Design: Retrospective cohort study.

Setting: Medicines Monitoring Unit, Ninewells Hospital, Dundee, UK.

Patients: 1760 CHF patients divided into four groups: those on no allopurinol, those on long term low dose allopurinol, those on short term low dose allopurinol, and those on long term high dose allopurinol.

Main outcome measures: Total mortality, cardiovascular mortality, cardiovascular hospitalisations, cardiovascular mortality or hospitalisations.

Results: Long term low dose allopurinol was associated with a significant worsening in mortality over those who never received allopurinol (relative risk 2.04, 95% confidence interval (CI) 1.48 to 2.81). This may be because low dose allopurinol is insufficient to negate the adverse effect of a high urate concentration. However, long term high dose (≥ 300 mg/day) allopurinol was associated with a significantly better mortality than longstanding low dose allopurinol (relative risk 0.59, 95% CI 0.37 to 0.95). This may mean that high dose allopurinol can fully negate the adverse effect of urate and return the mortality to normal.

These data obviously raise the possibility that reducing uric acid with allopurinol might also reduce cardiovascular events. This prospect is made even more likely because as well as reducing uric acid, which might be beneficial, allopurinol has a second and completely different action that might also reduce cardiovascular events. That second effect of allopurinol is to reduce superoxide anion production because xanthine oxidase is one of the main producers of superoxide anions.^9–11 The importance of this second effect of allopurinol is that superoxide anions are well known to inactivate endogenous nitric oxide and therefore allopurinol should boost endogenous vascular nitric oxide bioactivity.^{12, 13}

If the above theoretical benefits of allopurinol actually were to occur in practice, then one would expect that xanthine oxidase inhibition would be able to improve endothelial dysfunction in humans. In fact, three studies now clearly show this to be the case.^14–16

The prospect therefore arises that allopurinol might reduce cardiovascular events in at risk patients. Indeed, whether this is the case or not has become a key question in cardiovascular medicine. A full randomised placebo controlled trial would be the ideal way to answer this question. However, before any funding agency is likely to use their limited resources to fund such an expensive trial, more confirmatory data are required, especially data linking allopurinol directly to cardiovascular events rather than merely linking allopurinol with promising surrogates, which is all that we currently have. To perform such a study, the Medicines Monitoring Unit (MEMO) at Ninewells Hospital was used to identify retrospectively a cohort of patients with CHF in 1993. We then examined whether those CHF patients who received allopurinol had fewer cardiovascular events than those who did not receive allopurinol.

Clearly any comparison of the two groups had to take carefully into account the diuretic dose as this not only indicated the severity of the underlying CHF disease but also was the driving force for gout to appear. Another complicating factor that needed to be taken into account is that, at the same diuretic dose, those with a high urate concentration are known to have a much worse prognosis. Indeed, in the only study of patients with CHF, the relative risk of an above median urate concentration was as high as 4.23 and that risk was independent of diuretic dose.³

The importance of using allopurinol before 1 July 1993 as a factor is that it contains important information on the duration for which the patient was exposed to a putative beneficial treatment (allopurinol). Most treatments exhibit a duration–effect relation in terms of their ability to alter major clinical events.

The four groups differed (as expected) in certain parameters (table 1​1).

It is worth noting that all those on high dose allopurinol were also on allopurinol before 1993, which means that the fairest comparison for them is with those on low dose allopurinol who also used allopurinol before 1993. This is fairest because both groups were exposed to allopurinol's therapeutic effect for the same duration. Table 1​1 shows the demographic breakdown of the four groups. The data in table 1​1 suggest that although there were some demographic differences between the groups the differences were not all in the same direction and might well be expected in general to balance each other out. Importantly, these differences were taken into account by adjusting for these covariates in the proportional hazards regression. In the case record validation subset, 95% of patients labelled as having CHF did indeed have CHF and the allocation to receiving allopurinol or not was 100% accurate.

Figure 1​1 shows the Kaplan-Meier survival curves for the four allopurinol exposure groups. The curves show that total mortality was similar in all groups, except that the longstanding low dose allopurinol group had a worse mortality than the other three groups. This could be because the latter group was exposed to an inadequately treated urate concentration for a longer time. An alternative explanation is that low dose allopurinol is positively harmful when taken over a long period of time but this seems less likely since there are no known adverse effects of allopurinol and because high dose allopurinol was, if anything, beneficial.

It may be argued that all we have found here is that the longstanding low dose allopurinol group happened by chance to have a significantly worse mortality than all other groups and that overall allopurinol probably has no effect. Although this is certainly possible, the previous work relating high urate concentration to mortality (relative risk 4.23) makes it unlikely that our low dose results happened by chance. It would be quite a coincidence if longstanding low dose allopurinol use had increased mortality by chance in this study while longstanding high urate concentrations (which were very likely to have been present in our low dose allopurinol group) are already known to be linked to increased mortality from other studies. Therefore, it seems quite possible that the high risk associated with a longstanding high urate concentration is inadequately reduced by longstanding low dose allopurinol. That is why longstanding low dose allopurinol is associated with increased risk.

Our finding that longstanding high dose allopurinol was associated with a significantly lower mortality than longstanding low dose allopurinol should also be assessed along with the previous observation by Anker and colleagues³ that a high uric acid concentration identifies a group at particularly high risk (relative risk 4.23), irrespective of diuretic dose. Therefore, a possible conclusion from this study is that the ability of longstanding gout and a high uric acid concentration to identify a high risk group is little altered by long term low dose allopurinol. However, long term high dose allopurinol may be able to reverse that risk and return these patients to the risk normally found in patients with CHF who do not have gout. In fact, the relative risk of an above median urate concentration of 4.23³ means that it was never likely that, in this study, allopurinol would be associated with a better overall mortality than no allopurinol because, to do this, allopurinol would need to totally negate a relative risk of 4.23 plus provide an added benefit. No drug that improves mortality has ever had such a dramatic effect. This is why our finding that high dose allopurinol was associated with the same mortality as no allopurinol should not be dismissed since this is the most that allopurinol was ever likely to achieve in this kind of study.

Clearly, the allopurinol subgroups in this study were relatively small, which means that this study was more of a hypothesis generating pilot study rather than providing a definitive result. However, the difference we saw between high and low dose allopurinol does fulfill some of the criteria that epidemiologists look for to assess causation in observational studies.²¹ Firstly, the finding of a dose-response trend with any drug is generally seen to lend important support to the idea that the drug is exerting a true biological effect rather than that the findings are due to chance. This is especially true in the present study, where the low dose used (100 mg/day) is only 10% of the maximum recommended dose of allopurinol (< 1 g/day). Indeed, it would surprising if such a small dose of allopurinol (100 mg/day) were to have any effect on such a major complex event as death, especially since it is working against such a high relative risk for urate. Furthermore, it is worth noting that the two studies that showed that allopurinol improved endothelial dysfunction both used the higher, 300 mg/day dose of allopurinol, which also produced apparent benefit here.^{15, 16} Secondly, the difference between high and low doses was of reasonable magnitude with a significant risk ratio of 0.59 despite the low numbers. Thirdly, there are plausible biological mechanisms to explain such a finding (uric acid and superoxide anions).

It is worth commenting further on the limitations of the dataset available to us. Firstly, unfortunately we do not have uric acid data because the current computerised biochemistry records were not in operation in the early 1990s and because not every CHF patient would have a routine urate concentration determination unless they had symptoms to suggest gout. Secondly, the only data to reflect CHF disease severity are the furosemide (frusemide) doses. Although this is a fairly reliable measure of CHF severity, the ideal study would also have New York Heart Association functional classes and measures of left ventricular function to define CHF disease severity. Thirdly, because of limitations in the data available to use, we are unable to repeat this study in a larger cohort of patients, although we aim to do this after several years' more collection of data.