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More on NSAID adverse effects

Gastrointestinal AEs
Results
Renal failure
Results
Congestive heart failure
Results
Comment

But definitely the last word for a while. Bandolier has been pressed by readers to reprise this topic, and to include more than just the gastrointestinal adverse effects. Coincidentally there are several important studies just published that make this possible. A common motif is that adverse effects are problematical in the elderly.

Gastrointestinal AEs


Epidemiological studies associating NSAID use and upper GI problems and published in the 1990s have been reviewed and the data pooled [1] to give a much clearer picture of risks. To be included studies had to:


Results


Eighteen studies were found. All had specific definitions of exposure and outcome and similar ascertainment for comparison groups. All but two attempted to control for potential confounding factors, like age, sex, history of ulcer or concomitant medicines.

The main results are summarised in Figures 1 and 2. Compared with nonusers, NSAID users had a higher risk of upper GI bleed (UGIB) when they were current NSAID users and used a higher dose. The duration of use was unimportant, but different NSAIDs had different risks, with ibuprofen (especially doses below 2400 mg a day) being least harmful.

Figure 1: Risk of UGIB for NSAID users compared with nonusers

Figure 2: Risk of UGIB for particular NSAIDs, users compared with nonusers


The effect of ulcer history and age is shown in Figures 3 and 4. People with a history of ulcer or with a previous bleed who took NSAIDs were at much greater risk than those with no history of ulcer who took NSAIDs. Older folk who took NSAIDs were at greater risk than under 50s who took NSAIDs.

Figure 3: Effect of history of ulcer in users of NSAIDs

Figure 4: Effect of age in users of NSAIDs


In this set of high quality studies, there was a clear effect of size on the estimate of relative risk of upper gastrointestinal bleed with NSAID. The pooled estimate was 3.8 (3.6 to 4.1). With fewer than 1000 cases, the results of individual studies was highly variable (Figure 5).

Figure 5: Effect of size of study in determining overall relative risk of GI bleed, NSAID users compared with nonusers


Renal failure


People who work in renal units will tell you about the association between NSAIDs and acute renal failure. The problem has been to get a reliable estimate of the risk. There have been some small studies, but a new, large study from Tennessee gives us a better picture [1].

The study was conducted among all members of the Tennessee Medicaid programme aged 65 years or more in 1987-1991 and enrolled for at least one year. Those with first admission to hospital for acute renal failure (admission creatinine level of 180 μmol/L or more at admission) were the cases of community acquired acute renal failure. Controls were randomly selected for all persons in the study population. Exclusions were people with end stage renal disease and those with hospital acquired acute renal failure. NSAID exposure was ascertained from prescriptions filled in the year before the index date.

Results


There were 1,799 cases with an annual incidence of community acquired acute renal failure of 4.5 admissions per 1000. The median hospital stay was eight days. Thirty-six percent died within 30 days. Forty-two percent were classified as having new renal disease. The remainder were classified as having chronic renal failure with acute exacerbation based on a prior creatinine level above 122 μmol/L, a documented history of chronic renal failure or imaging studies compatible with chronic renal disease. There were 9,899 controls. Controls were less likely to be nursing home residents or be 85 years or older.

NSAID use was higher (18%) in cases than in controls (11%). For current NSAID use the odds ratio was 1.6 (95% confidence interval 1.3 to 1.9). Those who had stopped using NSAIDs within the past 30 days had no increased risk of renal failure. For certain NSAIDs where there was sufficient information, ibuprofen and indomethacin, there was a dose response for risk. For individual NSAIDs, ibuprofen, piroxicam, fenoprofen and indomethacin had the greatest increased risk, with odds ratios of about 2.

A previous detailed study [3], though on smaller numbers, indicated that previous renal disease, or gout, but particularly a joint history of gout plus previous renal disease were major risks for renal failure with NSAIDs. Patients using NSAIDs with half lives of 12 hours or more in the previous week had particularly increased risk of renal failure.

Congestive heart failure


It seems as if we also have to begin to worry about NSAIDs being related to congestive heart failure (CHF) in older people [4].

This study at two hospitals in New South Wales (population about 450,000) enrolled as cases consecutive patients between 1993 and 1995 where the medical officer admitting the case and the attending physician agreed that the primary reason for admission was CHF. Patients admitted for other reasons with incidental CHF were not included. Study nurses ensured that all included cases met Framingham criteria for CHF. Controls (target two per case) were patients of the same sex and within five years of age admitted to the same hospital, but with no clinical or radiological signs of CHF.

Results


There were 365 cases and 658 controls, with a mean age of 76 years. Most cases had moderate or severe CHF. Use of nonaspirin NSAIDs was 17% in the cases in the week before admission, compared with 12% in controls. The adjusted odds ratio was 2.1 (5% confidence interval 1.2 to 3.3) for all cases, and 2.8 (1.5 to 5.1) for the 272 cases with first admission for CHF (Table 1).

Table 1: NSAID use and history of heart disease on risk of developing CHF

Heart disease NSAID use Odds ratio (95% CI)
No history Nonuser 1
No history User 1.6 (0.7 to3.7)
History Nonuser 2.5 (1.4 to 4.3)
History User 26 (6 to 119)

CHF was far more likely in those patients with a prior history of heart disease, in which the odds ratio was 26 (5.8 to 119). Complicated statistical analysis confirmed the effect of pre-existing heart disease, and suggested that NSAIDs with longer half lives (naproxen, piroxicam, and tenoxicam) had much higher risk than those with short half lives (ibuprofen, diclofenac, for instance), though on small numbers in a subgroup analysis.

Comment


Table 2 puts all this into the perspective of an average PCG of 100,000 [5] for the over '65s. In this group there would be 18 hospital admissions every year for upper gastrointestinal bleeding, 10 for acute renal failure and 22 for congestive heart failure. These latter seem high, but in both cases the bulk of the events would be in those aged 75 and over. Age is certainly the issue.

Table 2: NSAID adverse effects in an older population of an average PCG

Event Cases per year
Upper GI bleed 18
Acute renal failure 10
Congestive heart failure 22
Information based on an average PCG of 100,000 patients where 3,800 over '65s take NSAIDs

For both renal failure and CHF NSAIDs seems to uncover incipient disease. For renal failure there are several, smaller, confirmatory studies, and for CHF at least one [6]. For both there appears to be a plausible mechanism, dose-response relationships, and particular association with NSAIDs with longer half lives. Renal failure has a high mortality, and CHF is also serious, as treatment is unlikely to restore patient's functioning to previous levels.

The good news is that for most older patients sensible assessment and pertinent guidance should mean that many of these events could be avoided. While the new coxibs are not associated with elevated risks of gastrointestinal bleeding, there is no evidence, or indeed likelihood, that they will not precipitate renal failure or CHF.

Put in a humanitarian and economic context, these 50 first hospital admissions a year (Table 2) per PCG of 100,000 population is equivalent to 30,000 admissions a year in the UK. Most are avoidable. Information we have suggests an average stay of about a week, costing about £1,400 each. That's something like £40 to £50 million a year for the NHS.

Reference:

  1. S Hernández-Diaz, LA García Rodriguez. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding and perforation: An overview of epidemiological studies published in the 1990s. Archives of Internal Medicine 2000 160: 2093-2099.
  2. MR Griffin, A Yared, WA Ray. Nonsteroidal antiinflamatory drugs and acute renal failure in elderly persons. American Journal of Epidemiology 2000 151:488-496.
  3. D Henry 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. British Journal of Clinical Pharmacology 1997 44: 85-90.
  4. J Page, D Henry. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: An underrecognized public health problem. Archives of Internal Medicine 2000 160:777-784.
  5. AL Blower, A Brooks, CG Fenn et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997 11: 283-91.
  6. ER Heerdink et al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Archives of Internal Medicine 1998 158:1108-1112.
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