Non Steroideal Antinflammatory Drugs & Cardiovascular Risk · Non Steroideal Antinflammatory Drugs...

Non Steroideal Antinflammatory Drugs

& Cardiovascular Risk

Andrea FanelliU.O. Anestesia e Medicina Perioperatoria

Istituti Ospitalieri di Cremona

NSAIDs

NSAIDsare widely used since they are indicated in the

treatment of several grades of



acute pain



acute pain

...and inflammation

aceclofenac; acemetacina; acido mefenamico; acido tiaprofenico;

amtolmetina guacile; celecoxib; cinnoxicam; dexibuprofene;

diclofenac; etoricoxib; fentiazac; flurbiprofene; furprofene;

ibuprofene; indometacina; ketoprofene; Lornoxicam; meloxicam;

nabumetone; naprossene; nimesulide: oxaprozina; piroxicam;

proglumetacina; sulindac; tenoxicam...

NOTAArtropatie su base connettivitica

Osteoartrosi in fase algica o infiammatoria

Dolore neoplastico

Attacco acuto di gotta SSN

time...should be used at the lowest effective dose for the shortest possible treatment duration

arthritic conditions

rheumatoid arthritis osteoarthritis

ankylosing spondylitis acute gout

acute musculo-skeletal disorders

periarthritis tendinitis

tenosynovitis bursitis

painful conditions resulting from trauma

fracture, low back pain, sprains, strains,

dislocations, orthopaedic, dental and

other minor surgery


1st week


1st week

2nd week


1st week

2nd week

3nd week


1st week

2nd week

3nd weekthink t

o change

GICVRHSA side effectstime

GI CV R H S A

side effectstime

GI CV R H S A

side effectstime

mechanisms of actionNSAIDs

NSAIDs therapeutic and adverse effects

prostanoid biosynthesisprostaglandin, thromboxane A2 and prostacyclin

Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in health and disease. J. Lipid Res. 50, S423–S428 (2009).



inflammatory reaction - resolutionerosion of cartilage & juxtaarticular bone

GI cytoprotection & ulcerationangiogenesis & cancer

hemostasis & thrombosisrenal hemodynamics & progression of kidney disease

atheroprotection & progression of atherosclerosis

Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in health and disease. J. Lipid Res. 50, S423–S428 (2009).

Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL.COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13926-31.

COX 1

COX 2

COX 3




COX 1

cytoprotection of the gastric mucosa

normal platelet function



COX 1

cytoprotection of the gastric mucosa

normal platelet function

adverse gastrointestinal effects and impaired platelet function



COX 2

induced in the presence of inflammation or cell injury

PGI2 acts as a vasodilator



COX 2



anti-inflammatory, anti-pyretic and analgesic properties


selectivity COX-1/COX-2


COX 2


COX 2

Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. Jun 22;96(13):7563-8 (1999).

http://www.ncbi.nlm.nih.gov/pubmed/10377455




COX-2


COX-2

coxib


COX-2

coxibClark D.W.J., Layton D., Shakir S.A.W. Do some inhibitors of COX-2 increase the risk of thromboembolic events? Linking pharmacology with pharmacoepidemiology. Drug Saf. (2004) 27 427–456.

Agency’s Committee for Medicinal

Products for Human Use

(CHMP)

2005



COX 2






COX 2




prothrombotic state


On September 30, 2004, Merck withdrew rofecoxib from the market

US$2.5 billion

On September 30, 2004, Merck withdrew rofecoxib from the market

US$2.5 billion

an old story about the peer review process

20002005

A medical Madoff

Scott Reuben SAGA

A medical Madoff

Scott Reuben SAGA

...at least 21 of Reuben's papers were pure fiction

http://www.anesthesiologynews.com/index.asp?section_id=3&show=dept&ses=ogst&issue_id=494&article_id=12634


A medical Madoff

Scott Reuben SAGA

...at least 21 of Reuben's papers were pure fiction

Vioxx......CelebrexNeurontin...

...Lyrica



What do we have?

coxib

celecoxibetoricoxib

What do we have?

coxib

celecoxibetoricoxib

Insufficienza cardiaca congestizia (NYHA II-IV)

Cardiopatia ischemica, arteriopatia periferica e/o

vasculopatia cerebrale accertate.

What do we have?

coxib

etoricoxib

What do we have?

coxib

etoricoxib

Pazienti ipertesi in cui la pressione arteriosa è

persistentemente al di sopra di 140/90 mmHg e

non è controllata adeguatamente.

daily practice

CV GI

daily practice

CV GI

68%

32%

Superior GI Inferior GI

GI bleeding79%

21%

Superior GI Inferior GI

GI perforation

cardiovascular riskNSAIDs &



(CHMP)

2005




(CHMP)

2005the benefits of NSAIDs

outweighed the risks




(CHMP)

2005a small increased risk ofthrombotic eventsassociated with non selective NSAIDs could not be excluded

the benefits of NSAIDs

outweighed the risks

MHRA PUBLIC ASSESSMENT REPORTNon-steroidal anti-inflammatory drugs and

cardiovascular risks in the general population. (2010)

Fosbøl et al. Risk of myocardial infarction and death associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009; 85: 190–197

Garcia Rodrìguez et al. Role of dose potency in the prediction of risk of myocardial infarction associated with non-steroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol 2008; 11: 1628–1636





CHMP started a new review in October 2011


retrospective, population-based cohort study with case-control analysis

8 852 non-fatal MI



8 852 non-fatal MI

All NSAIDS may be associated with a small increased risk of MIparticularly when used at high doses, for long-term treatment and in those with a history of CAD



8 852 non-fatal MI


Diclofenac has a thrombotic profile that shows greater similarity to the coxibs

Dose ≥100 mg per day may be associated with an increase in MI risk.



8 852 non-fatal MI


Ibuprofen does not increase the risk of MI at low doses but at high doses a risk similar to that of coxibs has been

observed



8 852 non-fatal MI


Naproxen is associated with a lower risk of MI than ibuprofen and diclofenac and at low doses is not associated with any discernable increase in risk



8 852 non-fatal MI


Naproxen is associated with a lower risk of MI than ibuprofen and diclofenac and at low doses is not associated with any discernable increase in risk

risk does not increase in association with use of NSAIDs for <30 days and that risk falls to baseline values within 3 months of stopping


healthy individuals

hospital admission or use of co-medication


Naproxen and Ibuprofenthe current treatment advice adequately reflects the knowledge

regarding the safety and efficacy of these medicines


Diclofenacthe latest evidence appears to show a consistent but small

increase in the risk of cardiovascular side effects compared with other NSAIDs, similar to the risks of COX-2 inhibitors

Hepatic reactionsnimesulide

Hepatic reactionsnimesulide

2003: maximum daily dose: 100 mg BID for a short a duration as possible Acute Pain

2007: the CHMP concluded that the data did not support a suspension of all marketing authorisations in Europe15

Da#$OsMed$$

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nimesulide

2007

n 8

Diclofenac

low dose Aspirin

Mechanism of cardiovascular increased risk of NSAIDs

25%secondary

incidence of MI& Stroke

Patrignani P, Tacconelli S, Bruno A, Sostres C, Lanas A. Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol. Sep;4(5):605-21 (2011).





low dose Aspirin


25%secondary

incidence of MI& Stroke

95%TXA2







nNSAIDs & coxib

PGI2

COX-2







nNSAIDs & coxib

PGI2

COX-2

increased platelet reactivity







nNSAIDs & coxib

PGI2

COX-2

increased platelet reactivity

95%TXA2








Diclofenac dose &CV risk



Diclofenac dose &CV risk

half-life and type of formulations

25

diclofenac and etoricoxib together account for

approximately one-third of all sales of NSAIDs

McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 2013 Feb;10(2):e1001388. doi: 10.1371/journal.pmed.1001388. Epub 2013 Feb 12.





GI adverse reactionsNSAIDs

the most frequent reactions related to NSAIDs

GI adverse reactionsNSAIDs

OsMed2012

January-September

OsMed2012

January-September

Top 30

OsMed2012

January-September

Top 30

self medication?

...are quite uncommon when compared with other

pharmacological classes

hepatic reactionsNSAIDs

Hussaini S.H., Farrington E.A. Idiosyncratic drug-induced liver injury: an overview. Expert Opin. Drug Saf. 6 673–684 (2007).

efficacy

GICVRHSA

efficacy

GI CV R H S A

efficacy

GI CV R H S A

the benefits of NSAIDs outweighed the risks

“fragile” patient


GI CV H R


GI CV H R

3.3-4.3% 2.2-2.8% 1.1-2.1% 1.1-2.1%

General Rules

General Ruleslowest effective dose for the shortest period of time

General Ruleslowest effective dose for the shortest period of timeavoid corticosteroids, anticoagulants, low-dose aspirin or antiplatelet agents


Use ‘safer’ NSAIDs (coxibs, diclofenac, nimesulide and ibuprofen)


Use ‘safer’ NSAIDs (coxibs, diclofenac, nimesulide and ibuprofen)

Less use of NSAIDs with the highest GI toxicity (ketorolac, piroxicam, and ketoprofen)

CV

avoid coxib and high dose of Diclofenac and Ibuprofen

CV

avoid coxib and high dose of Diclofenac and Ibuprofen

?Aspirin

CV

?Aspirin

CV

?Aspirin

naproxen

CV & GI

NSAIDs


1st week

2nd week

3nd week

Non Steroideal Antinflammatory Drugs & Cardiovascular Risk · Non Steroideal Antinflammatory Drugs...

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