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Stents are not enough? -and neither are oral antirestenotics

Stents are not enough? -and neither are oral antirestenotics. Dr Anthony Mathur London Chest Hospital Barts and the London NHS Trust. Overview. Why bother? Ideal oral therapy Mechanism Oral rapamycin data Other specific oral antirestenotics Other non-specific antirestenotics

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Stents are not enough? -and neither are oral antirestenotics

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  1. Stents are not enough?-and neither are oral antirestenotics Dr Anthony Mathur London Chest Hospital Barts and the London NHS Trust

  2. Overview • Why bother? • Ideal oral therapy • Mechanism • Oral rapamycin data • Other specific oral antirestenotics • Other non-specific antirestenotics • Local interpretation

  3. p-value <.0001 <.0001 0.0417 0.0067 <.0001 0.0002 0.0001 0.0002 0.0007 <.0001 0.0005 <.0001 0.0015 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 New* SIRIUS: Odds Ratio for TLR by Sub-group # events prevented per CYPHER™ Stent (%) Control (%) 1,000 patients 4.4 Overall 24.2 198 Male 3.8 26.9 231 Female 6.0 17.9 119 Diabetes 6.7 30.0 233 No Diabetes 3.9 22.3 184 LAD 4.3 23.5 192 Non LAD 4.6 25.0 204 Small Vessel 6.0 21.2 153 Large Vessel 1.4 32.3 309 Long Lesion 6.1 28.8 227 Short Lesion 2.7 19.8 171 Overlap 2.5 38.0 355 No Overlap 5.5 17.9 125 Odds Ratio + 95%CI *Combined results from E- and C- SIRIUS

  4. TAXUS IV: Sub-AnalysisTLR Across Vessel Size and Lesion Length Control TAXUS™ Stent TLR at 9 months Percent of patients < 2.5 RVD 2.5-3.0 RVD > 3.0 RVD Lesion Length Lesion Length Tertile analysis Note: Control=Bare metal ExpressTM Stent; Source: TAXUS IV (9 month follow-up) clinical trial

  5. Treatment of ISR Use Of Localised Intracoronary Beta Radiation In Treatment Of In-Stent Restenosis: The INHIBIT Randomized Controlled Trial Lancet 2002; 359: 551-557 Waksman et al

  6. Role for oral antirestenotics? • Primary therapy • Adjunctive therapy • Failure of therapy

  7. The ideal oral agent • Efficacy • Availability • Side effects • High target tissue levels • Tolerable systemic effects • Cost • for all PTCA patients? • for recalcitrant restenosis?

  8. ?

  9. Restenosis Process

  10. Strategies and Drugs

  11. Drug Modes of Action

  12. Oral Rapamycin • Pilot study of oral rapamycin to prevent restenosis in patients undergoing coronary stent therapy: Argentina Single-Center Study (ORAR Trial).Rodriguez et al, J Invasive Cardiol. 2003 Oct;15(10):581-4. • Oral rapamune to inhibit restenosis – preliminary results from the orbit studyWaksman et al, TCT 2003 • Pilot trial of oral rapamycin for recalcitrant restenosis.Brara et al, Circulation. 2003 Apr 8;107(13):1722-1724 vs.

  13. Binds to intracellular receptor protein (FKBP12) in target cells • Elevates p27Kip1 levels; inhibits cyclin/cyclin dependent kinase complexes • Reduces protein RB phosphorylation • Induces cell-cycle arrest in late G1 phase RAPAMYCIN S X CELLCYCLE G1 G2 G0 M CELL DIVISION Mechanism of action of Rapamycin Cytostatic not Cytotoxic

  14. RAPAMYCIN Pharmacokinetics: Rapamune is rapidly absorbed - peak concentration of approximately 1 hr after a single dose. The systemic availability of Rapamune is ~ 14%. A loading dose of 3 x maintenance dose will provide near steady state concentrations within 1 day in most patients. The mean volume of distribution of Rapamune is 12 ± 7.5 L/kg. 92% bound to human plasma proteins. Rapamune is metabolized by the cytochrome P450 hepatic system, then excreted in faeces & a 2.2% in urine.

  15. Effect of Systemic Rapamycin Delivery in a Porcine Coronary Restenosis Model • Rapamycin 3 d pre intervention • IM 0.5 mg/kg load dose • IM 0.25mg/kg 14 days • Analysis at 4 weeks p < 0.0001 Decreased pRb phosphorylation and elevated levels of p27 causing cell cycle arrest at G1/s Gallo, et. al. - Circulation 1999; 99:2164-2170

  16. ORBIT - Study Flow All Treated Patients n = 60 Rapamune 2 mg n = 30 Rapamune 5 mg n = 30 Angio FU at 6 Months 80% Clinical FU at 6 Months 93% Angio FU at 6 Months N/A Clinical FU at 6 Months N/A

  17. Methods INCLUSION CRITERIA • > 18 years of age • Stable or unstable angina with evidence of ischemia • Treatment of de novo lesions in 2 coronary arteries • Target lesion is 2.5- 4.0 mm in diameter (visual estimate) • Target lesion is 15- 30 mm in length (visual estimate) • Target lesion is > 50% and < 100% (visual estimate) • At least TIMI 1 coronary flow • Left ventricular ejection fraction (LVEF) > 20% • The patient is an acceptable candidate for CABG • Normal baseline CBC

  18. Methods Drug Administration and Pharmacology • Loading Dose 5 mg • Time of administration: immediate before or after PCI • Maintenance dose 2 mg or 5 mg /day • Duration 30 days • Rapamune levels at 24 h (17pts) 5.1 ± 3.1 ng/ml • Rapamune levels at 30 d (16 pts) 6.4 ± 4.2 ng/ml • Therapeutic levels 4-20 ng/ml

  19. ANGIOGRAPHIC CHARACTERISTICS I N=49 LESIONS

  20. RESULTS Drug Safety Profile 2 mg and Adverse Reactions Mean duration of taking the Rapamune 26.7 ± 7.8 days

  21. Results MAJOR CLINICAL EVENTS AT 6 MONTHS Patients n=28*, Lesions n=45 *One patient lost to follow-up one patient self withdrawn from study

  22. ORBIT - Conclusions • Overall the dose of 2 mg was well tolerated and 27/30 pts completed the 30 days treatment while only minor adverse effects related to the drug were reported. • There were no hematological or biochemical averse effects in hospital and at 30 days. • There were no early or late stent thromboses, no late aneurysms, and no other clinical, angiographic, or IVUS pathobiologic responses associated with rapamune. • The binary restenosis of 7.0 % and the low late loss 0.60mm suggest that systemic oral administration of rapamune may be a therapeutic option for patients undergoing PCI

  23. SCRIPPS V: SCripps Rapamycin to Inhibit Proliferation Post Stenting Paul S. Teirstein,, Mindy R. Fernandez, Prabhtej Brara, Mark A, Grise, Mehran Moussavian, John P. Reilly Scripps Clinic

  24. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Background • Potential benefits of oral rapamycin • Treatment for recalcitrant restenosis • Treatment vehicle for patients who cannot receive stents (ie, vessel too small, bifurcations, clopidogrel allergic) • Reduced cost

  25. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Study Objective • The objective of this study was to assess the clinical outcome following treatment of patients at exceptionally high risk for restenosis with oral rapamycin.

  26. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Methods • Patient inclusion: failed radiation for in-stent restenosis, or not candidate for brachytherapy • Rapamycin prescription: 6 mg loading dose within 4 hours of PCI then 2 mg / day x 30 days • Clopidogrel Rx for 6 months • Monthly telephone follow-up including CBC, LFT’s, lipid profile at 1, 3 and 5 weeks

  27. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Dosimetry: 6 mg load followed by 2 mg / day x 30 days • FDA approved dose for renal transplant patients • Loading dose provided after PCI to ensure confirmation of recurrent restenosis prior to treatment • Treatment duration of 30 days chosen to approximate the slow release sirolimus stent

  28. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Results: n = 22 patients with > 6 mos FU • Age (yrs) = 57.1 + 10.6 • Male = 14 (64%) • Diabetic = 9 (41%) • # of Prev Restenoses = 3.5 + 1.6 • Index to prior PCI (mos) = 7.8 + 8.9 • Radiation failure = 20 (91%) • Not radiation candidate = 2 (9%) • Native target = 22 (79%) • SVG target = 6 (21%)

  29. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Results: n = 22 patients with > 6 mos FU Discontinued rapamycin prior to 30 days = 11 (50%) - all reversible Leukopenia = 3(27.3%) Elevated LFT’s = 1 (9.1%) Elevated triglycerides = 3 (27.3%) Stomatitis = 1 (9.1%) Physician preference = 1 (9.1%) Flu symptoms = 1 (9.1%) Acne = 1 (9.1%) Treatment duration in patients who discontinued = 14.5 + 6.5 days

  30. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Results: n = 22 patients with > 6 mos FU N = 28 lesions Mean FU time = 10 + 2 months FU range = 6.5 - 12 months TLR = 15/28 (54%) Rx only 7-23 days = 5/13 (38%) Rx entire 30 days = 8/13 (62%)

  31. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Limitations • Very small patient numbers • No placebo group • Not randomized • No rapamycin levels obtained • No systematic angiographic follow-up • Successful animal trials started systemic rapamycin wellbefore PTCA. • Radiation failure patients may be uniquely resistant to cell cycle inhibitors.

  32. Oral Rapamycin for RecalcitrantIn-Stent Restenosis Can oral therapy provide adequate tissue levels? • Tissue levels post sirolimus stent are approx 2000 ng/gm, trough blood levels post oral rapamycin are approx 20 ng /ml. • Rapamycin binds to the FK binding protein • Rapamycin is relatively insoluble, 90% is sequestered in circulating cells • Oral rapamyincin provides tissue levels in the adventitia/media that are probably only a fraction of that achieved with sirolimus stents

  33. SCRIPPS V: SCripps Rapamycin to Inhibit Proliferation Post Stenting Clinical Implications • Frequent adverse effects and apparent lack of efficacy make oral rapamycin an unlikely restenosis treatment. • This data underscores the advantages of local, stent based, drug delivery which provides a high local dose, while maintaining a low systemic dose.

  34. Non specific agents……

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