Use of NSAIDs Risky for Osteoarthritis Patients

By Pat Anson, PNN Editor

It’s long been known that nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen can raise the risk of cardiovascular problems. A large new study in Canada has documented how NSAIDs can significantly raise the risk of heart disease, congestive heart failure and stroke in people with osteoarthritis.

Osteoarthritis (OA) is a joint disorder that leads to thinning of cartilage and progressive joint damage. NSAIDs are frequently used to treat the pain and inflammation caused by OA.

The Canadian study, published in the journal Arthritis & Rheumatology, looked at nearly 7,750 osteoarthritis patients in British Columbia and compared them with a control group of over 23,000 patients without OA. The average age of the participants was 65 and a little over half were women.

The risk of developing cardiovascular disease was found to be about 23% higher among people with OA than the control group. Researchers attributed about 41% of that increased risk to the use of NSAIDs.

NSAIDs appeared to play a significant role in several cardiovascular problems. The risk of congestive heart failure was 42% higher among people with OA, followed by a 17% greater risk of heart disease and a 14% greater risk of stroke.

"To the best of our knowledge, this is the first longitudinal study to evaluate the mediating role of NSAID use in the relationship between osteoarthritis and cardiovascular disease in a large population-based sample," said senior author Aslam Anis, PhD, of the School of Population and Public Health at the University of British Columbia.

"Our results indicate that osteoarthritis is an independent risk factor for cardiovascular disease and suggest a substantial proportion of the increased risk is due to the use of NSAIDs. This is highly relevant because NSAIDs are some of the most commonly used drugs to manage pain in patients with osteoarthritis."

The association of cardiovascular disease with NSAIDs is consistent with previous research.  A large international study in 2017, for example, found that prescription strength NSAIDs raises the risk of a heart attack as soon as the first week of use.

NSAIDs are used to alleviate pain and reduce inflammation, and are found in a wide variety of over-the-counter products, including cold and flu remedies. They are found in so many products -- such as Advil and Motrin -- that many consumers may not be aware how often they use NSAIDs. 

Canada adopted guidelines in 2017 that recommend NSAIDs as an alternative to opioid pain medication. The guideline makes no mention of the health risks associated with NSAIDs, but focuses on their cost effectiveness.

“NSAID-based treatment may have lower mean costs and higher effectiveness relative to opioids,” the guideline states. “Naproxen-based regimens in particular may be more cost effective compared to opioids and other NSAIDs, such as ibuprofen and celecoxib.”

Opioid guidelines released in 2016 by the U.S. Centers for Disease Control and Prevention also recommend NSAIDs as an alternative to opioids, but acknowledge the medications “do have risks, including gastrointestinal bleeding or perforation as well as renal and cardiovascular risks.”

In 2015, the Food and Drug Administration ordered warning labels for all NSAIDs to indicate they increase the risk of a fatal heart attack or stroke. The FDA warning does not apply to aspirin.

The European Society of Cardiology recommends limited use of NSAIDs by patients who are at risk of heart failure. People already diagnosed with heart failure should refrain from using NSAIDs altogether.

Researchers Identify Riskiest NSAIDs

By Pat Anson, Editor

The risk of non-steroidal anti-inflammatory drugs (NSAIDs) contributing to cardiovascular disease has been known for decades. But now we have a better idea which NSAIDs cause the most risk.

A large study published in the British Medical Journal found that use of any NSAID was associated with a 20 percent higher risk of being hospitalized with heart failure. Seven NSAIDs were found to be the riskiest, depending on the dose taken:

• diclofenac
• ibuprofen
• indomethacin
• ketorolac
• naproxen
• nimesulide
• piroxicam

In addition, two COX 2 inhibitors -- etoricoxib and rofecoxib – were also associated with a higher risk of heart failure.

“Our study, based on real world data on almost 10 million NSAIDs users from four European countries, provides evidence that current use of both COX 2 inhibitors and traditional individual NSAIDs are associated with increased risk of heart failure. Furthermore, the magnitude of the association varies between individual NSAIDs and according to the prescribed dose,” researchers reported.

The risk of heart failure doubled for people taking diclofenac, etoricoxib, indomethacin, piroxicam, or rofecoxib at very high doses. But even medium doses of indomethacin and etoricoxib were associated with increased risk. 

NSAIDs are used to alleviate pain and reduce inflammation, and are found in a wide variety of over-the-counter products – from headache relievers to cold and flu remedies. They are used in so many different products -- such as Advil and Motrin -- that many consumers may not be aware how often they use NSAIDs. 

An editorial in BMJ faulted the study for not going into more detail on the absolute risk between different NSAIDs.

“Information on absolute risks is valuable for clinicians and patients evaluating the balance between benefit and harm of treatment. Low risk patients might accept the small additional risk associated with treatment while higher risk patients might prefer to consider alternative treatments,” said Gunnar Gislason and Christian Torp-Pedersen, who are both professors of cardiology in Denmark.

“In some patients other pain treatments, such as paracetamol (acetaminophen) or a weak opiate, might be a good choice. For patients who do need NSAID treatment, it is important to consider the different risk profiles of the individual drugs. The selective COX 2 inhibitors and diclofenac have repeatedly been associated with higher cardiovascular risk, and therefore it seems prudent to avoid them and consider lower risk naproxen at the lowest effective dose.”

Several previous studies have found that NSAIDs increase the risk of cardiovascular disease and other health problems, but the exact cause has been unclear. A recent study at the University of California, Davis, found that NSAIDs reduced the activity of cardiac cells and led to cell death.

The European Society of Cardiology already recommends limited use of NSAIDs by patients who are at increased risk of heart failure. Those already diagnosed with heart failure should refrain from using NSAIDs completely.

Last year the U.S. Food and Drug Administration ordered warning labels for all NSAIDs to be strengthened to indicate they increase the risk of a fatal heart attack or stroke. The FDA said studies found the risk of serious side effects can occur in the first few weeks of using NSAIDs and could increase the longer people use the drugs. The revised warning does not apply to aspirin.

Study Finds Heart Disease Biggest Risk from Opioids

By Pat Anson, Editor

People who take opioid medication for chronic pain are far more likely to die prematurely from cardiovascular and respiratory problems than they are from accidental overdoses, according to researchers at Vanderbilt University.

Their study, published in JAMA, suggests that many opioid related deaths have been misclassified as overdoses and that public health policy should be more focused on the risks of opioids causing cardiovascular problems.

Researchers looked at a database of nearly 23,000 Medicaid patients in Tennessee who were prescribed either opioids; anti-seizure nerve medications such as pregabalin (Lyrica) and gabapentin (Neurontin); or a low dose antidepressant for chronic non-cancer pain.  

After four months, there were 185 deaths in the opioid group, a mortality rate that that was 1.6 times greater than the patients taking anti-seizure drugs or antidepressants. More than two-thirds of the excess deaths were due to causes other than accidental overdose.

Over twice as many patients died from cardiovascular and respiratory problems (89) than from overdoses (34).

“The increased risk of cardiovascular death could be related to adverse respiratory effects of long-acting opioids. Opioids can cause or exacerbate sleep-disordered breathing, including both obstructive and central sleep apnea,” wrote lead author Wayne Ray, PhD, of the Vanderbilt University School of Medicine.

“More than two-thirds of the excess deaths for patients in the long-acting opioid group were not coded as being due to unintentional overdose. If there is this degree of misclassification, then previous research on opioid mortality, most of which has focused on overdose deaths identified from death certificates, has substantially underestimated the true risks of opioids.”

The Centers for Disease Control and Prevention uses death certificate codes in its reports on mortality. The agency estimates that nearly 19,000 Americans died from overdoses of prescription pain medication in 2014. However, CDC researchers admit some of the overdoses may have been counted twice, and that some overdoses from illicit opioids such as heroin and fentanyl may have been counted as prescription drug deaths.

One weakness of the Vanderbilt study is that it only looked at mortality rates in the first few months of treatment and did not include deaths from long-term medication use.

“The study finding that prescription of long acting opioids was associated with increased cardiovascular and other non-overdose mortality adds to the already considerable known harms of the opioids and thus should be considered when assessing the benefits and harms of medications for chronic pain,” Ray wrote. “Nevertheless, for some individual patients, the therapeutic benefits from long-acting opioid therapy may outweigh the modest increase in mortality risk.”

The mortality rate for chronic pain patients who died in a hospital was higher for patients given antidepressants and anti-seizure drugs than it was for opioids.

Researchers Say NSAIDs Cause Heart Damage

By Pat Anson, Editor

Researchers have known for many years that non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of heart attack and stroke. Now they may finally be learning why the pain relievers can be harmful.

In experiments on heart cells from rats and mice, scientists at the University of California, Davis, found that NSAIDs reduced the activity of cardiac cells at pharmacological levels found in humans. Their study was recently published in the Journal of Molecular and Cellular Cardiology.

“We knew these non-steroidal anti-inflammatories had negative side effects for heart disease and stroke risk, “ said lead author Aldrin Gomes, a UC Davis associate professor of Neurobiology, Physiology and Behavior. “But now we have an idea of some of the mechanisms behind it.”

NSAIDs are widely used to treat everything from fever and headache to low back pain and arthritis. They are found in so many different products -- such as ibuprofen, Advil and Motrin -- that many consumers may not be aware how often they use NSAIDs. 

Several studies have found that NSAIDs increase the risk of cardiovascular disease and other health problems, but the exact cause has been unclear.

The UC Davis researchers compared naproxen, considered the safest over-the-counter NSAID, with a more potent anti-inflammatory, the prescription drug meclofenamate sodium (MS).

They found that MS increased reactive oxygen species, impaired mitochondrial function, decreased proteasome function, and increased cardiac cell death. Naproxen did not affect proteasome function or cause heart cells to die, but it did impair mitochondrial function and increase reactive oxygen species produced in cardiac cells.

“We were surprised to see that many of the NSAIDs we tested were causing the cardiac cell to die when used for prolonged periods,” said Gomes. “Some people are taking these drugs too often, and this is a problem. These drugs are abused.”

For moderate pain, Gomes suggests rubbing an anti-inflammatory topically onto the pained area, which would not expose the entire body to the drug. Taking an antioxidant like vitamin C before ingesting a NSAID may also reduce cardiac cell death.

Last year the U.S. Food and Drug Administration ordered warning labels for all NSAIDs to be strengthened to indicate they increase the risk of a fatal heart attack or stroke. The agency said studies have shown the risk of serious side effects can occur in the first few weeks of using NSAIDs and could increase the longer people use the drugs. The revised warning does not apply to aspirin.

The FDA said people who have a history of heart disease, particularly those who recently had a heart attack or cardiac bypass surgery, are at the greatest risk. But the risk is also present for people who don't have heart problems.

“Everyone may be at risk – even people without an underlying risk for cardiovascular disease,” said Judy Racoosin, MD, deputy director of FDA’s Division of Anesthesia, Analgesia, and Addiction Products.

In a major study published recently in the European Heart Journal, a number of leading heart specialists warned that there is no "solid evidence" that NSAIDs are safe.

"When doctors issue prescriptions for NSAIDs, they must in each individual case carry out a thorough assessment of the risk of heart complications and bleeding. NSAIDs should only be sold over the counter when it comes with an adequate warning about the associated cardiovascular risks. In general, NSAIDs are not be used in patients who have or are at high-risk of cardiovascular diseases," said co-author Christian Torp-Pedersen, a professor in cardiology at Aalborg University in Denmark.

Rheumatoid Arthritis Raises Death Risk

By Pat Anson, Editor

Rheumatoid arthritis (RA) is not only painful and disabling – new research indicates it raises the risk of an early death, especially for patients with seropositive RA.

In a study of nearly 1,000 women with RA, researchers at Brigham and Women’s Hospital (BWH) in Boston found that RA significantly increased the women’s risk of death from cardiovascular and respiratory disease. The women are enrolled in the Nurses' Health Study, which has followed more than 100,000 female registered nurses since 1976.

"Because the Nurses' Health Study is so large and has been following participants for so long, we were able to gather much more information about our subjects - we could follow them before and after diagnosis, take their health behaviors into account and determine specific causes of death. By doing so, we found strong evidence of increased risk for respiratory, cardiovascular and overall mortality for patients with RA," said lead author Jeffrey Sparks, MD, a physician in BWH's Division of Rheumatology, Immunology and Allergy.

RA is a chronic autoimmune disease in which the body’s own defenses attack joint tissues, causing swelling, inflammation and bone erosion. Because RA is incurable, treatments focus on suppressing the immune system to reduce inflammation and slow progression of the disease.

Sparks and his colleagues evaluated 964 women in the Nurses’ Health Study and compared their mortality rates to women in the study without RA. The team controlled for other risk factors, including smoking, a known cause of respiratory and cardiovascular mortality, as well as age, body mass index, physical activity and diet.

They found that RA was associated with a 40 percent increased risk of death and that many RA patients died of chronic obstructive pulmonary disease (COPD).

Researchers also looked at differences between the two types of RA, "seropositive" and "seronegative." Patients with seropositive RA have auto-antibodies related to RA, and generally have more severe symptoms. The team found that participants with seropositive RA had nearly three times the risk of respiratory mortality than women who did not have RA. Seronegative RA was not significantly associated with increased risk of respiratory mortality.

"We found that whether participants with RA were seropositive or seronegative really mattered - those who were seropositive were at higher risk, particularly for respiratory mortality," said Sparks. "We hope that this study will encourage patients and clinicians to be more aware that patients with RA are at increased risk of both respiratory and cardiovascular mortality, particularly patients with seropositive RA."

A recent study by researchers in Mexico found that RA patients with no prior symptoms of heart disease were at higher risk of a heart attack. Their risk was higher even without other cardiovascular risk factors such as smoking and diabetes.

Many health experts believe the inflammation triggered by RA in the joints may cause inflammation throughout the body, including the heart’s coronary arteries.

According to the Arthritis Foundation, more than 50 percent of premature deaths in people with rheumatoid arthritis result from cardiovascular disease. The heightened risk of heart disease applies to all forms of arthritis, including osteoarthritis, gout, lupus and psoriatic arthritis.