stents are not enough? -and neither are oral antirestenotics dr anthony mathur london chest hospital...
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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
Local interpretation
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
No Overlap
Short Lesion
Large Vessel
Non LAD
No Diabetes
Female
Overall
Odds Ratio + 95%CI
198
231
119
233
184
192
204
153
309
227
171
# events prevented per1,000 patients
Male
Diabetes
LAD
Small Vessel
Long Lesion
Overlap
CYPHER™Stent (%)
Control (%)
4.4 24.2
3.8 26.9
6.7 30.0
3.9 22.3
4.3 23.5
4.6 25.0
6.0 21.2
1.4 32.3
6.1 28.8
2.7 19.8
5.5 17.9
6.0 17.9
2.5 38.0 355
<.0001
<.0001
0.0417
0.0067
<.0001
0.0002
0.0001
0.0002
0.0007
<.0001
0.0005
p-value
<.0001
0.0015 125
New* SIRIUS: Odds Ratio for TLR by Sub-group
*Combined results from E- and C- SIRIUS
TAXUS IV: Sub-AnalysisTLR Across Vessel Size and Lesion
Length
0
10
20
30
<10 10-15 >15 <10 10-15 >15
Control
> 3.0 RVD2.5-3.0 RVD
< 2.5 RVD
Tertile analysis
TLR at 9 months
Percent of patients
TAXUS™ Stent
Lesion Length Lesion Length
Note: Control=Bare metal ExpressTM Stent; Source: TAXUS IV (9 month follow-up) clinical trial
Treatment of ISR
Use Of Localised Intracoronary Beta Radiation In Treatment Of In-Stent Restenosis: The INHIBIT Randomized Controlled Trial
Lancet 2002; 359: 551-557Waksman et al
Role for oral antirestenotics?
Primary therapy
Adjunctive therapy
Failure of therapy
The ideal oral agent
EfficacyAvailabilitySide effectsHigh target tissue levelsTolerable systemic effects
Cost for all PTCA patients? for recalcitrant restenosis?
?
Restenosis Process
Strategies and Drugs
Drug Modes of Action
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 study
Waksman et al, TCT 2003
• Pilot trial of oral rapamycin for recalcitrant restenosis.Brara et al, Circulation. 2003 Apr 8;107(13):1722-1724
vs.
G0
S
G1 G2
M
CELLCELLCYCLECYCLE
RAPAMYCINRAPAMYCIN
X
CELL DIVISION
• Binds to intracellular receptor protein Binds to intracellular receptor protein (FKBP(FKBP1212) in target cells) in target cells
• Elevates p27Elevates p27Kip1Kip1 levels; inhibits levels; inhibits cyclin/cyclin dependent kinase cyclin/cyclin dependent kinase complexescomplexes
• Reduces protein RB phosphorylationReduces protein RB phosphorylation
• Induces cell-cycle arrest in late GInduces cell-cycle arrest in late G1 1
phasephase
Cytostatic not Cytotoxic
Mechanism of action of 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.
RAPAMYCINRAPAMYCIN
Effect of Systemic Rapamycin Delivery in a Effect of Systemic Rapamycin Delivery in a Porcine Coronary Restenosis ModelPorcine Coronary Restenosis Model
Gallo, et. al. - Circulation 1999; 99:2164-2170Gallo, et. al. - Circulation 1999; 99:2164-2170
0
10
20
30
40
50
60
70
Control Rapamycin
HyperplasiaHematomaThrombus
p < 0.0001p < 0.0001
Decreased pRb phosphorylation Decreased pRb phosphorylation and elevated levels of p27 causing and elevated levels of p27 causing cell cycle arrest at Gcell cycle arrest at G1/s1/s
•Rapamycin 3 d pre intervention• IM 0.5 mg/kg load dose• IM 0.25mg/kg 14 days• Analysis at 4 weeks
ORBITORBIT - Study FlowAll TreatedAll Treated
PatientsPatientsn = 60n = 60
All TreatedAll Treated PatientsPatientsn = 60n = 60
Rapamune 2 mgRapamune 2 mg n = 30 n = 30
Rapamune 2 mgRapamune 2 mg n = 30 n = 30
Rapamune 5 mgRapamune 5 mg n = 30 n = 30
Rapamune 5 mgRapamune 5 mg n = 30 n = 30
Angio FU at 6 Months 80%
Clinical FU at 6 Months 93%
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
Angio FU at 6 Months N/A
Clinical FU at 6 Months N/A
MethodsMethods
> 18 years of age > 18 years of age Stable or unstable angina with evidence of ischemiaStable or unstable angina with evidence of ischemia
Treatment of de novo lesions in Treatment of de novo lesions in 2 coronary arteries 2 coronary arteries
Target lesion is 2.5- 4.0 mm in diameter (visual estimate)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 15- 30 mm in length (visual estimate)
Target lesion is > 50% and < 100% (visual estimate)Target lesion is > 50% and < 100% (visual estimate)
At least TIMI 1 coronary flowAt least TIMI 1 coronary flow
Left ventricular ejection fraction (LVEF) > 20%Left ventricular ejection fraction (LVEF) > 20%
The patient is an acceptable candidate for CABG The patient is an acceptable candidate for CABG
Normal baseline CBCNormal baseline CBC
INCLUSION CRITERIAINCLUSION CRITERIA
MethodsMethods
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
Drug Administration and Drug Administration and Pharmacology Pharmacology
N=49 lesionsN=49 lesions
Mean no. of diseased vessels Mean no. of diseased vessels 1.9 1.9 ± ± 0.6 0.6
Mean no. of treated lesions per patient Mean no. of treated lesions per patient 1.6 1.6 ±± 0.5 0.5
Left Main, %Left Main, % 00
RCA, %RCA, % 28.628.6
LAD, %LAD, % 40.840.8
LCX, %LCX, % 30.630.6
Lesion Length, mmLesion Length, mm 19.71 19.71 ±± 9.02 9.02
Reference vessel Diameter, mmReference vessel Diameter, mm 3.00 3.00 ±± 0.4 0.4
ANGIOGRAPHIC CHARACTERISTICS IANGIOGRAPHIC CHARACTERISTICS IN=49 LESIONSN=49 LESIONS
RESULTSRESULTS
Drug Safety Profile 2 mg Drug Safety Profile 2 mg and Adverse Reactionsand Adverse Reactions
Gastrointestinal Symptoms(Diarrhea, Constipation, Bloody Stools, Vomiting)
6 Ranging mild - severe, 2 pt discontinue the drug
Mucocutaneous SymptomsOral
Skin Rash
2
2
Mild – moderate, 1 pt discontinue the drug
Mild – moderate
OtherFever
Gum infection
Headache
Insomnia
1
1
1
1
Mild
Mild
Mild
Mild
Mean duration oftaking the Rapamune 26.7 ±± 7.8 days
Results Results
Death, Death, 00 00
Q-wave MI Q-wave MI 00 00
Non-Q-wave MI Non-Q-wave MI 33 10.7%10.7%
PTCAPTCA 33 6.6%6.6%
CABGCABG 33 6.6%6.6%
TLR TLR 7 7 15.6%15.6%
TVRTVR 77 15.6%15.6%
ALL MACEALL MACE 7 7 25.0% 25.0%
MAJOR CLINICAL EVENTS AT 6 MONTHSMAJOR CLINICAL EVENTS AT 6 MONTHS
Patients n=28*, Lesions n=45 Patients n=28*, Lesions n=45
*One patient lost to follow-up one patient self withdrawn from study
ORBIT 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
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
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
Potential benefits of oral rapamycinTreatment for recalcitrant restenosisTreatment vehicle for patients who
cannot receive stents (ie, vessel too small, bifurcations, clopidogrel allergic)
Reduced cost
Background
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
The objective of this study was to assess the clinical outcome following treatment of patients at exceptionally high risk for restenosis with oral rapamycin.
Study Objective
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
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
Methods
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
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
Dosimetry: 6 mg load followed by 2 mg / day x 30 days
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
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%)
Results: n = 22 patients with > 6 mos FU
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
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
Results: n = 22 patients with > 6 mos FU
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
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%)
Results: n = 22 patients with > 6 mos FUN = 28 lesions
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
Very small patient numbersNo placebo groupNot randomizedNo rapamycin levels obtainedNo systematic angiographic follow-upSuccessful animal trials started systemic rapamycin well before PTCA.Radiation failure patients may be uniquely resistant to cell cycle inhibitors.
Limitations
Oral Rapamycin for RecalcitrantIn-Stent Restenosis
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 proteinRapamycin is relatively insoluble, 90% is sequestered in circulating cellsOral rapamyincin provides tissue levels in the adventitia/media that are probably only a fraction of that achieved with sirolimus stents
Can oral therapy provide adequate tissue levels?
SCRIPPS V: SCripps Rapamycin to Inhibit
Proliferation Post Stenting
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.
Clinical Implications
Non specific agents……
Class of agent Name Rationale In vitro data Animal data Human data RCT?
ET receptor antagonist
Bosentan + + + ND
ACE inhibitors + + ++/-
?increaseY
AT II blockers Valsartan + + + (+) N
Serotonin reuptake inhibitors
sarpogrelate + + ++ve
Small studyY
HerbalSaiko-ka-
ryukotsu-boyei-to- + + -ve N
vitamins C and E + + + -ve Y
antioxidantProbucol/
folic acid+ + + +ve Y
carvidelol carvidelol + + + -ve Y
PDGF R kinase inhibitor
TKI 963 + + + ND
Steroids m/pred, pred + + + +ve if CRP Y
Kinase inhibitors tranilast + + + -ve Y
Ca blockers amlodipine + + ++/-
Meta analysisY
oestrogens + + + -ve N
NO donor molsidomine + + + -ve Y
IIb/IIIa + + + -ve Y
by permission – Smith and Keeble (give us a job please?)
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