& Cardiovascular Risk

Transcription

1 Non Steroideal Antinflammatory Drugs & Cardiovascular Risk Andrea Fanelli U.O. Anestesia e Medicina Perioperatoria Istituti Ospitalieri di Cremona

2 NSAIDs

3 NSAIDsare widely used since they are indicated in the treatment of several grades of

4 NSAIDsare widely used since they are indicated in the treatment of several grades of acute pain

5 NSAIDsare widely used since they are indicated in the treatment of several grades of acute pain...and inflammation

6

7 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... NOTA Artropatie su base connettivitica Osteoartrosi in fase algica o infiammatoria Dolore neoplastico Attacco acuto di gotta SSN

8 time

9 ...should be used at the lowest time 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

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

11 ...should be used at the lowest time effective dose for the shortest possible treatment duration 1st week

12 ...should be used at the lowest time effective dose for the shortest possible treatment duration 1st week 2nd week

13 ...should be used at the lowest time effective dose for the shortest possible treatment duration 1st week 2nd week 3nd week

14 ...should be used at the lowest time effective dose for the shortest possible treatment duration change 1st week weekthink to 2nd week 3nd

15 GI RHSA CV time side effects

16 time side effects GI CV R H S A

17 time side effects GI CV R H S A NSAIDs mechanisms of action

18 Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in health and disease. J. Lipid Res. 50, S423 S428 (2009). therapeutic and adverse effects NSAIDs prostanoid biosynthesis prostaglandin, thromboxane A2 and prostacyclin

19 Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in health and disease. J. Lipid Res. 50, S423 S428 (2009). therapeutic and adverse effects NSAIDs prostanoid biosynthesis prostaglandin, thromboxane A2 and prostacyclin

20 Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in health and disease. J. Lipid Res. 50, S423 S428 (2009). therapeutic and adverse effects NSAIDs prostanoid biosynthesis prostaglandin, thromboxane A2 and prostacyclin inflammatory reaction - resolution erosion of cartilage & juxtaarticular bone GI cytoprotection & ulceration angiogenesis & cancer hemostasis & thrombosis renal hemodynamics & progression of kidney disease atheroprotection & progression of atherosclerosis

21 therapeutic and adverse effects NSAIDs prostanoid biosynthesis prostaglandin, thromboxane A2 and prostacyclin

22 therapeutic and adverse effects NSAIDs prostanoid biosynthesis prostaglandin, thromboxane A2 and prostacyclin COX 1 COX 2 COX 3 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 Oct 15;99(21):

23 therapeutic and adverse effects NSAIDs COX 1 cytoprotection of the gastric mucosa normal platelet function 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 Oct 15;99(21):

24 therapeutic and adverse effects NSAIDs adverse gastrointestinal effects and impaired platelet function COX 1 cytoprotection of the gastric mucosa normal platelet function 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 Oct 15;99(21):

25 therapeutic and adverse effects NSAIDs COX 2 induced in the presence of inflammation or cell injury PGI2 acts as a vasodilator 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 Oct 15;99(21):

26 therapeutic and adverse effects NSAIDs anti-inflammatory, anti-pyretic and analgesic properties COX 2 induced in the presence of inflammation or cell injury PGI2 acts as a vasodilator 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 Oct 15;99(21):

27 selectivity COX-1/COX-2

28 selectivity COX-1/COX-2 COX 2

29 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): (1999).

30 therapeutic and adverse effects NSAIDs COX-2

31 therapeutic and adverse effects NSAIDs COX-2 coxib

32 therapeutic and adverse effects NSAIDs Agency s Committee for Medicinal Products for Human Use COX-2 (CHMP) 2005 coxib Clark 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)

33 therapeutic and adverse effects NSAIDs anti-inflammatory, anti-pyretic and analgesic properties COX 2 induced in the presence of inflammation or cell injury PGI2 acts as a vasodilator 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 Oct 15;99(21):

34 therapeutic and adverse effects NSAIDs anti-inflammatory, anti-pyretic and analgesic properties COX 2 induced in the presence of inflammation or cell injury prothrombotic state PGI2 acts as a vasodilator 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 Oct 15;99(21):

35 On September 30, 2004, Merck withdrew rofecoxib from the market US$2.5 billion

36 On September 30, 2004, Merck withdrew rofecoxib from the market US$2.5 billion an old story about the peer review process

37 A medical Madoff Scott Reuben SAGA

38 A medical Madoff Scott Reuben SAGA...at least 21 of Reuben's papers were pure fiction

39 A medical Madoff Scott Reuben SAGA...at least 21 of Reuben's papers were pure fiction Vioxx......Celebrex Neurontin......Lyrica

40 What do we have? celecoxib etoricoxib coxib

41 What do we have? celecoxib etoricoxib Insufficienza cardiaca congestizia (NYHA II-IV) Cardiopatia ischemica, arteriopatia periferica e/o vasculopatia cerebrale accertate. coxib

42 What do we have? etoricoxib coxib

43 What do we have? etoricoxib Pazienti ipertesi in cui la pressione arteriosa è persistentemente al di sopra di 140/90 mmhg e non è controllata adeguatamente. coxib

44 daily practice CV GI

45 daily practice CV GI

46 daily practice CV GI 32% 21% GI bleeding 68% GI perforation 79% Superior GI Inferior GI Superior GI Inferior GI

47 NSAIDs & cardiovascular risk Agency s Committee for Medicinal Products for Human Use (CHMP) 2005

48 NSAIDs & cardiovascular risk Agency s Committee for Medicinal Products for Human Use (CHMP) 2005 the benefits of NSAIDs outweighed the risks

49 NSAIDs & cardiovascular risk Agency s Committee for Medicinal Products for Human Use (CHMP) 2005 the benefits of NSAIDs outweighed the risks a small increased risk of thrombotic events associated with non selective NSAIDs could not be excluded

50 MHRA PUBLIC ASSESSMENT REPORT Non-steroidal anti-inflammatory drugs and cardiovascular risks in the general population. (2010) 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: Fosbøl et al. Risk of myocardial infarction and death associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009; 85:

51 MHRA PUBLIC ASSESSMENT REPORT Non-steroidal anti-inflammatory drugs and cardiovascular risks in the general population. (2010) 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: Fosbøl et al. Risk of myocardial infarction and death associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009; 85: CHMP started a new review in October 2011

52 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: retrospective, population-based cohort study with case-control analysis non-fatal MI

53 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: retrospective, population-based cohort study with case-control analysis non-fatal MI All NSAIDS may be associated with a small increased risk of MI particularly when used at high doses, for long-term treatment and in those with a history of CAD

54 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: retrospective, population-based cohort study with case-control analysis non-fatal MI All NSAIDS may be associated with a small increased risk of MI particularly 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.

55 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: retrospective, population-based cohort study with case-control analysis non-fatal MI All NSAIDS may be associated with a small increased risk of MI particularly 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

56 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: retrospective, population-based cohort study with case-control analysis non-fatal MI All NSAIDS may be associated with a small increased risk of MI particularly 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

57 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: retrospective, population-based cohort study with case-control analysis non-fatal MI All NSAIDS may be associated with a small increased risk of MI particularly 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

58 Fosbøl et al. Risk of myocardial infarction and death associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009; 85: healthy individuals hospital admission or use of co-medication

59 Fosbøl et al. Risk of myocardial infarction and death associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009; 85: healthy individuals hospital admission or use of co-medication

60 Fosbøl et al. Risk of myocardial infarction and death associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009; 85: healthy individuals hospital admission or use of co-medication

61 Fosbøl et al. Risk of myocardial infarction and death associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009; 85: healthy individuals hospital admission or use of co-medication

62 MHRA PUBLIC ASSESSMENT REPORT Non-steroidal anti-inflammatory drugs and cardiovascular risks in the general population. (2010) 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: Fosbøl et al. Risk of myocardial infarction and death associated with the use of non-steroidal antiinflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009; 85: CHMP started a new review in October 2011

63 CHMP started a new review in October 2011

64 CHMP started a new review in October 2011 Naproxen and Ibuprofen the current treatment advice adequately reflects the knowledge regarding the safety and efficacy of these medicines

65 CHMP started a new review in October 2011 Diclofenac the 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

66 CHMP started a new review in October 2011 Diclofenac the 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

67 Hepatic reactions nimesulide

68 Hepatic reactions nimesulide 2003: maximum daily dose: 100 mg BID for a short a duration as possible Acute Pain : the CHMP concluded that the data did not support a suspension of all marketing authorisations in Europe

69 9" Nimesulide) Consumo'DDD/1000'ab'die 10' 8" OsMed 2011 Consumo'DDD/1000'ab/die' 7" 6" 5" 4" 3" 2" Diclofenac) Ketoprofene) 1" Ibuprofene) 0" 2002" 2003" 2004" 2005" 2006" 2007" 2008" 2009" 2010" Consumo#DDD/1000#ab/die# #An;acidi#e#An;ulcera 10# 70# Nimesulide" Ketoprofene" Ibuprofene" Diclofenac" Da#$OsMed$$ Consumo#DDD/1000#ab/die# 65# 60# 55# 50# 45# 40# 35# 30# Variazione# annua#media# ## +11,1%# Variazione# annua#media# # +14,4%# Dal#2007,#la#variazione#annua# media#del#consumo#di# an;acidi#ed#an;ulcera#ha# subito#un'accelerazione#di# +3,3#pun;# 25# 20# FANS# 2002# 2003# 2004# 2005# 2006# 2007# 2008# 2009# 2010# 2011#

70 9" Nimesulide) Consumo'DDD/1000'ab'die 10' 8" OsMed 2011 Consumo'DDD/1000'ab/die' 7" 6" 5" 4" 3" 2" Diclofenac) Ketoprofene) 1" Ibuprofene) 0" 2002" 2003" 2004" 2005" 2006" 2007" 2008" 2009" 2010" Consumo#DDD/1000#ab/die# #An;acidi#e#An;ulcera 10# 70# Nimesulide" Ketoprofene" Ibuprofene" Diclofenac" Da#$OsMed$$ Consumo#DDD/1000#ab/die# 65# 60# 55# 50# 45# 40# 35# 30# Variazione# annua#media# ## +11,1%# Variazione# annua#media# # +14,4%# Dal#2007,#la#variazione#annua# media#del#consumo#di# an;acidi#ed#an;ulcera#ha# subito#un'accelerazione#di# +3,3#pun;# 2007 nimesulide 25# 20# FANS# 2002# 2003# 2004# 2005# 2006# 2007# 2008# 2009# 2010# 2011#

71 n 8 Diclofenac

72 low dose Aspirin 25% secondary incidence of MI & Stroke Mechanism of cardiovascular increased risk of NSAIDs 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): (2011).

73 low dose Aspirin 95% TXA2 25% secondary incidence of MI & Stroke Mechanism of cardiovascular increased risk of NSAIDs 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): (2011).

74 nnsaids & coxib PGI2 COX-2 Mechanism of cardiovascular increased risk of NSAIDs 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): (2011).

75 nnsaids & coxib increased platelet reactivity PGI2 COX-2 Mechanism of cardiovascular increased risk of NSAIDs 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): (2011).

76 nnsaids & coxib 95% TXA2 increased platelet reactivity PGI2 COX-2 Mechanism of cardiovascular increased risk of NSAIDs 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): (2011).

77 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:

78 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:

79 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:

80 Diclofenac dose &CV risk 25 half-life and type of formulations 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:

81 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 Feb;10(2):e doi: / journal.pmed Epub 2013 Feb 12.

82 NSAIDs GI adverse reactions the most frequent reactions related to NSAIDs

83 NSAIDs GI adverse reactions

84 OsMed 2012 January-September

85 OsMed 2012 January-September

86 OsMed 2012 January-September

87 OsMed 2012 January-September Top 30

88 OsMed 2012 January-September Top 30 self medication?

89 NSAIDs hepatic reactions...are quite uncommon when compared with other pharmacological classes Hussaini S.H., Farrington E.A. Idiosyncratic drug-induced liver injury: an overview. Expert Opin. Drug Saf (2007).

90 GI RHSA CV efficacy

91 GI CV R H S A efficacy

92 GI CV R H S A efficacy the benefits of NSAIDs outweighed the risks

93 fragile patient

94 fragile patient GI CV H R

95 fragile patient GI CV H R

96 fragile patient GI CV H R % % % %

97

98 General Rules

99 General Rules lowest effective dose for the shortest period of time

100 General Rules lowest effective dose for the shortest period of time avoid corticosteroids, anticoagulants, low-dose aspirin or antiplatelet agents

101 General Rules lowest effective dose for the shortest period of time avoid corticosteroids, anticoagulants, low-dose aspirin or antiplatelet agents Use safer NSAIDs (coxibs, diclofenac, nimesulide and ibuprofen)

102 General Rules lowest effective dose for the shortest period of time avoid 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)

103 CV

104 CV avoid coxib and high dose of Diclofenac and Ibuprofen

105 CV avoid coxib and high dose of Diclofenac and Ibuprofen? Aspirin

106 CV? Aspirin

107 CV? Aspirin naproxen

108 CV & GI NSAIDs

109 ...should be used at the lowest time effective dose for the shortest possible treatment duration 1st week 2nd week 3nd week