NSAIDs

Risk of intracranial haemorrhage with combination use of antidepressants and NSAIDs

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Concerns emerge over combining antidepressants with non-steroidal anti-inflammatory drugs (NSAIDs) as a study shows an increased risk of intracranial haemorrhage (ICH) in these patients.

Antidepressants and NSAIDs are both associated with gastrointestinal bleeding but not with ICH when used as monotherapy. Evidence now shows that the absolute risk of ICH in the first 30 days of combination treatment with an antidepressant and NSAID is 0.05 percent, with a hazard ratio (HR) of 1.6 vs treatment with an antidepressant alone (p<0.001). [BMJ 2015;351:h3517]

Subgroup analyses found no significant difference in ICH risk between the antidepressant drug classes for tricyclic antidepressants (HR, 1.7), selective serotonin reuptake inhibitors (HR, 1.4), and serotonin-norepinephrine reuptake inhibitors (HR, 0.4) vs all other drug classes. The risk of ICH, however, was greater in men (HR, 2.6) than women (HR, 1.2), but there was no association between ICH risk and patient comorbidities or other co-medications.

The retrospective analysis was performed using data from over 4 million Korean patients, taken from the Korean Health Insurance Review and Assessment Service database. All patients were treated with antidepressants between 2009 and 2013.

The study is the first population-based cohort study to highlight the risk of ICH associated with the combined use of antidepressants and NSAIDs. The potential risk of interaction posed by their concomitant use may be substantial, experts warn, especially with the increasing use of antidepressants and overuse of over-the-counter NSAIDs.

“The availability of over-the-counter analgesics is particularly important, as doctors often fail to consider the risks and potential interactions posed by non-prescribed drugs,” wrote Professor Stewart Mercer and colleagues of the University of Glasgow, Glasgow, UK and the University of Cambridge, Cambridge, UK in an accompanying editorial. [BMJ 2015;351:h3745]

“Most worryingly, conditions requiring NSAIDs and antidepressants commonly coexist; 65 percent of people with major depression also have chronic pain, with both morbidities sharing common psychological risk factors and neurobiological processes,” they wrote.

Vigilance in prescribing and assessment of individual patients’ risks and needs are recommended. According to Mercer and colleagues, knowing the patient and applying an empathic, person-centred approach to care may be “as important as having better guidelines and a better evidence base.”

Further research will be needed to address the risk of ICH with the individual treatments used alone, as well as the risks associated with long-term use of combination treatment.

NSAIDs Raise Bleeding, Thromboembolic Risk in Treated AF

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Patients with atrial fibrillation (AF) receiving antithrombotic treatment are at increased risk for bleeding if they also take a nonsteroidal anti-inflammatory drug (NSAID), even for a short period, a new nationwide Danish study has found.

The data suggest that a serious bleeding event occurs in up to 1 in 400 to 500 patients with AF exposed to an NSAID for 2 weeks and that the risk is elevated with both selective cyclooxygenase (COX)-2 inhibitors and nonselective NSAIDs.

The findings are important because NSAIDs are so widely available and commonly used, commented lead study author Morten Lamberts, MD, PhD, Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark.

“Any safety issues are a major public health concern,” said Dr Lamberts. “Patients should know that it’s possible that even over-the-counter drugs might put them at increased bleeding and thromboembolic risk.”

The study is published in the November 18 issue of Annals of Internal Medicine.
The researchers used data from the Denmark’s National Patient Registry, which contains information on hospitalizations and on dosage, strength, and date of dispensed prescription drugs. The analysis included 150,900 patients, median age 75 years, who were hospitalized with a first-time diagnosis of AF between 1997 and 2011. During a median follow-up of 6.2 years, 35.6% of patients were prescribed an NSAID.
Study participants had a mean HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score of 1.5 and mean CHA2DS2VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, sex) score of 2.8. Approximately 70% were being treated with an antiplatelet or oral anticoagulant.

Investigators categorized rofecoxib and celecoxib as selective COX-2 inhibitors and ibuprofen, diclofenac, and naproxen as nonselective NSAIDs. Since 2001, ibuprofen has been the only NSAID available in Denmark without a prescription, but only in low doses and in limited quantities. Since that time, this agent has accounted for 15% to 20% of all NSAID sales.

The study showed that serious bleeding events, including intracranial and gastrointestinal bleeding, occurred in 11.4% of the patients and thromboembolic events in 13.0%. The absolute risk for serious bleeding with 14 days of continuous NSAID exposure was 3.5 events per 1000 patients vs 1.5 events per 1000 patients without NSAID exposure, with an absolute risk difference of 1.9 events per 1000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1000 patients.

“This suggests a serious bleeding event in 1 of 400 to 500 patients exposed to an NSAID for 14 days,” the authors write.

NSAIDs Raise Bleeding, Thromboembolic Risk in Treated AF

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Patients with atrial fibrillation (AF) receiving antithrombotic treatment are at increased risk for bleeding if they also take a nonsteroidal anti-inflammatory drug (NSAID), even for a short period, a new nationwide Danish study has found.

The data suggest that a serious bleeding event occurs in up to 1 in 400 to 500 patients with AF exposed to an NSAID for 2 weeks and that the risk is elevated with both selective cyclooxygenase (COX)-2 inhibitors and nonselective NSAIDs.

The findings are important because NSAIDs are so widely available and commonly used, commented lead study author Morten Lamberts, MD, PhD, Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark.

“Any safety issues are a major public health concern,” said Dr Lamberts. “Patients should know that it’s possible that even over-the-counter drugs might put them at increased bleeding and thromboembolic risk.”

The study is published in the November 18 issue of Annals of Internal Medicine.
The researchers used data from the Denmark’s National Patient Registry, which contains information on hospitalizations and on dosage, strength, and date of dispensed prescription drugs. The analysis included 150,900 patients, median age 75 years, who were hospitalized with a first-time diagnosis of AF between 1997 and 2011. During a median follow-up of 6.2 years, 35.6% of patients were prescribed an NSAID.

Dr Morten Lamberts
Study participants had a mean HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score of 1.5 and mean CHA2DS2VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, sex) score of 2.8. Approximately 70% were being treated with an antiplatelet or oral anticoagulant.

Investigators categorized rofecoxib and celecoxib as selective COX-2 inhibitors and ibuprofen, diclofenac, and naproxen as nonselective NSAIDs. Since 2001, ibuprofen has been the only NSAID available in Denmark without a prescription, but only in low doses and in limited quantities. Since that time, this agent has accounted for 15% to 20% of all NSAID sales.

The study showed that serious bleeding events, including intracranial and gastrointestinal bleeding, occurred in 11.4% of the patients and thromboembolic events in 13.0%. The absolute risk for serious bleeding with 14 days of continuous NSAID exposure was 3.5 events per 1000 patients vs 1.5 events per 1000 patients without NSAID exposure, with an absolute risk difference of 1.9 events per 1000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1000 patients.

“This suggests a serious bleeding event in 1 of 400 to 500 patients exposed to an NSAID for 14 days,” the authors write.
The increased absolute risk for serious bleeding and thromboembolism existed across all antithrombotic regimens, for example single-antiplatelet therapy with either aspirin or clopidogrel, monotherapy with oral anticoagulants, or dual therapy with an oral anticoagulant and a single antiplatelet.
The study showed that the risk for serious bleeding with NSAID treatment was doubled compared with no NSAID treatment. The risk for thromboembolism was also increased.

Endpoint Hazard Ratio (95% Confidence Interval)

Serious bleeding 2.27 (2.14 – 2.40)
Thromboembolism 1.36 (1.27 – 1.45)

While all types of NSAIDs were associated with increased risk, diclofenac, naproxen, and rofecoxib (this last one is no longer marketed, according to Dr Lamberts) showed a particularly increased risk. For example, for diclofenac the hazard ratio for serious bleeding was 3.08 (95% confidence interval, 2.77 – 3.43).

The fact that the risk for serious bleeding occurred even within 2 weeks “is particularly worrisome as this suggests no safe therapeutic window,” said Dr Lamberts.

When researchers restricted the analysis to the years when over-the-counter NSAIDs weren’t available (1997 to 2001), the results for bleeding risk were similar. “Having nonregistered ibuprofen users potentially diluted into the larger non-NSAID group, one could speculate if the difference might be even larger than what we found,” said Dr Lamberts.

The risk for death after a nonfatal episode of serious bleeding during NSAID treatment was also increased, the study found. In addition, a high NSAID dose was associated with incremental risk for bleeding, suggesting a dose-response relationship.

Many patients with AF take NSAIDs to relieve pain. “I believe many individuals self-treat pain with NSAIDs because they’re available and accessible,” said Dr Lamberts.

The study results support previous recommendations that NSAIDs be discouraged unless other possibilities, such as physical therapy, acetaminophen, or alternative analgesics, have been exhausted.

Because non–vitamin K antagonist oral anticoagulants have a similar or better overall bleeding risk profile compared with warfarin, physicians might consider switching to one of those agents in patients needing NSAIDs, said the authors.

 

NSAIDs Linked to Leaks After GI Surgery

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Anastomotic leak association found in a statewide cohort study.

Postoperative nonsteroidal anti-inflammatory drug (NSAID) use was associated with anastomotic leak after nonelective colorectal surgery in a population-based surgical database.

The painkillers were associated with a 24% elevated risk for anastomotic leak at the surgical junction after adjustment for other factors (P=0.04), Timo W. Hakkarainen, MD, of the University of Washington Medical Center, Seattle, and colleagues reported online in JAMA Surgery.

The database included 13,082 bariatric or colorectal surgery patients at 47 hospitals participating in Washington’s statewide Surgical Care and Outcomes Assessment Program.

But the association between anastomotic leaks within 90 days of surgery and NSAIDs — used by 24% of the patients — was only significant in the nonelective colorectal surgery group.

In that group, the odds of a leak were 70% higher with NSAID use (rate 12.3% versus 8.3% without NSAID use, P=0.01).

The study considered only post-operative use of the anti-inflammatory drugs, without information on preexisting use for cardiovascular prevention.

As postoperative use of NSAIDs have risen with availability of IV formulations, there have been concerns raised by small studies that NSAIDs impair anastomotic healing in the GI tract, Hakkarainen and colleagues noted.

“The results of this large statewide cohort study show that, among patients undergoing nonelective colorectal resection, postoperative NSAID administration is associated with a significantly increased risk for anastomotic complications. Given that other analgesic regimens are effective and well tolerated, these data may be enough for some surgeons to alter practice patterns,” the study concluded.

Leak was defined by reoperation, rescue stoma, revision of an anastomosis, or percutaneous drainage of an abscess. Results were controlled for age, sex, procedure type (bariatric or colorectal), operative approach, protective ostomy, comorbid conditions, body mass index, a low serum albumin level, and other postoperative analgesic use.

Risk-adjusted 90-day mortality was similar between groups.

Limitations included lack of data on which NSAID was used, at what dose, or how long.

Further study is needed to determine if there’s a dose effect, what the mechanism might be, if it’s limited to certain formulations, and if overall recovery is affected, the group added.