Presenter : Dr. Shantibhushan K Kamble, PG Guide: Dr. S. B. Patel

Drug Eluting Stents (Des)

Introduction• Cardiovascular diseases cause more than 15 million deaths in the world

each year. (WHO; Geneva).

• They account for 50% of all deaths in several developed countries.

• Healthcare costs (estimated at $50–150 billion per year)

• Newer techniques like per cutaneous interventions(PCI) by using stent

increases survival rate and decreases morbidity.

• Advantage: Requires only a short (1-day) hospitalization,

greatly decrease recovery time and expense compared to coronary bypass surgery.

• lower elective mortality rate than bypass surgery (0.4–1.0%, compared to a rate of 1–3

Historical Account ….• 3000 B.C. — Egyptians perform bladder

catheterizations using metal pipes.

• 400 B.C. — Catheters prepared from hollow

reeds and pipes are used in cadavers.

• 1711 — Hales conducts the first cardiac

catheterization of a horse using brass pipes, a

glass tube and the trachea of a goose.

• 1844 — French physiologist Bernard coins the

term "cardiac catheterization" .

• 2004 — Boston Scientific gets its Taxus drug-

eluting stent approved.

Metallic stents

• First introduced in the U.S. in 1994

• These devices differ from each other with respect to :

i) Composition (e.g., stainless steel, cobalt chromium alloy, or nickel chromium alloy),

ii) Architectural design, and

iii) Delivery system (i.e, the balloon catheter that delivers the stent).

Metallic stents

Bare-metal stents provide structural support the

artery after angioplasty.

Bare-metal stents help to prevent the artery from

re-narrowing.

However, about 25% of the time, the arteries

may become blocked up again after placement

of a bare-metal stent

Drug releasing stents

Drug releasing stents are coated with an anti-proliferative drug, which allows drug elution into the coronary wall for weeks after stent implantation.

Studies have shown that they are better than bare metal stents as they reduce the incidence of re-stenosis and overall cardiac adverse events.

Drug releasing stents

A drug-coated stent is a bare-metal stent with a special

drug coating.

It also support the artery to kept open after angioplasty.

In addition, the stent releases a drug over time to further

reduce the chance of re-blockage.

Arteries commonly become blocked up again about 7%

of the time with drug-coated stents compared to about

25% for bare-metal stents

Types of Stent

Parts of DES

• Parts of DES

– Stent Platform– Coating– Drug

Indications of using Stents

Drug-eluting stents (DES) are generally superior to bare-metal stents as regards Major Adverse Cardiac Events

(MACE, generally defined as death, myocardial infarction, or the need for a repeat revascularization procedure.)

Stents are indicated to improve the diameter of the coronary artery lumen, when narrowing causes ischemia (to the muscle supplied by that artery)

What Are the Risks of Coronary Stenting

• The risk of complications is higher in:

People aged 75 and older

People who have kidney disease or diabetes

Women

People who have poor pumping function in

their hearts

People who have extensive heart disease

and blockages

Risks Bleeding from the blood vessel where the catheter was

placed.

Damage to blood vessels from the catheter.

An allergic reaction to the dye given during the angioplasty.

An arrhythmia (irregular heartbeat).

Damage to the kidneys caused by the dye used.

Heart attack (3–5 percent of people).

Stroke (less than 1 percent of people).

Complications From Stents

• Restenosis

– There is a chance that the artery will become narrowed or blocked again in time, often within 6 months of angioplasty

Complications From Stents

• Blood Clots

Taking medicine as prescribed by your

doctor can lower the risk of blood clots.

People with medicine Coated stents are

usually advised to take an anti clotting drug,

such as clopidogrel and aspirin, for months

to years to lower the risk of blood clots.

Complication from stentPathopysiology of stent thrombosis

Types Of DrugAnti-Neoplastics Anti-Proliferative Migration

Inhibitors  

Enhanced Healing Factors

Sirolimus Taxol (paclitaxel) Batimistat BCP671

Tacrolimus Actinomycin Prolyl Hydrosylase Inhibitors

VEGF

Everolimus Methotraxate Halofunginone Estradiols

Leflunomide Angiopeptin C-preteinase Inhibitors

NO Donor Compounds

M-Prednisolone Vincristine Probucol EPC antibodies

Dexamethasone Mitomycine    

Cyclosporine Statins    

Mycophenolic Acid C MYC antisense    

Mizoribine Abbott ABT-578    

G0

Resting

Cell Cycle Inhibition

Celldivision

Cell cycle

G1 G2

M

S

XPaclitaxel

SirolimusEverolimusABT-578 X

First Generation Stent

• Sirolimus eluting stent

• Paclitaxel eluting stent

Sirolimus The first Approved DES in Europe (2002).

After a larger pivotal trial, the device received FDA approval

and was released in the U.S. in 2003.

It is an immunosuppresant drug , that inhibits the cytokine

stimulated proliferation of T cells.

MOA:

Binds to FK-binding protein-12(FKBP-12)

FKBP-12 binds to specific cell cycle regulatory protein , the

mammalian target of rapamycin (mTOR) kinase

mTOR inhibition prevents cell cycle progression from G1 to S.

sirolimus• Sirolimus is released from the CYPHER stent

• It is dependent upon concentration of drug both inside and

outside the polymer matrix.

• Approximately 50 percent of the total drug is eliminated within

the first 10 days of implantation.

• The drug is 90 percent removed from the stent by about 60

days

• Completely removed by about 90 days

• Peak drug concentration occurs about 4 hours

sirolimus• Indications : In pt with symptomatic ischemic disease due lesion of length <

30 mm in native coronary arteries with reference diameter of >2.5 to < 3.5 mm

• Contraindications: Hypersensitivity to sirolimus Hypersensitivity to polymer

• ADRs’: Arrhythmias Myocardial infarction Pesudoanuerysm Vessel spasm

Paclitaxel• Paclitaxel-eluting stents led to FDA approval of the Taxus stent

in 2004.

• Paciltaxel is in the antineoplastic family of compounds

• Mechanism of Action:

Paciltaxel binds to microtubules in dividing cells and causes

them to assemble, thereby preventing mitosis.

• Indications:

For improving luminar diameter for the treatment of de novo

lesion in native coronary arteries > 2.5 to < 4mm in diameter in

lesion < 28 mm in length.

Paclitaxel

• Contraindications:

Allergy Not on antiplatelets & anticoagulants Infection at the site of access Irregular heart beat Total occlusion of vessels

• ADR’s:

Abnormal liver values Anemia GI disturbances Loss of hair Muscle pain

Why need 2nd generation DES

• Further reduce in restenosis.• To prevent inhibition of endothelial cells.• Reduction of risk of stent thrombosis.

• Second generation stentZotarolimus eluting stent Everolimus eluting stent

Zotarolimus

Zotarolimus is an immunosuppressant

MOA :

• Binds to FKBP 12,leading to the formation of a

trimetric complex with the protein kinase mTOR

• Inhibition of mTOR activity

• Inhibition of cell cycle progression from the GI to

the S phase.

Indications:

In atherosclerosis to the degree that it has caused

their coronary arteries to narrow.

Zotarolimus Contraindications:

• Allergic to Zotarolimus or the metal or polymer coating that is in

the stent.

• Cannot take blood thinners or aspirin

• Those who have an arterial blockage that is so severe that the

catheter balloon cannot be inflated for placing the stent.

ADRs’

• Although actual side effects are not completely known

• S/E on IV rash, abdominal pain, infection, headache, dry skin,

hematuria, diarrhea, anemia and application site reaction

EverolimusIt is a novel semisynthetic Macrolide immunosuppresant Synthesized by chemical modification of rapamycin (sirolimus )

MOA:

Inhibition of mTOR appears to be the mechanism by which everolimus inhibits cell proliferation.

Indications:

Pt with symptomatic heart disease due to denovo coronary artery lesions ( length ≤ 28mm) with reference vessel diameter of 2.25 mm to 4.25mm.

.

Everolimus• Contraindications :

Pt who can not receive antiplatelates Pt with lesion that prevent complete angioplasty balloon

inflation or proper placement of stent. With hypersensitivity to everolimus related compounds

• ADR’s:

Abrupt closure Allergy & Hypersensitivity to contrast agent or cobalt. Bleeding complications MI

How successful is Angioplasty and stenting?

• Angioplasty/ stenting is successful in treating the narrowing/blockage of the artery in the vast majority of patients (over 70%).

• In the small number of patients in whom the procedure is unsuccessful, a surgical bypass operation may be offered as an alternative.

Comparative Studies SES PES P value

Major adverse cardiac events

6.2 percent 10.8percent 0.009

MI 2.8percent 3.5 percent 0.49

Angiographic restenosis 6.6 percent 11.7 percent 0.02

Target-lesion revascularization

4.8percent 8.3percent 0.03

Endeavor III Study

• At 9 months follow up target rate

revascularization rate was 9.8 % in

zotarolimus eluting stent compared to

3.5% (p-0.04) in sirolimus eluting stent .

• However at 24 months both showed same

results.

Spirit III Trial

At 12 mths Everolimus-eluting stent

paclitaxel eluting stent (taxus)

P value

Major adverse cardiac event

5.8% 9.9% <0.01

Target vessel revascularization

3.3% 5.6% <0.05

Life after stenting• Going Home

Most people go home 1 to 2 days after the procedure.

Instructions from your doctor

• Medications Medicine to prevent blood clots from forming.

e.g..Aspirin and Clopidogrel

Taking medicine as directed is very important.

If a stent was inserted, the medicine reduces the risk that blood clots will

form in the stent.

Blood clots in the stent can block blood flow and cause a heart attack.

• Recovery & RecuperationMost people recover from angioplasty and return to work about one week

after being sent home

• Lifestyle Changes Making healthy lifestyle changes can help treat CAD and maintain the good

results from angioplasty Quit smoking if you smoke. Be physically active.

Lose weight if you're overweight or obese. Reduce stress. Take medicines as your doctor directs to lower high blood pressure or

high blood cholesterol.

Life after stenting

Future prospective

• Possible upcoming drug in future

– Many research and development activities are under way.

Dexamethasone

Estradiol

Pimecrolimus

Cobalt chrome alloy VS stainless steel

• More Strong.

• More radio-opaque

• Struts can be thinner which seems to

reduce the degree of restenosis.

• less nickel than 316L stainless steel and

so may cause less allergy.

Bioabsorbable stents

• Since stent itself is foreign body, so

prothrombogenic.

• Igaki-Tamai stent- from poly L lactic polymer

• 25 pts have implanted it , with target lesion

revascularization rate of 6.7% at 6 moths.

• BVS STENT - Release everolimus from

poly L lactic polymer .

DES Producing Companies

Johnson & Johnson / sirolimus (CYPHER)

Medtronic / zotarolimus (ENDEAVOR)

Abbot / Everolimus ( XIENCE )

Boston Scientific ( TAXUS)

Biosensors Int. (BIOMATRIX)

Cost of stent

• Sirolimus Stent approximately 80,000-

100,000.

• Supralimus Stent approximately 60,000.

• Bare metal Stent- 20,000 - 40,000.

In Our Hospital

• In our hospital and in most of the hospitals

we use only drug eluting stents

• Sirolimus is used always

• Occasionally Supralimus

• Rarely Bare metal stents are used

summ• Cardiovascular diseases are main cause of premature

mortality and morbidity in the world• Many treatments are available for T/t of cardiac

disease like medications , PCI, change in the dietary habits

• The drug eluting stents are promising one ,which prevents or decrease this mortality and morbidity due CVDs.

• Many trial shows that Sirolimus eluting stents are best and commonly used world wide.

• In case of Failure of DES alternatives are available in forms of coronary artery bypass grafting.

Thank you !