AHA Updates NSAID Advice for Heart Disease Patients
From Medscape Medical News
February 28, 2007 — The American Heart Association (AHA) has issued new guidance discouraging the use of both cyclooxygenase 2 (COX-2) inhibitors and regular nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with known heart disease or those thought to be at high risk of getting heart disease.
The statement, published online in the February 26 Rapid Access issue of Circulation, recommends a new stepwise approach to the treatment of musculoskeletal pain in such patients, starting with nonpharmacologic treatments, such as physical therapy and exercise, weight loss to reduce stress on joints, and heat or cold therapy. If this does not provide enough pain relief, acetaminophen, aspirin, and even short-term use of narcotic analgesics are recommended as first-line drugs. Then, NSAIDs with the lowest COX-2 selectivity should be used next, and the more selective COX-2 inhibitors should be placed at the bottom of the list and used only as a last resort.
The statement says that all drugs should be used at the lowest dose necessary to control symptoms and prescribed for the shortest time possible.
The stepwise approach to pharmacologic therapy for musculoskeletal symptoms in patients with or at risk for cardiovascular disease includes the following drugs to be administered in this order:
Acetaminophen, tramadol, narcotic analgesics (short-term)
Nonacetylated salicylates
Non-COX-2 selective NSAIDs
NSAIDs with some COX-2 activity
COX-2 selective NSAIDs
Lead author of the AHA statement, Elliott Antman, MD, of the Brigham and Women's Hospital in Boston, Massachusetts, told heartwire that when using a NSAID, clinicians should start with naproxen as this is one of the least COX-2 selective agents. He said the available data suggest that naproxen has a neutral effect on the heart. "There haven't been that many trials with naproxen, so we don't know for sure, but the previous view that naproxen may be cardioprotective as it was associated with a lower rate of cardiac events than COX-2 inhibitors is now known to be wrong. We now know that COX-2 inhibitors definitely increase risk, and it appears that naproxen is neutral in this regard."
Once the decision is made to prescribe a NSAID, the statement says that several additional points should be considered. These include:
In patients at increased risk for thrombotic events, low-dose aspirin plus a proton-pump inhibitor could be added.
COX inhibitors can lead to impaired renal perfusion, sodium retention, and increases in blood pressure, which may contribute to their adverse cardiovascular effects. Therefore, renal function and blood pressure should be monitored in subjects taking COX-2 inhibitors, and extra caution should be exerted when these drugs are given to subjects with preexisting hypertension, renal disease, and heart failure.
The statement says that more data are also needed on the cardiovascular safety of conventional NSAIDs. But until such data are available, the use of any COX inhibitor, including over-the-counter NSAIDs, for long periods should only be considered in consultation with a clinician.
Now Enough Data to Make Firm Recommendations
Dr. Antman told heartwire that the AHA statement has been issued at the current time because there is now enough evidence to make some firm recommendations on the use of COX-2 inhibitors and NSAIDs in patients with or at risk for heart disease. "There have been several "advisories" and notes of caution issued on this subject during the past few years, but there have been numerous different reports on this issue, and there is confusion in the minds of both clinicians and patients about how to treat musculoskeletal pain in heart disease patients. The AHA feels it is important to have very clear guidance for clinicians on this and now is a good time to issue this guidance as we now have incontrovertible evidence that COX-2 inhibitors increase the risk of MI [myocardial infarction], and there is also now strong evidence to suggest that this is also a problem with regular NSAIDs," he commented.
Reasonable Approach for All Patients
Dr. Antman said that while the advice in this AHA statement is aimed particularly at the treatment of musculoskeletal pain in patients with or at high risk for heart disease and that patients at a low risk for heart disease can probably be treated more liberally, he would still recommend that this stepped-care strategy is a reasonable approach for all patients, as the patient's exact risk for heart disease is often unclear.
Hypertension — A Problem With All Painkillers?
Another study published in the February 26 issue of the Archives of Internal Medicine suggests that acetaminophen and aspirin, as well as NSAIDs, may increase the risk for hypertension. Referring to this article, Dr. Antman told heartwire that this is a separate concern that may be related to the inhibition of prostaglandins. "We know that NSAIDs can increase blood pressure. This is in addition to their pro-thrombotic effects. They have a double negative. While aspirin and acetaminophen may also have an effect on blood pressure, aspirin is known to be cardioprotective and acetaminophen appears to have neutral thrombotic effect."
Some Question Narcotics as First-Line Treatment
Heartwire asked a few cardiologists with an interest in this field and some rheumatologists for their thoughts on the AHA statement. While all appear to support the recommendation that COX-2 inhibitors should be last on the list, some experts have questioned the advice to give a narcotic before a non-COX-2 selective NSAID, particularly naproxen.
One to voice this opinion was cardiologist Scott Solomon, MD, of the Brigham and Women's Hospital in Boston, Massachusetts. "I think the recommendation of using narcotics in the short term prior to using non COX-2 selective NSAIDS will be quite controversial, and I will be surprised if the rheumatology community will concur with this. Overall, there are very little data on cardiovascular risk with non-selective NSAIDS, although that is not the same as saying there is no risk. Physicians need to weigh any potential cardiovascular risks of non-selective NSAIDs together with the clear increased risk of GI bleeding against risk of abuse with narcotics," he commented to heartwire.
Rheumatologist, Michael Weinblatt, MD, also of Brigham and Women's Hospital, concurred. "I totally agree with Dr Solomon's concerns about initial use of narcotics. It should also be noted that multiple different diseases are grouped in the musculoskeletal family including rheumatoid arthritis which is a systemic inflammatory disease with increased morbidity and mortality. I would not agree with the recommendations that initial therapy of that disease focus on non-pharmacologic approaches. In fact the initial approach of RA [rheumatoid arthritis] is institution of therapeutic doses of anti-inflammatory drugs and disease modifying therapies. The use of narcotics as an initial therapy for rheumatoid arthritis is not supported by the extensive rheumatology literature," he said.
Dr. Antman responds that it is important that clinicians read the entire scientific statement to appreciate the context in which the recommendations are being made. He notes that the statement makes it clear that both safety and efficacy should be considered and the least risky medication should be tried first. "Clearly, if a physician felt that even a short course of narcotic analgesics posed an unacceptable risk of abuse in a given patient, that would not be an appropriate option to consider in the first line of the stepped care approach. On the other hand it can be argued that a short course of narcotic analgesics in the appropriately chosen patient with known heart disease or who is at risk for heart disease may well be a more desirable early option to try rather than jumping quickly to riskier drugs such as those with more COX 2 selectivity," he said.
Adressing Dr. Weinblatt's comments, Dr. Antman says, "The focus of our statement was on the selection of oral drugs from a cardiovascular risk perspective rather than to provide guidelines for disease management to rheumatologists. Our statement is not at all inconsistent with the rheumatology guidelines that recommend topical agents and oral therapy for tendonitis/bursitis; topical and intra-articular agents and oral agents for noninflammartory conditions; and disease modifying therapies followed by oral agents in inflammatory conditions."
Naproxen an Exception?
Eric Topol, MD, who was one of the first to identify the cardiac problems with COX-2 inhibitors, also feels strongly that narcotics should not be given before naproxen. "I use naproxen as the first line agent since it has never been invoked as having cardiovascular toxicity. The data (in the AHA statement) indicting all NSAIDs is over the top in my opinion."
Dr. Antman responds that "The AHA statement provides a compilation of the latest available data on the more traditional NSAIDs and clearly shows an increased risk of CV [cardiovascular] events whether one is looking at randomized trials, observational studies, or registries. Most of the data as summarized in the table in the statement indicate a risk with ibuprofen or diclofenac. The available data on naproxen, a non-COX-2 selective NSAID, suggest it is probably neutral with respect to cardiovascular risk and therefore as per our recommendations indeed it should be tried prior to NSAIDs with some COX-2 activity and certainly before the COX-2 selective NSAIDs."
Others Support of AHA Stance
Other cardiologists contacted by heartwire were supportive of the AHA statement, even the recommendation for early use of narcotics. Harlan Krumholz, MD, described the statement as "an important distillation of the published literature," and Debabrata Mukherjee, MD, of the University of Kentucky, in Lexington, said he thought the stepwise approach advocated was "a very reasonable approach." Dr. Mukherjee added, "We still have concerns about coxibs and they should only be used as a last resort in patients with or at risk of heart disease. I think short term use of tramadol or narcotics prior to even naproxen is reasonable as we now understand the risks of even non-selective NSAIDs and the concern of an aspirin-NSAID interaction. Although one has to be judicious in using narcotics in individuals with prior history of drug or substance abuse and they should not be used for more than few weeks."
Circulation. Published online February 26, 2007.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
Describe the physiologic effects of COX inhibitors.
Identify current recommendations for the use of analgesics in musculoskeletal pain.
Clinical Context
The use of analgesics has become controversial, in part due to the possibility of cardiovascular events associated with COX. The 2 major COX isoenzymes are COX-1 and COX-2. COX-1 is expressed at a relatively constant rate in most tissues, whereas COX-2 production is increased with inflammation. Activation of both COX-1 and COX-2 increase the production of prostaglandin H2, which in turn serves as a precursor to prostacyclin, thromoboxane A2, and several other prostaglandins.
COX-2 expression is reduced in the gastrointestinal tract, which explains why analgesics that selectively inhibit COX-2 can reduce the relative risk for gastrointestinal tract bleeding compared with other COX inhibitors. The current advisory statement from the American Heart Association balances this benefit vs the possibility of increased cardiovascular risk associated with these medications.
Study Highlights
COX-2 inhibition can result in an increased risk for thrombosis due to increased activity of thromboxane A2 and reduced activity of prostacyclin. In addition, all NSAIDs can increase sodium and water retention, increasing the risk for exacerbations of hypertension and heart failure. Finally, COX-2 up-regulation may reduce myocardial ischemia and infarction during acute cardiac events, and inhibition of this isoenzyme can increase infarct size and lead to myocardial rupture.
"Nonselective" NSAIDs also differ with regard to COX selectivity. Diclofenac has greater COX-2 selectivity than ibuprofen, which in turn has greater COX-2 selectivity compared with naproxen.
Initial treatment of musculoskeletal pain should include nonpharmacologic therapy, including physical therapy, heat/cold, and orthotics. Acetaminophen and aspirin are probably the best initial choices for analgesia, although these agents should be used at the lowest possible dose for the shortest possible period.
For patients who fail conservative therapy for musculoskeletal pain, NSAIDs may be chosen as a next step. Clinicians and patients should realize that the use of NSAIDs may slightly increase the risk for cardiovascular and cerebrovascular events. With this in mind, clinicians should try to use NSAIDs with lower selectivity for COX-2.
Naproxen is probably the NSAID associated with the lowest risk for thrombosis. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) questioned the safety of naproxen, but this trial had significant limitations.
Patients with a history of gastrointestinal tract bleeding or who are at high risk for bleeding who require analgesia should be prescribed acetaminophen first. For these patients who require NSAID therapy, proton-pump inhibitors have been demonstrated to reduce the risk for recurrent gastrointestinal tract bleeding among patients receiving low-dose aspirin.
Patients with active atherosclerotic processes are at increased risk for the thromboembolic complications of COX-2 inhibitors. Renal function and blood pressure should be monitored during treatment with COX-2 inhibitors.
Ibuprofen, but not rofecoxib, acetaminophen, or diclofenac, appears to reduce the physiologic efficacy of aspirin in preventing thrombosis. Current recommendations call for delaying ibuprofen dosing until at least 30 minutes after taking aspirin or at least 8 hours prior to aspirin dosing.
February 28, 2007 — The American Heart Association (AHA) has issued new guidance discouraging the use of both cyclooxygenase 2 (COX-2) inhibitors and regular nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with known heart disease or those thought to be at high risk of getting heart disease.
The statement, published online in the February 26 Rapid Access issue of Circulation, recommends a new stepwise approach to the treatment of musculoskeletal pain in such patients, starting with nonpharmacologic treatments, such as physical therapy and exercise, weight loss to reduce stress on joints, and heat or cold therapy. If this does not provide enough pain relief, acetaminophen, aspirin, and even short-term use of narcotic analgesics are recommended as first-line drugs. Then, NSAIDs with the lowest COX-2 selectivity should be used next, and the more selective COX-2 inhibitors should be placed at the bottom of the list and used only as a last resort.
The statement says that all drugs should be used at the lowest dose necessary to control symptoms and prescribed for the shortest time possible.
The stepwise approach to pharmacologic therapy for musculoskeletal symptoms in patients with or at risk for cardiovascular disease includes the following drugs to be administered in this order:
Acetaminophen, tramadol, narcotic analgesics (short-term)
Nonacetylated salicylates
Non-COX-2 selective NSAIDs
NSAIDs with some COX-2 activity
COX-2 selective NSAIDs
Lead author of the AHA statement, Elliott Antman, MD, of the Brigham and Women's Hospital in Boston, Massachusetts, told heartwire that when using a NSAID, clinicians should start with naproxen as this is one of the least COX-2 selective agents. He said the available data suggest that naproxen has a neutral effect on the heart. "There haven't been that many trials with naproxen, so we don't know for sure, but the previous view that naproxen may be cardioprotective as it was associated with a lower rate of cardiac events than COX-2 inhibitors is now known to be wrong. We now know that COX-2 inhibitors definitely increase risk, and it appears that naproxen is neutral in this regard."
Once the decision is made to prescribe a NSAID, the statement says that several additional points should be considered. These include:
In patients at increased risk for thrombotic events, low-dose aspirin plus a proton-pump inhibitor could be added.
COX inhibitors can lead to impaired renal perfusion, sodium retention, and increases in blood pressure, which may contribute to their adverse cardiovascular effects. Therefore, renal function and blood pressure should be monitored in subjects taking COX-2 inhibitors, and extra caution should be exerted when these drugs are given to subjects with preexisting hypertension, renal disease, and heart failure.
The statement says that more data are also needed on the cardiovascular safety of conventional NSAIDs. But until such data are available, the use of any COX inhibitor, including over-the-counter NSAIDs, for long periods should only be considered in consultation with a clinician.
Now Enough Data to Make Firm Recommendations
Dr. Antman told heartwire that the AHA statement has been issued at the current time because there is now enough evidence to make some firm recommendations on the use of COX-2 inhibitors and NSAIDs in patients with or at risk for heart disease. "There have been several "advisories" and notes of caution issued on this subject during the past few years, but there have been numerous different reports on this issue, and there is confusion in the minds of both clinicians and patients about how to treat musculoskeletal pain in heart disease patients. The AHA feels it is important to have very clear guidance for clinicians on this and now is a good time to issue this guidance as we now have incontrovertible evidence that COX-2 inhibitors increase the risk of MI [myocardial infarction], and there is also now strong evidence to suggest that this is also a problem with regular NSAIDs," he commented.
Reasonable Approach for All Patients
Dr. Antman said that while the advice in this AHA statement is aimed particularly at the treatment of musculoskeletal pain in patients with or at high risk for heart disease and that patients at a low risk for heart disease can probably be treated more liberally, he would still recommend that this stepped-care strategy is a reasonable approach for all patients, as the patient's exact risk for heart disease is often unclear.
Hypertension — A Problem With All Painkillers?
Another study published in the February 26 issue of the Archives of Internal Medicine suggests that acetaminophen and aspirin, as well as NSAIDs, may increase the risk for hypertension. Referring to this article, Dr. Antman told heartwire that this is a separate concern that may be related to the inhibition of prostaglandins. "We know that NSAIDs can increase blood pressure. This is in addition to their pro-thrombotic effects. They have a double negative. While aspirin and acetaminophen may also have an effect on blood pressure, aspirin is known to be cardioprotective and acetaminophen appears to have neutral thrombotic effect."
Some Question Narcotics as First-Line Treatment
Heartwire asked a few cardiologists with an interest in this field and some rheumatologists for their thoughts on the AHA statement. While all appear to support the recommendation that COX-2 inhibitors should be last on the list, some experts have questioned the advice to give a narcotic before a non-COX-2 selective NSAID, particularly naproxen.
One to voice this opinion was cardiologist Scott Solomon, MD, of the Brigham and Women's Hospital in Boston, Massachusetts. "I think the recommendation of using narcotics in the short term prior to using non COX-2 selective NSAIDS will be quite controversial, and I will be surprised if the rheumatology community will concur with this. Overall, there are very little data on cardiovascular risk with non-selective NSAIDS, although that is not the same as saying there is no risk. Physicians need to weigh any potential cardiovascular risks of non-selective NSAIDs together with the clear increased risk of GI bleeding against risk of abuse with narcotics," he commented to heartwire.
Rheumatologist, Michael Weinblatt, MD, also of Brigham and Women's Hospital, concurred. "I totally agree with Dr Solomon's concerns about initial use of narcotics. It should also be noted that multiple different diseases are grouped in the musculoskeletal family including rheumatoid arthritis which is a systemic inflammatory disease with increased morbidity and mortality. I would not agree with the recommendations that initial therapy of that disease focus on non-pharmacologic approaches. In fact the initial approach of RA [rheumatoid arthritis] is institution of therapeutic doses of anti-inflammatory drugs and disease modifying therapies. The use of narcotics as an initial therapy for rheumatoid arthritis is not supported by the extensive rheumatology literature," he said.
Dr. Antman responds that it is important that clinicians read the entire scientific statement to appreciate the context in which the recommendations are being made. He notes that the statement makes it clear that both safety and efficacy should be considered and the least risky medication should be tried first. "Clearly, if a physician felt that even a short course of narcotic analgesics posed an unacceptable risk of abuse in a given patient, that would not be an appropriate option to consider in the first line of the stepped care approach. On the other hand it can be argued that a short course of narcotic analgesics in the appropriately chosen patient with known heart disease or who is at risk for heart disease may well be a more desirable early option to try rather than jumping quickly to riskier drugs such as those with more COX 2 selectivity," he said.
Adressing Dr. Weinblatt's comments, Dr. Antman says, "The focus of our statement was on the selection of oral drugs from a cardiovascular risk perspective rather than to provide guidelines for disease management to rheumatologists. Our statement is not at all inconsistent with the rheumatology guidelines that recommend topical agents and oral therapy for tendonitis/bursitis; topical and intra-articular agents and oral agents for noninflammartory conditions; and disease modifying therapies followed by oral agents in inflammatory conditions."
Naproxen an Exception?
Eric Topol, MD, who was one of the first to identify the cardiac problems with COX-2 inhibitors, also feels strongly that narcotics should not be given before naproxen. "I use naproxen as the first line agent since it has never been invoked as having cardiovascular toxicity. The data (in the AHA statement) indicting all NSAIDs is over the top in my opinion."
Dr. Antman responds that "The AHA statement provides a compilation of the latest available data on the more traditional NSAIDs and clearly shows an increased risk of CV [cardiovascular] events whether one is looking at randomized trials, observational studies, or registries. Most of the data as summarized in the table in the statement indicate a risk with ibuprofen or diclofenac. The available data on naproxen, a non-COX-2 selective NSAID, suggest it is probably neutral with respect to cardiovascular risk and therefore as per our recommendations indeed it should be tried prior to NSAIDs with some COX-2 activity and certainly before the COX-2 selective NSAIDs."
Others Support of AHA Stance
Other cardiologists contacted by heartwire were supportive of the AHA statement, even the recommendation for early use of narcotics. Harlan Krumholz, MD, described the statement as "an important distillation of the published literature," and Debabrata Mukherjee, MD, of the University of Kentucky, in Lexington, said he thought the stepwise approach advocated was "a very reasonable approach." Dr. Mukherjee added, "We still have concerns about coxibs and they should only be used as a last resort in patients with or at risk of heart disease. I think short term use of tramadol or narcotics prior to even naproxen is reasonable as we now understand the risks of even non-selective NSAIDs and the concern of an aspirin-NSAID interaction. Although one has to be judicious in using narcotics in individuals with prior history of drug or substance abuse and they should not be used for more than few weeks."
Circulation. Published online February 26, 2007.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
Describe the physiologic effects of COX inhibitors.
Identify current recommendations for the use of analgesics in musculoskeletal pain.
Clinical Context
The use of analgesics has become controversial, in part due to the possibility of cardiovascular events associated with COX. The 2 major COX isoenzymes are COX-1 and COX-2. COX-1 is expressed at a relatively constant rate in most tissues, whereas COX-2 production is increased with inflammation. Activation of both COX-1 and COX-2 increase the production of prostaglandin H2, which in turn serves as a precursor to prostacyclin, thromoboxane A2, and several other prostaglandins.
COX-2 expression is reduced in the gastrointestinal tract, which explains why analgesics that selectively inhibit COX-2 can reduce the relative risk for gastrointestinal tract bleeding compared with other COX inhibitors. The current advisory statement from the American Heart Association balances this benefit vs the possibility of increased cardiovascular risk associated with these medications.
Study Highlights
COX-2 inhibition can result in an increased risk for thrombosis due to increased activity of thromboxane A2 and reduced activity of prostacyclin. In addition, all NSAIDs can increase sodium and water retention, increasing the risk for exacerbations of hypertension and heart failure. Finally, COX-2 up-regulation may reduce myocardial ischemia and infarction during acute cardiac events, and inhibition of this isoenzyme can increase infarct size and lead to myocardial rupture.
"Nonselective" NSAIDs also differ with regard to COX selectivity. Diclofenac has greater COX-2 selectivity than ibuprofen, which in turn has greater COX-2 selectivity compared with naproxen.
Initial treatment of musculoskeletal pain should include nonpharmacologic therapy, including physical therapy, heat/cold, and orthotics. Acetaminophen and aspirin are probably the best initial choices for analgesia, although these agents should be used at the lowest possible dose for the shortest possible period.
For patients who fail conservative therapy for musculoskeletal pain, NSAIDs may be chosen as a next step. Clinicians and patients should realize that the use of NSAIDs may slightly increase the risk for cardiovascular and cerebrovascular events. With this in mind, clinicians should try to use NSAIDs with lower selectivity for COX-2.
Naproxen is probably the NSAID associated with the lowest risk for thrombosis. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) questioned the safety of naproxen, but this trial had significant limitations.
Patients with a history of gastrointestinal tract bleeding or who are at high risk for bleeding who require analgesia should be prescribed acetaminophen first. For these patients who require NSAID therapy, proton-pump inhibitors have been demonstrated to reduce the risk for recurrent gastrointestinal tract bleeding among patients receiving low-dose aspirin.
Patients with active atherosclerotic processes are at increased risk for the thromboembolic complications of COX-2 inhibitors. Renal function and blood pressure should be monitored during treatment with COX-2 inhibitors.
Ibuprofen, but not rofecoxib, acetaminophen, or diclofenac, appears to reduce the physiologic efficacy of aspirin in preventing thrombosis. Current recommendations call for delaying ibuprofen dosing until at least 30 minutes after taking aspirin or at least 8 hours prior to aspirin dosing.
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