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:
- Be case control or cohort studies on non-aspirin NSAIDs
- Include data on bleeding, perforation, or other serious upper gastrointestinal
tract event resulting in hospital admission or referral to a specialist
- Have data to calculate relative risk
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:
- 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.
- MR Griffin, A Yared, WA Ray. Nonsteroidal antiinflamatory drugs and acute
renal failure in elderly persons. American Journal of Epidemiology 2000
151:488-496.
- 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.
- 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.
- 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.
- 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.
|
previous
or
next
story in this issue
