Non-steroidal anti-inflammatory drugs (NSAIDs)
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f3195 (Published 27 June 2013) Cite this as: BMJ 2013;346:f3195All rapid responses
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The paper says regarding use of NSAID in pregnancy,
1. "A large epidemiological study has found that both classes of NSAID may lead to abortion in the first trimester, with an odds ratio of 2.43 (95% confidence interval 2.12 to 2.79) compared with women not taking NSAIDs.
2. Both classes of NSAID may also delay labour."
In the first statement there is an argument that low dose of aspirin and heparin are the treatments of choice in antiphospholipid syndrome (a cause of recurrent abortions)1. So, it is not universally true that NSAIDs would cause abortions as aspirin prevents abortions in APS.
As regarding 2nd statement, there is inconclusive evidence that COX inhibitors would prevent preterm labour. There are inadequate data to make any recommendation about using COX inhibitor in practice to prevent preterm labour2. Future research should also include follow-up of the babies to examine the short-term and long-term effects of COX inhibitors2.
References:
1. Costedoat-Chalumeau N, Guettrot-Imbert G, Leguern V, Leroux G, Le Thi Huong D, Wechsler B, Morel N, Vauthier-Brouzes D, Dommergues M, Cornet A, Aumaître O, Pourrat O, Piette JC, Nizard J. [Pregnancy and antiphospholipid syndrome]. Rev Med Interne. 2012 Apr;33(4):209-16. doi: 10.1016/j.revmed.2012.01.003. Epub 2012 Feb 14. French.
2. Khanprakob T, Laopaiboon M, Lumbiganon P, Sangkomkamhang US. Cyclo-oxygenase (COX) inhibitors for preventing preterm labour. Cochrane Database Syst Rev. 2012 Oct 17;10:CD007748. doi: 10.1002/14651858.CD007748.pub2. Review.
Competing interests: No competing interests
We thank Drs Francisco José Fernández-Fernández and Alejandra Martín-Fernández for their interest in our article and the possible effect of proton pump inhibitors (PPI) on the absorption of concomitant NSAIDs from the gastro-intestinal tract. Their argument is that the usual acidic environment of the stomach will be rendered neutral by the PPI. In these conditions, the ionised, hydrophilic, form of the NSAID will be more abundant. This form of the NSAID, being more water-soluble, would result in less efficient absorption through the stomach wall. These matters were investigated extensively some years ago when aspirin was used in large doses to treat arthritis.
However, the vast bulk of absorption of NSAIDs occurs in the upper small intestine, despite the pH in this environment approaching neutral. Most absorption occurs in the upper small bowel because of the very large surface area of the duodenum and its vascularity. Therefore one would not expect a decrease in bioavailability of the NSAID with concomitant PPI.
Recently this matter has been thoroughly investigated because of formulation of fixed dose combinations of NSAIDs and PPIs. These fixed-dose combination products of PPI plus NSAID have been shown to be bioequivalent for the NSAID content in comparison to the NSAID alone. An example is the combination of naproxen with esomeprazole. (1) The benefit of the combination is the better upper gastrointestinal tolerability because of the PPI and there is no loss of efficacy of the NSAID.
Low-dose aspirin may be a special case – the dose is small for cardiovascular prophylaxis. Aspirin is the active form of the drug with respect to inhibiting platelet function. However, aspirin is very quickly broken down to salicylate that is not active against platelets. Any delay in absorption of aspirin may reduce the antiplatelet efficacy of low dose aspirin. The PPI-induced change in gastric pH or possible slowing of gastric emptying (2) would be enough to reduce the bioavailability of aspirin and thus the effect on platelets. However, the effect of concomitant PPI upon aspirin bioavailability remains uncertain. (3, 4) Moukarbel et al, (2012) conclude that there is insufficient evidence at present to support a clinically significant interaction between PPI and low dose aspirin used as cardiovascular prophylaxis. (5)
References
(1) Dillon S. Naproxen/esomeprazole fixed-dose combination. Drugs Aging 2011; 28(3):237-248
(2) Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric emptying: a systematic review. Dig Dis Sci 2010; 55:2431-2440
(3) Adamopoulos AB, Sakizlis GN, Nasothimiou EG, Anastasopoulou I, Anastasakou E, Kotsi P, Karafoulidou A, Stergiou GS. Do proton pump inhibitors attenuate the effect of aspirin on platelet aggregation? A randomized crossover study. J Cardiovasc Pharmacol. 2009; 54:163–168.
(4) Wurtz M, Grove EL, Kristensen SD, Hvas AM. The antiplatelet effect of aspirin is reduced by proton pump inhibitors in patients with coronary artery disease. Heart 2010; 96:368–371.
(5) Moukabel GV, Bhatt DL. Antiplatelet therapy and proton pump inhibition. Clinician update. Circulation 2012; 125:375-380
Competing interests: ROD has been involved with consultancies with several drug companies on patents and advice on paracetamol, ibuprofen, selective COX-2 inhibitors, and other drugs used for osteoarthritis; all payments for consultancies were made to a trust fund at St Vincent’s Hospital. We acknowledge the assistance of the National Health and Medical Research Council programme grant (568612) for clinical research relating to patient safety.
We thank Dr Johnson for his question about our recommendation that a COX-II selective NSAID is preferred to a non-COX selective, conventional NSAID in patients co-prescribed low-dose aspirin. Dr Johnson is concerned that COX-II selective NSAIDs are now well known to be associated with increased cardiovascular risk. (1) The answer to his question is however, unfortunately not straight forward, as we don't yet have definitive, patient based, clinical ‘outcome’ evidence for our recommendation although there is considerable human data that is supportive.
We do know that low-dose aspirin prescribed for cardiovascular prophylaxis should be continued. Low-dose aspirin inhibits platelet aggregation by irreversibly inactivating the platelet’s ability to synthesize and release the prostaglandin thromboxane A2. Thromboxane promotes platelet aggregation. Platelets ‘inhibited’ by aspirin are permanently 'incapacitated'. The result is the platelet’s ability to clump together and contribute to a thrombus is impaired significantly. This effect is not dependent on the patient taking the dose of aspirin every day because of the irreversible effect on the platelets, so the effect of aspirin last days. This is why aspirin is an effective prophylactic therapy in patients at significant risk of cardiovascular events such as a myocardial infarction.
All conventional, non-COX selective NSAIDs, also block platelets by inhibiting thromboxane synthesis but in contrast to aspirin, this effect is reversible. This is why an NSAID is not a satisfactory substitute for low-dose aspirin as a prophylactic therapy for cardiovascular events. As the blood concentration of the NSAID declines, the effect on the platelets also declines and is lost. This loss of platelet inhibitory effect is more pronounced for NSAIDs with shorter half-lives in the body such as ibuprofen, where for significant parts of the 24 hour day, platelets will not be inhibited. This problem is compounded if compliance with the NSAID is not perfect.
There is one other important complication. This effect of aspirin is blocked by concomitant therapy with all non-selective, conventional NSAIDs, except for diclofenac. (2) Also, we now know that the non-selective, conventional NSAIDs also increase the risk of cardiovascular events occurring. Diclofenac happens to be the most risky of the non-selective NSAIDs, and approximately equivalent to available COX-II selective NSAIDs such as celecoxib. (3)
An important distinguishing feature of the COX II selective drugs is that they do not block the effects of aspirin on platelets. Also, the risk for upper GI adverse effects with COX II selective drugs is less than with conventional NSAIDs.
These are the reasons why we suggest that prescribing low doses of a COX-II selective drug is reasonable in patients concomitantly taking low dose aspirin. The effects of the aspirin on platelets will be assured and this will offset the increased risk from the selective COX-II inhibitor. Finally, trying to avoid any NSAID, or at least limiting exposure to them, in patients at risk of cardiovascular disease is recommended.
References
1. Day RO, Graham GG. Non-steroidal anti-inflammatory drugs (NSAIDs). BMJ 2013;346:f3195
2. Solomon DH, Goodson NJ. The cardiovascular system in rheumatic disease: the newest “extraarticular” manifestation? J Rheumatol 2005;32:1415-7.
3. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper
gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; doi:10.1016/S0140-6736(13)60900-[Epub ahead of print.]
Competing interests: ROD has been involved with consultancies with several drug companies on patents and advice on paracetamol, ibuprofen, selective COX-2 inhibitors, and other drugs used for osteoarthritis; all payments for consultancies were made to a trust fund at St Vincent’s Hospital. We acknowledge the assistance of the National Health and Medical Research Council programme grant (568612) for clinical research relating to patient safety.
We thank Dr Pace for his suggestion that limiting exposure to NSAIDs in patients with inflammatory arthritis such as rheumatoid arthritis (RA) is worthwhile. Our article focussed more on the overwhelming use of NSAIDs in osteoarthritis, a non-inflammatory arthritis however we are pleased that Dr Pace has raised matter of inflammatory arthritis. There is an increased risk for cardiovascular events such as myocardial infarction in patients with uncontrolled inflammation (1) and also in most patient groups taking NSAIDs that have been examined. (2) If inflammation is well controlled by anti-rheumatic drugs such as methotrexate or biological agents, the need for continuing NSAID therapy for symptomatic relief of pain and stiffness will be reduced and possibly eliminated. It is logical as Dr Pace suggests, that the stimulus for prescribers to test the need for ongoing NSAID therapy periodically should be greater in the face of additional cardiovascular risk factors such as diabetes, hypertension, raised cholesterol and smoking. These additional factors should be addressed also of course. (3)
However, there have been few studies specifically examining the cardiovascular risks of taking NSAIDs in RA patients. A very recent, well conducted, large, controlled, cohort study from Denmark presented surprising results. RA patients taking NSAIDs had a significantly lower risk for cardiovascular events than the non-RA controls who took NSAIDs over a median follow-up period of 4.9 years (hazard ratio 1.22 in RA [95% Confidence Interval 1.09 – 1.37] and hazard ratio 1.51 in matched, non-RA controls [95% CI 1.36 to 1.66]). (4) This was also the pattern found for individual NSAIDs with the exception of rofecoxib (now withdrawn) and diclofenac where risks were greater.
Therefore, inflammatory arthritis appears to be a special case, where NSAIDs appear to be protective against cardiovascular disease. It seems that this might be related to the NSAIDs contribution to better control of inflammation and pain in RA. Part of this protective effect might be because increased physical activity is possible when pain and stiffness is reduced. (4) In contrast to the more prevalent non-inflammatory musculoskeletal conditions, it is reasonable in treating inflammatory arthritis to be less concerned about the cardiovascular risks of NSAIDs if their use is contributing usefully to symptom control.
1. Peters MJL, Symmons DPM, McCarey D et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010; 69:325-31
2. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; doi:10.1016/S0140-6736(13)60900- [Epub ahead of print.]
3. Solomon DH, Peters MJL, Nurmohamed MT, Dixon W. Motion for debate: The data support evidence-based management recommendations for cardiovascular disease in rheumatoid arthritis. Arthritis & Rheumatism 2013; 65(7):1675-1683
4. Lindhardsen J, Gislason GH, Jacobsen S et al. Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study. Annals Rheumatic Disease 2013; 00: 1-7.doi”10.1136/annrheumdis-2012-203137
Competing interests: ROD has been involved with consultancies with several drug companies on patents and advice on paracetamol, ibuprofen, selective COX-2 inhibitors, and other drugs used for osteoarthritis; all payments for consultancies were made to a trust fund at St Vincent’s Hospital. Payment to ROD was made for expert testimony regarding a veterinary anti-arthritic product unrelated to NSAIDs. We acknowledge the assistance of the National Health and Medical Research Council programme grant (568612) for clinical research relating to patient safety.
From this article, I'm not sure what best practice is for our patients taking low dose aspirin for cardiovascular protection who also may benefit from an NSAID from time to time. Do the authors advise giving a low dose COX-2 inhibitor, despite known concerns with these drugs?
Competing interests: No competing interests
The indications and safety of non-steroidal anti-inflammatory drugs (NSAIDs) are extensively discussed in the article by Day and Graham.1 The importance of reviewing the need for long term use of such drugs is however, insufficiently emphasized.
Inflammatory conditions such as rheumatoid arthritis (RA) are inherently associated with an increased risk of cardiovascular disease.2 This risk may be augmented by the concurrent long term use of NSAIDs for such conditions.
Biological agents such as anti-tumour necrosis factor (anti-TNF) are now established in the treatment of RA. They reduce inflammation and pain by reducing the frequency and severity of flares in the short term as well as by reducing joint erosions, damage and deformity in the longer term.3
The need for long term NSAIDs in patients with RA who respond to biological agents should be constantly reviewed at every contact event with any health professional. In such situations, the efficacy of ongoing treatment with NSAIDs may be evaluated by their temporary withdrawal and the subsequent regular assessment of the effect thereof on pain levels.
The practice of long term, continuous use of NSAIDs for inflammatory conditions that respond to the newer biological agents should be constantly challenged and the withdrawal of such NSAIDs should be considered. This may result in a reduction of, besides other adverse effects, cardiovascular disease and comorbidity in such conditions.
1. Day RO, Graham GG. Non-steroidal anti-inflammatory drugs (NSAIDs). BMJ 2013;346:f3195
2. Sandoo A, Kitas GD, Carroll D, Veldhuijzen van Zanten JJ. The role of inflammation and cardiovascular disease risk on microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional and longitudinal study. Arthritis Research & Therapy 2012;14(3):R117.
3. Pisetsky DS, Ward MM. Advances in the treatment of inflammatory arthritis. Best Practice & Research in Clinical Rheumatology 2012;26(2):251-61.
Competing interests: No competing interests
We thank Dr Oscar Jolobe for his helpful remarks regarding concomitant use of proton pump inhibitors (PPI) to reduce the risk of serious upper gastrointestinal bleeding and ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs). It is good to be reminded that PPIs can cause interstitial nephritis that can lead to renal failure. (1)
This potentially devastating adverse effect is quite uncommon, but may be more likely in the elderly and when higher dose rates of PPI are employed. (2) A case-control study estimated the crude absolute risk in individuals currently exposed to PPI at 12 (95% CI 9.0-15.6) per 100,000 patient years of exposure, the risk rising substantially over the age of 60. (2) The surveillance regimen recommended in our paper for identifying the adverse renal and cardiovascular effects of newly commenced NSAIDs will suffice also to detect the important but rare adverse effect of PPI, namely interstitial nephritis. Thus, regular assessment of weight, blood pressure, urine analysis and plasma urea, electrolytes and creatinine as recommended in our article, with even greater attention in older patients is warranted.(3)
References
1. Ray S, Delaney M, Muller AF. Proton pump inhibitors and acute interstitial nephritis BMJ 2010;341:c4412
2. Blank M. Proton Pump Inhibitors and Interstitial Nephritis. Diss. University of Otago, 2013.
3. Day R O, Graham GG
Non-steroidal anti-inflammatory drugs(NSAIDs)
BMJ 2013;347:34-37
Competing interests: ROD has been involved with consultancies with several drug companies on patents and advice on paracetamol, ibuprofen, selective COX-2 inhibitors, and other drugs used for osteoarthritis; all payments for consultancies were made to an audited trust fund at St Vincent’s Hospital.
Day and Graham (1) have provided an extremely useful summary of the balancing of risks and benefits required when prescribing cyclo-oxygenase inhibitors. However in concentrating on the apparent cardiovascular safety of high-dose naproxen, it is disappointing that they did not explore the potential benefits of flurbiprofen when considering cardiovascular risk.
The non-steroidal anti-inflammatory agent flurbiprofen is widely available at low cost as a generic and anti-platelet effects were reported as long ago as the early 1970s (2). More recent studies have shown that, similar to naproxen, therapeutic levels of flurbiprofen significantly inhibit platelet aggregation and importantly at least in in vitro studies, do not affect the anti-platelet effects of aspirin (3).
As Day and Graham point out naproxen is generally regarded as the NSAID with the lowest cardiovascular risk, typically having a neutral effect: in contrast to the increased risk associated with high-dose coxibs or ibuprofen or diclofenac (4). However the anti-platelet effect of flurbiprofen has actually been shown to be associated with a significant reduction in adverse cardiovascular events. In randomized double-blind trial of therapy following successful thrombolysis or angioplasty for acute myocardial infarction, flurbiprofen (50 mg twice daily) was significantly better than placebo: after 6 months reinfarction was reduced by 71.5% and revascularisation by 50% (5). As would be expected, gastrointestinal bleeding was increased 3-fold, comparable to rates with other NSAIDs (1,4). Flurbiprofen is licenced for use as an anti-platelet agent in France and advocated in guidelines to reduce thrombotic episodes (6).
Although less commonly used clinically and not used at all as a comparator in any of the recent large coxib trials, flurbiprofen seems to have clinically effective protective effects against cardiovascular events. Further larger scale studies would further inform our decision-making but it would be wise to consider flurbiprofen as an option when increased cardiovascular risk is a concern.
1. Day R and Graham G Non-steroidal anti-inflammatory drugs (NSAIDs). BMJ (2013) 346: 3195
2. Davies T, Lederer DA, McNichol S, McNichol GP. The effect of flurbiprofen (2-(2-flouro-4-biphenylyl)proprionic acid) on platelet function and blood coagulation. Throm Res (1974) 5: 667-83
3. Yokoyama H, Ito N, Soeda S, Ozaki M, Watanabe M, Kashiwakura E, Kawada T, Ikeda N, Tokuoka K, Kitagawa Y, Yamada Y. Influence of non-steroidal anti-inflammatory drugs on antiplatelet effect of aspirin.. J Clin Pharm Ther (2013) 38: 12-5
4. Coxib and traditional NSAID Trialists (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet (2013) doi: 10.1016/S0140-6736(13)60900-9. [Epub ahead of print]
5. Broucher ML. Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infaction. Eur Heart J (1993) 14: 951-7
6. Nalpoleon B, Boneu B, Maillard L, Samama C-M, Schved J-F, Gay G, Ponchon T, Sautereau D, Canard J-M. Guidelines of the French Society for Digestive Endoscopy (SFED). Management of Patients on anticoagulants or antiplatelet agents before digestive endoscoopy. Endoscopy (2006) 38: 632-638
Competing interests: No competing interests
We were delighted to see the BMJ Therapeutics series covering non-steroidal anti-inflammatory agents; a class of drugs that have perhaps been unfairly maligned and shunned of late. Whilst Prof’s Day and Graham correctly focus on their clinical use as analgesics, we would like to draw attention to their potential as immunomodulatory agents.
Clinicians commonly associate prostaglandins (PG), the predominant downstream product of cyclooxygenase action on arachadonic acid, with inflammation (and thus inevitably pro-inflammatory effects), however their action is inherently more complex. Individual PG’s have been demonstrated to display significant diversity in their actions, including multi-modal anti-inflammatory properties[1]. In addition they play a pivotal role in signaling the onset of[2], and subsequently facilitating, the resolution of inflammation[3 4]. Dysregulation in their concentration, distribution or duration of production appears to contribute to pathogenic states, either via the non-resolution of inflammation or its corollary, ‘injurious’ resolution[5 6].
In animal models inhibition of PGE2 in the context of either primary[7] or secondary infection[8] is protective, the central mechanism appearing to be restoration of bacterial phagocytosis and NADPH-mediated killing by macrophages[9 10]. In-vitro, cyclooxygenase inhibition appears to prime or augment the innate immune response via alleviating the immunosuppressive prostanoid burden, working synergistically with antibiotics to kill both anti-biotic sensitive and resistant bacteria[11]. Recent clinical observational data has repeatedly demonstrated a morbidity and mortality benefit from the use of non-steroidal anti-inflammatory drugs[12], especially aspirin[13-16], in severe infection and sepsis, prompting a re-assessment of earlier work[17]. Targeted inhibition of cyclooxygenase, or more likely specific antagonism of individual PG’s and/or their receptors, may thus offer an appealing immunomodulatory therapeutic target in certain patient populations[18]. Whilst stratified prospective trials will be required to verify this potential[19], these old drugs may yet possess new and unexpected tricks.
References
1. Scher JU, Pillinger MH. The anti-inflammatory effects of prostaglandins. J Investig Med 2009;57(6):703-8.
2. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2001;2(7):612-9.
3. Rajakariar R, Hilliard M, Lawrence T, Trivedi S, Colville-Nash P, Bellingan G, et al. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2. Proc Natl Acad Sci U S A 2007;104(52):20979-84.
4. Morris T, Stables M, Hobbs A, de Souza P, Colville-Nash P, Warner T, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol 2009;183(3):2089-96.
5. Nathan C, Ding A. Nonresolving inflammation. Cell 2010;140(6):871-82.
6. Fullerton JN, O'Brien AJ, Gilroy DW. Pathways mediating resolution of inflammation: when enough is too much. J Pathol 2013.doi: 10.1002/path.4232. PMID:23794437
7. Aronoff DM, Bergin IL, Lewis C, Goel D, O'Brien E, Peters-Golden M, et al. E-prostanoid 2 receptor signaling suppresses lung innate immunity against Streptococcus pneumoniae. Prostaglandins Other Lipid Mediat 2012;98(1-2):23-30.
8. Brogliato AR, Antunes CA, Carvalho RS, Monteiro AP, Tinoco RF, Bozza MT, et al. Ketoprofen Impairs Immunosuppression Induced by Severe Sepsis and Reveals an Important Role for Prostaglandin E2. Shock 2012;38(6):620-29.
9. Serezani CH, Chung J, Ballinger MN, Moore BB, Aronoff DM, Peters-Golden M. Prostaglandin E2 suppresses bacterial killing in alveolar macrophages by inhibiting NADPH oxidase. Am J Respir Cell Mol Biol 2007;37(5):562-70.
10. Medeiros AI, Serezani CH, Lee SP, Peters-Golden M. Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling. J Exp Med 2009;206(1):61-8.
11. Stables MJ, Newson J, Ayoub SS, Brown J, Hyams CJ, Gilroy DW. Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria. Blood 2010;116(16):2950-9.
12. Sossdorf M, Otto GP, Boettel J, Winning J, Losche W. Benefit of low-dose aspirin and non-steroidal anti-inflammatory drugs in septic patients. Crit Care 2013;17(1):402.
13. Winning J, Reichel J, Eisenhut Y, Hamacher J, Kohl M, Deigner HP, et al. Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms. Platelets 2009;20(1):50-7.
14. Winning J, Neumann J, Kohl M, Claus RA, Reinhart K, Bauer M, et al. Antiplatelet drugs and outcome in mixed admissions to an intensive care unit. Crit Care Med 2010;38(1):32-7.
15. Eisen DP, Reid D, McBryde ES. Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis. Crit Care Med 2012;40(6):1761-7.
16. Eisen DP. Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti-inflammatory drugs on sepsis. Intensive Care Med 2012;38(8):1249-57.
17. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 1997;336(13):912-8.
18. Arons MM, Wheeler AP, Bernard GR, Christman BW, Russell JA, Schein R, et al. Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 1999;27(4):699-707.
19. Cohen J, Opal S, Calandra T. Sepsis studies need new direction. The Lancet Infectious Diseases 2012;12(7):503-5.
Competing interests: No competing interests
Re: Non-steroidal anti-inflammatory drugs (NSAIDs)
We thank Dr Beales for his suggestion that flurbiprofen might be considered as a comparatively safe option amongst NSAIDs because in vitro studies suggest it does not block the interaction of aspirin on platelets.(1) This is intriguing as COX-II selective NSAIDs have this property but not most non-selective, conventional NSAIDs with one exception, namely diclofenac. Confirmation of this lack of inhibition of aspirin interaction with platelets needs to be replicated at low, antiplatelet doses of aspirin.
Further, Dr Beales notes the efficacy of flurbiprofen in reducing re-infarction post angioplasty or thrombolytic therapy. The mechanism is likely to be inhibition of platelet aggregation seen with all non-COX-II selective NSAIDs.
It is of note that flurbiprofen has a short half-life of elimination, around 6 hours,(2). and was administered twice daily in a clinical trial on reinfarction.(3) This dosage rate would have to be maintained to be reasonably confident of continuous flurbiprofen-induced platelet inhibition.
We agree with Dr Beales that large-scale studies on cardiovascular outcomes in patients chronically exposed to flurbiprofen for musculoskeletal conditions would be helpful. We would go further and suggest that these sorts of study are necessary before accepting that this drug be preferred in patients if cardiovascular risk is a concern. In particular, clinical trials of the R enantiomer would be of interest. The R enantiomers of the ‘profen’ drugs are considered not to block prostaglandin synthesis from arachidonic acid but recent work indicates that they may have analgesic activity through inhibition of the oxidation of endocannabinoids by COX-2.4 Unlike the enantiomers of several profens, such as ibuprofen, the R enantiomers of ketoprofen and flurbiprofen are not converted to their S enantiomers which appear to be non-selective NSAIDs.
References
1 Yokoyama H, Ito N, Soeda S, Ozaki M, Watanabe M, Kashiwakura E, et al. Influence of non-steroidal anti-inflammatory drugs on antiplatelet effect of aspirin. J Clin Pharm Ther 2013;38: 12-5
2 Geisslinger G, Lotsch J, Menzel S, Kobal G, Brune K. Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers. Brit J Clin Pharmacol 1994; 37:392-394
3 Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL. Carter BD, et al. (R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2. Nature Chem Biol 2011;7(11):803-9.
4 Brochier ML Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction. The Flurbiprofen French Trial. Eur Heart J 1993;14(7):951-7.
Competing interests: ROD has been involved with consultancies with several drug companies on patents and advice on paracetamol, ibuprofen, selective COX-2 inhibitors, and other drugs used for osteoarthritis; all payments for consultancies were made to a trust fund at St Vincent’s Hospital. We acknowledge the assistance of the National Health and Medical Research Council programme grant (568612) for general toxicological research relating to patient safety.