Authors’ comments – Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data - On absolute increases in risk and persistence of elevated risk
CCBYNCOpen access
Rapid response to:
Research
Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data
Authors’ comments – Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data - On absolute increases in risk and persistence of elevated risk
In the individual patient data (IPD) meta-analysis of NSAIDs in real-world use, the IPD (1) were drawn from the elderly (≥ 65 years) in the RAMQ study and general populations in the Finland (all ages), GPRD (≥ 45 years) and Saskatchewan studies (40-84 years) (Appendix 2 - Table 1).
Odds ratio point estimates of acute myocardial infarction (MI) for current use indicate an associated relative increase in risk of 20% to 50% overall, with possible increases of 75% for ibuprofen and naproxen. (1 ) Absolute increases in risk are not readily available from this IPD meta-analysis pooling a population-based case-control study (Finland) and nested case-control studies (RAMQ, GPRD, Saskatchewan), although they could be calculated for each study. The overall baseline cardiovascular disease risk in this IPD meta-analysis may be inferred from the prevalence of comorbidities for each population (Table 1).
Randomised controlled trials (RCTs) inform on the incidence rate of acute MI with the common available NSAIDs. In the PRECISON trial studying patients with established cardiovascular disease or an increased risk of the development of cardiovascular disease, the overall rate of acute myocardial infarction with celecoxib, ibuprofen, or naproxen was 0.40 (on-treatment population) to 0.44 (intention-to-treat population) per 100 person-years of follow-up. (2) In the Trelle network meta-analysis of RCTs, the rate of acute myocardial infarction with celecoxib, diclofenac, ibuprofen, or naproxen was 0.46 per 100 person-years of follow-up. (3) The denominator, person-years, combines persons and time by summing the periods of time at risk for each of the subjects. (4) Since one person-year could correspond to one person at risk of acute MI observed over one year or to 365 persons observed for one day (or to other scenarios of number of persons at risk and durations of follow-up), an incidence rate may not be the best metric for making clinical decisions.
A more useful approach to managing risk of acute myocardial infarction with NSAIDs might be to personalize counselling and make treatment decisions based on a person’s baseline risk calculated from the Framingham Risk Score, which estimates coronary heart disease risk at 10 years and is widely used in routine practice. Without use of NSAIDs, one could expect that the number of cases of acute myocardial infarction will be fewer than 1 case per year per 100 persons in those at low risk (less than or equal to 10% over 10 years), 1 to 2 cases per year per 100 persons in those at intermediate risk (10-20% over 10 years), and greater than 2 cases per year per 100 persons in those at high risk (>20% over 10 years).
Assuming an increase in the relative risk of acute MI of 20 to 50% across NSAID doses and durations studied in the IPD meta-analysis,1 the number of excess acute myocardial infarctions associated with use of common NSAIDs might range from fewer to 0.2 to 0.5 case per year per 100 persons in those at low coronary risk or < 0.2-0.5% annually (< 2 to 5 cases per 1000 persons per year) up to 0.4 to 1 or more cases per year per 100 persons in those at high coronary risk or > 0.4 to 1% annually (> 4 to 10 cases per 1000 patients per year). Hence the absolute percentage increase of excess MIs due to NSAID exposure is likely to range from 0.2% to 1% annually.
With use of ibuprofen > 1200 mg/day or naproxen > 750 mg/day for one to four weeks, the results of the IPD meta-analysis are compatible with a possible 75% relative increase in risk of acute myocardial infarction. With use for longer than one month, the risk of acute MI did not seem to continue to increase further but risk of acute MI remained constantly elevated with continued use of common NSAIDs. However, in our pooled analysis, follow-up stopped once a patient had experienced a first acute myocardial infarction.
In summary, the meta-analysis of patient-level data suggests that use of common NSAIDs increases a person’s relative risk of acute MI by about 20 to 50% overall and possibly by 75% with high-dose ibuprofen or naproxen used for one to four weeks. Our study does not allow an estimate for the risk of second heart attacks. Depending on the individual baseline heart attack risk, it seems reasonable to conclude that the absolute risk due to use of NSAIDs is on average increased by about 0.5-1% per year. With use for one to seven days, the IPD meta-analysis does not allow determining on which day or at what dose the risk of acute MI starts increasing over and above a person’s baseline level. Other studies are in progress to try elucidating this.
Michèle Bally, BPharm, MSc, PhD
Epidemiologist and researcher, University of Montreal Hospital Research Center (CRCHUM), Montreal, Canada
James M Brophy, MD, FRCP(c), FACC, FCCS, PhD
Professor of Medicine and Epidemiology, McGill University, Montreal, Canada
1. Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ. 2017;357:j1909.
2. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519-29.
3. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.
4. A Dictionary of Epidemiology. Edited by Miquel Porta. Fifth edition. Published in print January 2008 | ISBN: 9780195314496. Published online January 2014. p. 240. http://www.irea.ir/files/site1/pages/dictionary.pdf.
Competing interests:
Author JMB reports serving on the Data Monitoring Committee for the PRECISION trial, which was sponsored by Pfizer, during the conduct of the study
12 May 2017
Michèle Bally
Epidemiologist and researcher
Dr James M Brophy
University of Montreal Hospital Research Center (CRCHUM)
Rapid Response:
Authors’ comments – Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data - On absolute increases in risk and persistence of elevated risk
In the individual patient data (IPD) meta-analysis of NSAIDs in real-world use, the IPD (1) were drawn from the elderly (≥ 65 years) in the RAMQ study and general populations in the Finland (all ages), GPRD (≥ 45 years) and Saskatchewan studies (40-84 years) (Appendix 2 - Table 1).
Odds ratio point estimates of acute myocardial infarction (MI) for current use indicate an associated relative increase in risk of 20% to 50% overall, with possible increases of 75% for ibuprofen and naproxen. (1 ) Absolute increases in risk are not readily available from this IPD meta-analysis pooling a population-based case-control study (Finland) and nested case-control studies (RAMQ, GPRD, Saskatchewan), although they could be calculated for each study. The overall baseline cardiovascular disease risk in this IPD meta-analysis may be inferred from the prevalence of comorbidities for each population (Table 1).
Randomised controlled trials (RCTs) inform on the incidence rate of acute MI with the common available NSAIDs. In the PRECISON trial studying patients with established cardiovascular disease or an increased risk of the development of cardiovascular disease, the overall rate of acute myocardial infarction with celecoxib, ibuprofen, or naproxen was 0.40 (on-treatment population) to 0.44 (intention-to-treat population) per 100 person-years of follow-up. (2) In the Trelle network meta-analysis of RCTs, the rate of acute myocardial infarction with celecoxib, diclofenac, ibuprofen, or naproxen was 0.46 per 100 person-years of follow-up. (3) The denominator, person-years, combines persons and time by summing the periods of time at risk for each of the subjects. (4) Since one person-year could correspond to one person at risk of acute MI observed over one year or to 365 persons observed for one day (or to other scenarios of number of persons at risk and durations of follow-up), an incidence rate may not be the best metric for making clinical decisions.
A more useful approach to managing risk of acute myocardial infarction with NSAIDs might be to personalize counselling and make treatment decisions based on a person’s baseline risk calculated from the Framingham Risk Score, which estimates coronary heart disease risk at 10 years and is widely used in routine practice. Without use of NSAIDs, one could expect that the number of cases of acute myocardial infarction will be fewer than 1 case per year per 100 persons in those at low risk (less than or equal to 10% over 10 years), 1 to 2 cases per year per 100 persons in those at intermediate risk (10-20% over 10 years), and greater than 2 cases per year per 100 persons in those at high risk (>20% over 10 years).
Assuming an increase in the relative risk of acute MI of 20 to 50% across NSAID doses and durations studied in the IPD meta-analysis,1 the number of excess acute myocardial infarctions associated with use of common NSAIDs might range from fewer to 0.2 to 0.5 case per year per 100 persons in those at low coronary risk or < 0.2-0.5% annually (< 2 to 5 cases per 1000 persons per year) up to 0.4 to 1 or more cases per year per 100 persons in those at high coronary risk or > 0.4 to 1% annually (> 4 to 10 cases per 1000 patients per year). Hence the absolute percentage increase of excess MIs due to NSAID exposure is likely to range from 0.2% to 1% annually.
With use of ibuprofen > 1200 mg/day or naproxen > 750 mg/day for one to four weeks, the results of the IPD meta-analysis are compatible with a possible 75% relative increase in risk of acute myocardial infarction. With use for longer than one month, the risk of acute MI did not seem to continue to increase further but risk of acute MI remained constantly elevated with continued use of common NSAIDs. However, in our pooled analysis, follow-up stopped once a patient had experienced a first acute myocardial infarction.
In summary, the meta-analysis of patient-level data suggests that use of common NSAIDs increases a person’s relative risk of acute MI by about 20 to 50% overall and possibly by 75% with high-dose ibuprofen or naproxen used for one to four weeks. Our study does not allow an estimate for the risk of second heart attacks. Depending on the individual baseline heart attack risk, it seems reasonable to conclude that the absolute risk due to use of NSAIDs is on average increased by about 0.5-1% per year. With use for one to seven days, the IPD meta-analysis does not allow determining on which day or at what dose the risk of acute MI starts increasing over and above a person’s baseline level. Other studies are in progress to try elucidating this.
Michèle Bally, BPharm, MSc, PhD
Epidemiologist and researcher, University of Montreal Hospital Research Center (CRCHUM), Montreal, Canada
James M Brophy, MD, FRCP(c), FACC, FCCS, PhD
Professor of Medicine and Epidemiology, McGill University, Montreal, Canada
1. Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ. 2017;357:j1909.
2. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519-29.
3. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.
4. A Dictionary of Epidemiology. Edited by Miquel Porta. Fifth edition. Published in print January 2008 | ISBN: 9780195314496. Published online January 2014. p. 240. http://www.irea.ir/files/site1/pages/dictionary.pdf.
Competing interests: Author JMB reports serving on the Data Monitoring Committee for the PRECISION trial, which was sponsored by Pfizer, during the conduct of the study