Our retrospective cohort study is certainly not as definitive as a fully randomised controlled trial (RCT) but there are some well recognised advantages of this kind of study over an RCT. For example, the average age in many RCTs involving patients with CHF is often 62 years, whereas the average age of these patients in the real world is usually higher, the average age in this study being 68 years. The other criticism of many RCTs in CHF is that comorbidity often excludes a patient from taking part in an RCT, whereas comorbid conditions are extremely common in real life elderly CHF patients. Thus, an advantage of our retrospective study is that neither age nor comorbidity nor indeed any factor at all led to a patient being excluded, which means that the population that we studied was representative of patients with routine ischaemic CHF in the UK.
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.
We have found that long term low dose allopurinol is associated with increased mortality while long term high dose allopurinol was associated with the same mortality as in those who received no allopurinol. One possible interpretation of these results is that low dose allopurinol inadequately reduces the adverse effects associated with a longstanding high urate concentration but that high dose allopurinol does reduce the risks associated with a high urate concentration in CHF. It also raises the hypothesis that patients with CHF who have gout ought to receive ≥ 300 mg allopurinol/day even if a lower dose keeps the gout under clinical control. Further work is required to see whether the hypothesis raised by these results is true.