uric acid threshold for increased CAD mortality

A recent article assessed the threshold values of serum uric acid (SUA) associated with increased total and cardiovascular mortality over a 20-year period (see uric acid cad mortal hth2020 in dropbox, or DOI: 10.1161/HYPERTENSIONAHA.119.13643), the URRAH study (Uric Acid Right for Heart Health) from a working group of the Italian Society of Hypertension

Details:

--multicenter retrospective observational study collecting data from several large population-based longitudinal studies in Italy

--22,714 people included in analysis

    --mean age 57, 49% male, 25% smokers, BMI 27, waist circumference 90cm, BP 143/85, SUA 4.9 mg/dL, total chol 212/HDL 55/TG 108

    --gout 1%, diabetes 11%, CKD 17%/mean eGFR 83, htn 64%

    --meds: allopurinol 1%, ACE-I 15%, ARB 11% (?which), CCB 9%, b-blocker 9%, diuretic 17%, statin 5%

--primary endpoints: total mortality (death from any cause) and cardiovascular mortality (CVM: death from fatal MI, stroke, sudden cardiac death, heart failure)

--multivariate assessments controlled for age, sex, smoking, diabetes, hypertension, total cholesterol, alcohol use, creatinine and CKD, hematocrit, and use of diuretics

--median follow-up 134 months: 3279 deaths, of which there were 1515 cardiovascular deaths

Results:

--association between SUA and primary outcome, by multivariate regression analysis:

    --total mortality: 53% increased per 1 mg/dL increase of SUA, HR 1.53 (1.21-1.93), p<0.001

    --CVM: twice as high per 1 mg/dL increase of SUA, HR 2.08 (1.46-2.97), p<0.001

--in this multivariate analysis, they also found 3 statistically significant interactions with SUA: age, CKD, and diabetes

--cutoff values of SUA to discriminate increased risk
    --total mortality: 4.7 mg/dL (4.3-5.1 mg/dL), with sensitivity of 0.68 and specificity of 0.47

    --CVM: 5.6 mg/dL (5.0-6.2 mg/dL), with sensitivity of 0.47 and specificity of 0.69

        --by sex: male cutoff 5.4 mg/dL (4.8-6.6); female 4.7 mg/dL (4.4-5.1)

    --the SUA cutpoints for total mortality remained significant after adjustment for the Heart Score (which, unfortunately, they did not define), with HR 1.51 (1.40-1.63), p<0.001

        --ie, adding SUA to their Heart Score improved its predictive value

--their graphs show an increasing separation of survival curves over time, comparing either SUA levels above vs below their cutpoints of 4.7 mg/dL, and 5.6 mg/dL

Commentary:

--this article follows the 2018 European Society of Cardiology/Europ Soc Hypertension management guidelines, which comments that “there is emerging evidence that an increase in serum uric acid to levels lower than those typically associated with gout is independently associated with increased CV risk in both the general population and in hypertensive patients”, and that “measurement of uric acid is recommended as part of the screening of hypertensive patients” (see htn esc guidelines 2019 eurhrtj2018 in dropbox, or doi:10.1093/eurheartj/ehy339) [my emphasis added]

--several other studies (but not all) have also found a relationship between SUA levels and CVM, as found above. for relevant prior blogs, see:

    --http://gmodestmedblogs.blogspot.com/2017/07/hyperuricemia-and-cardiometabolic.html a Japanese study finding that SUA was associated with several of the other cardiovascular risk factors (hypertension, dyslipidemia, CKD, BMI)

    --http://gmodestmedblogs.blogspot.com/2016/03/hyperuricemia-allopurinol-decreases.html a Danish study suggesting that treating hyperuricemia with allopurinol led to fewer cardiovascular events

    --http://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html  provides an interesting evolutionary perspective on hyperuricemia, as well as a Taiwanese study finding a dramatic decrease in cardiovascular events by treating hyperuricemia

    -- http://gmodestmedblogs.blogspot.com/2019/03/gout-drug-feboxustat-gets-fda-boxed.html reviews the FDA warning on prescribing febuxostat; it also cites a mendelian randomization study suggesting that uric acid levels were likely causally associated with cardiovascular disease. another larger review found convincing evidence that lowering SUA levels helped gout and nephrolithiasis, though the relationship with CVM was "highly suggestive" (see uric acid cad review bmj2017 in dropbox, or doi: 10.1136/bmj.j2376)

--one comment on the blog yesterday on SGLT2's decreasing gout risk (by Anthony Ishak, specialty pharmacist at Beth Israel-Deaconness Hosp in Boston) was that it would have been useful to know what antihypertensives the people were on in that trial. His comment was that there are some antihypertensives that are effective in lowering gout risk, noting that losartan and amlodipine are particularly effective (see https://www.ncbi.nlm.nih.gov/pubmed/31977576 for an analysis of the ALLHAT study finding decreased incident gout in those on amlodipine, as opposed to chlorthalidone, or lisinopril). a prior study looked at many antihypetensivests and found that losartan (not other ARBs) and several calcium-channel blockers (amlodipine, nifedipine, diltiazem) all decrease the risk of gout (see htn and uric acid losartan ccbs bmj 2012 in dropbox, or Choi HK. BMJ2012;344:d8190). In fact, the 2012 Am Coll of Rheumatology guidelines on managing hyperuricemia list losartan as an "effective therapeutic option" to lower uric acid levels.  for the blog yesterday reviewing the association between SGLT-2's and incident gout, see http://gmodestmedblogs.blogspot.com/2020/01/sglt2s-decrease-gout-risk.html

limitations of the study;

--this was a retrospective observational study, so attribute to assess causality (ie, there could be unknown confounders and risk of selection bias)

--there was no dietary risk assessment, and there are several common foods/substances that increase uric acid levels (eg beer/alcohol, seafoods including shellfish but also tuna/haddock/cod/trout/sardines, organ meats, turkey, beef, fructose/high fructose corn syrup)

--this study only included white people in Italy, which may limit generalizability to others

--the overall SUA levels were quite low. so does these results apply to those with higher levels??

--the mortality risk score by their Heart Score was also low. so, does this translate to those at higher baseline cardiovascular risk?? 

--and, overall, this was a pretty healthy population, so would these results apply to a sicker population??  would these levels of SUA matter if the patient had lots of comorbidities?

and, perhaps the most important question: there are complex interactions with many of the components of the metabolic syndrome and SUA levels. is uric acid truly causative of cardiovascular or all-cause mortality? or is it a marker of some mixture of other risk factors?

    --there are the above mentioned studies suggesting that allopurinol (which seems to be pretty targeted in just lowering uric acid levels) decreases these clinical events

    --and there are studies suggesting that uric acid itself is a bad actor: eg, that hyperuricemia induces endothelial dysfunction (eg, see https://www.sciencedirect.com/science/article/pii/S0085253815506510 , or uric acid independ RF cad nature2018 in dropbox/DOI:10.1038/s41598-018-22997-0)

so, what does this all mean?

--for one thing, it does reinforce that SUA is a reasonable test to do, especially in those patients who may be at somewhat elevated cardiovascular risk

    --and the results, based on the above cutpoints, probably should add to our decision-making about how aggressive to be in cardiovascular risk reduction, especially since they found that adding SUA seemed to improve the risk assessment over the traditional cardiovascular risk factors

--for an elevated SUA level, what should we do?

    --seems reasonable to strongly reinforce healthy lifestyle (with particular reference to decreasing foods that increase uric acid levels, eg sodas with high fructose corn syrup, alcohol, etc)

    --also, seems reasonable to be more aggressive in medical therapy for the other risk factors (improving lipid levels, hypertension control, diabetes control, stopping smoking), since adding another risk factor seems to increase the adverse effects of the others in a greater than just additive fashion [eg, people with hyperlipidemia as well as hypertension, in the Framingham Study, increased the specific attributable risk of hypertension to cardiovascular disease]

    --and, per the above comment, we should consider using more losartan, amlodipine, nifedipine or diltiazem as preferred antihypertensives in those with high uric acid levels

    --but, we should probably have a large RCT targeting SUA levels in non-gouty patients prior to just going ahead now and starting urate lowering therapy (which is not benign) just based on an SUA level of 5 or 6....

geoff​

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