebrile; RR 18/min JVP 7-8cm Normal S1, S2. No murmurs/rubs/gallops Chest clear Abdomen lax and non-tender 1+ peripheral edema 9

10 Initial cardiac workup A. Cardiac catheterization B. ECG C. Labs including cardiac enzymes D. Echocardiography E. B, C and E. Initial cardiac workup A. Cardiac catheterization B. ECG C. Labs including cardiac enzymes D. Echocardiography E. B, C and E. Diagnosis Echocardiography: Anteroseptal and apical hypokinesis Moderate LV impairment LVEF 30-35% A. Prior anterior MI B. Currently having an anterior MI C. Hibernating myocardium D. Normal E. A, B, or C could be correct 10

11 Diagnosis A. Prior anterior MI B. Currently having an anterior MI C. Hibernating myocardium D. Normal E. A, B, or C could be correct Next step in investigation A. Stress test B. Nuclear perfusion study C. Stress echocardiography D. Cardiac catheterization E. None needed medical management is appropriate Next step in investigation A. Stress test B. Nuclear perfusion study C. Stress echocardiography D. Cardiac catheterization E. None needed medical management is appropriate 1 month later Presented to the ED in respiratory distress Unchanged ECG Now in heart failure clinically. Low level troponin rise 11

Next step in investigation A. ASA, plavix, Gp IIb/IIIa inhibitor B.

A, B and C E. Functional cardiac stress test A, B and C E.

12 Next step in investigation A. ASA, plavix, Gp IIb/IIIa inhibitor B. Increase outpatient medical therapy C. Cardiac catheterization D. A, B and C E. Functional cardiac stress test Next step in investigation A. ASA, plavix, Gp IIb/IIIa inhibitor B. Increase outpatient medical therapy C. Cardiac catheterization D. A, B and C E. Functional cardiac stress test QuickTime and a decompressor are needed to see this picture. 12

13 Follow-up Cypher drug-eluting stent implanted Remains well and pain-free 6 months later LVEF 60% Case 2 70M with exertional chest and back pain. Hypertension and type 2 diabetes recently diagnosed Ex-smoker Physical exam: 80bpm reg, 150/80, afebrile, RR 14bpm Normal heart sounds and breath sounds. No heart failure Next step? Exercise stress test positive but refused cardiac catheterization. Medical management: Aspirin, atenolol, statin 6 months later exertional symptoms getting more frequent and severe. HR 57/min BP 150/90 RR 14/min Normal cardiac and respiratory examination A. Cardiac catheterization B. CT aortogram C. Nuclear perfusion study D. Exercise echocardiography 13

14 CT aortogram No dissection 4.2 cm mass in kidney consistent with renal cell carcinoma Triple vessel disease and probable renal cell cancer A. Medical management B. PCI with BMS C. PCI with DES D. Coronary artery bypass graft surgery Follow-up 1 month post successful CABG X4 Soon to have nephrectomy 14

15 New Drug-Eluting Stents 2008 Stent thrombosis and clopidogrel duration Peri-operative management of patients with PCI COURAGE trial Case studies New and Evolving Therapies Already on the Market since 2003: Cypher sirolimus Taxus paclitaxel New DES for 2008: Endeavor zotarolimus Promus everolimus (Boston Scientific) Xience everolimus (Abott) Prasugrel Similar to clopidogrel (Plavix) Anti-platelet agent Use in ACS and post-pci Not on the market yet Triton TIMI 38 - Results Wiviott et al. NEJM 2007; 357: Wiviott et al. NEJM 2007; 357:

Wiviott et al. NEJM 2007; 357:2001-2015 Percutaneous Aortic Valve Replacement (pavr) Surgical AVR remains the gold standard.

Enrolling patients with severe calcific AS at unacceptably high surgical risk Valve is made of bioprosthetic material attached to a stent,

via the femoral artery approach. All had severe, symptomatic aortic stenosis + too high risk for surgical AVR. Average age was 82 ± 7 years.

16 Wiviott et al. NEJM 2007; 357: Percutaneous Aortic Valve Replacement (pavr) Surgical AVR remains the gold standard. pavr is in clinical trials in Canada and USA. Device approved in Europe. Enrolling patients with severe calcific AS at unacceptably high surgical risk Valve is made of bioprosthetic material attached to a stent, mounted on a balloon Deployed within the aortic valve orifice, crushing the calcified leaflets Canadian Human Trial 2007 First 50 patients pavr via the femoral artery approach. All had severe, symptomatic aortic stenosis + too high risk for surgical AVR. Average age was 82 ± 7 years. 1 procedural death. 30-day mortality 12%. Expected surgical mortality by the EuroSCORE was 28%. Procedural success 76% in the first 25 patients; 96% in the second 25 patients - a significant learning curve. Webb, J et al. Circulation

Percutaneous Mitral Valve Repair Valve area increased from 0.6 ± 0.2 cm 2 to 1.7 ± 0.4 cm 2. Mean echo gradient 46 ± 17 -> 11 ± 5 mmhg.

Mitraclip in clinical trials to treat MR Clips the anterior and posterior MV leaflets together EVEREST 1 trial initial 24 patients with clip

After stenting, clopidogrel duration: 1 month for BMS 12 months at least for DES 12 months following ACS 2.

17 Percutaneous Mitral Valve Repair Valve area increased from 0.6 ± 0.2 cm 2 to 1.7 ± 0.4 cm 2. Mean echo gradient 46 ± 17 -> 11 ± 5 mmhg. Peri-procedural stroke in 4%. LVEF improved from 53 ± 15% to 57 ± 13% (p<0.0001) and this was sustained for the 1 year follow-up interval. Mitraclip in clinical trials to treat MR Clips the anterior and posterior MV leaflets together EVEREST 1 trial initial 24 patients with clip deployed, reduction in MR in most Ongoing larger clinical trials Webb, J et al. Circulation 2007 Feldman et al JACC 2005 Summary 1. After stenting, clopidogrel duration: 1 month for BMS 12 months at least for DES 12 months following ACS 2. COURAGE shows that optimal medical Rx is equivalent to PCI in preventing death and MI. PCI is superior in treating angina & ischemia Patients with angina and/or ischemia should have cardiac catheterization 17

18 Summary (2) 3. Revascularization requires a complex decision-making process, taking into account patient and lesion characteristics. DES are a good option for some patients. BMS are a good option for some patients. Thankyou for your attention There is no one-size-fits-all option! 4. There are many exciting new devices on the horizon 18

Update on Interventional Cardiology for the Internist. Andrew Boyle MBBS, PhD Assistant Clinical Professor of Medicine UCSF Division of Cardiology

Update on Interventional Cardiology for the Internist Andrew Boyle MBBS, PhD Assistant Clinical Professor of Medicine UCSF Division of Cardiology Disclosures No financial conflict of interest Off-label