Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout

Fu-Shun Yen; Chih-Cheng Hsu; Hsin-Lun Li; James Cheng-Chung Wei; Chii-Min Hwu

doi:10.1371/journal.pone.0234909

. 2020 Jun 23;15(6):e0234909. doi: 10.1371/journal.pone.0234909

Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout

Fu-Shun Yen ¹, Chih-Cheng Hsu ^2,^3,⁴, Hsin-Lun Li ^5,⁶, James Cheng-Chung Wei ^7,^8,^9,^*, Chii-Min Hwu ^10,^11,^*

Editor: Hans-Peter Brunner-La Rocca¹²

PMCID: PMC7310696 PMID: 32574194

Abstract

Objectives

Although studies have demonstrated the association of hyperuricemia with cardiovascular (CV) diseases, few have explored the effect of urate-lowering therapy (ULT) on the incidence of CV diseases. Therefore, we compared the risks of hospitalized coronary artery disease (CAD), stroke, heart failure (HF), and all-cause mortality between ULT users and nonusers among patients with gout.

Methods

We performed this retrospective cohort study using Taiwan’s population-based National Health Insurance Research Database. In total, 5218 patients with gout were included from 2000 to 2012. We compared the incidence rates (IRs) of hospitalized CAD, stroke, HF, and all-cause mortality between ULT users and matched nonusers.

Results

The IRs of hospitalized stroke were 0.6 and 1.0 per 100 person-years for ULT users and nonusers, respectively, after adjusting for age, sex, residence, comorbidities, and medications. ULT users showed lower adjusted hazard ratios (aHR) for hospitalized stroke (aHR: 0.52, p < 0.001) and all-cause mortality (aHR: 0.6, p = 0.02) than nonusers. Subgroup analyses revealed that uricosuric agents and xanthine oxidase inhibitors were significantly associated with lower risks of hospitalized stroke and all-cause mortality, respectively. The effect of uricosuric agents on the decrease in hospitalized stroke risk indicated a dose–response relationship.

Conclusions

Our study showed lower risks of hospitalized stroke and all-cause mortality in ULT users than in nonusers among patients with gout. Therefore, patients with gout may receive ULT to mitigate the risks of hospitalized stroke and mortality.

Introduction

Serum uric acid (SUA) has been reported to be related closely to cardiovascular (CV) diseases since the nineteenth century [1]. After years of research and relevant advances, the relationship between SUA and CV diseases has been elucidated recently. A meta-analysis reported increased risk ratios of 1.22 and 1.12 for coronary artery disease (CAD) in women and men with hyperuricemia, respectively [2]. Another meta-analysis of prospective cohort studies revealed a 12% increase in mortality with every 1 mg/dL increase in uric acid (UA) among patients with CAD [3]. Hyperuricemia is also associated with a high risk of incident heart failure (HF), which follows a dose–response trend [4]. Few studies have investigated the relationship between SUA and stroke. Only Kim et al. conducted a systemic review establishing that hyperuricemia induced higher risks of stroke incidence (relative risk, 1.41) and mortality (relative risk, 1.26) [5]. Conversely, some studies have reported that because hyperuricemia always appeared with several metabolic diseases, after controlling for these confounders, no significant association was observed between hyperuricemia and CV diseases [2, 6, 7]. Therefore, hypouricemic intervention studies should be conducted to clarify whether the high level of SUA is the cause of or an accompanying condition in atherosclerotic CV diseases.

Some animal studies and randomized clinical trials in adolescents with early hypertension (HT) have shown that urate-lowering therapy (ULT) significantly decreased blood pressure [8, 9]. HT is one of the most common causes of stroke, and stroke is a leading cause of mortality [10], with more than half of stroke survivors experiencing severe and permanent disability [11]. By decreasing blood pressure, ULT is a potential promising strategy to prevent the development or progression of stroke. Few studies have reported the benefits of allopurinol use in preventing CV events and increasing survival [12–14]. Because the effect of ULT on the risks of CV diseases and mortality remains inconclusive, we conducted this retrospective cohort study to evaluate the risks of hospitalized stroke, CAD, HF, and all-cause mortality between ULT users and nonusers in patients with gout.

Materials and methods

Data source

In 1995, the Taiwanese government initiated the single-payer National Health Insurance (NHI) program to increase healthcare accessibility, and physicians are required to provide the claims data of each patient visit to the NHI Administration. Thus, the NHI Research Database (NHIRD) contains the medical utilization records of insured persons as well as their information on location, sex, age, investigations, diagnoses, prescriptions, and details of each outpatient or inpatient visit [15]. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to code disease diagnoses. The National Health Research Institutes has made available to researchers a randomly sampled dataset from 2000 to 2013 including the data of 1 million individuals (LHID 2000), which was used in this study. This study was approved by the Research Ethics Committee of China Medical University and Hospital (CMUH-104-REC2-115). Because the identifying information in the NHIRD was de-identified and encrypted, we were exempt from obtaining informed consent.

Study design

From the NHIRD 2000, we selected patients with gouty arthritis (ICD-9-CM: 274.00–274.03 and 274.8–274.9) aged between 20 and 79 years from 2000 to 2012 as our study population. Patients who had received ULT with allopurinol (M04AA01), febuxostat (M04AA03), benzbromarone (M04AB03), probenecid (M04AB01), and sulfinpyrazone (M04AB02) were included in the case cohort, whereas the control cohort included patients who were diagnosed as having gouty arthritis and were not prescribed ULT during the follow-up period. The main outcomes were all-cause mortality, hospitalized CAD, hospitalized stroke, and hospitalized HF. We used the date of first ULT and a date randomly assigned within the observation period as the index dates for the case and control cohorts, respectively. The exclusion criteria were patients aged less than 20 years or more than 80 years; who died or were hospitalized with the diagnosis of CAD, stroke, or HF within 6 months after the index date; who underwent chemotherapy or were diagnosed as having cancer by the index date; and who had missing data on sex, age, or region. The study population was followed up until patients were admitted for CAD, stroke, or HF; patient data were censored for death; patient withdrawal from the NHI program; or the end of 2013.

Statistical analysis

We performed propensity score matching for age, sex, residential area, index year, and year of gouty arthritis diagnosis between cases and controls at a 1:1 ratio in a logistic regression model [16]. The standardized mean difference (SMD) was applied to the strata of sex, age, area, comorbidity, drugs, and follow-up period to verify the comparability between these two groups. We matched the frequency distribution of the case and control cohorts by sex, age, area, comorbidity [i.e., HT (ICD-9-CM: 401–405 and A26), diabetes mellitus (DM) (250.x0, 250.x2, and A181), CAD (410–414), stroke (362.34 and 430.x–438.x), HF (428), hypercholesterolemia (272, 278, and A189), peripheral vascular diseases (093.0, 437.3, 440.x, 441.x, 443.1–443.9, 47.1, 557.1, 557.9, and V43.4), atrial fibrillation (427.3), rheumatologic diseases (446.5, 710.0–710.4, 714.0–714.2, 714.8, and 725.x), renal diseases (403.01, 403.11, 403.91, 404.02, 404.03, 404.12, 404.13, 404.92, 404.93, V42.0, V45.1, V56.x, and 790), and alcohol-related diseases (291.x, 303.x, 305.0, 357.5, 425.5, 535.3, 571.0–571.3, 980.0, and E947.3)], and drugs [i.e., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, calcium channel blockers, diuretics, potassium-sparing diuretics, other antihypertensives, metformin, sulfonylureas, insulin, statin, and aspirin]. The incidence rate (IR) of events was defined as the number of events divided by the observed person-years. To assess the dose–response trend, we analyzed the risk of hospitalized stroke according to three equally distributed cumulative durations of uricosuric agent treatment (≤1, 1–5, or >5 months); and the cumulative mean defined daily dose (DDD) of uricosuric agents (≤0.5, 0.5–0.8, and >0.8 DDD/month) relative to nonuse of ULT. We obtained the cumulative mean DDD by dividing the cumulative DDD by the duration of uricosuric agent use. DDD is a technical unit of measurement, defined as the assumed average daily maintenance dose for a drug. The WHO set the DDD at 100 mg, 1 g, 300 mg, 400 mg, and 80 mg for benzbromarone, probenecid, sulfinpyrazone, allopurinol, and febuxostat, respectively. We derived crude hazard ratios (cHRs), adjusted hazard ratios (aHRs), and 95% confidence intervals (CIs) using multivariable Cox proportional hazards regression models. Patient data were censored after a single defined CV event. Separate Cox models were used to evaluate the effects of ULT for different outcomes. The Kaplan–Meier method was used to derive the cumulative incidence of hospitalized stroke and all-cause mortality in ULT users and nonusers. Their statistical significance was detected using the log-rank test. All analyses were performed using the SAS 9.4 software program (SAS Institute, Cary, NC, USA). The null hypothesis of no effective difference between the two groups was rejected if p < 0.05.

Results

The flowchart for the selection of the ULT case cohort and non-ULT control cohorts from the NHIRD is shown in Fig 1. In total, we identified 2609 patients. The distribution of ULT users and nonusers before and after matching is presented in Table 1. Before matching, ULT nonusers had a lower ratio of men, were older, and had more comorbidities and shorter follow-up time than ULT users. After balancing these variables, 80.5% of the matched patients were men, and the mean age [standard deviation (SD)] of ULT users and nonusers was 48 (15.1) and 48.2 (14.9) years, respectively. The mean (SD) follow-up time of ULT users and nonusers was 4.52 (2.81) and 4.27 (2.8) years, respectively.

Table 1. Baseline characteristics of the study cohorts receiving or not receiving urate-lowering therapy.

	Before matching					After matching
	Urate-lowering therapy					Urate-lowering therapy
	No		Yes			No		Yes
	4059		5307			2609		2609
	n	%	n	%	SMD	n	%	n	%	SMD
Sex
Female	1173	28.9	687	12.9	0.41	516	19.8	502	19.2	0.01
Male	2886	71.1	4620	87.1	0.41	2093	80.2	2107	80.8	0.01
Age, years
20–39	1204	29.7	2114	39.8	0.21	874	33.5	907	34.8	0.03
40–59	1804	44.4	2095	39.5	0.11	1131	43.3	1104	42.3	0.02
60–79	1051	25.9	1098	20.7	0.12	604	23.2	598	22.9	0.01
Mean (SD)	49.6	14.8	46.3	15.2	0.22	48.2	14.9	48	15.1	0.01
Area
North	1887	46.5	2447	46.1	0.01	1189	45.6	1179	45.2	0.01
Central	865	21.3	1158	21.8	0.01	556	21.3	548	21	0.01
South	1180	29.1	1497	28.2	0.02	771	29.6	793	30.4	0.02
Other	127	3.1	205	3.9	0.04	93	3.6	89	3.4	0.01
Comorbidity
Hypertension	1213	29.9	1648	31.1	0.03	809	31	801	30.7	0.01
DM	459	11.3	394	7.4	0.14	239	9.2	248	9.5	0.01
CAD	491	12.1	515	9.7	0.08	293	11.2	293	11.2	<0.001
Stroke	273	6.7	305	5.7	0.04	176	6.7	176	6.7	<0.001
Heart failure	100	2.5	115	2.2	0.02	61	2.3	65	2.5	0.01
Hypercholesterolemia	1165	28.7	1390	26.2	0.06	709	27.2	702	26.9	0.01
Peripheral vascular diseases	135	3.3	109	2.1	0.08	64	2.5	66	2.5	0.005
Atrial fibrillation	35	0.9	43	0.8	0.01	24	0.9	25	1	0.004
Rheumatologic diseases	172	4.2	99	1.9	0.14	76	2.9	66	2.5	0.02
Renal diseases	121	3	182	3.4	0.03	88	3.4	87	3.3	0.002
Alcohol-related diseases	131	3.2	170	3.2	0.001	84	3.2	94	3.6	0.02
CCI(SD)	0.27	0.77	0.20	0.67	0.11	0.24	0.73	0.25	0.76	0.01
Drug
ACE inhibitors/ARBs	774	19.1	1054	19.9	0.02	514	19.7	519	19.9	0.005
β-blockers	1325	32.6	1553	29.3	0.07	822	31.5	813	31.2	0.01
Calcium-channel blockers	1069	26.3	1385	26.1	0.01	702	26.9	702	26.9	<0.001
Diuretics	940	23.2	1108	20.9	0.06	584	22.4	580	22.2	0.004
Potassium sparing diuretics	120	3	98	1.8	0.07	64	2.5	66	2.5	0.005
Other antihypertensive	498	12.3	668	12.6	0.01	336	12.9	349	13.4	0.01
Metformin	275	6.8	263	5	0.08	160	6.1	163	6.2	0.005
sulfonylurea	284	7	297	5.6	0.06	171	6.6	178	6.8	0.01
Insulin	92	2.3	129	2.4	0.01	67	2.6	73	2.8	0.01
Statin	383	9.4	320	6	0.13	208	8	213	8.2	0.01
Aspirin	680	16.8	779	14.7	0.06	432	16.6	423	16.2	0.01
mean of follow-up period of outcome	3.58	2.58	6.66	3.66	0.95	4.27	2.8	4.52	2.81	0.09

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SMD, standardized mean difference, ≤0.10 indicates a negligible difference between the two cohorts; outcomes consisting of all-cause mortality, hospitalized coronary artery disease, hospitalized stroke, and hospitalized heart failure.

Table 2 shows that ULT users were 0.52 times less susceptible to the risk of hospitalized stroke compared with ULT nonusers (IR per 100 person-years: 0.6 vs 1.0, 95% CI = 0.39–0.7, p < 0.001). Risks of ischemic stroke (aHR: 0.41) and all-cause mortality (aHR: 0.6) were also lower in ULT users than in ULT nonusers. We also assessed the composite outcomes of all-cause mortality and hospitalized CAD, stroke, and HF between ULT users and nonusers; the IR of ULT users vs nonusers was 1.2 vs 1.6 (aHR = 0.52, 95% CI = 0.55–0.86, p < 0.001).

Table 2. Incident rates of mortality, CAD, stroke, and heart failure between urate-lowering drug users vs. nonusers.

Outcome	Urate-lowering therapy
	No			Yes			cHR (95%CI)	P	aHR (95%CI)	P
	Event	PY	IR	Event	PY	IR	cHR (95%CI)	P	aHR (95%CI)	P
All-cause mortality	57	11745	0.5	37	12233	0.3	0.62 (0.41,0.94)	0.02	0.6 (0.39,0.92)	0.02
CV death	22	11745	0.2	16	12233	0.1	0.7 (0.37,1.33)	0.27	0.61 (0.31,1.19)	0.15
Hospitalized CAD	88	11480	0.8	94	11955	0.8	1.02 (0.76,1.37)	0.89	1.01 (0.75,1.35)	0.97
Hospitalized stroke	118	11326	1.0	74	12019	0.6	0.59 (0.44,0.79)	<.001	0.52 (0.39,0.7)	<.001
Ischemic stroke	64	11326	0.57	32	12019	0.27	0.47 (0.31,0.72)	<.001	0.41 (0.27,0.64)	<.001
Hemorrhagic stroke	15	11326	0.13	15	12019	0.12	0.94 (0.46,1.93)	0.88	0.88 (0.42,1.83)	0.72
Hospitalized heart failure	31	11688	0.3	32	12147	0.3	0.99 (0.6,1.62)	0.96	0.91 (0.55,1.52)	0.72

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IR, incidence rate, per 100 person-years; CI, confidence interval; p, p value; cHR, crude hazard ratio; aHR, adjusted hazard ratio, controlling for sex, age, area, every comorbidity, and drug in Table 1.

The subgroup analysis of hospitalized stroke (S1 Table) revealed that patients taking uricosuric agents; patients with underlying HT or stroke without underlying DM, CAD, stroke, or HF; and patients using ACE inhibitors, ARBs, β-blockers, calcium channel blockers, or diuretics could have a significantly low risk of hospitalized stroke. The subgroup analysis of all-cause mortality (S2 Table) indicated that patients taking xanthine oxidase (XO) inhibitors; male patients; patients with underlying stroke without underlying HT, DM, CAD, or hypercholesterolemia; and patients using β-blockers or diuretics not using ACE inhibitors, ARBs, or calcium channel blockers could demonstrate a significantly low risk of all-cause mortality.

The cumulative incidence of hospitalized stroke and all-cause mortality in ULT users and nonusers, obtained using the Kaplan–Meier method, is presented in Fig 2. The p values obtained from the log-rank test were <0.001 and 0.02 for hospitalized stroke and all-cause mortality, respectively.

Uricosuric agent users with a cumulative therapy duration of ≤1, 1–5, and >5 months were, respectively, 0.5, 0.56, and 0.31 times less likely to develop hospitalized stroke compared with nonusers, as presented in S3 Table (p for trend < 0.001). Uricosuric agent users with cumulative mean DDDs of (per month) ≤0.5, 0.5–0.8, and >0.8 were 0.45, 0.38, and 0.39 times less likely, respectively, to experience hospitalized stroke than nonusers (p for trend < 0.01).

Discussion

Our study demonstrated that ULT was associated with lower risks of hospitalized stroke and all-cause mortality in patients with gout. Subgroup analyses also revealed that uricosuric agents and XO inhibitors were associated with lower risks of hospitalized stroke and decreased risk of mortality, respectively. A dose–response trend was observed in the effects of uricosuric agents on the decrease in hospitalized stroke risk. Recent literature has demonstrated that SUA plays a clear and independent role in the development of CV diseases. First, SUA was demonstrated to stimulate platelet-derived growth factor receptor-β (PDGFR-β) phosphorylation through the mitogen-activated protein kinase pathway and to induce vascular smooth muscle cell proliferation in cultured rat aortic cells [17]. Hyperuricemia, which is associated with endothelial cell dysfunction and increased reactive oxygen species production, can increase senescence and apoptosis of vascular cells, resulting in accelerated atherosclerosis [18]. Second, UA increases the circulating levels of inflammatory mediators, and these proinflammatory effects of UA add to its proatherogenic properties [19]. Third, gout, characterized by intermittent inflammatory attacks, also increases the risks of morbidity and mortality from CV diseases [20].

XO inhibitors [12, 13, 14, 21, 22] were reported to be associated with decreased risks of composite CV and mortality outcomes, and our results are consistent with these findings. In our study, ULT was significantly associated with lower risks of composite outcomes, that is, all-cause mortality and hospitalized CAD, stroke, and HF, in patients with gout. A study revealed that SUA was an independent predictor of stroke or excess mortality in patients with DM, HT, and atrial fibrillation; elderly persons; and the general population [5]. It has also been demonstrated to be related to carotid atherosclerosis [23], arterial wave reflection [24], and intercellular adhesion molecule-1 levels [25]. These data suggest the development or progression of stroke may be attenuated by ULT. Our study demonstrated that ULT was associated with a reduced risk of hospitalized stroke, and this benefit is mostly driven by the diminution of ischemic stroke. Uricosuric agents are more effective than XO inhibitors in decreasing hospitalized stroke, which may indicate that this protective effect might be due to increasing SUA excretion and may not be due to the decrease in XO activity. ULT has been reported to reduce blood pressure [8, 9], with a greater impact on stroke than on heart disease [26]. This may explain our result of ULT being associated with a low risk of stroke and with no significant risk of CAD and heart failure.

The causal relationship of SUA and all-cause mortality is controversial. The Framingham Heart Study did not report a significant association between SUA and all-cause mortality [6], whereas other studies have revealed that a high level of SUA significantly increased the risk of all-cause mortality [27], and that allopurinol use significantly reduced mortality [12, 21, 28, 29]. In our study, ULT users showed a lower risk of all-cause mortality than the nonusers. The subgroup analysis disclosed that XO inhibitors were more strongly associated with a lower risk of death than uricosuric agents, which might indicate that this protective effect occurs through the reduction of XO activity and pro-oxidants and not solely with the increased excretion of UA. A meta-analysis reported that hyperuricemia marginally increased the risk of CAD events [2]. Norman et al. disclosed that high-dose allopurinol significantly prolonged the time to ST depression in patients with stable angina [30]. However, allopurinol users demonstrated a decrease [31] or no significant change [32] in the risk of myocardial infarction compared with nonusers. No significant differences were observed in hospitalized CAD and CV death between ULT users and nonusers in our study. Therefore, whether SUA is a risk factor for the development or progression of CAD remains unclear. One meta-analysis reported that an increase of SUA by 1 mg/dL increased the odds of HF by 19% [4]. Allopurinol has been suggested to improve a range of surrogate HF markers [33]; however, a clinical study failed to observe the therapeutic effects of allopurinol in patients with HF [34]. No significant differences were observed in hospitalized HF between ULT users and nonusers in our study. However, the IR of hospitalized HF was low in our study, which might be explained by the relatively young age of our study sample.

The strengths and limitations of our study warrant discussion. First, randomized clinical trials with long-term follow-up were not eligible and unavailable to answer our study questions. We therefore performed a large series cohort study with propensity score matching of 30 clinical variables to maximally balance the possible confounders. However, physicians may not prescribe ULT for patients with milder gout or fewer recurrent attacks of gout. Some patients also may not be followed up and may not take UA tests or adhere to the ULT regimen. These confounders may influence our outcomes. Second, the database does not contain information on smoking status, alcohol consumption, physical activity, and body mass index of patients, which might have influenced the results of our censored outcomes. Third, we could not obtain the blood pressure levels of patients or their biochemical blood test results, such as UA, blood glucose, hemoglobin A1C, cholesterol and creatinine. Patients with lower UA levels may not require ULT. Without confirmation of UA or crystal identification, other forms of arthritis may be misdiagnosed as gout. These potential biases also require attention. Fourth, the cumulative duration and mean dosage of ULT were short and low, respectively. This might be explained by the physicians’ poor adherence to treatment guidelines for gout or the poor adherence of patients to hypouricemic agent use. Fifth, our results may not be applicable to hyperuricemic patients without attacks of gout because we selected patients with gout. Finally, our study was a retrospective cohort study with inevitable existing biases; a randomized control study is required to confirm our results.

Thus, our study results revealed that ULT was associated with low risks of hospitalized stroke and all-cause mortality. Uricosuric agents seemed to reduce the risk of admitted stroke in a dose–response manner. Patients with gout may need to be on constant ULT to attenuate the risks of stroke and death.

Supporting information

S1 Table. Incidence and hazard ratio of hospitalized stroke between cohorts receiving or not receiving urate-lowering therapy.

(DOCX)

Click here for additional data file.^{(35.2KB, docx)}

S2 Table. Incidence and hazard ratio of all-cause mortality between cohorts receiving or not receiving urate-lowering therapy.

(DOCX)

Click here for additional data file.^{(27.3KB, docx)}

S3 Table. Cox model measured hazard ratios of hospitalized stroke associated with variables restricted on uricosuric agents.

(DOCX)

Click here for additional data file.^{(15.7KB, docx)}

Acknowledgments

This manuscript was edited by Wallace Academic Editing.

Data Availability

Data are available from the National Health Insurance Research Database (NHIRD) published by Taiwan National Health Insurance (NHI) Bureau. The data utilized in this study cannot be made available in the paper, the supplemental files, or in a public repository due to the ‘‘Personal Information Protection Act’’ executed by Taiwan’s government, starting from 2012. Requests for data can be sent as a formal proposal to the NHIRD (http://nhird.nhri.org.tw) or by email to nhird@nhri.org.tw.

Funding Statement

This work was supported in part by the Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW108-TDU-B-212-133004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 107-2321-B-039 -004-), Tseng-Lien Lin Foundation (Taichung, Taiwan), and Katsuzo and Kiyo Aoshima Memorial Funds (Japan), The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0234909.r001

Decision Letter 0

Hans-Peter Brunner-La Rocca

25 Feb 2020

PONE-D-19-31773

Urate-lowering therapy may mitigate the risk of hospitalized stroke in patients with gout

PLOS ONE

Dear Dr. Hwu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

In addition to the reviewer's comments, I would like to to consider the following points:

- The authors should address the differences between stroke reduction and effects on CAD and HF in more detail. In other words, why do they think that different effects were seen? Is this pure coincidence or is there some specific rational possibly responsible for this? To me, it may be an indication for significant co-founding factors that could not be taken into account, indicating the limitation of the analysis present. The authors addressed some limitation in this regard, but I would like to see some discussion about the differences mentioned above.

- The authors should be much more cautious about their conclusion. This is a retrospective study, matching was limited as many factors were not available, there was other chance of bias as indicated by the authors. Together, this means that the study is not more than hypothesis generating and the authors should be clear on this.

- I agree with the reviewer that the discussion could be shortened significantly despite the request for additional thoughts to be discussed. The previous findings of retrospective analyses should be summarized and less extensive information in this regard is required.

- Please present the tables in a way that they can be easily read.

We would appreciate receiving your revised manuscript by Apr 10 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

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Reviewer #1: Yes

**********

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Reviewer #1: Yes

**********

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Reviewer #1: No

**********

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Reviewer #1: Yes

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Reviewer #1: Yen Et Al—To authors

In this manuscript, the authors use a large national dataset to perform a retrospective cohort study, to examine the risks of hospitalized CAD, stroke, heart failure and all-cause mortality among urate lowering therapy users vs non-users. They find a decrease in stroke and all cause mortality in the urate lowering therapy users compared to non-users. Interestingly, they observe that stroke decreases are found in patients taking uricosurics, but mortality is decreased only in patients taking xanthine oxidase inhibitors.

Overall, this is a worthwhile and well-carried out study. However, there are a number of loose ends that require consideration.

1. The authors go to great lengths to propensity-match the urate lowering therapy users vs non-users and are to be commended. However, these efforts still obscure a deeper question: why were some individuals not being prescribed urate lowering therapy for established gout? Did they have milder gout, such that they did not meet criteria for treatment (for example, under American College of Rheumatology treatment guidelines, which specify that most patients should receive urate lowering therapy if they have ≥2 gout flares/year)? If they did have milder gout, would that affect the outcomes? Or did they have lower serum urate levels, such that their physicians did not feel compelled to add a urate lowering therapy? If so, would that bias the outcomes? Is it possible their physicians were less conscientious than the physicians who did prescribed urate lowering therapy, and could the cardiovascular outcomes be a result of physician attention or inattention rather than the effect of the urate lowering drug itself? Or did the patients not receive urate lowering therapy because they themselves were less compliant with medical care, putting them at a more general risk for adverse cardiovascular outcomes? These questions need to be addressed.

2. The Discussion is way too long—it should be cut by 30-50%. However, it also is lacking certain important elements. For instance, I note that the entire discussion centers around the impact of urate, and urate-lowering, on cardiovascular disease. While this concern is appropriate, it totally misses the point that this is a study not one of asymptomatic hyperuricemics, but of gout patients who have additional issues besides hyperuricemia (e.g., intermittent inflammatory attacks). This warrants discussion. At least from a point of view of rigorous logic, the question of whether urate-lowering therapy will reduce cardiovascular events in patients with hyperuricemia without gout must remain speculative.

3. The lack of available serum urate levels is a problem that deserves more attention in the text. First of all, did the patients who received urate lowering have higher urate levels at the start than those in the not urate-lowering group? Second, were the urate-lowering drugs actually successful in lowering urate—which might have provided insight into compliance with the medications as well as their mechanism of cardiovascular effect? It is surprising that serum urate levels were not available in patients getting urate lowering therapy.

4. While not at all the fault of the investigators, the data has inconsistencies that deserve more comment. For example, how is it possible to have more all cause mortality (presumably hospitalized cardiovascular death), without also having cardiovascular death? Are there other, perhaps unanticipated causes of death that are reduced with urate lowering?

5. It is interesting that the impact of urate lowering turned out not to be a generalized phenomenon, but was specific to the drug in question. If two drugs that lower urate by different mechanisms have different and non-overlapping protective effects (i.e., uricosurics reducing stroke, and xanthine oxidase inhibitors reducing all-cause mortality), how can one conclude that both are due to the same outcome of urate lowering and not other, unrecognized, divergent effects? This deserves additional consideration.

6. The authors twice mention that no prior study has addressed the ability of urate lowering to reduce the development or progression of stroke. The recently-published FREED trial looked at urate-lowering with febuxostat versus a control group, and found an overall decrease in a composite outcome (cerebrovascular, cardiovascular and renal events and all deaths), but found no decrease with febuxostat (despite urate lowering) in cardiovascular events. This study should be noted.

7. Can the authors clarify—it looks like the patients were censored after a single defined cardiovascular event. Is this correct? So then, subsequent events in the same patient (of a similar or different type) were not counted? This deserves to be explicitly mentioned.

8. The manuscript title is a bit inaccurate, since it addresses the reduction in stroke but not all cause mortality that the authors observed.

**********

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Reviewer #1: No

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PLoS One. 2020 Jun 23;15(6):e0234909. doi: 10.1371/journal.pone.0234909.r002

Author response to Decision Letter 0

23 Mar 2020

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

March 23, 2020

Dear Dr. Hans-Peter Brunner-La Rocca:

Re: Document reference No. PONE-D-19-31773

Please find attached a revised version of our document “Urate-lowering therapy may mitigate the risk of hospitalized stroke in patients with gout”. We would like to resubmit for publication as an original article in PLOS ONE.

Your comments and those of the reviewers were highly insightful and enabled us to improve the quality of our document. In the following pages are our responses to each comment from the reviewer(s) as well as your own comments.

Revisions in the text are shown yellow highlights. We hope that our revisions to the document combined with our accompanying responses will be sufficient to render our document suitable for publication in PLOS ONE.

We look forward to hearing from you soon.

Yours sincerely,

Chii-Min Hwu

Faculty of Medicine, National Yang-Ming University School of Medicine, and Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital

Tel.: +886 2 28757516

Fax: +886 2 28751429

E-Mail: chhwu@vghtpe.gov.tw

Address: No. 201, Sec. 2 Shi-Pai Rd., Chung-Cheng Build. 11F Room522, Taipei 112, Taiwan.

Responses to the comments of Reviewer 1

physicians were less conscientious than the physicians who did prescribed urate lowering therapy, and could the cardiovascular outcomes be a result of physician attention or inattention rather than the effect of the urate lowering drug itself? Or did the patients not receive urate lowering therapy because they themselves were less compliant with medical care, putting them at a more general risk for adverse cardiovascular outcomes? These questions need to be addressed.

Response: Thank you for your suggestions! It may be because most patients went to the outpatient clinics as an urgent gout attack; sometimes, the patients couldn’t be checked uric acid levels without fasting. In Taiwan, without recent (6 months) data of uric acid levels, the doctor can’t prescribe ULT to their gout patients. It is also possible that the patients did not come back for the uric acid test. The less compliance of patients to testing uric acid or taking urate lowering agents may further put them at a higher risk of adverse cardiovascular events. The milder gout of patients or the attention/inattention of physicians might also influence the prescribing of urate-lowering therapy. We added these limitations in the section of discussions at lines 287-290” Patients may have lower uric acid levels, so physicians don’t prescribe ULT for them. Without confirmation of uric acid or crystal identification, patients with some forms of arthritis may be misdiagnosed as gout. These potential biases also require attention.” and at lines 279-283 “However, patients with milder gout or less recurrent gouty attack may make physicians not feel compelled to prescribe ULT for them. Some patients may not come back for uric acid tests, or have poor adherence to urate-lowering medications; these confounding factors may influence our assessed outcomes.“

Response: Thank you for your suggestions. We cut half of the second paragraph and other statements in the discussion section; and added the statement about gout with inflammatory attack at lines 211-212” 3. Gout itself, with intermittent inflammatory attacks, also exerts increased risks of morbidity and mortality from CV diseases [20].” We also added the limitation at lines 293-294 “Fifth, because we selected patients with gout, our results may not be applicable to hyperuricemic patients without gouty attack.” to make our manuscript clearer.

Response: It is a pity that the administrative dataset is lack of serum urate levels. We have added this limitation at lines 285-290 “Third, we could not obtain the blood pressure levels of patients or their biochemical blood test results, such as UA, blood glucose, HBA1C, cholesterol, LDL, and creatinine. Patients may have lower uric acid levels, so physicians don’t prescribe ULT for them. Without confirmation of uric acid or crystal identification, patients with some forms of arthritis may be misdiagnosed as gout. These potential biases also require attention.”

4. While not at all the fault of the investigators, the data has inconsistencies that deserve more comment. For example, how is it possible to have more all-cause mortality (presumably hospitalized cardiovascular death), without also having cardiovascular death? Are there other, perhaps unanticipated causes of death that are reduced with urate lowering?

Response: Our study revealed that ULT in patients with gout could lower the risks of hospitalized stroke and all-cause mortality (Table 2, page 15). However, the decreased magnitude of hospitalized stroke by ULT may not be big enough to significantly decrease the risk of CV death.

Response: We agree with your opinions. We changed the statement at lines 240-242” which might indicate that this protective effect occurs through the increasing excretion of SUA and not through the decrease in XO activity.” To describe the different mechanisms of uricosuric agents in reducing stroke, we modified the statement at lines 258-260 as ” which might indicate that the protection of death occurs through the reduction of xanthine oxidase activity and pro-oxidants, not solely by increasing excretion of uric acid.” By adding this statement, we provide additional consideration for the different mechanisms of xanthine oxidase inhibitors in reducing all-cause mortality.

Response: Thank you for your suggestions! We deleted the statement of “no prior study has addressed the ability of urate lowering to reduce the development or progression of stroke.” and changed it (at line 238) into ”Our study demonstrated that ULT might reduce the risk of hospitalized stroke”. We added the statement about Freed trial at lines 222-225 ”The Febuxostat for Cerebral and CaRdiorenovascular Events PrEvention StuDdy (FREED) trial compared febuxostat with a control group [22], and demonstrated a significant reduction of the composite outcome (cerebral, cardiovascular and renal events and all deaths); but found no decrease in cardiovascular events.” to make our discussion more complete.

Response: Thank you! We clarified the definition of outcomes by adding statements at line 134-136 as “and the patients were censored after a single defined cardiovascular event. Separate Cox models were conducted to evaluate effects of ULT for different outcomes.”

8. The manuscript title is a bit inaccurate, since it addresses the reduction in stroke but not all cause mortality that the authors observed.

Response: Thank for your reminding! We have changed the title as” Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in persons with gout”.

Attachment

Submitted filename: O-2019-009200 R1 Response Letter .doc

Click here for additional data file.^{(54.5KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0234909.r003

Decision Letter 1

Hans-Peter Brunner-La Rocca

26 Mar 2020

PONE-D-19-31773R1

Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in persons with gout

PLOS ONE

Dear Dr. Hwu,

Thank you for submitting your manuscript to PLOS ONE. Before we can further consider your resubmission, I would like you to

a) also reply specifically to my comments in a similar way as you did for the reviewer's comments, and

b) use track changes instead of highlighting the changed / added text in yellow. The reviewer asked to shorten your discussion significantly and you mention that you did. However. it is impossible to see the specific changes that you have made. So you do not only need to highlight what is added, but also what has been deleted.

We would appreciate receiving your revised manuscript by May 10 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. Please include in this version both the reply what you did and the additional reply to my comments.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. Please use the original submission as reference and not your revised version that all changes including text that has been deleted is clearly highlighted.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

PLoS One. 2020 Jun 23;15(6):e0234909. doi: 10.1371/journal.pone.0234909.r004

Author response to Decision Letter 1

1 Apr 2020

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

March 30, 2020

Dear Dr. Hans-Peter Brunner-La Rocca:

Re: Document reference No. PONE-D-19-31773

Please find attached a revised version of our document “Urate-lowering therapy may mitigate the risk of hospitalized stroke and mortality in patients with gout”. We would like to resubmit for publication as an original article in PLOS ONE.

Revisions in the text are shown with tracked changes. We hope that our revisions to the document combined with our accompanying responses will be sufficient to render our document suitable for publication in PLOS ONE.

We look forward to hearing from you soon.

Yours sincerely,

Chii-Min Hwu

Faculty of Medicine, National Yang-Ming University School of Medicine, and Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital

Tel.: +886 2 28757516

Fax: +886 2 28751429

E-Mail: chhwu@vghtpe.gov.tw

Address: No. 201, Sec. 2 Shi-Pai Rd., Chung-Cheng Build. 11F Room522, Taipei 112, Taiwan.

Responses to the comments of Editor

1. The authors should address the differences between stroke reduction and effects on CAD and HF in more detail. In other words, why do they think that different effects were seen? Is this pure coincidence or is there some specific rational possibly responsible for this? To me, it may be an indication for significant co-founding factors that could not be taken into account, indicating the limitation of the analysis present. The authors addressed some limitation in this regard, but I would like to see some discussion about the differences mentioned above.

Response: Thank you for your suggestions, we added the mention at lines243-245 as: “Previous studies indicated that ULT may reduce blood pressure [8,9], blood pressure has a greater impact on stroke than on heart diseases [26]; which may explain our results that ULT associated with lower risk of stroke and with no significant risk of CAD and heart failure. “

2. The authors should be much more cautious about their conclusion. This is a retrospective study, matching was limited as many factors were not available, there was other chance of bias as indicated by the authors. Together, this means that the study is not more than hypothesis generating and the authors should be clear on this.

Response: Thank you for your suggestions! We modified our conclusions at lines 45-46, 203-204, 293-294 as” Our study revealed that ULT was associated with lower risks of hospitalized stroke and all-cause mortality compared with the absence of ULT in patients with gout.”

3. I agree with the reviewer that the discussion could be shortened significantly despite the request for additional thoughts to be discussed. The previous findings of retrospective analyses should be summarized and less extensive information in this regard is required.

Response: We tried to shorten the discussion, summarize previous analytic findings with less extensive information, and added the requested thoughts in the discussions.

4. Please present the tables in a way that they can be easily read.

Response: We corrected the tables 1 and 2 to let them be easily read.

Responses to the comments of Reviewer 1

Response: Thank you for your reminding! It may be because most patients went to the outpatient clinics as an urgent gout attack; sometimes, the patients couldn’t be checked uric acid levels without fasting. In Taiwan, without recent (6 months) data of uric acid levels, the doctor can’t prescribe ULT to their gout patients. It is also possible that the patients did not come back for the uric acid test. The less compliance of patients to testing uric acid or taking urate lowering agents may further put them at a higher risk of adverse cardiovascular events. The milder gout of patients or the attention/inattention of physicians might also influence the prescribing of urate-lowering therapy. We added these limitations in the section of discussions at lines 284-286” Patients may have lower uric acid levels, so physicians don’t prescribe ULT for them. Without confirmation of uric acid or crystal identification, patients with some forms of arthritis may be misdiagnosed as gout. These potential biases also require attention.” and at lines 276-280 “However, patients with milder gout or less recurrent gouty attack may make physicians not feel compelled to prescribe ULT for them. Some patients may not come back for uric acid tests, or have poor adherence to urate-lowering medications; these confounding factors may influence our assessed outcomes. “

Response: Thank you for your suggestions. We have shortened about 40% of the discussion with tracked changes; and added the statement about gout with inflammatory attack at lines 215-217” 3. Gout, with intermittent inflammatory attacks, also exerts increased risks of morbidity and mortality from CV diseases [20].” We also added the limitation at lines 290-291 “Fifth, because we selected patients with gout, our results may not be applicable to hyperuricemic patients without gouty attack.” to make our manuscript clearer.

Response: It is a pity that the administrative dataset is lack of serum urate levels. We have added this limitation at lines 282-287 “Third, we could not obtain the blood pressure levels of patients or their biochemical blood test results, such as UA, blood glucose, HBA1C, cholesterol, LDL, and creatinine. Patients may have lower uric acid levels, so physicians don’t prescribe ULT for them. Without confirmation of uric acid or crystal identification, patients with some forms of arthritis may be misdiagnosed as gout. These potential biases also require attention.”

Response: Our study revealed that ULT in patients with gout was associated with lower risks of hospitalized stroke and all-cause mortality (Table 2, page 16). However, the decreased magnitude of hospitalized stroke by ULT may not be big enough to significantly reduce the risk of CV death.

Response: We agree with your opinions. We changed the statement at lines 240-242 to describe the different mechanisms of uricosuric agents in reducing stroke” which might indicate that this protective effect occurs through the increasing excretion of SUA and not through the decrease in XO activity.”. We modified the statement at lines 256-258 as” which might indicate that the protection of death occurs through the reduction of xanthine oxidase activity and pro-oxidants, not solely by increasing excretion of uric acid.” By adding this statement, we provide additional consideration for the different mechanisms of xanthine oxidase inhibitors in reducing all-cause mortality.

Response: Thank you for your suggestions! We deleted the statement of “no prior study has addressed the ability of urate lowering to reduce the development or progression of stroke.” and changed it (at line 238-239) into” Our study demonstrated that ULT might reduce the risk of hospitalized stroke”. We added the statement about Freed trial at lines 224-228” The Febuxostat for Cerebral and CaRdiorenovascular Events PrEvention StuDdy (FREED) trial compared febuxostat with a control group [22], and demonstrated a significant reduction of the composite outcome (cerebral, cardiovascular and renal events and all deaths); but found no decrease in cardiovascular events.” to make our discussion more complete.

Response: Thank you! We clarified the definition of outcomes by adding statements at line 135-137 as “and the patients were censored after a single defined cardiovascular event. Separate Cox models were conducted to evaluate effects of ULT for different outcomes.”

8. The manuscript title is a bit inaccurate, since it addresses the reduction in stroke but not all cause mortality that the authors observed.

Response: Thank for your reminding! We have changed the title as” Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout”.

Attachment

Submitted filename: Response Letter PLOS ONE ULT AND STROKE Hsu.doc

Click here for additional data file.^{(58KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0234909.r005

Decision Letter 2

Hans-Peter Brunner-La Rocca

22 Apr 2020

PONE-D-19-31773R2

Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout

PLOS ONE

Dear Dr. Hwu,

As you can see in the comment by the reviewer, there are remaining issues. It is important that the interpretation of data is not speculative, unless clearly stated as such or stated as hypothesis that needs further tested. In addition, I agree with the reviewer that the discussion should be shortened.

We would appreciate receiving your revised manuscript by Jun 06 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: I thank the authors for their responses and resubmission. The manuscript is improved, but unfortunately I do not yet feel that the authors have fully responded to this reviewers comments. In my opinion, two specific issues remain to be addressed:

1. There continues to persist language that implies causality between ULT and benefit in the interpretation of the data. It is fine to discuss possible causality in sections where mechanisms are being speculated about, but not in sections where the meaning of the data should be interpreted rigorously. Just as one example, at the beginning of the Discussion the authors now appropriately state that “ULT in patients with gout was ASSOCIATED with lower risks of hospitalized stroke and all-cause mortality.” However, in the very next sentence they continiue to state that “A subgroup analysis revealed that uricosuric agents HAVE A SIGNIFICANT EFFECT on the decrease of hospitalized stroke, and XO inhibitors HAVE A BENEFICIAL EFFECT on survival.” This causal statement is simply not the case from the data; instead the term “association” should be applied here as it is in the first sentence. The authors need to go through the manuscript and strip any inference of causality out of the interpretation of their data; they may leave such inferences in more speculative sections where they are discussing the possible meaning of their data.

2. The discussion is still too long! It is 9 paragraphs and no reader will have patience for that. Much of the excessive content comes from the heaping up of examples that could be reduced to a summary sentence with multiple references, which would shorten the manuscript significantly. Honestly, there are very few good reasons for a discussion that focuses on the interpretation of a study to go more than 4 or 5 paragraphs.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

PLoS One. 2020 Jun 23;15(6):e0234909. doi: 10.1371/journal.pone.0234909.r006

Author response to Decision Letter 2

4 May 2020

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

May 4, 2020

Dear Dr. Hans-Peter Brunner-La Rocca:

Re: Document reference No. PONE-D-19-31773R2

Please find attached a revised version of our document “Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout”. We would like to resubmit for publication as an original article in PLOS ONE.

We look forward to hearing from you soon.

Yours sincerely,

Chii-Min Hwu

Faculty of Medicine, National Yang-Ming University School of Medicine, and Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital

Tel.: +886 2 28757516

Fax: +886 2 28751429

E-Mail: chhwu@vghtpe.gov.tw

Address: No. 201, Sec. 2 Shi-Pai Rd., Chung-Cheng Build. 11F Room522, Taipei 112, Taiwan.

Responses to the comments of Editor

1. As you can see in the comment by the reviewer, there are remaining issues. It is important that the interpretation of data is not speculative, unless clearly stated as such or stated as hypothesis that needs further tested.

Response: We have gone through the whole paper and corrected the interpretation at page 3, 18, 19, 20 and 21 of the tracked manuscript to make it not speculative.

2. In addition, I agree with the reviewer that the discussion should be shortened.

Response: We tried to shorten the discussion by using summary sentence with multiple references at page 19, 20 and 21 to make the mention more concise.

Responses to the comments of Reviewer 1

1. I thank the authors for their responses and resubmission. The manuscript is improved, but

unfortunately, I do not yet feel that the authors have fully responded to this reviewer’s comments. In my opinion, two specific issues remain to be addressed. There continues to persist language that implies causality between ULT and benefit in the interpretation of the data. It is fine to discuss possible causality in sections where mechanisms are being speculated about, but not in sections where the meaning of the data should be interpreted rigorously. Just as one example, at the beginning of

the Discussion the authors now appropriately state that “ULT in patients with gout was ASSOCIATED with lower risks of hospitalized stroke and all-cause mortality.” However, in the very next sentence they continue to state that “A subgroup analysis revealed that uricosuric agents HAVE A SIGNIFICANT EFFECT on the decrease of hospitalized stroke, and XO inhibitors HAVE A BENEFICIAL EFFECT on survival.” This causal statement is simply not the case from the data; instead the term “association” should be applied here as it is in the first sentence. The authors need to go through the manuscript and strip any inference of causality out of the interpretation of their data; they may leave such inferences in more speculative sections where they are discussing the possible meaning of their data.

Response: Thank you for your encouragement. We have gone through the whole paper and corrected the interpretation at page 3, 18, 19, 20 and 21 of the tracked manuscript to make it not speculative.

Response: We learned much from your recommendations. We have shortened the discussion by using summary sentence with multiple references at page 19, 20 and 21 to make the mention more concise.

Attachment

Submitted filename: O-2019-009200 R3 Response Letter.doc

Click here for additional data file.^{(43.5KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0234909.r007

Decision Letter 3

Hans-Peter Brunner-La Rocca

14 May 2020

PONE-D-19-31773R3

Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout

PLOS ONE

Dear Dr. Hwu,

I have not sent the revisions to the reviewers again as you addressed the points adequately. However, I have to remind you that there is no type editing by the journal and the text needs to be written in correct English. This is, unfortunately, not yet the case. You really need to have the text revised by an native English speaking person. In particular, the revised text contains various mistakes. E.g. where you changed to indicate an association instead of a causative effect you always write only "associated", instead of "were associated" (e.g. the abstract: "Subgroup analyses revealed that uricosuric agents significantly associated with lower risk of hospitalized stroke, and XO inhibitors significantly associated with lower risk of all-cause mortality". It should be "... uricosuric agents were significantly associated with lower risk..." etc. There are also other examples where you simply have no verb as part of the sentence. You also tend to omit articles (the, a), which is not good English.

I understand that this is difficult for you, but there is no other option as this is the policy of PLOS ONE.

We would appreciate receiving your revised manuscript by Jun 28 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

PLoS One. 2020 Jun 23;15(6):e0234909. doi: 10.1371/journal.pone.0234909.r008

Author response to Decision Letter 3

28 May 2020

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

May 28, 2020

Dear Dr. Hans-Peter Brunner-La Rocca:

Re: Document reference No. PONE-D-19-31773R2

Your recommendations are very important and enable us to improve the quality of our document. In the following pages are our responses to your comments.

We look forward to hearing from you soon.

Yours sincerely,

Chii-Min Hwu

Faculty of Medicine, National Yang-Ming University School of Medicine, and Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital

Tel.: +886 2 28757516

Fax: +886 2 28751429

E-Mail: chhwu@vghtpe.gov.tw

Address: No. 201, Sec. 2 Shi-Pai Rd., Chung-Cheng Build. 11F Room522, Taipei 112, Taiwan.

Responses to the comments of Editor

1. I have not sent the revisions to the reviewers again as you addressed the points adequately. However, I have to remind you that there is no type editing by the journal and the text needs to be written in correct English. This is, unfortunately, not yet the case. You really need to have the text revised by a native English speaking person. In particular, the revised text contains various mistakes. E.g. where you changed to indicate an association instead of a causative effect you always write only "associated", instead of "were associated" (e.g. the abstract: "Subgroup analyses revealed that uricosuric agents significantly associated with lower risk of hospitalized stroke, and XO inhibitors significantly associated with lower risk of all-cause mortality". It should be "... uricosuric agents were significantly associated with lower risk..." etc. There are also other examples where you simply have no verb as part of the sentence. You also tend to omit articles (the, a), which is not good English. I understand that this is difficult for you, but there is no other option as this is the policy of PLOS ONE.

Response: Thank you for your encouragement and recommendations! We have asked native English speaking persons (Katie Fonseca and Sam Nagel) to revise our text, especially focus on some mistakes you raised.

Attachment

Submitted filename: Response to Reviewers_31773R3.docx

Click here for additional data file.^{(22KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0234909.r009

Decision Letter 4

Hans-Peter Brunner-La Rocca

5 Jun 2020

Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout

PONE-D-19-31773R4

Dear Dr. Hwu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Hans-Peter Brunner-La Rocca, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0234909.r010

Acceptance letter

Hans-Peter Brunner-La Rocca

9 Jun 2020

PONE-D-19-31773R4

Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout

Dear Dr. Hwu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Hans-Peter Brunner-La Rocca

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Incidence and hazard ratio of hospitalized stroke between cohorts receiving or not receiving urate-lowering therapy.

(DOCX)

Click here for additional data file.^{(35.2KB, docx)}

S2 Table. Incidence and hazard ratio of all-cause mortality between cohorts receiving or not receiving urate-lowering therapy.

(DOCX)

Click here for additional data file.^{(27.3KB, docx)}

S3 Table. Cox model measured hazard ratios of hospitalized stroke associated with variables restricted on uricosuric agents.

(DOCX)

Click here for additional data file.^{(15.7KB, docx)}

Attachment

Submitted filename: O-2019-009200 R1 Response Letter .doc

Click here for additional data file.^{(54.5KB, doc)}

Attachment

Submitted filename: Response Letter PLOS ONE ULT AND STROKE Hsu.doc

Click here for additional data file.^{(58KB, doc)}

Attachment

Submitted filename: O-2019-009200 R3 Response Letter.doc

Click here for additional data file.^{(43.5KB, doc)}

Attachment

Submitted filename: Response to Reviewers_31773R3.docx

Click here for additional data file.^{(22KB, docx)}

Data Availability Statement

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PERMALINK

Urate-lowering therapy may mitigate the risks of hospitalized stroke and mortality in patients with gout

Fu-Shun Yen

Chih-Cheng Hsu

Hsin-Lun Li

James Cheng-Chung Wei

Chii-Min Hwu

Roles

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Materials and methods

Data source

Study design

Statistical analysis

Results

Fig 1. Flowchart of selecting the urate-lowering therapy cohort and the control cohort from the National Health Insurance Research Database.

Table 1. Baseline characteristics of the study cohorts receiving or not receiving urate-lowering therapy.

Table 2. Incident rates of mortality, CAD, stroke, and heart failure between urate-lowering drug users vs. nonusers.

Fig 2. Cumulative incidence of (A) hospitalized stroke and (B) all-cause mortality in patients receiving and not receiving urate-lowering therapy.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Hans-Peter Brunner-La Rocca

Roles

Author response to Decision Letter 0

Decision Letter 1

Hans-Peter Brunner-La Rocca

Roles

Author response to Decision Letter 1

Decision Letter 2

Hans-Peter Brunner-La Rocca

Roles

Author response to Decision Letter 2

Decision Letter 3

Hans-Peter Brunner-La Rocca

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Author response to Decision Letter 3

Decision Letter 4

Hans-Peter Brunner-La Rocca

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Acceptance letter

Hans-Peter Brunner-La Rocca

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Associated Data

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Data Availability Statement

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PERMALINK

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