non steroideal antinflammatory drugs & cardiovascular risk · non steroideal antinflammatory...
TRANSCRIPT
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
NSAIDsare widely used since they are indicated in the
treatment of several grades of
acute pain
NSAIDsare widely used since they are indicated in the
treatment of several grades of
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
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
time...should be used at the lowest effective dose for the shortest possible treatment duration
time...should be used at the lowest effective dose for the shortest possible treatment duration
1st week
time...should be used at the lowest effective dose for the shortest possible treatment duration
1st week
2nd week
time...should be used at the lowest effective dose for the shortest possible treatment duration
1st week
2nd week
3nd week
time...should be used at the lowest effective dose for the shortest possible treatment duration
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).
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).
NSAIDs therapeutic and adverse effects
prostanoid biosynthesisprostaglandin, thromboxane A2 and prostacyclin
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).
NSAIDs therapeutic and adverse effects
prostanoid biosynthesisprostaglandin, thromboxane A2 and prostacyclin
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
NSAIDs therapeutic and adverse effects
prostanoid biosynthesisprostaglandin, thromboxane A2 and prostacyclin
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
cytoprotection of the gastric mucosa
normal platelet function
NSAIDs therapeutic and adverse effects
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
cytoprotection of the gastric mucosa
normal platelet function
adverse gastrointestinal effects and impaired platelet function
NSAIDs therapeutic and adverse effects
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 2
induced in the presence of inflammation or cell injury
PGI2 acts as a vasodilator
NSAIDs therapeutic and adverse effects
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 2
induced in the presence of inflammation or cell injury
PGI2 acts as a vasodilator
anti-inflammatory, anti-pyretic and analgesic properties
NSAIDs therapeutic and adverse effects
selectivity COX-1/COX-2
selectivity COX-1/COX-2
COX 2
selectivity COX-1/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).
COX-2
NSAIDs therapeutic and adverse effects
COX-2
coxib
NSAIDs therapeutic and adverse effects
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
NSAIDs therapeutic and adverse effects
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 2
induced in the presence of inflammation or cell injury
PGI2 acts as a vasodilator
anti-inflammatory, anti-pyretic and analgesic properties
NSAIDs therapeutic and adverse effects
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 2
induced in the presence of inflammation or cell injury
PGI2 acts as a vasodilator
anti-inflammatory, anti-pyretic and analgesic properties
prothrombotic state
NSAIDs therapeutic and adverse effects
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
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
daily practice
CV GI
68%
32%
Superior GI Inferior GI
GI bleeding79%
21%
Superior GI Inferior GI
GI perforation
cardiovascular riskNSAIDs &
Agency’s Committee for Medicinal
Products for Human Use
(CHMP)
2005
cardiovascular riskNSAIDs &
Agency’s Committee for Medicinal
Products for Human Use
(CHMP)
2005the benefits of NSAIDs
outweighed the risks
cardiovascular riskNSAIDs &
Agency’s Committee for Medicinal
Products for Human Use
(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
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
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
retrospective, population-based cohort study with case-control analysis
8 852 non-fatal MI
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
retrospective, population-based cohort study with case-control analysis
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
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
retrospective, population-based cohort study with case-control analysis
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
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.
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
retrospective, population-based cohort study with case-control analysis
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
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
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
retrospective, population-based cohort study with case-control analysis
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
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
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
retrospective, population-based cohort study with case-control analysis
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
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
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
healthy individuals
hospital admission or use of co-medication
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
healthy individuals
hospital admission or use of co-medication
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
healthy individuals
hospital admission or use of co-medication
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
healthy individuals
hospital admission or use of co-medication
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
CHMP started a new review in October 2011
CHMP started a new review in October 2011
Naproxen and Ibuprofenthe current treatment advice adequately reflects the knowledge
regarding the safety and efficacy of these medicines
CHMP started a new review in October 2011
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
CHMP started a new review in October 2011
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$$
0"
1"
2"
3"
4"
5"
6"
7"
8"
9"
2002" 2003" 2004" 2005" 2006" 2007" 2008" 2009" 2010"
Consum
o'DDD/1000'ab
/die'
Consumo'DDD/1000'ab'die10'
Nimesulide" Ketoprofene" Ibuprofene" Diclofenac"
Nimesulide)
Diclofenac)
Ketoprofene)
Ibuprofene)
2011OsMed
20#
25#
30#
35#
40#
45#
50#
55#
60#
65#
70#
2002# 2003# 2004# 2005# 2006# 2007# 2008# 2009# 2010# 2011#
Consum
o#DDD/1000#ab
/die#
Consumo#DDD/1000#ab/die#–#An;acidi#e#An;ulcera10#
Variazione#annua#media#200242007##+11,1%#
Variazione#annua#media#200742010#+14,4%#
Dal#2007,#la#variazione#annua#media#del#consumo#di#
an;acidi#ed#an;ulcera#ha#subito#un'accelerazione#di#
+3,3#pun;#
FANS#
Da#$OsMed$$
0"
1"
2"
3"
4"
5"
6"
7"
8"
9"
2002" 2003" 2004" 2005" 2006" 2007" 2008" 2009" 2010"
Consum
o'DDD/1000'ab
/die'
Consumo'DDD/1000'ab'die10'
Nimesulide" Ketoprofene" Ibuprofene" Diclofenac"
Nimesulide)
Diclofenac)
Ketoprofene)
Ibuprofene)
2011OsMed
20#
25#
30#
35#
40#
45#
50#
55#
60#
65#
70#
2002# 2003# 2004# 2005# 2006# 2007# 2008# 2009# 2010# 2011#
Consum
o#DDD/1000#ab
/die#
Consumo#DDD/1000#ab/die#–#An;acidi#e#An;ulcera10#
Variazione#annua#media#200242007##+11,1%#
Variazione#annua#media#200742010#+14,4%#
Dal#2007,#la#variazione#annua#media#del#consumo#di#
an;acidi#ed#an;ulcera#ha#subito#un'accelerazione#di#
+3,3#pun;#
FANS#
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
Mechanism of cardiovascular increased risk of NSAIDs
25%secondary
incidence of MI& Stroke
95%TXA2
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).
Mechanism of cardiovascular increased risk of NSAIDs
nNSAIDs & coxib
PGI2
COX-2
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).
Mechanism of cardiovascular increased risk of NSAIDs
nNSAIDs & coxib
PGI2
COX-2
increased platelet reactivity
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).
Mechanism of cardiovascular increased risk of NSAIDs
nNSAIDs & coxib
PGI2
COX-2
increased platelet reactivity
95%TXA2
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).
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
Mechanism of cardiovascular increased risk of NSAIDs
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
Mechanism of cardiovascular increased risk of NSAIDs
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
Diclofenac dose &CV risk
Mechanism of cardiovascular increased risk of NSAIDs
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
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
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
“fragile” patient
GI CV H R
“fragile” patient
GI CV H R
“fragile” patient
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
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)
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)
Less use of NSAIDs with the highest GI toxicity (ketorolac, piroxicam, and ketoprofen)
CV
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
time...should be used at the lowest effective dose for the shortest possible treatment duration
1st week
2nd week
3nd week