Physician Commentary: Neurology Community Responds to Diclofenac Cardiovascular Risks

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center (mrc@mdedge.com) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center (mrc@mdedge.com) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center (mrc@mdedge.com) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California