Clinical Risk Management: NSAIDs

The withdrawal of rofecoxib (Vioxx^®) in September 2004 ignited debate regarding the safety of all non-steroidal anti-inflammatory drugs (including selective COX-₂ and non-selective NSAIDs). Drug regulatory agencies^1,2 have since formulated recommendations on appropriate use of NSAIDs.

This therapeutic brief asks you to review the clinical risk management of your veteran patients who use NSAIDs (excluding low dose aspirin), particularly those with diabetes and heart failure.

NSAIDs have effective analgesic and anti-inflammatory properties but their potential to cause serious adverse effects is well known. Patients with heart failure, diabetes, and those aged over 65 years are at particular risk of cardiovascular and renal adverse effects.

In the year April 2004 to March 2005, 105,476 of the 317,908 veterans who were dispensed at least one medicine also received a NSAID (33%).³ 34% of veterans dispensed medicines for diabetes and 33% of veterans dispensed medicines for heart failure were also dispensed at least one NSAID.³

Osteoarthritis is a common reason for use of NSAIDs. Paracetamol is first-line pharmacological treatment for osteoarthritis.⁴ For patients whose pain is not adequately relieved by regular paracetamol, NSAIDs may be considered.

NSAIDs: Major risks

Gastrointestinal (GI) effects

GI complications can occur with all NSAIDs, including the selective COX-₂ NSAIDs.^5-7 Avoid use in patients with active peptic ulcer or GI bleeding and, where possible, in those with a past history of peptic ulcer disease.⁸

Cardiovascular and renal effects

Because there is an increased risk of thrombotic events with COX-₂ selective NSAIDs, particularly at high doses, the Therapeutic Goods Administration in Australia advises that they should not be prescribed for patients with increased risk of cardiovascular events, such as heart attacks.¹

Similarly, European authorities state that COX-₂ selective NSAIDs are contraindicated in patients with established ischaemic heart disease and/or cerebrovascular disease or peripheral arterial disease, and that caution is necessary if prescribing COX-₂ selective NSAIDs to patients with risk factors for heart disease such as hypertension, hyperlipidaemia, diabetes, or smoking.²

All NSAIDs, including selective COX-₂ NSAIDs, inhibit prostaglandin synthesis thereby causing salt and water retention. This can worsen heart failure or hypertension.

The beneficial effects of diuretics and ACE inhibitors/angiotensin II receptor blockers (A₂RB) for heart failure and hypertension can be antagonised by NSAIDs.

NSAIDs, including COX-₂ NSAIDs, may cause or exacerbate kidney impairment. NSAIDs, ACE inhibitors, and diuretics, individually or in combination, are implicated in the majority of cases of iatrogenic acute renal failure and the combination of these three drug groups (the “triple whammy”) should be avoided. Reduced renal blood flow due to heart failure, dehydration, or renal disease increases the risk of this effect.⁹

NSAIDs increase the risk of hyperkalaemia in patients on ACE inhibitors and A₂RB, particularly those with diabetes or renal impairment.

Why are patients with heart failure or diabetes at higher risk from NSAIDs?

Heart failure:

May be exacerbated by the salt and fluid retention caused by NSAIDs. NSAIDs have been associated with substantially increased hospital admission due to heart failure. The heart failure disease burden from these drugs may be similar to that for serious GI complications.¹⁰

Diabetes:

The American Heart Association indicates that patients with diabetes belong in the same risk catagory as patients with known cardiovascular disease.¹¹ Concurrent use of an NSAID with an ACE inhibitor may increase the risk of renal impairment. NSAIDs can increase blood pressure¹² and small increases in blood pressure in hypertensive diabetic patients are associated with a substantial increase in the risk of cardiovascular morbidity.¹³

NSAIDs: Alternatives in osteoarthritis

Non-pharmacological measures:

Weight loss, exercise and physiotherapy. Continue once drug therapy is introduced.

Paracetamol:

Comparable efficacy and better safety profile than NSAIDs for patients with mild to moderate joint pain.⁴

Is first-line treatment and should be used regularly - ie 1000mg (2x500mg) four times daily for standard paracetamol tabs.

Modified-release paracetamol tablets eg Panadol Osteo^® & Duatrol SR^® may aid compliance (1330mg (2 x 665mg tabs) three times daily).^{✝ 14}

✝ Available under the PBS as a restricted benefit for the relief of persistent pain associated with osteoarthritis.

Topical NSAIDs:

Can help if symptoms are mild and may be used with regular paracetamol; serious systemic adverse effects are less likely than with oral NSAIDs.⁸

Paracetamol + low-dose/intermittent NSAID

Intra-articular corticosteroids:

Useful for localised inflammatory disease in selected patients.

Glucosamine:

Symptom relief in mild to moderate osteoarthritis of the knee. Additional monitoring of blood glucose may be warranted in people with diabetes.¹⁵

NSAIDs: Clinical risk management of high risk patients

Choice of NSAID

There is little difference in efficacy between agents.⁸ Maximal analgesic and anti-inflammatory effects of NSAIDs are usually seen in 2 weeks; if no response in 3 weeks, try a different NSAID.⁸

Use the lowest effective dose for the shortest duration possible

The incidence of adverse effects of NSAIDs increases in a linear fashion with dose.¹⁹ For patients whose symptoms are well controlled, attempt NSAID dose reduction and try on an as-needed basis.⁴

Both high-dose and long plasma half-life NSAIDs (eg naproxen, piroxicam) have been associated with an increased risk of precipitation of heart failure¹⁰ or renal impairment.¹⁶

Choose an NSAID with a lower risk of adverse GI events, eg low-dose ibuprofen (<1200mg/day) or diclofenac^8,17 or celecoxib.

Do not use more than one oral NSAID at the same time; only use in patients on low-dose aspirin if absolutely necessary.⁷ Regardless of which NSAID is used (including the more selective COX-₂ NSAIDs) co-administration with low dose aspirin increases the risk of GI events.

Consider a gastroprotective agent

Consider a proton pump inhibitor^✝✝ or misoprostol (not H₂-antagonists¹²) in those at moderate or high risk of GI adverse events:

• age over 65 years
• concomitant medications known to increase upper GI adverse events (e.g. anticoagulants, steroids, low-dose aspirin, and bisphosphonates)
• serious co-morbidity (e.g. cardiovascular disease), or
• prolonged use of maximum recommended doses of non-selective NSAIDs.¹⁸

✝✝ The prescriber must certify that the patient satisfies criteria set out in the Pharmaceutical Benefits Schedule.

Assess and monitor renal, cardiovascular and gastrointestinal risk

Current expert opinion suggests:

Check renal function, electrolytes and blood pressure at baseline. Repeat after one week (high risk patients) or 2 to 4 weeks (standard monitoring).

• Estimate glomerular filtration rate (GFR) by calculating creatinine clearance (see below).
• Check electrolytes, with particular attention to hyperkalaemia which may occur in the absence of marked renal dysfunction.
• Monitor for marked weight gain or increased oedema.
• Ask your patient to weigh themselves daily and to report an increase in weight of 1.5kg or more over 24 hours.
• Monitor for signs and symptoms of GI complications.
• Measure complete blood count and liver function and repeat at least once a year.

Calculate creatinine clearance (Clcr) in mL/min using Cockcroft-Gault equation

^*If patient’s actual body weight is less than the ideal body weight the actual body weight should be used.⁸

Emerging Issues

What to tell my patient

• Instruct patients on how to use paracetamol appropriately and discuss alternative ways to manage pain.
• Explain that anti-inflammatory medicines can affect the heart by increasing fluid and salt retention, and that they can cause or worsen heart and kidney disease.
• Advise patients to stop the NSAID and contact you immediately if they notice sudden weight gain, swollen feet or ankles, increased tiredness or breathlessness, gastrointestinal problems (e.g. black stools or dark, coffee-coloured vomit) or any other unwanted effects.
• For diabetic patients, emphasise their increased risk of cardiovascular & kidney problems, which can be further increased by the use of NSAIDs.
• Encourage patients to discuss with you their use of over-the-counter medicines, including those for pain or arthritis e.g. paracetamol, ibuprofen.
• Advise that lifestyle interventions (physical activity, maintaining a healthy bodyweight and healthy eating) are life-long.

References

1. McEwen J. Expanded information on COX-2 inhibitors for doctors and pharmacists (amended). Australian Government Department of Health and Ageing Therapeutic Goods Administration; 14 February 2005. Available at: http://www.tga.gov.au/media/2005/050214_cox2.pdf (accessed 05/07/05)
2. European Medicines Agency. European Medicines Agency concludes action on COX-2 inhibitors. London: 27 June 2005. Available at: http://www.emea.eu.int/Cox2inhibitors.htm (accessed 05/07/05)
3. Veterans Datamart, University of South Australia, QUMPRC. Accessed June 2005.
4. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000; 43: 1905-15.
5. Adverse Drug Reactions Advisory Committee (ADRAC). Celecoxib: early Australian reporting experience. Aust Adverse Drug React Bull 2000; 19: 6.
6. Committee on Safety of Medicines/Medicines Control Agency. In focus: rofecoxib (Vioxx). Current Problems 2000; 26: 13.
7. Committee on Safety of Medicines/Medicines Control Agency. Non-steroidal anti-inflammatory drugs (NSAIDs) and gastrointestinal (GI) safety. Current Problems 2002; 28: 5.
8. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2005.
9. Adverse Drug Reactions Advisory Committee (ADRAC). ACE inhibitor, diuretic and NSAID: a dangerous combination. Aust Adverse Drug React Bull 2003; 22: 14-15.
10. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000; 160: 777-84.
11. Grundy SM, et al. Prevention Conference VI: Diabetes and Cardiovascular Disease: executive summary: conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2002; 105: 2231-9.
12. Hawkey CJ, Langman MJS. Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors. Gut 2003; 52: 600-8.
13. Sowers JR, et al. Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT) Investigators. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med 2005; 165: 161-8. Erratum. ibid: 551.
14. Schedule of Pharmaceutical Benefits for Approved Pharmacists and Medical Practitioners. Effective from 1 April 2005. Available at: http://www.health.gov.au/pbs (accessed 10/06/05)
15. Towheed TE, et al. Glucosamine therapy for treating osteoarthritis. Available in The Cochrane Database of Systematic Reviews 2005, Issue 2. Chichester: John Wiley; 2005.
16. Henry D, et al. Consumption of non-steroidal anti-inflammatory drugs and the development of functional renal impairment in elderly subjects: results of a case-control study. Br J Clin Pharmacol 1997; 44: 85-90.
17. Henry D, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996; 312: 1563-6.
18. National Institute for Clinical Excellence. Guidance on the use of cyclo-oxygenase (cox)-II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for osteoarthritis and rheumatoid arthritis. Issued July 2001; reviewed May 2004.
19. Clinical Evidence: Non-steroidal anti-inflammatory drugs. Search date January 2004. London: BMJ Publishing Group, 2004.
20. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005: 330 (7504):1366.

Return to top