Key questions regardingNSAIDs* What are the benefits and risks fromNSAIDs? How do I reduce the GI risks? How do I reduce the CV risks? Are there specific safety concerns withetoricoxib ? What does the prescribing data Iook like?*Note by NSAIDs we mean traditional NSAIDs (e.g. diclofenac, naproxen,ibuprofen); etodolac, meloxicam, or coxibs (e.g. celecoxib, etoricoxib)
NICE Full Clinical Guideline 59: Osteoarthritis. Feb 2008Benefits and risks ofNSAIDs
Estimate of hospital-relatedadmissions due to NSAID adversereactionsBandolier 2000;79:6–8Event due to NSAID Estimated number of cases peryear per primary care group(PCG)Upper GI bleed 18Acute renal failure 10Congestive heart failure 22Information based on an average PCG of 100,000 patients where 3,800patients aged over 65 years take NSAIDs
NSAIDs: Renal risksMHRA DSU. May 2009Renal risk
No strong evidence to suggest NSAIDs have aconsistent benefit over paracetamol, although somepatients obtain greater symptom relief from NSAIDs Clinicians should consider offering paracetamol forpain relief in addition to core treatment; regular dosingmay be required Paracetamol (and/or topical NSAIDs) should beconsidered ahead of oral NSAIDs, COX-2 inhibitors oropioidsParacetamol>< NSAIDs?NICE Full Guideline 59: Osteoarthritis, Feb 2008NICE Full Clinical Guideline 59: Osteoarthritis. Feb 2008
Using Paracetamol ?Pincus T, et al. J Rheumatol 2000;27:1020–1027Wolfe F, et al. Arthritis Rheumatol 2000;43:378–385
Risk of upper GI ulcer bleedingLanas A, et al. Gut 2006;55:1731–38Hospital-based, case-control studyin Spain2777 consecutive patients withendoscopy-proved major upper GIbleeding (peptic lesions) and 5532matched controlsUse of NSAIDs increased risk(RR 5.3;95%CI 4.5 to 6.2)No increased risk for NSAIDs +PPI (RR 0.9, 95%CI 0.7 to 1.3)Rofecoxib increased the risk(RR 2.1; 95%CI 1.1 to 4.0)No increased risk with celecoxib(RR 1.0; 95%CI 0.4 to 1.6)0123456789101112131415ControlAceclofenacDiclofenacIbuprofenNaproxenLornoxicamKetoprofenIndomethacinMeloxicamKetorolacCelecoxibRofecoxibParacetamolAdjustedRR
NSAIDs: GI risks Ibuprofen offers the lowest GI risk; Coxibs areassociated with reduced GI risk relative to mostNSAIDs at equivalent dosesMeReC Extra 30. November 2007 When offering treatment with an oral NSAID/coxibinhibitor, the first choice should be either astandard NSAID or a coxib (other thanetoricoxib 60mg). In either case, these shouldbe co-prescribed with a proton pump inhibitor(PPI), choosing the one with the lowestacquisition cost.NICE. Osteoarthritis Guideline CG59. February 2008
Coxibs and cardiovascularriskMHRA. Safety of selective and non-selective NSAIDsOctober 2006 Coxibs are associated with an increasedthrombotic risk. Risk varies according to underlying patient riskfactors Population risk is about 3 additional events (mainlyMI) per 1000 patients per year compared withplacebo. Dose-related adverse effects may manifest earlyand the risk may persist throughout treatment
Traditional NSAIDs and CVriskMHRA. Safety of selective and non-selective NSAIDs. October 2006 Diclofenac 150mg daily has a similar excess thromboticrisk to that of etoricoxib▼ and possibly other coxibs Naproxen 1000mg daily may be associated with a lowerrisk of thrombotic events than coxibs. Although some riskwith naproxen cannot be entirely ruled out, epidemiologicalevidence suggests that naproxen is not associated with anexcess risk of MI Ibuprofen may be associated with a small thrombotic riskat high doses (e.g. 2400mg daily), whereas at low doses(e.g. 1200mg daily) evidence does not suggest anincreased thrombotic risk in the short term
CV Issues With COX-2Selectiveand Traditional NSAIDs In placebo-controlled randomized trials, COX-2selective NSAIDs ↑’ed the risk of thrombotic CV events Observational studies suggest ↑ CV risk for sometraditional NSAIDs CV risk of high-dose naproxen may be different: Meta-analysis of randomized trials: CV risk of high-dose naproxen appears lower than COX-2 inhibitors 2005-6 FDA and European regulatory agencies addeda warning of an increased thrombotic CV risk for allNSAIDs (both COX-2 selective and traditional)20Kearney et al. BMJ. 2006;332:1302; Solomon et al. NEJM. 2005;352:1071; Bresalier et al. NEJM 2005;352:1092;FDA. At: http://www.fda.gov/bbs/topics/news/2005/NEW01171.html. Accessed October 2006;CHMP. At: http://www.emea.eu.int/pdfs/human/opiniongen/nsaids.pdf. Accessed October 2006.
Questions arising with COX-2selective and traditional NSAIDtherapiesThese studies raise many questions:1. Does greater COX-2 selectivity increase CV riskvs. traditional NSAID?2. Is high-dose naproxen, with its sustainedantiplatelet effect, different?3. Would use of aspirin attenuate the increased riskseen with NSAIDs?Need large randomized trials comparing CV outcomesbetween different NSAID agents21
Primary Endpoint: Cumulative Incidence of ThromboticCV Events22Etoricoxib (320 events)Diclofenac (323 events)MonthsNo. of patients at risk*EtoricoxibDiclofenac16,81916,48313,359 10,733 8277 6427 4024 80581538326213790110,14212,8007.06.05.04.03.02.01.006 12 18 24 30 36 420Cumulativeincidence(%)with95%CIEtoricoxib vs diclofenacHR = 0.9595% CI = (0.81-1.11)*Per protocol population.
23Cumulative Incidence of Confirmed Upper GIEvents (Perforations, Ulcers, and Bleeds)*POBs†MonthsNo. of patients at riskEtoricoxibDiclofenac174121728913704 10972 8400 6509 4063 82182038676306802710396131903.02.52.01.51.00.506 12 18 24 30 36 420Cumulativeincidence(%)with95%CIEtoricoxib vsdiclofenacHR = 0.6995% CI = (0.57-0.83)*ITT (14 days) population. 50.6% of patients were on gastroprotective agents.Etoricoxib (176 events)Diclofenac (246 events)†No significant difference in perforations, obstructions, or major bleeds.
24“Our results show that patients with arthritis treatedwith the COX-2 selective NSAID etoricoxib and thosegiven the traditional NSAID diclofenac have nearlyidentical rates of thrombotic cardiovascular events.”Cannon CP, Curtis S, FitzGerald GA, et al. Lancet. 2006:368 (published online) www.thelancet.comDr. Loren Laine is presenting preliminary GI subgroupdata at Am. Coll. Rheumatology in Wash DC todayFor the lower risk upper GI clinical events with etoricoxib: Generally consistent benefit in ASA and PPI subgroups
Etoricoxib and blood pressureMHRA. DSU July 2008 EMA review of etoricoxib Patients whose BP is persistently above 140/90 mmHgand inadequately controlled must not receive etoricoxib High BP should be controlled before starting treatment,and should be monitored for 2 weeks after the start oftreatment and regularly thereafter
Key messages All NSAIDS (both coxibs and traditional NSAIDs)are associated with CV, renal and GI side effects Where NSAIDs are required, base prescribing onthe safety profiles of individual NSAIDs taking intoaccount individual patient risk factors Generally, prescribe NSAIDS at the lowesteffective dose and for the shortest period of timenecessary to control symptoms. Reviewprescribing regularly.
Key messages The risks of CV side effects with diclofenac andcoxibs are similar Low-dose ibuprofen and naproxen areassociated with the lowest CV risk Consider co-prescribing a PPI with an NSAID,especially to those at high risk of GI sideeffects, and when used for long-periods of time