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NSAIDs and Cardiovascular risk– Danish Nationwide Cohort Studies
Gunnar Gislason MD, PhD, FESC, FACC
Professor of Cardiology
Gentofte Hospital, University of Copenhagen
Disclosures
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 2 of 58
• Research Grants• Pfizer, Bristol-Meyers Squibb,
• Advisory activity• Pfizer, AstraZeneca
• Speaker fees• AstraZeneca, Bristol-Meyers Squibb, Pfizer
• Investigator• Bayer, Sanofi-Aventis, Pfizer, Novartis,
• Other• Executive board member - The Danish Institute of Rational
Pharmacotherapy
Denmark
• Northen Europe• Scandinavia• 16,640 square miles
• Population of 5.6 million• Caucasians 90%
• Healthcare system• Goverment run
- Tax financed
• Free of charge- Equal access to everyone
• Education• Literacy rate 99%• Free of charge
• High-level social security system
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 3 of 58
121250-1233
280254-0534
180677-3457
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The Danish Nationwide Registers
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 5 of 58
• The Danish Civil Register• Basic demographic data and vital status
• The Danish National Patient Register• All hospitalizations in Denmark since 1978
• The Danish Register of Medicinal Product Statistics• All claimed prescriptions from Danish pharmacies since 1995
• The Integrated Database for Labour Research• Socioeconomic status, education level, taxed income
• The Danish Causes of Death Register• Immediate and contributing cause of death according
to death certificates
The scope of the problem- NSAID use in Denmark 1997-2005
Fosbøl et al, Pharmacoepidemiol Drug Saf. 2008;17(8):822-33
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The scope of the problem- NSAID use in Denmark 1997-2005
Fosbøl et al, Pharmacoepidemiol Drug Saf. 2008;17(8):822-33
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Clinical Pharmacology & Therapeutics 2009;85(2):190-7
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Selection of the study population
Fosbøl et al, Clin Pharmacol Ther 2009;85(2):190-7
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Selection of the study population
Median age (IQR) 39 (25-51) yearsMales 58%
Fosbøl et al, Clin Pharmacol Ther 2009;85(2):190-7
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Median age (IQR) 43 (26-56) yearsMales 72%
Use of NSAIDs
55.3
29.3
16.8
4 3.1
No NSAID Ibuprofen Diclofenac Naproxen COX-2
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Average duration of NSAID treatment
0 10 20 30
Median duration of treatment (Days)
40
Naproxen
Diclofenac
Ibuprofen
Celecoxib
Rofecoxib 13 (12-27)
Fosbøl et al, Clin Pharmacol Ther 2009;85(2):190-7
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19 (9-33)
14 (14-14)
14 (9-19)
24 (24-31)
Median (IQR)
Death rates stratified by exposure group
No NSAID
Rofecoxib
Celecoxib
Ibuprofen
Diclofenac
Naproxen
De
ath
s p
er
10
00
pe
rso
n-y
ea
rs
60
55
50
45
40
35
30
25
20
15
10
5
0
Fosbøl et al, Clin Pharmacol Ther 2009;85(2):190-7
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Number-Needed-To-Harm (NNH)
No NSAID
Rofecoxib
Celecoxib
Ibuprofen
Diclofenac
Naproxen
De
ath
s p
er
10
00
pe
rso
n-y
ea
rs
15
45
10
5
0
40
35
30
25
20
50
60
55
NNH 24
Fosbøl et al, Clin Pharmacol Ther 2009;85(2):190-7
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NNH104
NNH24
NNH 446 NNH
1,329
NSAIDs and risk of MI or death in healthy individuals – Cox regression analysis
Fosbøl et al, Clin Pharmacol Ther 2009;85(2):190-7
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NSAIDs and risk of MI or death in healthy individuals – Case-Crossover analysis
Fosbøl et al, Clin Pharmacol Ther 2009;85(2):190-7
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Circulation 2006;113:2906-13
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Population characteristics
Gislason et al, Circulation 2006;113:2906-13
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• 58,432 patients with first-time MI 1995-2002• Age ≥ 30 years• Alive at discharge
• Mean age 68 (SD ±12.9) years• 63% males
• NSAID use identified by claimed prescriptions• 21,093 (36.1%) used NSAID after discharge
• Analyses by Cox proportional-hazard models
Gislason et al, Circulation 2006;113:2906-13
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 19 of 58
Average dosages
Gislason et al, Circulation 2006;113:2906-13
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Duration of NSAID exposure
0 100 200 300
Median duration of treatment (Days)
400
Other NSAIDs
Diclofenac
Ibuprofen
Celecoxib
Rofecoxib 39 (14-224)
Gislason et al, Circulation 2006;113:2906-13
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40 (20-181)
37 (10-463)
20 (10-272)
83 (20-461)
Median (IQR)
Death rates stratified by NSAID exposure group
No NSAID
Rofecoxib
Celecoxib
Ibuprofen
Diclofenac
Other NSAIDs
De
ath
s p
er
10
00
pe
rso
n-y
ea
rs
75
50
25
0
100
200
175
150
125
Gislason et al, Circulation 2006;113:2906-13
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Number-Needed-To-Harm (NNH)
No NSAID
Rofecoxib
Celecoxib
Ibuprofen
Diclofenac
Other NSAIDs
De
ath
s p
er
10
00
pe
rso
n-y
ea
rs
25
75
125
175
0
50
100
150
200
NNH 13
Gislason et al, Circulation 2006;113:2906-13
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NNH 24
NNH 14
NNH 45
NNH 143
NSAID use and risk of death after MI
Gislason et al, Circulation 2006;113:2906-13
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NSAID use and risk of Recurrent MI
Gislason et al, Circulation 2006;113:2906-13
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Hazard Ratio
0,50,60,07,08,911,5 2 3
4 5 6 7 8 910
Rofecoxib any use
Rofecoxib <= 25 mg
Rofecoxib > 25 mg
Celecoxib any use
Celecoxib <= 200 mg
Celecoxib > 200 mg
Ibuprofen any use
Ibuprofen <= 1200 mg
Ibuprofen > 1200 mg
Diclofenac any use
Diclofenac < 100 mg
Diclofenac =>100 mg
Other NSAIDs any use
No use
Risk of Death associated NSAID use in patients with MI
15 200,50,60,70,08,91
1,5 2 3 4 5 6 7 8 910
Odds Ratio
Cox regression analysis
Gislason et al, Circulation 2006;113:2906-13
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Case-crossover analysis
Archives of Internal Medicine 2009;169(2):141-9
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Population characteristics
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• 107,092 patients with first-time heart failure admission 1995-2004• Age ≥ 30 years• Alive at discharge
• Mean age 75 (SD ±11.6) years• 52% males
• NSAID use identified by claimed prescriptions• 36,354 (34%) used NSAID after discharge
• Analyses by Cox proportional-hazard models
Gislason et al, Arch Intern Med. 2009;169(2):141-9
Average dosages
Gislason et al, Arch Intern Med. 2009;169(2):141-9
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Average duration of NSAID treatment
0 50 100 150
Median duration of treatment (Days)
200
Other NSAIDs
Naproxen
Diclofenac
Ibuprofen
Celecoxib
Rofecoxib 42 (14-154)
Gislason et al, Arch Intern Med. 2009;169(2):141-9
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60 (20-197)
97 (30-211)
40 (20-108)
64 (25-179)
Median (IQR)
56 (20-150)
Death rates stratified by NSAID exposure group
No NSAID
Rofecoxib
Celecoxib
Ibuprofen
Diclofenac
Naproxen
Other NSAIDs
De
ath
s p
er
10
00
pe
rso
n-y
ea
rs
350
300
250
200
150
100
50
0
Gislason et al, Arch Intern Med. 2009;169(2):141-9
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Number-Needed-To-Harm (NNH)
No NSAID
Rofecoxib
Celecoxib
Ibuprofen
Diclofenac
Naproxen
Other NSAIDs
De
ath
s p
er
10
00
pe
rso
n-y
ea
rs
50
150
250
350
0
100
200
300NNH
Gislason et al, Arch Intern Med. 2009;169(2):141-9
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9 NNH11NNH
14
NNH53
NNH51
NNH43
NSAID use and risk of death
Gislason et al, Arch Intern Med. 2009;169(2):141-9
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NSAID use and risk of acute myocardial infarction
Gislason et al, Arch Intern Med. 2009;169(2):141-9
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NSAID use and risk of readmission for heart failure
Gislason et al, Arch Intern Med. 2009;169(2):141-9
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Haz
ard
Rat
io1,5
2
2,5
1
0,9
0,8
Rofecoxib Celecoxib
Ibuprofen
Haz
ard
Rat
io
1,5
2
2,5
1
0,9
0,8
Diclofenac
Naproxen
Risk group
Low Intermediate High
Haz
ard
Rat
io
1,5
2
2,5
1
0,9
0,8
Other NSAID
Risk group
Low Intermediate High
Gislason et al, Arch Int Med 2009;169:141-9NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 36 of 58
The association between drug use and risk of death according to risk subgroup
The high (>31.4%), intermediate (17.9%-31.4%), and low (<17.9%)mortality risk categories represent tertiles of predicted 1-year mortality risk in a propensity-based analysis
Circulation 2011;123:2226-35
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Duration of NSAID treatment and risk of death/re-MI after Myocardial Infarction
Schjerning Olsen A et al. Circulation. 2011;123:2226-35
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Duration of NSAID treatment and risk of death/re-MI
Hazard Ratio(Horizontal bars indicate 95% CI)
0,9 1,5 21
> 90 days
30-90 days
14-30 days
7-14 days
0-7 days
Schjerning Olsen A et al. Circulation. 2011;123:2226-35
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Duration of NSAID treatment and risk of death/re-MI
Schjerning Olsen A et al. Circulation. 2011;123:2226-35
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 40 of 58
Circulation 2012;126:1955-63
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Olsen A S et al. Circulation. 2012;126:1955-63
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Risk of coronary death or re-MI associated with NSAID treatment according to time passed after first-time MI
0,9 1,5
Hazard Ratio(Horizontal bars indicate
95% CI)
21
1 year
2 years
3 years
4 years
5 years
+6 years
Olsen A S et al. Circulation. 2012;126:1955-63
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Risk of coronary death or re-MI associated with NSAID treatment according to time passed after first-time MI
Olsen A S et al. Circulation. 2012;126:1955-63
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Relation of non-steroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in atrial fibrillation – A nationwide cohort study
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 45 of 58
Morten Lamberts, MD†§; Gregory YH Lip, MD§$; Morten Lock Hansen, MD, PhD†$; Jesper Lindhardsen, MD†; Jonas Bjerring Olesen, MD†; Jakob Raunsø, MD, PhD†, Anne-Marie Schjerning Olsen, MD†; Per KraghAndersen (note), Emil L Fosbøl, MD, PhD†*; Christian Torp-Pedersen, MD, DMSc†$; Gunnar H Gislason, MD,PhD†‡¥$
[ $ Joint senior authors ]
Submitted
Population characteristics
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• 150,900 AF patients included• Mean age 73.2 (SD 12.7) years• 47% female• Mean follow-up 4.3 years
• 53,732 (35.6%) claimed a prescription of NSAID
Outcomes
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• Primary outcome• Serious bleeding
- Hospitalization or death due to bleeding event> Intracranial, Gastrointestinal, Respiratory, Urinary, bleeding
anemia
- Number of Events 17,187 (11.4%)
• Secondary outcomes• Thromboembolism
- Hospitalization or death due to ischemic stroke or systemic arterial thromboembolism
- Number of Events 19,561 (13.0%)
• All-cause Death
NSAID use and risk of bleeding or thromboembolism – stratified by risk group
Lamberts M et al, Submitted
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 48 of 58
NSAID use and risk of bleeding in patients with Atrial Fibrillation
Lamberts M et al, Submitted
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 49 of 58
NSAID use and risk of thromboembolism in patients with Atrial Fibrillation
Lamberts M et al, Submitted
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PLoS ONE 2013;8(1):e54309
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Distribution of specific primary causes of death according to NSAID exposure
Olsen A S et al. PLoS ONE 2013;8(1):e54309
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NSAID use and specific causes of death after Myocardial Infarction
Olsen A S et al. PLoS ONE 2013;8(1):e54309
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Limitations
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• Observational design• Treatment is non-randomized• Causality cannot be firmly established
• Lack of detailed clinical information• Prognostic factors e.g. LVEF, BMI, Blood Pressure,
smoking, lipid levels
• Confounding-by-indication• The precise indication for treatment unknown
• Effect of unmeasured confounders
Strengths
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• Nationwide Study cohort• Eliminates selection bias• Includes all individuals independent of
socioeconomic status, race, gender, affiliation to specific healthcare systems or employment
• Large population increases statistical power• Completeness of data• Robust results
• Different analytical methods and sensitivity analyses
Conclusions
NSAIDS and CV risk Gunnar Gislason MD, PhD, FESC, FACC slide 56 of 58
• NSAIDs are associated with increased risk of cardiovascular adverse outcomes and death• Thromboembolic events• Bleeding risk in patients receiving antithrombotic
therapy
• The risk is increased in presumably healthy individuals and in patients with established cardiovascular disease
• Dose-dependent increase in risk• The risk of NSAIDs increases early after initiation of
treatment• The risk of NSAIDs is persistent over time
Conclusions
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• Individual NSAIDs have different risk profile• COX-2 selective NSAIDs associated with higher risk
- Rofecoxib, Celecoxib
• Naproxen has the most favorable risk profile
• Diclofenac in daily dosages >100 mg has very unfavorable safety profile• Similar risk profile as Rofecoxib (Vioxx®)
- Rofecoxib withdrawn from the market in 2004
• The risk is increased already from start of treatment
• Persistently increased risk during long-term treatment
Clinical Implications
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• Use of NSAIDs should be limited• Especially among high-risk individuals and patients
with established cardiovascular disease• Careful assessment of the balance between risk
and benefit if NSAID treatment cannot be avoided
• Diclofenac and COX-2 selective NSAIDs should be avoided• No additional benefits compared to other NSAIDs
with more favorable risk profile
• Combination of NSAIDs and antithrombotic agents should be avoided due to increased bleeding risk