Nonsteroidal Anti-Inflammatory Drugs-The Clinical Dilemmas

Nonsteroidal Anti-Inflammatory Drugs-The Clinical Dilemmas D. M. McCARTHY Division of Gastroenterology, University of New Mexico School of Medicine, and Veterans’ Administration Medical Center, Albuquerque, New Mexico, USA

McCarthy DM. Nonsteroidal anti-inflammatory drugs-the clinical dilemmas. Scand J Gastroenterol 1992;27 Suppl 1929-16.

Physicians using nonsteroidal anti-inflammatory drugs (NSAIDs) are concerned that effective anti- inflammatory doses cause few gastrointestinal side effects. Among the causes of discontinuing therapy, upper gastrointestinal symptoms and the development of ‘ulcer’ complications are major concerns; endoscopic findings in asymptomatic users are not. Initial symptoms, poorly correlated with endoscopic findings, are relieved by anti-ulcer drugs and ameliorate with time of NSAID use in most patients. Symptoms accompanied by epigastric tenderness, or unrelieved by H2 antagonists, or resulting in cessation of NSAID therapy are more predictive of underlying ulcers. Complications probably arise in several ways, including as hemorrhages due to interference with platelet function, and as complications due to exacerbations of underlying ulcer disease or of ulcers caused by the NSAIDs. Pathogenesis and effective prophylaxis (yet to be established) may therefore vary in different patients, a clinical dilemma.

Key words: Aspirin; death; Helicobacter pylori; hemorrhage; hospitalization; nonsteroidal anti-inflammatory drugs; perforation; symptoms; ulcer complications

Denis M . McCarthy, M . D. , V A - W A F Medical Center-IllF, 2100 Ridgecrest Drive S . E . , Albuquerque, NM 87108, USA

For all that is talked and written about nonsteroidal anti- inflammatory drugs (NSAIDs), remarkably little is known about the issues of greatest importance to clinicians. What is known has only rarely been learned from prospective controlled studies. Surveys of physicians’ concerns show that they rely heavily on NSAIDs in treating painful inflammatory conditions and find few other drugs comparably useful. When considering the use of any NSAID, practitioners are concerned with three main issues. First, the drug must possess adequate anti-inflammatory efficacy. Second, the patient must be willing and able to take the drug, with minimal symptomatic side effects: the GI side effects of principal concern are upper abdominal symptoms, especially epigastric pain, heartburn, and dyspepsia. Finally, ‘ulcer’ complications, such as hemorrhage, perforation, obstruction, and death, should be rare. Physicians in practice are not much concerned about asymptomatic erosions or ulcers seen at endoscopy, unless these relate to symptoms or progress to complicated ulcers. Therapy is seen as useful only insofar as it relieves symptoms and prevents or minimizes complications that result in hospitalization or death.

SYMPTOMS

Upper gastrointestinal symptoms due to aspirin (ASA) and NSAIDs have been extensively reviewed ( 1 4 ) . Overall, 8- 61% of patients using an NSAID have adverse GI symptoms at some time due to the drug, and about 10-12% of patients for whom the drug is prescribed discontinue treatment because of symptoms (4,6). The incidence of GI symptoms

varies widely among clinical studies of NSAIDs, and most studies do not quantitate them, describe their progression with time, or relate their severity to dose of drug. Symptoms are commonest with aspirin, and differences between other NSAIDs appear small (1). Symptoms are commoner in elderly patients with rheumatic diseases than in normal controls (4) and are highest at the start of therapy, thereafter declining spontaneously in most patients.

Symptoms are poorly correlated with endoscopic findings, being absent in most of those with lesions at endoscopy: many patients with prominent symptoms have normal findings at endoscopy. These statements on the whole have not been related to dose of drug or stage of treatment. In all, 15.9% of long-term users have epigastric pain twice daily or more, regardless of the drug used ( 5 ) . Lack of pain does not on its own predict the absence of endoscopic abnormalities but, when combined with lack of epigastric tenderness, has a negative predictive value of 90% (4). The presence or absence of symptomsdoesnot predict the riskofcomplications, probably because of the analgesic properties of the drugs, and life- threatening or fatal complications may develop in asymptomatic patients (7). Whether such complications arise from ulcers caused by NSAIDs or from underlying ulcer disease exacerbated by NSAID therapy remains unclear (see below), but of interest is the fact that NSAID-induced dyspeptic symptoms are commoner in those seropositive for Helico- bacterpylori before therapy (8). Seropositive patients tend to become symptomatic repeatedly when various NSAIDs are given in succession and more frequently have a history of peptic ulcer than asymptomatic NSAID users (8).

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10 D. M. McCarthy

mrCI MET I D I NE 400mg. bd

I I t 0 1 2 3 4

a w

------i- PLACEBO 5 -

400mg. bd I I t

0 1 2 3 4 weeks

Fig. 1. Improvement of global symptom score during 4 weeks’ treatment with 400 mg cimetidine twice daily versus placebo. (0) = P < 0.05; (00) = P < 0.01. (From Ref. 6).

In most cases symptoms tend to be relieved by antacids, anti-secretory drugs, sucralfate, or food, although such relief is not well studied (5 ,6 ,9 , 10). Several ongoing studies are examining symptomatic relief by H2 antagonists, ome- prazole, and prostaglandin analogues. One large study of cimetidine by Bjilsma et al. (6) if of considerable interest for several reasons. In their prospective study more than 85% of rheumatic subjects had epigastric pain at the start of co-therapy with 800 mg cimetidine at night and an NSAID, and interestingly, more than 60% had heartburn, an esophageal symptom. Until quite recently ASA and NSAIDs were not thought to have much to do with esophageal injury, but this is now changing (1 1,12). Nausea occurred in more than 40% and vomiting in about 20% of cases. Over the course of 8 weeks, symptom scores fell, in both those on cimetidine and those on placebo, nausea and vomiting remitting com- pletely and epigastric pain and heartburn persisting in about 20% of cases. In the first 4 weeks cimetidine-treated patients had significantly less symptoms than those taking placebo (Fig. l ) , but thereafter refractory symptoms were present in about 20% of either group. This study suggests that in most patients symptoms diminish with time, regardless of therapy. Whether this is good (development of tolerance or adaptation) or bad (mounting analgesic effect of NSAIDs, regardless of the condition of the gastroduodenal mucosa) remains unclear, but it is of considerable importance.

Preliminary data from another recent study suggest that persistent symptoms may be of ominous significance. In a 3- month prospective placebo-controlled study, 213 chronic arthritis patients with epigastric symptoms due to naproxen, ibuprofen, aspirin, or an other NSAID were randomized to 400 mg cimetidine three times daily or placebo, to be taken with the NSAID continued over a 3-month period (13). At the end of the 3rd month ulcers >3mm were found significantly less frequently in the cimetidine-treated (6.9%) than in placebo-treated patients (15.7%; P = 0.038). How- ever, the authors noted that among withdrawals due to ASA/NSAID symptoms, persistent symptoms increased the

Table I. Relative risks and 95% confidence intervals (CI) for each ASA/NSAID outcome (at left) treated with the drug in parentheses (case-control studies) (from Ref. 14)

Gastric ulcer (aspirin) 4.67 CI = 3.06-7.14 Gastric ulcer (non-aspirin NSAID) 4.03 CI = 2.80-5.78 Gastrointestinal hemorrhage (aspirin) 3.30 CI = 2 . 3 9 4 5 4 Gastrointestinal hemorrhage (NSAID) 3.09 CI = 2.26-4.40 Ulcer perforation (aspirin) No data: uncommon Ulcer perforation (NSAID) 5.93 CI = 4.00-8.81 Duodenal ulcer (aspirin) 1.71 CI = 0.69-1.98 Duodenal ulcer (NSAID) 3.16 CI = 1.78-5.61 Death (aspirin) No data Death (NSAID) 7.62 CI = 6.17-9.41

likelihood of finding an ulcer 31-fold. Furthermore, symptom relief by cimetidine was associated with an ulcer prevalence of 1.9% (P < 0.01). These data suggest that, although difficult to interpret, persistent symptoms while taking NSAIDs should not be taken lightly and require investigation. Needed urgently are prospective long-term studies that relate the type, severity, and duration of symptoms to different doses of various NSAIDs and examine their progress over time.

COMPLICATIONS OF NSAID-ASSOCIATED ULCERS

Estimates of the magnitude of the risk of developing an ‘ulcer’ complication during NSAID use vary widely de- pending on the data base used in making the estimate, the population in whom the risk was assessed, and when in the course of NSAID therapy the risk was calculated. Many studies include upper GI bleeding from an unknown source as an ‘ulcer’ complication-an assumption that may not be valid, especially in ASA users (see below)-and treat hospitalizations for bleeding from an undetermined source as an ‘ulcer complication’.

RELATIVE RISKS OF COMPLICATIONS

These are best estimated from case-control or cohort studies, in which the frequency of the adverse event in NSAID users is compared with the frequency in age- and sex-matched controls not using the drugs. Recently, two major reviews using meta-analysis techniques have reviewed the magnitude of these hazards 14,15). A summary of these risks, taken from the estimates of Hawkey (14), is shown in Table I . The other estimates are quite comparable but were computed with different methods (15).

On the whole, the risk of developing a complication of either a gastric or duodenal ulcer while taking any dose of ASA or NSAID at times close to the event is increased three- to five-fold, although relative risk or odds ratio data are difficult to obtain for aspirin because of its widespread nonprescription use as an over-the-counter drug. There is no doubt that such events occur with aspirin, but relative risks remain uncertain. Furthermore, the base-line values

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NSAIDs-The Clinical Dilemma 11

Table 11. Risks of hospitalization for developing an ulcer complication due to an NSAID, in men and women over age 65 years, and relative frequency of the various complications in all NSAID users compared with their frequency in all those not using NSAIDs. (From Ref. 26)

Hospitalization rates/1000 patient-years, over age 65 years ( n = 4195) Taking NSAIDs No NSAIDs Age group

(years) Men Women All Men Women All +NSAID/-NSAID ~

65-74 14.7 11.8 25.5 4.6 2.9 7.5 3.4 75-84 18.9 18.1 37.0 6.5 3.9 10.4 3.5 85 + 16.9 27.7 44.6 9.9 5.9 15.8 2.8

< . J L T 2

Bleeding 49 % 52% Perforation 8% 4% Obstruction 3% 4% Death 10% 9%

for the absolute risks of each outcome in the populations from which these samples are taken are not precisely known. In studies that apply to all NSAID users regardless of the presence or absence of underlying GI (especially peptic ulcer), the relative risk of a complication, particularly bleeding, is highest in the first 14 weeks after starting ASA or NSAID therapy. In contrast, in prospective NSAID trials, which have excluded patients with a previous history of ulcers or bleeding, this high initial risk is not seen, and the risk of complication is constant for up to 3 years (16).

The relative likelihood of death associated with NSAID therapy is worth comment in that it differs in the two meta- analysis studies (14, ls), being 7.62 (95% confidence interval (CI, 6.17-9.41) in the study of Hawkey (14) and 4.79 (CI, 3.64-6.22) in that of Gabriel et al. (15), the confidence intervals barely overlapping. Both studies clearly predict a markedly increased mortality in NSAID users compared with controls, but the attributable mortality is hard to estimate. Various studies have estimated that 22% of peptic ulcer hemorrhages (17), 25% of peptic ulcer deaths (18), and 29% of hospitalizations (19) are attributable to NSAID use. In a careful study, Henry et al. from Australia (20) calculated that 20-30% of all ulcer complications requiring hospitalization of patients more than 60 years were attributable to NSAIDs. However, compared with the outcome in ulcer patients developing complications while not on NSAIDs, but matched for age and sex, the case fatality rate in NSAID users was not increased (20). Preliminary data from South Carolina (21) and Germany (22) support this conclusion. Hence, the attributable mortality arises from the increased risk of developing the complication and not from the complication being associated with a poor outcome in the NSAID user. In studies reporting very high death rates in NSAID users, causes of death were not specified and attributable mortality was not calculated (7,23). Since the mortality of peptic ulcer disease unrelated to NSAIDs is highest in the elderly, and since the elderly NSAID user may often die from diseases not associated with NSAIDs, mortality data must be analyzed with considerable care

before attribution. There is also a definite need for more data on the incidence of death and complications from peptic ulcer disease unrelated to NSAID use, in age/sex-matched control populations.

HOSPITALIZATIONS

In a U.S. study of 4524 adults without previous ulcer disease or aspirin intolerance, who took 1 g/day of ASA or placebo for 3 years, the age- and smoking-adjusted relative risk of hospitalization for duodenal ulcer was 10.7 times higher (95% CI, 2.5-45.5) and for gastric ulcer 9.1 times higher (95% CI, 1.2-71.4) in aspirin users than in controls (16). In a separate study, the comparable figure for hospitalization for ulcer (site unspecified) among all users of various NSAIDs, with no exclusion for prior peptic ulcer disease or any other similar factor, was 4.1 (95% CI, 3.5-4.7), but patients in the study (19) were not monitored prospectively. A subset of these latter patients, those concurrently receiving corticosteroids and NSAIDs, had a 15-fold increased risk of hospitalization compared with nonusers of either drug (24). Theselatterstudies(19.24)includeavarietyof patients,some of whom took small doses of drugs for a short time and others who took large doses for prolonged periods. The base-line risk of hospitalization for peptic ulcer unrelated to NSAID use in an elderly U.S. Medicaid population has been estimated at 5.6/1000 patient-years (19ta figure almost identical to the value of 5.46/1000 patient years, which can be calculated from the incidence of ulcers observed in the placebo group (37 of 2257 over 3 years) in the aspirin study (16).

A key question remains which was not addressed in these studies (16, 19,24): among those who use the drugs long- term, how many develop a serious complication each year? Since this risk may vary with the dose and type of NSAID, the following estimates from populations using different doses of different drugs must be taken with some caution. Nevertheless, three different cohort studies have now come up with comparable estimates of risk. The U.S. FDA estimates, based on pre-marketing IND studies of six drugs,

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12 D. M. McCarthy

that 2 4 % of long-term users develop a serious complication each year (25). This is comparable to the estimate of 1-3% per year from the Tennessee Medicaid population (26) and 1.6% per year from the ARAMIS study on patients with rheumatoid arthritis (27). All of these estimates suggest that about 2% of long-term therapy patients develop a serious ulcer complication each year. If one takes the basal risk of developing a peptic ulcer not due to NSAIDs as about 5.5/ 1000 patient-years and multiplies it by the relative risk of 4.1 (for NSAIDs), a figure of 2.25%/year emerges, in rough agreement with the studies quoted above. Thus, complications are not so rare as to be unmeasurable in clinical trials designed to monitor the effects of prophylactic regi- mens on clinical outcomes of therapy. The actual hospitalization rates due to NSAIDs in elderly patients and the relative incidences of various complications are shown in Table 11. All of the complications are commoner in NSAID users, but their relative frequency seems unaffected by the use of NSAIDs. This lack of effect of NSAIDs on the relative frequency of complications while inceasing their overall frequency suggests that drug-exacerbated peptic ulcer disease may be the main source of NSAID-induced complications.

The literature is replete with clinical studies dealing with complications of ‘ulcers’ associated with ASA or NSAID therapy. But almost no two studies are alike in methods, with differences in population studied, case exclusion and selection, defined end points (for example, severe hemorrhage, * outpatient bleeds, * microbleeding, 5 anemia), surveillance, type and dose of drug(s), duration of exposure, and so forth. Thus, attempts to combine study results is difficult. In the following sections I have chosen to abstract key points important to clinicians.

HEMORRHAGE DUE TO ASPIRIN AND NSAIDs

Taking a broad view of the literature, ASA alone emerges as a major cause of minor bleeding. When major bleeds occur after ASA ingestion, one should consider the possi- bility of additional factors contributing to the problem. Such factors include the existence of underlying gastrointestinal disease (for example, peptic ulcer, cancer), underlying liver disease (complicated by coagulopathy, thrombocytopenia, varices, portal hypertensive gastropathy, and so forth), co- exposure to other drugs (NSAIDs, steroids, KCI, anti- coagulants), or active drinking. Most aspirin bleeds can be managed conservatively.

When exposure to drugs is assessed solely by history- taking, NSAIDs cause 21-30% and ASA 14% of major GI bleeds (28,29). While aspirin causes more microbleeding and anemia than most other NSAIDs, there is little evidence that microbleeding has anything to do with the risk of major GI bleeding (30). However, despite this reassurance, aspirin taken even briefly or intermittently, and in doses as low as 30 mg/day, is occasionally associated with severe hem-

orrhage, perhaps because of its effects on platelet function

When exposure to aspirin is based on additional evidence (plasma salicylate, plasma thromboxane BZ, and use of a structured questionnaire), more than 70% of both upper and lower GI bleeds in a community hospital occurred in patients exposed to some form of salicylate within the previous 5-7 days (36). Less than 50% of such bleeds arose from ulcers. On the other hand, when a gastric or duodenal ulcer bleeds, there is more than a 70% chance that the bleed was induced by ASA or NSAIDs (28), the former being commoner if all upper GI bleeds are included (37). Thus, bleeding ‘ulcers’ are seen mostly in the context of ASA/NSAID use. The question is, are these peptic ulcers caused to bleed by ASA or NSAIDs, or do these drugs cause ulcers that then bleed? Both mechanisms may occur.

Patients with a history of peptic ulcer or previous upper gastrointestinal bleeding are inherently likely to bleed again from their underlying disease, whether or not they are given ASA or NSAIDs. In a study of 875 patients with GI bleeding and2682controls, Laporte et al. (37) found that such patients bled far more frequently than those lacking such a history (odds ratio 5.5 in those with a confirmed diagnosis of PUD, and 14.5 in those with previous hemorrhage). However, the odds ratio estimate for all NSAIDs did not differ between patients with (7.4) and without (8.0) a history of NSAID use (37). Thus, the principal effect of drug exposure (mainly aspirin) was to increase the risk of bleeding rather than the risk of ulcer: many appeared to have bled from pre-existing disease.

The risk of all complications due to NSAIDs, chief among which is hemorrhage, is dose-dependent (19). Both direct (38-40) and indirect (32) evidence points to the risk of hemorrhage due to aspirin being similarly dose-dependent. The amounts of aspirin associated with hemorrhage (reviewed above) are far lower than those predictably associated with developing a gastric ulcer (41). Furthermore, when ulcers bleed on ASA or NSAIDs, duodenal ulcers, not due to aspirin, based on epidemiologic or case control studies (Table I), and gastric ulcers are equally likely sources of the bleeding (7, 16,17,37). Overall, these data support the hypothesis that aspirin and perhaps some NSAIDs in low doses exhibit anti-platelet effects causing bleeding from pre- existing ulcers or other lesions. Higher doses taken chronically may cause gastric ulcers, some of which then bleed or perforate. It is also of interest that the risk of aspirin causing a hemorrhage persists indefinitely so long as therapy continues and is relatively constant (16,31,37) but is markedly reduced within 5-7 days of withdrawing the drug (31), a time very comparable to the life of the platelet.

This section is not meant to imply that all ASA/NSAID bleeding is due to an effect on platelets but rather that evidence exists that this may be an important, if uncommon, hazard of long-term low-dose aspirin therapy, a hazard with little effect on overall mortality (42). For other NSAIDs and

(31-35).

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for aspirin in higher doses, many other mechanisms may apply, especially during long-term therapy.

PERFORATION

Several epidemiologic studies have suggested that the rising frequency of perforation in elderly women may be related to increased consumption of nonsteroidal drugs, in the United Kingdom (23,43,44) but not in West Germany (45) or the USA (46). The highest risk group, those more than 64 years old, were not included in the U.S. study. None of these studies provide data on ASA, a widely used nonprescription drug and the drug most commonly related to ulcer perforation in Danish and Australian studies (47,48). British studies have frequently implicated indomethacin (49), and an Irish study pointed to an antral location of indomethacin ulcers (50).

The subgroup showing the greatest rise in the incidence of perforation are elderly women in the U.K., and in these the greatest rise is in duodenal ulcer perforations (44). In this last study women aged 65-74 years doubled and women aged more than 75 years trebled their rate of perforation over a 30-year period, to rates of 24-54 per 100,000 population per year. This is certainly higher than the base-line whole population rate for aspirin-associated perforation of about 9/100,000 observed in Australia in the pre-NSAID era (48). This last study also noted a predilection for an antral or prepyloric location of drug-associated ulcers that perforate.

Summarizing these reports, the incidence of perforated ulcer, especially duodenal ulcer, appears to be rising rapidly in some countries in older women. The reasons for this are unclear but may be related to increasing use of NSAIDs. The association between ASA or NSAIDs and perforation is much less clear than that applying to ASA or NSAIDs and hemorrhage, and the percentage of perforations attributable to drugs is unknown. The role of aspirin may be underestimated owing to the lack of adequate data on aspirin consumption but is unlikely to explain the whole problem. As shown in the Danish study, retrospective inquiries about drug use are notoriously unreliable (47): a prospective study of a small subgroup (22 of 195 patients) revealed anti- inflammatory drug use before the perforation in 82% of cases, compared with 18% who were recorded as using the drugs in the retrospective part of the study. This suggests that retrospective studies may underestimate the true dimen- sions of the problem. Hemorrhages occur three to five times more frequently than perforations in ASA/NSAID users (23,43,51). Mortality increases with age, is higher with gastric than duodenal ulcer complications, and is probably worse for perforation or perforation-plus-hemorrhage than for hemorrhage alone (23). The effects of aspirin, smoking, and H. pylori infection on these epidemiologic trends war- rant further study.

RISK FACTORS

As discussed under hospitalization (above), it is apparent that the most of those using ASA/NSAIDs long-term have little trouble and derive considerable benefit from therapy. Perhaps 10-16% have troublesome symptoms, and about 2% per year are hospitalized for severe complaints. Since no therapies have, as yet, on the basis of randomized double- blind placebo-controlled trials, reduced symptoms or prevented complications when given prophylactically, it becomes important to ask whether all users are similarly at risk.

While at first sight this might seem a simple task, in practice it is made difficult by trying to interpret studies that for various reasons used different methods and, above all, studied different populations. For instance, eight pre-marketing studies performed by the FDA before regulatory approval of NSAID drugs excluded subjects with a history of ulcer disease or GI bleeding, as did most long-term aspirin trials for heart attack or stroke, and prophylactic trials aimed at preventing NSAID-induced gastroduodenal injury with misoprostol and some H,-antagonists. In these trials the potential contribution of underlying ulcer disease to drug- associated complications could not be evaluated, and ulcer complications have been very rare or absent, even in the placebo groups.

On the other hand, most epidemiologic studies tend to admit all patient categories, including those with underlying ulcer or other GI disease, and furnish the best estimates of population risks. From such unrestricted studies there arises the concern that in excluding those most at risk from prophylactic drug trials, we may have frustrated attempts to define the minority of patients at high risk, the group in whom prophylaxis of some kind might be cost-effective and clini- cally worthwhile.

It is clear that the risks of hospitalization, namely for hemorrhage and possibly for perforations are increased in those who use ASA/NSAIDs long-term. There is growing but not yet irrefutable evidence that those with peptic ulcer disease or a tendency to it may be especially at risk. This evidence comes from several directions. In studies of typical peptic ulcer disease, ulcer recurrence after healing is commoner in NSAID users (52). In various studies the incidence of ASA/NSAID-associated hemorrhage (15,29,37) and of fatal ulcer hemorrhage (20,51,53) has been higher in those with a previous history of ulcer or gastrointestinal hemorrhage than in those without such a history. One study showed that among arthritis patients who developed peptic ulcers on NSAIDs there was an unexpectedly high prevalence of blood group 0 (54), a genetic blood type associated with enhanced prevalence of duodenal ulcer (55). The risks and complication patterns of peptic ulcer disease-unrelated to NSAIDs-increase in the same age groups as NSAID- associated ulcers (26). In NSAID users the risk of hospitalization or death is significantly increased by a previous

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14 D. M. McCarthy

history of H2 antagonist (relative risk, 3.9) or antacid (relative risk, 2.3) use before NSAID therapy (27).

More recently, various studies have linked GI problems due to NSAIDs with other risk factors known to be important in peptic ulcer disease in the absence of NSAIDs. These observations include the following. Smoking, known to exacerbate peptic ulcer disease in H. pylori-infected patients (57), also increases ulcer risk in NSAID users (10). Sero- positivity to H. pylori (present in 95% of duodenal ulcer and in over 70% of gastric ulcer patients) in advance of NSAID therapy predicted a significantly increased risk of developing upper GI symptoms on NSAID administration (8). Sero- positive subjects were likely to have had similar intolerance to various other oral NSAIDs tried previously. The patients were also more likely to have a history of peptic ulcer (8). While complications of NSAID-associated ulcers occur commonly from duodenal ulcers, such ulcers are excep- tionally rare in H. pylori-negative NSAID users (57). Finally, in a small prospective study, patients with H. pylori infection had more gastritis before therapy, and gastritis deteriorated significantly more while taking naproxen than did gastritis in otherwise similar uninfected naproxen-treated patients

Taken together, all of these observations suggest that peptic ulcer disease, or perhaps associated chronic active gastritis, may deteriorate during NSAID therapy, increasing the risk of ulceration and complication (59). This is not to say that all complications during NSAID therapy arise from pre-existing ulcer disease but rather that this is one mechanism that may contribute significantly to the problem. This belief is widely held by practitioners but thus far is not well supported by formal studies. Other studies have failed to find that such factors predicted an unfavorable outcome of NSAID therapy, but in many the data were not collected or analyzed in ways assured of eliciting the relevant infor- mation. The issue remains unresolved.

(58 ) .

MAGNITUDE OF RISKS

The crude risk of developing an ulcer complication from NSAID therapy, including hemorrhage, perforation, or obstruction, has been estimated at about 1 per 5000 pre- scriptions (17,44), a prescription constituting 1 month’s supply of drug. This is a crude risk estimate for the whole population, which includes low-dose, intermittent, and short-term as well as long-term NSAID use but does not include the risk of aspirin therapy, which is of uncertain magnitude. As pointed out above, regular long-term users face a risk of hospitalization for an ulcer complication of about 2%, each year on drug (25-27).

Endoscopic studies, however, show that about two out of every three patients have endoscopic evidence of gastric injury, with about 15% having a gastric ulcer and 10% a duodenal ulcer at any one time (10). The prevalence of DU and GU in age/sex-matched controls not on NSAIDs has

not been determined in these studies, so the number of ulcers attributable to the drugs, as distinct from those found in NSAID users but perhaps of other etiologies, is uncertain. Furthermore, whether all are true peptic ulcers or merely gastric erosions with a different natural history is also uncertain. Nevertheless, complications are clearly uncommon in the face of a high prevalence of endoscopic lesions.

HOW DO COMPLICATIONS ARISE

A key question remains: what mechanisms cause some ASA/ NSAID users with ulcers to go on to develop complications? There are three basic hypotheses advanced to explain this progression; all or none of these may be correct. The first hypothesis assumes that NSAIDs cause diffuse initial injury, which is generally followed by adaptation of the mucosa with an increased ability to tolerate insult without significant injury. In this view most patients would never develop a deep ulcer, but a few individuals, with either localized or generalized mucosal failure to adapt, develop deep ulcers that progress to complications. Against this hypothesis is lack of evidence as to the relevance of adaptation in man.

Most of what we know about adaptation comes from animal studies and applies mostly to low doses of drug and mainly to studies with aspirin and indomethacin, the only drugs shown to be accompanied by adaptation in some human studies (60,61); other studies found no adaptation in man (62,63). It appears that adaptation does not occur in man if injury is prevented (64). Since adaptation occurs during oral indomethacin therapy, which inhibits gastric mucosal cyclooxygenase, it does not appear to be mediated by prostaglandins (61). Studies by Eastwood & Quimby (65), in rats treated for 1 month with aspirin, showed that chronic injury caused a marked cellular proliferative response in the gastric fundus, a lesser effect in duodenum, and little or no increase in antral cell turnover. This failure of the antrum to mount a proliferative response to injury might underlie its susceptibility to ASA/NSAID injury. Recently, similar changes in human gastroduodenal mucosa in response to NSAID injury have been described (66) but are in conflict with data suggesting reduced rates of cell proliferation at the edges of ulcers in NSAID users (67). The clinical relevance of adaptation has not been established.

The second view of complications is that in patients with underlying peptic ulcers or a susceptibility to them (for example, duodenitis, H. pylori infection, or chronic active antral gastritis), ASA or NSAID use adversely affects the balance between factors injurious or protective to the mucosa. Increased severity of the ulcer diathesis leads to complication(s). This view is supported by the evidence (above) that a previous history of ulcer or gastrointestinal hemorrhage is predictive of an adverse outcome of NSAID use, at least in some people.

The third view, and one much supported by the results of low dose aspirin trials (31-42), is that the main effect of

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ASA and some NSAIDs is to inhibit platelets and platelet- dependent clotting mechanisms, thus precipitating gastrointestinal hemorrhage, particularly in the presence of pre- existing lesions in the GI tract. A t this time it seem possible or probable that all three mechanisms may operate in different individuals and that more than one mechanism may apply in some. T h e major implication is that different forms of prophylaxis may prove useful in different patients. A t present there are no studies that established in randomized, double-blinded controlled trials that any form of drug therapy has lowered the morbidity or mortality attending chronic NSAID use in elderly subjects, particularly in those with a history of ulcers or bleeding. H o w to manage these high-risk patients is the major dilemma facing clinicians a t present.

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Documents

Nonsteroidal Anti-Inflammatory Drugs-The Clinical Dilemmas