allopurinol decreases heart disease??

 A recent randomized trial found that allopurinol by itself did not decrease the risk of cardiovascular endpoints, in the ALL-HEART study (see allopurinol not dec IHD Lancet2022 in dropbox, or Lancet 2022; 400: 1195–205)

 

Details:

-- 5721 participants were enrolled in a multicenter, prospective, randomized, open-label but blinded-endpoint trial in England and Scotland

-- eligible patients included those at least 60 years old, with ischemic heart disease, but no history of gout

-- mean age 72, 76% male, 99% white

-- smoking history 9% current/58% former/34% never, blood pressure 132/72, BMI 29, eGFR 30-44 in 2%/45-59 in 7%/>60 in 91%

-- baseline serum uric acid level 0.35 mmol/L (6 mg/dL)

-- history of MI 47%; angina 65% (mostly Canadian Cardiovascular Society grade 0-1, though 14% had grade 2); other evidence of ischemic heart disease in 69% with mean duration of 10 years

-- dyslipidemia 34%, hypertension 57%, diabetes 22%

-- 91% were on statins, 3% ezetimibe, 87% antiplatelet drugs, 9% anticoagulants, 66% beta blockers, 48% ACE inhibitors, 90% ARBs, 56% antianginal medications, 30% calcium blockers

-- participants were randomly assigned to receive allopurinol up-titrated to 600 mg a day (300 mg a day in those with eGFR 30-59 at baseline)

 

-- primary outcome: composite of cardiovascular endpoints of nonfatal MI, nonfatal stroke, and cardiovascular death

-- secondary outcomes included nonfatal MI, nonfatal stroke, cardiovascular death, all-cause mortality, hospitalizations for acute coronary syndrome, coronary revascularization, hospitalization for acute coronary syndrome or coronary revascularization, hospitalization for heart failure, all cardiovascular hospitalizations, quality-of-life, and cost-effectiveness

-- serious adverse events were recorded

-- mean follow-up was 4.8 years

 

Results:

-- serum uric acid levels on allopurinol: decreased from 0.34 mmol per liter to 0.18 mmol per liter (about 6 to 3 mg/dL)

-- primary endpoint:

    -- allopurinol: 314 (11.0%), 2.47 events per 100 patient years

    -- usual care: 325 (11.3%), 2.37 events per 100 patient years

        -- HR 1.04 (0.89-1.21), not statistically significant

-- deaths from any cause:

   -- allopurinol: 288 (10.1%)

    --usual care: 303 (10.6%) 

            -- HR 1.02 (0.87-1.20), not statistically significant

-- secondary analysis: all of the individual secondary outcomes were not statistically significantly different between the groups 

-- subgroup differences by baseline values were not statistically significant for: urate levels,  eGFR, age greater or less than 70, males versus females, diabetes, myocardial infarction, heart failure, peripheral arterial disease, stroke, or the combination of stroke or TIA  

-- the results of the above were broadly similar in the on-treatment analysis 

-- the quality-of-life assessments were not different between the groups 

-- no health economic benefit of allopurinol 

-- adverse events: 

    -- allopurinol: 29%, serious adverse events 2%  

    -- of note, the total number of “any serious adverse event” was more in the usual care group than for those on allopurinol (2194 vs 2036 events), including adverse effects categorized as endocrine, infections, nervous system problems, neoplasms, renal/urinary, respiratory, surgical/medical procedures. However, all of these differences were not statistically significant. No patient reported Stevens-Johnson syndrome 

 

Commentary: 

-- several studies have found that high serum uric acid concentrations are associated with adverse cardiovascular outcomes, and that urate lowering therapy (ULT) may reduce cardiovascular risk:

    -- for example, a 20 year observational Italian study of patients with low serum uric acid levels (4.9 m/dL) did find a graded increase in total mortality as well as cardiovascular mortality with increasing levels of serum uric acid,  SUA (see http://gmodestmedblogs.blogspot.com/2020/01/uric-acid-threshold-for-increased-cad.html )

    -- another study found that patients with gout but not treated with ULT versus controls had a significantly increased risk of both cardiovascular and all-cause mortality; those with gout treated with ULT versus those with gout not treated with ULT had a 70% decreased cardiovascular mortality and a 50% decreased all cause mortality (see http://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html )

        -- this blog also has a review of a Scientific American article arguing that both great apes and humans lack the uricase enzyme which breaks down uric acid. they argue that this loss of enzyme evolved because of significant changes in food availability and starvation, and this evolutionary change allowed for increased storage of energy in fat cells to help deal with cycles of food scarcity; this increased fat storage in our current times of plenty (especially in resource-rich countries) is part of the current problems of obesity, diabetes, heart disease, hypertension, dyslipidemia, etc, etc, etc

-- small interventional studies have found significant benefit of allopurinol on endothelial function, flow-mediated vascular dilation, blood pressure, left ventricular mass, carotid intima-media thickness progression, and arterial stiffness

-- a few smaller randomized controlled trials documented benefit of allopurinol in terms of endothelial function and decreasing oxidative stress (clinical outcomes were not assessed, though these outcomes are highly associated with poorer outcomes):

    -- a study of patients with chronic heart failure compared allopurinol 300 mg versus 600 mg versus placebo in one study and another study of 1000 mg of probenecid versus placebo, found that allopurinol significantly improved endothelial function by profoundly reducing vascular oxidative stress, though this was not found with similar uric acid lowering by probenicid (see https://www.ahajournals.org/doi/epub/10.1161/CIRCULATIONAHA.106.651117 ): ie, it seemed to be the allopurinol and not just lowering uric acid levels

    -- another RCT assessed high-dose allopurinol (up to 600 mg a day) on patients with coronary artery disease receiving optimal anti-atheroscerlosis treatment (as of 2011), also finding that endothelial function was significantly improved on allopurinol versus placebo and that vascular oxidative stress was completely abolished by allopurinol (see https://www.sciencedirect.com/science/article/pii/S0735109711019486 )

 

-- given these findings, this current study was designed to answer the question of whether allopurinol, not in the setting of people with clinical gout, had benefit from allopurinol therapy. And it found no benefit

 

Limitations:

-- this trial was limited to older patients with documented long-standing ischemic heart disease ( >10 years). In this group of patients there was no clear benefit from allopurinol, but this does not exclude benefit in those who had less advanced chronic atherosclerotic disease or were younger or were given allopurinol as primary prevention for significant hyperuricemia

    -- another potential limitation is that these chronically sick patients were on a very large number of medications that could counteract some of the protective effect of allopurinol (eg, statins and antiplatelet drugs improve endothelial function; statins decrease oxidative stress; and many of the drugs improve mortality); so, the added role of allopurinol could well be minimized by the combination of patients with very advanced disease who were on meds that have benefits that might overlap those of allopurinol

-- the demographics of this study were limited: all participants were in England and Scotland, with 76% males and 99% white, limiting generalizability to other areas

-- not only did these patients not have a history of gout, but the mean baseline serum uric acid level was 0.35 mmol/L, which translate to 6 mg/dL. These low uric acid levels may also limit generalizability to those with uric acid significantly higher than this

-- this was an open-label study with no placebo group and relied on patient-reported outcomes, creating a potential bias in terms of the accuracy of these outcomes

    -- also, having no placebo group makes it likely that the usual care group (who were on no added medication) would likely not report adverse outcomes. And, the trend found in this study of actually finding increased problems in the usual care group might reflect significant under-reporting

 

So, a few points about this study:

-- This study was designed as a large prospective study to clarify the role of urate lowering therapy by allopurinol, since the observational studies had somewhat conflicting results. However, the design of the study and the patients involved makes it hard for the study to really answer this question, as noted above

--  I personally would not start a patient on allopurinol who had just asymptomatic hyperuricemia unless the level was really high and likely to lead to gout or kidney stones (and certainly not at the level of 6 mg/dL as in this study)

    -- and I would encourage nonpharmacologic management, especially the avoidance of fructose and high-fructose corn syrup which really increase uric acid levels (I have had a few patients whose uric acid levels have decreased 1-1.5 mg/dL just by cutting out sodas)

    -- in those with gout needing urate-lowering meds, i would be very hesitant in prescribing allopurinol to those from East Asia, since they have a higher incidence of HLA-B*5801 and the attendant increased risk of severe allopurinol cutaneous reactions (if they need treatment, it makes sense either to check for this haplotype or prescribe feboxustat)

    -- in those with chronic kidney disease (and including the vast majority of my elderly patients), I would start low (allopurinol 50mg/d) and increase slowly to the target dose; there is substantial benefit to this approach in avoiding severe allopurinol reactions

-- for the recent gout guidelines, see http://gmodestmedblogs.blogspot.com/2020/06/new-gout-management-guidelines.html

 

-- I am concerned about a "new study bias"

    -- i think there is a tendency among us (or the popular press, if a study makes it there) that the newest study is the best and most definitive one

    -- I personally am pretty impressed with the several older studies that largely suggested that allopurinol has significant cardiovascular protective effect (and some finding renal protection as well) and that the more detailed physiological studies provide impressive background as to why allopurinol is likely protective. (though a mendelian randomization study did not find this to be the case)

    -- the background issue here is that given the huge trove of studies coming out, it is very hard for us clinicians to be able to read many articles deeply and critically. Though the abstract here did make it clear that this was a group of people “aged 60 years or older with ischaemic heart disease but no history of gout”, the take-away may well be that allopurinol does nothing (and they do comment, I think inappropriately,  that “the generalizability of the ALL-HEART study findings to the population with ischaemic heart disease is likely to be high”. 

        -- perhaps the abstract might state something like “in this large randomized clinical trial specifically of patients older than 60 with long-standing cardiovascular disease in England and Scotland and relatively low baseline serum uric acid levels, there was no apparent benefit of allopurinol”. though there might be some ego involved in overstating the importance and generalizability of their findings.......

 

 

geoff

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