Case Study 9: COX-2-selective NSAIDs

Transcription

1 Case Study 9: COX-2-selective NSAIDs July 2000

2 Scenario Kevin is a seventy year old male who presented five months ago with painful tender swelling in the right knee and hip pain which was aggravated by movement. After clinical examination it was concluded Kevin was suffering from osteoarthritis. Serology was normal and biochemistry was unremarkable except for urea 8.7mmol/L and creatinine 0.14mmol/L. He has been well controlled to date with paracetamol 1g four times daily, although for the past three weeks he has noticed recurrence of joint symptoms. Kevin s other medications include enalapril 10mg twice daily for heart failure. He also has mild reflux which is controlled by occasional doses of antacid and moderating his alcohol intake. Inside Results In summary page 3 In detail page 4 Expert commentaries Prof. Richard Day page 7 Dr Mary Surveyor page 10 References page 12 2

3 Case Study Results Results in summary At the time of data analysis 62 responses had been received to this case study following a satellite broadcast on COX-2-selective NSAIDs in April Most respondents identified Kevin to be at high risk for complications if an antiinflammatory drug was prescribed. Eighty one percent of respondents chose to initiate non-drug therapy and 35% chose new drug therapy. Ten respondents (16%) would initiate both types of therapies. Physiotherapy, exercise, heat and/or ice management and weight reduction were the most common non-drug therapies initiated. Also topical anti-inflammatories and glucosamine were some of the options chosen as new drug therapy. Of the respondents who initiated an anti-inflammatory agent, COX-2-selective NSAIDs were more commonly (48%) chosen than the conventional NSAIDs (37%). The greater rate of selection of COX-2-selective NSAIDs may have been as a result of respondents completing the case study following a satellite broadcast on this topic. Celecoxib (Celebrex ) mg/day in 1-2 divided doses was most frequently prescribed (46%) and shorter acting conventional NSAIDs such as diclofenac and ibuprofen were the next most frequently prescribed. Sixteen percent prescribed diclofenac mg/day in 2-3 divided doses and 16% prescribed ibuprofen mg/day in 2-3 divided doses. Seventy three percent of respondents correctly identified the risks of prescribing either a COX-2-selective NSAID or a conventional NSAID. The risks are that both types of NSAIDs can precipitate heart failure and renal failure. At the time of writing, conventional NSAIDs are more likely to exacerbate dyspeptic symptoms compared to celecoxib. However, the newer COX-2-selective agent, rofecoxib (Vioxx ) has been reported to have an equivalent incidence of dyspepsia as the conventional NSAIDs (ibuprofen, diclofenac). 1 Most respondents would look at Kevin s urea, creatinine & electrolytes or renal function tests, renal artery perfusion, creatinine clearance and concurrent medications when deciding on an anti-inflammatory prescription, given his altered renal function. Eighty nine percent of respondents identified lower incidence of gastrointestinal adverse effects occur with COX-2-selective NSAIDs and 82% of these respondents chose this as the only advantage of COX-2-selective NSAIDs over conventional NSAIDs. 3

4 Results in detail Question 1 Would you initiate new therapy in response to recurrence of symptoms? All respondents would initiate a new therapy. Eighty one percent would initiate new non-drug therapy and 35% would prescribe new drug therapy -16% of respondents would do both. The most common forms of therapies selected are outlined in the table below. Therapy Percentage Respondents* Non-drug Physiotherapy 45 Exercise 44 Heat and/or ice treatment 23 Weight reduction 15 Rest 5 Aspiration/ surgical review 5 Compression/ support bandage 3 Acupuncture 3 Drug Topical anti-inflammatory agents 15 Glucosamine 11 Topical analgesics- capsaicin 3 Unspecified 5 * respondents may have made more than one response Question 2 If you decide to initiate an anti-inflammatory drug, what agent would you select? What dose and frequency would you select? The majority of respondents (92%) selected an anti-inflammatory drug while 2% chose not to initiate drug therapy. Six percent of respondents did not specify the agent to be used. COX-2-selective NSAIDs were more commonly selected by the respondents (48%) than conventional NSAIDs (37%). The table below outlines the choices selected. COX-2-selective NSAID COX-2-selective NSAID Dose and frequency Percentage Respondents Celecoxib mg/day 46 in 1-2 divided doses 100mg/day in one dose mg/day in 1-2 divided doses 2 Unspecified 4 4

5 Conventional NSAIDs NSAID Dose and frequency Percentage Respondents* Diclofenac mg/day 16 in 2-3 divided doses Ibuprofen Ketoprofen 50mg/day in 2 divided doses 4 Unspecified mg/day 16 in 2-3 divided doses 600mg/day in 3 divided doses 4 Unspecified mg/day 2 in 1-2 divided doses Piroxicam 10-20mg/day 2 in 2 divided doses NSAID +/ - Paracetamol Unspecified 5 * respondents may have chosen more than one conventional NSAID Question 3 What are the risks of using a conventional NSAID or COX-2-selective NSAID in this patient? Seventy three percent of the respondents correctly identified the risks of using conventional NSAIDs or COX-2-selective NSAIDs in this patient. These respondents selected all options except COX-2-selective NSAID, celecoxib, exacerbating dyspeptic symptoms. The responses for each of the risk factors are shown in the table below. Risks of using conventional NSAIDs Percentage Respondents Precipitation of heart failure 85 Precipitation of renal failure 92 Exacerbation of dyspeptic symptoms 98 Risks of using COX-2-selective NSAID Percentage Respondents Precipitation of heart failure 82 Precipitation of renal failure 95 Exacerbation of dyspeptic symptoms 6 Question 4 What additional information would help you to determine whether it is safe to use a conventional NSAID or a COX-2-selective NSAID in a patient with altered renal function? Most commonly respondents would look at Kevin s serum creatinine or renal function (26%) and also concurrent medications he was taking (23%). The table below summarises the additional information the respondents would seek. 5

6 Relevant additional information Percentage Respondents* For altered renal function Urea, creatinine & electrolyte/ renal function 26 Concurrent medications 23 Creatinine clearance 11 Renal artery perfusion/ renal ultrasound 10 Co-existing diseases 9 Degree of hydration 8 History of NSAID usage 6 Age 3 24 hour urine protein excretion 3 Pharmacokinetics of both NSAIDs 2 Other information Past history of gastrointestinal complaints 10 Assessment of severity of pain 3 Allergy- sulphonamides and/or aspirin 2 Other 6 Unspecified 16 * respondents may have made more than one response Question 5 Is there any advantage in selecting a COX-2-selective drug over a traditional NSAID in this patient? All the respondents who answered yes to the above question (89%) identified that COX-2-selective NSAIDs have a lower risk than conventional NSAIDs with respect to gastrointestinal (GI) adverse effects. Sixty five percent of these respondents indicated that there was a lower risk of GI ulceration and/or lower incidence of dyspepsia with COX-2-selective NSAIDs. Eighty two percent of the respondents who answered yes to the question found no advantage in terms of pain relief or renal and cardiovascular effects. Eight percent of respondents found no advantage in selecting a COX-2-selective drug over a traditional NSAID while three percent were unsure of any advantage. The respondents who specified other benefits of COX-2-selective NSAIDs commented on compliance issues such as convenient daily dosing, less need for companion drugs such as H 2 antagonists and reduced potential for drug interactions. 6

7 Expert commentary Professor Richard Day Professor of Clinical Pharmacology, University of New South Wales Director of Clinical Pharmacology & Toxicology, Rheumatologist St Vincent s Hospital, Sydney Kevin s case is a commonly encountered problem of degenerative knee and hip joints in an elderly individual with intermittent gastro-oesophageal reflux, renal impairment and cardiac failure treated with the ACE inhibitor, enalapril. His risk factors for NSAID-induced upper gastrointestinal (GI) bleeding are his age (>65 years) and possibly cardiac failure. He does not have the risk factors of previous upper GI peptic ulcer or concurrent intake of glucocorticosteroid therapy. Reflux symptoms are not a risk factor for serious upper gastrointestinal adverse reactions but the symptoms are likely to be worsened by NSAIDs. It was gratifying that most respondents to the questions would prescribe new nondrug therapy, particularly physical therapy. There is good randomised controlled evidence for the benefits of physical therapy, weight reduction and education and counselling. There is some evidence that the complementary therapy glucosamine may have some benefit in osteoarthritis, notably in reducing pain and stiffness. Proof of long term benefit by way of slowing of loss of cartilage is lacking however. Question 1 Would you initiate new therapy in response to recurrence of symptoms? Because the patient has noted the re-occurrence of joint symptoms it is appropriate that just about all respondents would initiate new therapy. The additional non-drug therapies worth considering include joint protection by measures such as avoidance of stairs and reduction of weight and weight-bearing activities. The cardiac failure, concurrent ACE inhibitor therapy, renal impairment and GI reflux symptoms should lead to caution in prescribing a nonsteroidal anti-inflammatory drug or a COX-2- selective NSAID. Question 2 If you decide to initiate an anti-inflammatory drug, what agent would you select? Interestingly, 8% of respondents would not select an anti-inflammatory drug even though the question implied that a decision to prescribe an NSAID had already been taken. I have some sympathy with this view as it is very worthwhile to explore the patient s compliance with paracetamol 1g QID. Often patients have difficulty taking tablets 4 times a day. The history and questions do not make it clear whether Kevin will continue on paracetamol. It s a good option to continue the paracetamol and add an NSAID because this approach reduces the dose of NSAID needed and thereby lowers the risk for serious upper GI adverse effects. 7

8 COX-2-selective agents were preferred (48%) but quite a proportion of respondents were happy to commence a conventional NSAID (37%). Kevin has one definite (age) and one likely (cardiac failure) risk factor for upper GI adverse effect so prescription of the COX-2-selective agent is reasonable. However, the selection of a low dose of one of the safer NSAIDs (ibuprofen or diclofenac) may lead to adequate pain relief with very little increased GI risk. The dose of NSAID or COX-2-selective inhibitor should be the lowest that produces reasonable symptom relief. Optimally, patient control of dosage such that reduction or even cessation of anti-inflammatory drug in periods of reduced pain is appropriate. Avoidance of conventional NSAIDs with long half lives such as piroxicam or slow release ketoprofen is appropriate in osteoarthritis cases such as Kevin s as the risk for serious upper GI adverse effects is greater. The relationship between indigestion like symptoms and the presence of a peptic ulcer is poor. It does seem that there is a somewhat reduced rate of dyspeptic and indigestion like symptoms with COX-2-selective NSAIDs in comparison to conventional NSAIDs. This would be another practical reason for considering a COX- 2-selective NSAID for Kevin. There would be nothing wrong with trying the cheaper (for non-concession cardholders) conventional NSAID first for tolerance and switching to a COX-2-selective NSAID if reflux symptoms are a problem. With respect to the selection of a COX-2-selective drug, there is only one choice available on PBS at this time, namely celecoxib (Celebrex ). An appropriate dose would be the lowest that would relieve the symptoms, used for the shortest possible time. Therefore, mg/day in single or divided doses is reasonable. It would be optimal to have the patient control the dosage according to symptoms. It is possible that 100mg once daily would be sufficient to control the symptoms in some people. Question 3 What are the additional risks of using a conventional NSAID or COX-2-selective NSAID in this patient? The additional risks from the traditional NSAID and COX-2-selective NSAID for Kevin were well recognised by most respondents. Respondents knew that COX-2- selective agents as well as the conventional NSAIDs can precipitate heart failure in those with controlled heart failure. A particular risk might be patients taking both ACE inhibitors and diuretics. 2 Both NSAIDs and COX-2-selective NSAIDs can precipitate further renal impairment in those with evidence of renal impairment, as with Kevin. Many fewer respondents were aware that the COX-2-selective NSAIDs could exacerbate or cause GI dyspeptic symptoms, although this is somewhat less likely to occur than with conventional NSAIDs. 8

9 Question 4 What additional information would help you to determine whether it is safe to use a conventional NSAID or a COX-2-selective NSAID in a patient with altered renal function? This was a difficult question, perhaps a bit unclear. We knew already that Kevin had a raised plasma creatinine and urea and that he had heart failure treated with enalapril. The majority of respondents identified that these facts were most important pieces of additional information required. I take this to mean that respondents thought these factors should be monitored if the decision to prescribe an anti-inflammatory is taken. I agree with this and the suggestion by 9% of respondents to understand comorbidities e.g. cardiovascular (and their severities) at baseline and a component of monitoring. Other monitoring would be symptoms and clinical signs of cardiac failure, weight and blood pressure. A decision not to prescribe because the concerns about the cardiovascular and renal systems were too great might also be reasonable. It comes down to the benefit that might accrue versus the risks. It is important to know whether the patient has sulfur drug allergy as celecoxib is contraindicated. Similarly, aspirin allergy remains a contraindication with conventional NSAIDs and COX-2-selective drugs at this time. Question 5 Is there any advantage in selecting a COX-2-selective drug over a traditional NSAID in this patient? The majority of respondents felt that there was an advantage of using a selective COX-2 drug over traditional NSAIDs in this patient. This question is a re-run of question 2 to some extent, although question 5 is somewhat loaded to result in a positive response! The only advantage for Kevin is lowering the risk of GI ulceration and bleeding but this is the most important risk with NSAIDs. Also, perhaps there will be less reflux symptoms and this might mean less use of concurrent gastroprotective agents such as antacids or H 2 antagonists. As noted above there might not be too much benefit if the dose of NSAID needed is low, a safe NSAID is chosen and perhaps the need for NSAIDs turns out to be intermittent. Cost to the patient might be the motive for not selecting the COX-2-selective drug but this is unlikely to be the case with Kevin who at the age of 70 should be on the old age pension and eligible for $3.20 PBS prescription costs. I agree with most respondents that there is no obvious advantage in terms of symptom relief, or risk of renal or cardio-vascular adverse effects. 9

10 Dr Mary Surveyor General Practitioner, Osborne, Western Australia This case of a 70-year-old male with osteoarthritis in a single large joint is a common presentation. The history of initial pain relief with 4g per day of paracetamol, but subsequent recurrence of symptoms is also a typical story. The responses by the 62 general practitioners show a very good identification of the main issues. The fact that 81% chose initially to initiate non-drug therapy shows a good awareness of the benefits of non-drug therapy and the possible complications if an anti-inflammatory is prescribed. There was also a good knowledge of the side effect profiles of both COX-2-selective NSAIDs and the non-selective NSAIDs, with most respondents identifying the similar effects on cardiac failure and renal function of both groups. Question 1 Would you initiate new therapy in response to recurrence of symptoms? Most of the suggested non-drug therapies were appropriate and are likely to assist with pain relief in a reasonable number of patients. The fact that only one joint appears to be affected makes local treatments with heat or ice, topical antiinflammatories and other therapies especially worth trying. Although weight reduction may be helpful for a number of other reasons, it is probably unlikely to give much relief of knee joint pain and certainly not in the shortterm. Question 2 If you decide to initiate an anti-inflammatory drug, what agent would you select? A somewhat greater number chose the COX-2-selective NSAID on the grounds of a better side effect profile with respect to gastrointestinal adverse effects. This is most likely due to the patient s reported history of dyspepsia and the evidence that there is a lower incidence of dyspepsia caused by celecoxib than with conventional NSAIDs. This is a reasonable choice to make. However, I do not think one can criticise those who selected a more conventional NSAID, since the history only revealed mild reflux requiring occasional doses of antacid. There is no history of ulceration or gastric bleeding, which would be much more significant and warrant extreme caution in using a conventional NSAID. In spite of their relative gastric safety, COX-2-selective NSAIDs may cause dyspepsia and this may be due to reflux, so the choice of a COX- 2-selective NSAID over a conventional NSAID might well make no difference to side effects and would certainly be more expensive. In general those who would use a conventional NSAID were more likely to select the relatively safer NSAIDs such as diclofenac and ibuprofen. 10

11 The vast majority chose appropriate doses of which drug they would use, although a few chose unusually high initial doses of celecoxib, where the recommended dose in osteoarthritis is 200mg daily. A dose of ibuprofen of only 600mg is likely to be ineffective, unless the patient is very small (no weight is given). It is generally not recommended to give more than one NSAID nor to combine both types, as this is likely to increase side effects, especially in older patients. Question 3 What are the additional risks of using a conventional NSAID or COX-2-selective NSAID in this patient? The respondents correctly identified the similar risks of exacerbating cardiac failure or renal failure in this man who is known to have impaired renal function, with both groups of NSAIDs. The lesser risk of dyspeptic symptoms with the currently available COX-2-selective NSAID, celecoxib was also accurately listed by most respondents. Question 4 What additional information would help you to determine whether it is safe to use conventional NSAID or a COX-2-selective NSAID in a patient with altered renal function? The use of the word safe is perhaps an overstatement. Few if any drugs are completely safe. The issue is one of relative risk as compared to alternative drugs or no drugs. It is highly desirable to know the patient s age, weight and serum creatinine, so that the creatinine clearance can be calculated. For example if this 70 year old man weighs 70kg with serum creatinine of 0.14mmol/L, his creatinine clearance would be 43ml/min (indicates mild renal impairment), a level at which renally excreted drugs may need dosage adjustment. It is also helpful to have some baseline information before commencing a new drug, so that its effects on renal function can be monitored and dose can be reduced if creatinine clearance is seriously reduced. The combination of an ACE inhibitor and an NSAID needs to be watched and especially if the patient is also on a diuretic. 2 Hyperkalaemia is a risk if renal perfusion is reduced, so serum potassium should be monitored. The patient s heart failure may also be exacerbated and control of hypertension reduced. It is also necessary to check for aspirin allergy and in the case of celecoxib, sulphonamide allergy is a contraindication. NSAIDs may affect warfarin and lithium levels, so the use of other medications should be checked and monitored as needed. Question 5 Is there any advantage in selecting a COX-2-selective drug over a traditional NSAID in this patient? As already discussed under question 2, there may be a slight advantage of the COX-2- selective NSAID in relation to dyspepsia, but the benefit may be minimal when the pre-existing problem is only mild reflux. 11

12 References 1. Langman MJ, Jensen DM,Watson DJ, Harper SE, Zhao PL, Quan H, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282: ADRAC, Thomas MC. Diuretics, ACE inhibitors and NSAIDs the triple whammy. MJA 2000;172: