NSAIDs Associated With Cardiovascular Risk

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

View on the News

Time to Reevaluate NSAIDs

The cardiotoxicity of NSAIDs is particularly worrisome because many patients have both cardiovascular disease and musculoskeletal disease, Wayne A. Ray, Ph.D., noted in an editorial accompanying Dr. Trelle's study (BMJ Jan. 11, 2011;342:c6618 [doi:10.1136/bmj. c6618]).

What Dr. Trelle's study adds to the existing literature on NSAIDs is the potentially powerful technique known as network meta-analysis, which can extract more information from the data when certain assumptions are met, compared with traditional analyses, he wrote. The strength of the technique is that it uses all of the data, but it has some inherent weaknesses that should inspire caution when interpreting estimates based on indirect comparisons, explained Dr. Ray.

For example, no large, placebo-controlled trials compared etoricoxib vs. placebo. Risks of etoricoxib vs. placebo were estimated based on a chain of direct comparisons in separate trials – etoricoxib vs. diclofenac; diclofenac vs. rofecoxib or celecoxib, and finally rofecoxib or celecoxib vs. placebo.

Based on all the studies, what are the best strategies for clinicians who are considering NSAIDs for patients at high risk of cardiovascular disease? Avoid COX-2 inhibitors, especially in higher doses, Dr. Ray advised. Avoid diclofenac. Remember that ibuprofen may attenuate the antiplatelet effects of aspirin.

For now, naproxen seems to be the safest NSAID in terms of cardiovascular risk.

With any NSAID, consider also prescribing gastroprotective drugs.

NSAIDs are not the only option for treatment of musculoskeletal symptoms. Clinicians also prescribe paracetamol, low-dose opioid analgesics, and newer drugs, but without large-scale comparison studies, it's impossible to tell which is best for both efficacy and safety, Dr. Ray wrote. “Perhaps it is time for a larger, more systematic evaluation of a broader range of alternatives,” he suggested.

DR. WAYNE A. RAY is a professor and director of pharmacoepidemiology at Vanderbilt University, Nashville, Tenn. Dr. Ray has received financial support from Pfizer, was a paid expert witness in a lawsuit by the state of Texas against Merck, and is a paid expert in an insurance company action against the maker of Prempro.

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

View on the News

Time to Reevaluate NSAIDs

The cardiotoxicity of NSAIDs is particularly worrisome because many patients have both cardiovascular disease and musculoskeletal disease, Wayne A. Ray, Ph.D., noted in an editorial accompanying Dr. Trelle's study (BMJ Jan. 11, 2011;342:c6618 [doi:10.1136/bmj. c6618]).

What Dr. Trelle's study adds to the existing literature on NSAIDs is the potentially powerful technique known as network meta-analysis, which can extract more information from the data when certain assumptions are met, compared with traditional analyses, he wrote. The strength of the technique is that it uses all of the data, but it has some inherent weaknesses that should inspire caution when interpreting estimates based on indirect comparisons, explained Dr. Ray.

For example, no large, placebo-controlled trials compared etoricoxib vs. placebo. Risks of etoricoxib vs. placebo were estimated based on a chain of direct comparisons in separate trials – etoricoxib vs. diclofenac; diclofenac vs. rofecoxib or celecoxib, and finally rofecoxib or celecoxib vs. placebo.

Based on all the studies, what are the best strategies for clinicians who are considering NSAIDs for patients at high risk of cardiovascular disease? Avoid COX-2 inhibitors, especially in higher doses, Dr. Ray advised. Avoid diclofenac. Remember that ibuprofen may attenuate the antiplatelet effects of aspirin.

For now, naproxen seems to be the safest NSAID in terms of cardiovascular risk.

With any NSAID, consider also prescribing gastroprotective drugs.

NSAIDs are not the only option for treatment of musculoskeletal symptoms. Clinicians also prescribe paracetamol, low-dose opioid analgesics, and newer drugs, but without large-scale comparison studies, it's impossible to tell which is best for both efficacy and safety, Dr. Ray wrote. “Perhaps it is time for a larger, more systematic evaluation of a broader range of alternatives,” he suggested.

DR. WAYNE A. RAY is a professor and director of pharmacoepidemiology at Vanderbilt University, Nashville, Tenn. Dr. Ray has received financial support from Pfizer, was a paid expert witness in a lawsuit by the state of Texas against Merck, and is a paid expert in an insurance company action against the maker of Prempro.

Major Finding: Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo.

Data Source: Network meta-analysis of 31 large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo in 116,429 patients with 117,218 patient-years of follow-up.

Disclosures: The Swiss National Science Foundation funded the study. The investigators reported having no conflicts of interest.

Each of seven NSAIDs was associated with significantly increased risk for MI, stroke, or death from cardiovascular disease, compared with placebo, in the most comprehensive meta-analysis of the subject so far.

The relative risks with any individual NSAID, compared with placebo, often were double, triple, or quadruple the risk with placebo, the study found. The absolute numbers of MIs and other cardiovascular outcomes were small, but the network meta-analysis design of the study “provides the best available evidence on the safety of this class of drugs,” Dr. Sven Trelle and his associates reported.

Contrary to some previous reports, the current study also found no suggestion that this increased cardiovascular risk is specific to cyclo-oxygenase-2 (COX-2) inhibitors. Therefore the use of all NSAIDs – and the over-the-counter availability of some of them – should be reconsidered, Dr. Trelle stated in a report published online by BMJ (Jan. 11, 2011;342:c7086[doi/10.1136/bmj.c7086]).

Dr. Trelle of the University of Bern, Switzerland, acknowledged that therapeutic options for chronic musculoskeletal pain are limited, but cautioned that “cardiovascular risk needs to be taken into account when prescribing” any NSAID.

The meta-analysis included any large, randomized controlled trials comparing any NSAID with other NSAIDs or placebo. Data were available for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, and lumiracoxib. The risk for a cardiovascular event had to increase by more than 30% to be considered significant.

Overall, naproxen appeared to be the least harmful NSAID in terms of cardiovascular outcomes. Risks were greatest with ibuprofen, diclofenac, etoricoxib, and lumiracoxib.

Four NSAIDs were associated with significantly increased risk for myocardial infarction (the primary outcome in the current analysis) in 29 of the trials that reported 554 MIs. The relative risk for MI doubled with rofecoxib or lumiracoxib, was 35% higher with celecoxib, and was 61% higher with ibuprofen, compared with placebo. Evidence was lacking for increased MI risk with the other three NSAIDs.

Among secondary outcomes, stroke risk increased with all NSAIDs in 26 trials that reported 377 strokes. The increased risk was significant with four of the drugs, roughly doubling with naproxen and tripling with ibuprofen, diclofenac, etoricoxib, or lumiracoxib, compared with placebo.

Twenty-six trials reported 312 deaths from cardiovascular disease, accounting for 46% of all deaths in the trials. All NSAIDs except naproxen were associated with higher risk for cardiovascular death, which increased by 58% with rofecoxib, roughly doubled with ibuprofen, celecoxib, or lumiracoxib, and increased approximately fourfold with diclofenac or etoricoxib, compared with placebo.

All the NSAIDs were associated with increased risk for death from any cause, compared with placebo, and the increase was significant for all except naproxen. There were 676 deaths from any cause in 28 trials, and the risk of death roughly doubled with any of the other six NSAIDs.

Looking at a composite of nonfatal MI, nonfatal stroke, or cardiovascular death in 30 trials that reported 1,091 composite events, the risk increased with all the NSAIDs and increased significantly with all but naproxen.

View on the News

Time to Reevaluate NSAIDs

The cardiotoxicity of NSAIDs is particularly worrisome because many patients have both cardiovascular disease and musculoskeletal disease, Wayne A. Ray, Ph.D., noted in an editorial accompanying Dr. Trelle's study (BMJ Jan. 11, 2011;342:c6618 [doi:10.1136/bmj. c6618]).

What Dr. Trelle's study adds to the existing literature on NSAIDs is the potentially powerful technique known as network meta-analysis, which can extract more information from the data when certain assumptions are met, compared with traditional analyses, he wrote. The strength of the technique is that it uses all of the data, but it has some inherent weaknesses that should inspire caution when interpreting estimates based on indirect comparisons, explained Dr. Ray.

For example, no large, placebo-controlled trials compared etoricoxib vs. placebo. Risks of etoricoxib vs. placebo were estimated based on a chain of direct comparisons in separate trials – etoricoxib vs. diclofenac; diclofenac vs. rofecoxib or celecoxib, and finally rofecoxib or celecoxib vs. placebo.

Based on all the studies, what are the best strategies for clinicians who are considering NSAIDs for patients at high risk of cardiovascular disease? Avoid COX-2 inhibitors, especially in higher doses, Dr. Ray advised. Avoid diclofenac. Remember that ibuprofen may attenuate the antiplatelet effects of aspirin.

For now, naproxen seems to be the safest NSAID in terms of cardiovascular risk.

With any NSAID, consider also prescribing gastroprotective drugs.

NSAIDs are not the only option for treatment of musculoskeletal symptoms. Clinicians also prescribe paracetamol, low-dose opioid analgesics, and newer drugs, but without large-scale comparison studies, it's impossible to tell which is best for both efficacy and safety, Dr. Ray wrote. “Perhaps it is time for a larger, more systematic evaluation of a broader range of alternatives,” he suggested.

DR. WAYNE A. RAY is a professor and director of pharmacoepidemiology at Vanderbilt University, Nashville, Tenn. Dr. Ray has received financial support from Pfizer, was a paid expert witness in a lawsuit by the state of Texas against Merck, and is a paid expert in an insurance company action against the maker of Prempro.