NSAIDS

Mechanism of NSAID action

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EFFICACY OF NSAIDS• About 60% of patients will respond to

any NSAID• Those who do not respond to one

may well respond to another• Pain relief starts from the first dose,

with full analgesic effects obtained within a week

• Anti-inflammatory effects may not be achieved for up to 3 weeks

[BNF 63 March 2012]

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Medicines Use and SafetyGOOD

QOL

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• No strong evidence to suggest NSAIDs have a consistent benefit

• Some patients obtain greater symptom relief from NSAIDs at the cost of side effects

• Clinicians consider offering NSAIDS for pain relief in addition to core treatment;

• Regular dosing may be required• Paracetamol and/or topical NSAIDs should

be considered ahead of oral NSAIDs, COX-2 inhibitors or opioids

NPC QIPP/NICE OA

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Medicines Use and SafetyBAD

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NSAID ADVERSE EFFECTS ( IN AN OLDER POPULATION)

BASED ON AN AVERAGE PCG OF 100,000 PATIENTS WHERE 3,800 OVER '65S TAKE NSAIDSBANDOLIER 2000;79:6-8

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Event Cases per year

Upper GI bleed 18

Acute renal failure 10

Congestive heart failure 22

GI INVOLVEMENT IN NSAIDSDYSPEPSIAREFLUX ESOPHAGTISPILL INDUCED ESOPHAGTISGASTRIC EROSIONSGASTRIC ULCERDU. ULCERSSMALL BOWEL ULCERSCOLON ULCERS GI BLEEDINGPERFORATIONACUTE LIVER INJURY

GIT-- LESIONS DEPEND ONTYPE OF NSAIDSDURATIONCO MORBODITIESCOMEDICATIONAGE

THERE IS A POOR CORRELATION WITH CLINICAL SYMPTOMS AND ACTUAL LESIONS

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RISK OF UPPER GI BLEEDING

LANAS A ET AL GUT 2006;55:1731–38

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0123456789

101112131415

Adju

sted

RR

Slow-release NSAIDs Pose Greater Risk of GI BleedingPersistent exposure to the drug is an important independent determinant;

In fact, drugs with a long half-life or slow-release formulation were associated overall with a greater risk than NSAIDs with a short half-life.

Lowest GI toxicity with coxibs, i.e., celecoxib and rofecoxib, which supports the notion that sparing of COX-1 in the GI tract and possibly in platelets translates clinically to a lower upper GI risk."

Am Col Rheumatology.

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GI ADVERSE EFFECTSRisk factors include

- Age over 65- History of GI bleed or ulcer- Concurrent use of drugs that increase the risk of GI adverse events- Heavy smoking or alcohol use- Prolonged NSAID use- Particular NSAID and high dose- Serious co-morbidity

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Medicines Use and Safety

Age Chance of GI bleed due to NSAID

Risk in any one year

Chance of death due to NSAID GI bleed

Risk in any one year

16-45 1 in 2100 1 in 12353

45-64 1 in 646 1 in 3800

65-74 1 in 570 1 in 3353

>75 1 in 110 1 in 647

[Bandolier NSAIDs and adverse effects]

Non-steroidal Anti-inflammatory Drugs Use and Risk of Upper Gastrointestinal Adverse Events in Cirrhotic Patients

Yen-Chieh Lee

Liver International. 2012;32(5):859-866.  

Managing GI Toxicity

From a clinical point of view, the main goal in the management of patients receiving NSAIDs is the prevention of GI complications rather than acute mucosal lesions.

Targeting Modifiable Risk Factors

Lowest effective NSAID dose Lowest possible period of time. 

The Addition of Gastroprotectants to NSAIDsMISOPROSTIL(Misoprostol Ulcer Complications Outcomes Safety Assessment trial [MUCOSA] 

H2-receptor antagonists 

Proton pump inhibitors (PPIs)

PPIs reduced the risk of upper GI complications.

PPI use was associated with risk reduction among both tNSAID and low-dose aspirin users and among patients taking NSAIDs and clopidogrel.

Based on all these studies, the American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association 2008 Expert Consensus Document

PPI AS STANDARD OF CARE

1) Use the lowest effective dose for the shortest period of time

2) Avoid concomitant therapy with corticosteroids, anticoagulants, low-dose aspirin or antiplatelet agents

3)Use 'safer' NSAIDs (coxibs, diclofenac, aceclofenac and ibuprofen)

4)Less use of NSAIDs with the highest gastrointestinal toxicity (ketorolac, piroxicam, and ketoprofen)

5)Eradicate Helicobacter pyloriinfection in patients with prior ulcer history ?

Clinical Guidelines

No gastrointestinal risk factors: use tNSAIDs (no need for prevention strategies)

One or more gastrointestinal risk factors: coxib (standard dose) alone or nonselective NSAID + PPI or misoprostol

Clinical Guidelines

If history of ulcer bleeding: coxib + PPI. Eradicate H. pyloriinfection. Avoid nonselective NSAIDs

Prescribing Coxibs Instead of tNSAIDs.

A meta-analysis of 112 large-scale RCTs

The risk of symptomatic ulcers and serious GI complications associated with coxibs (celecoxib, rofecoxib, etoricoxib and lumiracoxib) were lower than that of nonspecific NSAIDs .

The Cochrane Collaboration concluded that compared with nonselective NSAIDs, coxibs (celecoxib, valdecoxib, etoricoxib, limiracoxib and rofecoxib) produced significantly fewer gastroduodenal ulcers (RR: 0.26; 95% CI: 0.23–0.30) and ulcer complications (RR: 0.39; 95% CI: 0.31–0.50), as well as fewer treatment withdrawals caused by GI symptoms.

Management of GI Risk With Asprin

Aspirin the main reason for hospitalizations due to GI bleeding

Low-dose aspirin increases the risk of UGIB.

A meta-analysis of 14 randomized clinical trials,  absolute rate increase of major UGIB with aspirin above placebo of 0.12% per year .

Risk factors for GI bleeding with asprin include age ≥70, ulcer history, co-therapy with NSAIDs, coxibs, anticoagulants or other antiplatelet agents.  

Those at risk should be on GI prevention therapy

 . The use of an alternative platelet inhibitor, such as clopidogrel,

The use of co-therapy with a gastroprotective agent

Eradicating H pylori

Management of Patients With Peptic Ulcers or Dyspepsia Associated With NSAID Use

Nonsteroidal anti-inflammatory drugs and coxib therapy delay the healing of active peptic ulcers.

In patients who develop a peptic ulcer during NSAID or coxib treatment, the drug should be stopped, patients treated with PPI therapy and H. pylori eradicated if the infection is present.

If patients are unable to discontinue NSAID therapy, patients need to be treated with PPI twice a day co-therapy until the ulcer is healed, which must be confirmed by endoscopy.

NSAIDs & Lower GI DamageStudies have shown that more than 50% of patients on NSAIDs or low-dose aspirin may have mucosal lesions or mucosal breaks in the small bowel.

 Clinically significant GI bleeding and perforation, diarrhoea, mucosal ulceration, symptomatic diverticular disease and strictures due to fibrous diaphragms may occur

Similar or higher mortality frequency for complications from the lower GI tract when compared with those from the upper GI tract.

NSAID use might damage the lower GI tract (small bowel, colon or anus), with a rate of bleeding events that is believed to be approximately a third of that of upper GI bleeding.

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CV Effects of NSAIDs

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HAZARD RATIOS FOR COMPOSITE ENDPOINT OF DEATH AND MI DURING THE INITIAL TREATMENT PERIOD NSAID Death and MI

HR, 95%CINo use 1·00 Ibuprofen 1·31 (1·15–1·49)* Diclofenac 2·50 (2·18–2·88)*

Naproxen 1·45 (1·08–1·94)†Rofecoxib 3·50 (2·88–4·26)*

Celecoxib 3·05 (2·53–3·68)**p<0.0001; †p=0.01 MHRA Jan 2010

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MHRA 2006• Non selective NSAIDs - small increased risk of thrombotic events (eg heart attack or stroke)

• Coxibs - about three additional thrombotic events per 1000 patients per year in the general population

• Diclofenac - thrombotic risk profile similar to that of at least one coxib (etoricoxib)

• Naproxen and ibuprofen (1200mg or less) no increased risk

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Medicines Use and Safety

Rofecoxib and lumiracoxib were associated with the highest risk of MI;

Ibuprofen and diclofenac were associated with the highest risk of stroke .

Etoricoxib and diclofenac were associated with the highest risk of death due to CV causes.

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RENAL RISKS• On going reports of renal failure in

patients taking NSAIDs• Patients at risk of renal impairment or

failure (particularly elderly people) should avoid NSAIDs if possible.

• If NSAID is essential, renal function should be monitored during treatment

• Contributing risk factors include co-administration of ACE inhibitors, diuretics

MHRA Drug Safety Update May 2009

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NICE CG 59 OSTEOARTHRITIS 2008• All oral NSAIDs/COX-2 inhibitors have

analgesic effects of a similar magnitude

• They vary in their potential GI, liver and cardio-renal toxicity

• When choosing the agent and dose, healthcare professionals should take into account individual patient risk factors, including age

• Consideration should be given to appropriate assessment and/or ongoing monitoring of these risk factors

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SUMMARY

• Consider individual patient risk factors and safety profiles of individual NSAIDs

• Lowest effective dose for shortest period of time

• Low-dose ibuprofen (≤1200mg per day) first choice NSAID: low GI and CV risk

• Low-dose ibuprofen or naproxen 1000mg/day for patients with CV risk

• Consider a PPI with any NSAID to reduce the risk of adverse GI effects, particularly if high GI risk (includes anybody aged 65 years or older) and long-term NSAID users

MeReC Extra 30 Nov 2007

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Medicine is the art of entertaining the patient, as the body heals itself.”

Thank you

Evidence Based MedicinePatient oriented clinical medicineGoal oriented medical therapy