Smooth muscle pharmacology & interventional cardiology

Transcription

1 LAST LECTURE Smooth muscle & interventional cardiology By: Pascal Bernatchez Classic Vascular -chronic -systemic Local Vascular -acute -targeted High blood pressure Blood pressure control Atherosclerosis Endothelial Injury Thrombus PTCA Stent Drug eluting stents Patient burden In-sent restenosis Lipid lowering drugs Platelet/SMC!!!!! Endothelial dysfunction atherosclerosis Which one comes first? Step 1: Endothelial activation Step 2: ecrosis + Calcification blood pressure management lipid management EC dysfunction Atherosclerosis Arteriosclerosis risk factors Hypertension Endothelial permeability Leukocyte migration Endothelial adhesion Leukocyte adhesion Macrophage accumulation Formation of necrotic core Formation of fibrous cap R.Ross,.Engl.J.Med., 1999

2 PTCA What is PTCA? Stenosis and angioplasty Medication?

3 Damage Plaxitaxel Cirrolimus\ Cobalt chromium : multi step process (lecture X) Angioplasty injury Angioplasty injury Platelet adhesion pdgf

4 Angioplasty injury Stents Stenosis and stenting

5 Paclitaxel/Taxol Paclitaxel/Taxol -Anti-cancer agent -Anti-mitotic -As a potent stabilizer of microtubules. Since microtubule disassembly is essential for the transition from the G2 to the M phase in the mitotic cell cycle, stabilization arrests mitosis and cell proliferation. -Microtubule dysfunction also inhibits cell migration, reducing the infiltration of vascular smooth muscle cells and leukocytes into the zone of injury caused by stents Sirolimus/Rapamycin Sirolimus/Rapamycin -Immunosuppressant possesses anti-proliferative properties -Stent: The metal of the stent has a soft, plastic coating It slowly releases Sirolimus into the artery wall around the stent Eighty percent (80%) of the sirolimus is released during the first 30 days. The rest is released by the end of 90 days Controlled-release, nonresorbable, elastomeric polymer coating

6 Sirolimus/Rapamycin ne w engl a nd jou r na l The A -Decrease rate of restenosis by 40-70% compared to BMS medicine of Drug eluting stents B Bare-metal stent Drug-eluting stent Antiproliferative -% Stenosis/total lumen diameter: Stent platform Drug release Stent platform Polymer coating biodegradation Polymer coating Sirolimus: 3.5% of diameter BMS: 18.5% of diameter Polymer coating C Arterial injury Paclitaxel Sirolimus C 47H5147 MW 854 Everolimus C 51H7913 MW 914 C 52H79512 MW 966 H H H H Inhibition H3C H H Proliferation and migration of vascular smooth-muscle cells and extracellularmatrix formation H H H H Paclitaxel: 3.3% BMS: 12.2% Zotarolimus C 53H 8314 MW 958 H H Activation of vascular smooth-muscle cells H H H3C 5100 patients study CH3 Binding to β-tubulin subunit of microtubules Binding to FKBP12 Polymerization of tubulin Inhibition of mtr G 0 phase Inhibition of microtubule disassembly Up-regulation of p27kip1 G1 phase M phase (cell division) Cell cycle S phase G2 phase stenosis, which is manifested as myocardial in- peat revascularization, myocardial infarction, and Draft 3 12/17/2012stent thrombosis.30,31 Randomized comparisons farction in 10 to 20% of patients.28,29 Author Holmes ra showed similar outcomes for stents releasing 1 Fig # Drug-Eluting Coronary Everolimus-Eluting Stents Title everolimus and those releasing sirolimus with Artery Stents In randomized trials, everolimus-eluting respect to rates of death, myocardial infarction, DE Ingelfinger stents ame ME improved clinical outcomes as compared with and repeat revascularization A large trial Williams Artist Pub Date paclitaxel-eluting stents, reducing the1/17/2013 risks of re- showed lower rates of stent thrombosis with CLR FIGURE AUTHR PLEASE TE: Figure has been redrawn and type has been reset Please check carefully 256 n engl j med 368;3 nejm.org january 17, 2013 The ew England Journal of Medicine Downloaded from nejm.org by Pascal icolas Bernatchez on January 17, For personal use only. o other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. Delayed restenosis Stent thrombosis Aspirin: should not be interrupted Clopidogrel: no longer that day -5 to day +2 if other surgery ormally a month of clopidogrel after PTCA or stent, now increased at 6 to 12mo Reopro: -Work well for a year -ther types of surgeries need cessation of platelet therapy -Delayed reendothelialization -Thrombosis causes Death or MI so HUGE ATI PLATELET THERAPY

7 A Primary utcome 60 B Death 2380 o. at Risk o. at Risk P=0.005 by log-rank test 5-Yr event rate: 26.6% vs. 18.7% Years since Randomization P=0.049 by log-rank test 5-Yr event rate: 16.3% vs. 10.9% tients with myocardial infarction in that group). All the procedural myocardial infarctions in the trial were non Q-wave events. Myocardial infarctions that occurred more than 30 days after the index procedures were reported in 81 of 99 patients (82%) in the group and in 29 of 48 patients (60%) in the group. There were fewer strokes in the group than in the group (P = 0.03) (Table 2, and Fig. 2B in the Supplementary Appendix). The The new england journal of medicine Years since Randomization Figure 1. Kaplan Meier Estimates of the Composite Primary utcome and Death Shown are rates of the composite primary outcome of death, myocardial infarction, or stroke (Panel A) and death from any cause (Panel B) truncated at 5 years after randomization. The P value was calculated by means of the log-rank test on the basis of all available follow-up data n engl j med 367;25 nejm.org december 20, year rates were 2.4% in the group and 5.2% in the group. f these strokes, the majority (87%) were ischemic and 13% were hemorrhagic. In the first 30 days after the procedure, 3 patients in the group and 16 in the group had a stroke (Table 3). The excess of strokes in the group occurred in the first 30 days after randomization. An IH Stroke Scale score of more than 4 (severely disabling) at the time of the event was reported in 27% of patients in the group, as compared with 55% of those in the group. A score on the Rankin scale of more than 1 at the time of the stroke was reported in 60% of patients in the group, as compared with 70% in the group. Secondary utcomes Rates of cardiovascular death (63.7% of all deaths) did not differ significantly between the two study groups (P = 0.12 by the log-rank test), nor did rates of major adverse cardiovascular and cerebrovascular events at 30 days (P = 0.68 by the log-rank test). However, at 1 year after the procedure, there was a significant difference in rates of major adverse cardiovascular and cerebrovascular events, with 16.8% in the group versus 11.8% in the group (P = 0.004) (Table 3, and Fig. 2C in the Supplementary Appendix). This difference was attributed largely to the preponderance of repeat revascularization events by 1 year in the group, as compared with the group, with repeat events in 12.6% and 4.8% of patients in the two groups, respectively (hazard ratio, 2.74; 95% CI, 1.91 to 3.89; P<0.001) (Fig. 2D in the Supplementary Appendix). Prespecified Subgroup Analyses The greater benefit of versus was consistent across all prespecified subgroups (Fig. 2). The analysis according to the category of SYTAX score showed no significant subgroup interaction (P = 0.58). At 5 years, the absolute difference in the rate of the primary outcome in the group, as compared with the group, was similar in the three SYTAX subgroups (6 percentage points for a low SYTAX score, 10 percentage points for an intermediate score, and 8 percentage points for a high score). The hazard ratios for the group, as compared with the group, according to SYTAX subgroup were 1.14, 1.46, and 1.46, respectively. Similarly, for the rate of major adverse cardiovascular and cerebrovascular events at 1 year, The ew England Journal of Medicine Downloaded from nejm.org at UIVERSITY F BRITISH CLUMBIA on August 16, For personal use only. o other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved. A Primary utcome o. at Risk B Death o. at Risk Years since Randomization P=0.005 by log-rank test 5-Yr event rate: 26.6% vs. 18.7% tients with myocardial infarction in that group). All the procedural myocardial infarctions in the trial were non Q-wave events. Myocardial infarctions that occurred more than 30 days after the index procedures were reported in 81 of 99 patients (82%) in the group and in 29 of 48 patients (60%) in the group. There were fewer strokes in the group than in the group (P = 0.03) (Table 2, and Fig. 2B in the Supplementary Appendix). The The new england journal of medicine Years since Randomization P=0.049 by log-rank test 5-Yr event rate: 16.3% vs. 10.9% Figure 1. Kaplan Meier Estimates of the Composite Primary utcome and Death Shown are rates of the composite primary outcome of death, myocardial infarction, or stroke (Panel A) and death from any cause (Panel B) truncated at 5 years after randomization. The P value was calculated by means of the log-rank test on the basis of all available follow-up data n engl j med 367;25 nejm.org december 20, year rates were 2.4% in the group and 5.2% in the group. f these strokes, the majority (87%) were ischemic and 13% were hemorrhagic. In the first 30 days after the procedure, 3 patients in the group and 16 in the group had a stroke (Table 3). The excess of strokes in the group occurred in the first 30 days after randomization. An IH Stroke Scale score of more than 4 (severely disabling) at the time of the event was reported in 27% of patients in the group, as compared with 55% of those in the group. A score on the Rankin scale of more than 1 at the time of the stroke was reported in 60% of patients in the group, as compared with 70% in the group. Secondary utcomes Rates of cardiovascular death (63.7% of all deaths) did not differ significantly between the two study groups (P = 0.12 by the log-rank test), nor did rates of major adverse cardiovascular and cerebrovascular events at 30 days (P = 0.68 by the log-rank test). However, at 1 year after the procedure, there was a significant difference in rates of major adverse cardiovascular and cerebrovascular events, with 16.8% in the group versus 11.8% in the group (P = 0.004) (Table 3, and Fig. 2C in the Supplementary Appendix). This difference was attributed largely to the preponderance of repeat revascularization events by 1 year in the group, as compared with the group, with repeat events in 12.6% and 4.8% of patients in the two groups, respectively (hazard ratio, 2.74; 95% CI, 1.91 to 3.89; P<0.001) (Fig. 2D in the Supplementary Appendix). Prespecified Subgroup Analyses The greater benefit of versus was consistent across all prespecified subgroups (Fig. 2). The analysis according to the category of SYTAX score showed no significant subgroup interaction (P = 0.58). At 5 years, the absolute difference in the rate of the primary outcome in the group, as compared with the group, was similar in the three SYTAX subgroups (6 percentage points for a low SYTAX score, 10 percentage points for an intermediate score, and 8 percentage points for a high score). The hazard ratios for the group, as compared with the group, according to SYTAX subgroup were 1.14, 1.46, and 1.46, respectively. Similarly, for the rate of major adverse cardiovascular and cerebrovascular events at 1 year, The ew England Journal of Medicine Downloaded from nejm.org at UIVERSITY F BRITISH CLUMBIA on August 16, For personal use only. o other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved Endothelial dysfunction and restenosis Endothelial dysfunction and restenosis Flow mediated dilation Diabetes LAST LECTURE Death, Myocardial Infarction, or Stroke (%) Death from Any Cause (%) Death, Myocardial Infarction, or Stroke (%) Death from Any Cause (%) Classic Vascular -chronic -systemic Local Vascular -acute -targeted High blood pressure Blood pressure control Atherosclerosis Endothelial Injury Thrombus PTCA Stent Patient burden In-sent restenosis Lipid lowering drugs Platelet/SMC EJM 367:25, 2012 Drug eluting stents

8 Conclusion - In-Stent stenosis Delayed restenosis -DES have a fantastic effect on restenosis and revascularization (decreased need of second procedure). -Impaired reendothelialization -Exam? pascal.bernatchez@ubc.ca