Mortality With Upper Gastrointestinal Bleeding and Perforation: Effects of Time and NSAID Use

Sebastian Straube; Martin R Tramèr; R. Andrew Moore; Sheena Derry; Henry J. McQuay

Disclosures

BMC Gastroenterol 

In This Article

Discussion

Interpretation of these results needs to be tempered by the limitations of the data. These are substantial, and include differences in study architecture, population characteristics, risk factors, definitions of mortality, reporting of outcomes according to diagnosis (perforation or ulcer bleed), and descriptions of use of NSAIDs, aspirin, or other ulcerogenic drugs. All of these are likely to impact on the magnitude of any mortality estimate, and influence any judgement on how mortality is influenced by temporal or therapeutic variables. Fifty-nine of 65 included studies were observational, where we lack any quality assessment tools that reproducibly detect bias.

For example, Figure 1 shows dramatic differences in mortality estimates between different study designs, though small numbers of actual deaths and cases imparts real uncertainty in some cases, perhaps beyond the conventional calculation of confidence intervals. Which of these designs most accurately captures the mortality rate is an interesting point. It could be argued, for instance, that randomised trials with low mortality rates reflect publication bias, or perhaps the stringent application of guidelines in inclusion criteria limits exposure of at-risk patients and that, consequently, external validity or applicability of these data may be limited. However that may be, all study designs agree that mortality with upper gastrointestinal bleeding or perforation is clinically significant.

We could see no clear reason for the different mortality rates between different study designs in which there were at least 200 deaths (case control, yellow cards, cohorts, and case series). It could be argued that the reason for this is that yellow card reporting selects more serious events, and a subsequently higher mortality rate, but that would still leave a two-fold difference of 6% to 12% mortality. Case mix probably contributes a great deal, and while meta-regression might help to quantify the extent, inconsistent reporting of patient characteristics puts limits on its power to do that. An analysis based on individual patient data would be more powerful, but it is unlikely that sufficient consistent patient data could be obtained retrospectively. These difficulties point to the need for a large ongoing prospective study capturing key demographic and diagnostic data and outcomes, an approach likely to distinguish both temporal changes and the influence of drugs, like NSAIDs, that influence gastrointestinal bleeding.

Information from 61,067 cases and 5,001 deaths was available, with more than four times as much information on mortality in patients with upper gastrointestinal bleeding or perforation published during the period between 1997 and 2008 than previously (Table 1). Results showed a significant and important reduction in mortality over time, by an average of 4%, meaning that 1 fewer person in every 20 who had an upper gastrointestinal bleed or perforation now dies, compared with before 1997. This major decrease in mortality probably reflects improved standards of care, as has been described in other settings.[8,9,10,15] Despite these improvements, still on average 1 in 13 cases of upper gastrointestinal bleeding or perforation dies.

It is important to stress that the figure is an average. Known risk factors for increased mortality will be increased age, comorbid conditions, and position of the bleed or perforation.[2,3] We accepted all studies reporting mortality with upper gastrointestinal bleeding, and typically these occurred in older adults in whom medicines may also increase risk of a bleed or perforation, and possibly of mortality.

At least 9% of the total cases (5,526) were prescribed an NSAID or aspirin in the period before a bleed or perforation. Not unexpectedly, mortality in this subgroup of patients was significantly higher than for all cases. NSAIDs and aspirin are known to increase the risk of upper gastrointestinal bleeding or perforation.[16] Also, NSAIDs and aspirin, when administered in analgesic doses, may delay diagnosis of, for instance, a painful perforation. Finally, NSAIDs and aspirin, through platelet inhibition, are likely to further increase the bleeding in a patient with a bleeding ulcer. It is less evident, though, why in patients with a bleed or perforation who were exposed to NSAIDs or aspirin, average mortality increased from about 15% before 1997 to about 21% after 1997. If improvement in standards of care has led to a decrease in overall mortality over time, this would imply that this improvement was not evident in cases taking NSAIDs or aspirin, which is unlikely to be the case. Overall mortality is probably a poor estimate of the non-NSAID using population because it includes patients using NSAIDs, aspirin, and sometimes both.[17] Therefore the true excess mortality in patients taking NSAIDs may be higher than that estimated.

A number of publications have pointed out that small numbers of events have the potential to produce the wrong answer because of the random play of chance.[18,19,20] It was possible to examine the effects of size in this analysis (Table 1). Two observations are helpful. Firstly, limiting studies with rare events to at least a study size of 200 cases, in this data set, would have meant that 95% of the information was captured in half the studies, and would not have altered the results. Secondly, relying on analyses with small numbers can produce an aberrant result, as was seen in the analysis of mortality in patients with bleed or perforation taking NSAIDs or aspirin. In the smaller studies with fewer than 200 cases each, and with a total of 31 deaths only, the event rate was less than a third that seen in larger studies with many more cases. For all cases, even smaller studies amassed almost 250 deaths, and the event rate was consistent with larger studies. This reiterates previous observation and theory[18,19,20] that with a small number of events in individual studies or in systematic reviews or meta-analyses, incorrect results may occur by the random play of chance.

Despite the limitations this study is important because of the large number of patients and events, with most information coming from more recently published studies. Even an average mortality rate is helpful in explaining the implications of therapy to individual patients, as well in calculating the economic implications of prescribing policies.

The limitations of the studies included in this review highlight how better investigational criteria might be applied in future to better understand and more reliably quantify the relationship between a gastrointestinal bleed or perforation and death. Only very large prospective studies that detail diagnosis, medication, comorbid conditions, and report the details separately for those with the event and those who die are likely to be useful, as a nationwide study from Spain exemplifies.[4]

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