Stents are not enough? -and neither are oral antirestenotics Dr Anthony Mathur London Chest Hospital...

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




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


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


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


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


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


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


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


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


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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Stents are not enough? -and neither are oral antirestenotics Dr Anthony Mathur London Chest Hospital...

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