Expansion of Rotation 5 Week 2 PICO

Clinical Question: As in the past, please briefly outline the scenario and state your clinical question as concisely and specifically as possible

A 60M, new patient to the office has a history of hypertension, gout and CABG. He is prescribed allopurinol for prevention, and he asks about this new drug he saw on TV Uloric (febuxostat).

What is the cardiovascular safety in febuxostat versus allopurinol in the prevention of gout?

PICO Question:

Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week

PICO search terms:

P	I	C	O
Gout	Allopurinol	Febuxostat	Cardiovascular safety
Podagra	Aloprim	Uloric	Adverse effects
Gouty Arthritis	Zyloprim		Cardiovascular events
			Cardiovascular risk

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on.  This will likewise be a revision and refinement of what you have already done.

Cochrane review: termàallopurinol vs febuxostat cardiovascular safety. I narrowed the results to between 2011 and 2021 and obtained 8 trials and 0 reviews. I looked specifically for articles discussing cardiovascular risk that were randomized trials. Two of the trials were discussing gout treatment specifically in diabetic patients I excluded those. Several were not discussing cardiovascular risk at all so I excluded those. The articles I chose to read from here discussed the CARES trial which led me to look for that trial and pick it. I found it on clinicaltrials.gov.

PubMed: termà allopurinol vs febuxostat cardiovascular safety. I narrowed results between 2011-2021. Looked for journals that were Medline indexed. I found 157 results. I looked for systematic reviews, meta analysis and randomized control studies. I excluded studies comparing the two medications in anything other than cardiovascular outcomes (for example in those with chronic kidney disease or diabetes)

Gale health and medicine: termà allopurinol vs febuxostat and cardiovascular safety. I narrowed my articles by date, within 10 years. I also selected only peer reviewed journals. I received 21 results. I narrowed down further by looking for article discussing cardiovascular outcomes, several articles looked at chronic kidney disease, or just comparing the effectiveness without comparing the cardiovascular outcomes.

Science direct: termà allopurinol vs febuxostat and cardiovascular safety. I narrowed my results from after 2011 and I obtained 137 results. I narrowed down further by looking for article discussing cardiovascular outcomes, several articles looked at chronic kidney disease, or just comparing the effectiveness without comparing the cardiovascular outcomes. I found a meta analysis just discussing the cardiovascular outcomes of febuxostat but not compared to allopurinol so I excluded that.

In the end I chose 5 articles: 2 RCTs and 3 Cohort studies. I was not able to find any meta analysis or systematic review that looked specifically at the outcome I was searching for. However each of the Cohort studies and RCTs had large sample sizes, and therefore I felt the evidence from these articles is still quite strong.

Articles Chosen (5 or more) for Inclusion (please copy and paste the abstract with link):

Please pay attention to whether the articles actually address your question and whether they are the highest level of evidence available.  If you cannot find high quality articles, be prepared to explain the extensiveness of your search and why there aren’t any better sources available.

Please note that if the evidence is not in the abstract, you must clearly summarize the evidence in your posting. 

Article #	Citation:	Abstract
1 (White et al.)	White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, Hunt B, Castillo M, Gunawardhana L; CARES Investigators. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018 Mar 29;378(13):1200-1210. doi: 10.1056/NEJMoa1710895. Epub 2018 Mar 12. PMID: 29527974.	Background: Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease. Methods: We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization). Results: In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis. Conclusions: In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).
2 (Mackenzie et al)	Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, Ralston SH, Walters M, Robertson M, De Caterina R, Findlay E, Perez-Ruiz F, McMurray JJV, MacDonald TM; FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020 Nov 28;396(10264):1745-1757. doi: 10.1016/S0140-6736(20)32234-0. Epub 2020 Nov 9. PMID: 33181081.	Background: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. Methods: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. Findings: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. Interpretation: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.
3 (Ching et al)	Ching-Yen Su, Li-Jiuan Shen, Song-Chou Hsieh, Lian-Yu Lin, Fang-Ju Lin, Comparing Cardiovascular Safety of Febuxostat and Allopurinol in the Real World: A Population-Based Cohort Study, Mayo Clinic Proceedings ,Volume 94, Issue 7, 2019, Pages 1147-1157, ISSN 0025-6196, https://doi.org/10.1016/j.mayocp.2019.03.001. (https://www.sciencedirect.com/science/article/pii/S0025619619302526)	To determine and compare the risk of cardiovascular events and mortality of febuxostat and allopurinol use. Patients and Methods We conducted a cohort study using the Taiwan National Health Insurance Research Database. New users of febuxostat and allopurinol between April 1, 2012 and December 31, 2015 were identified, and the two groups were 1:1 matched by propensity score, benzbromarone use history, renal impairment, and time of drug initiation. The risk of major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), heart failure (HF) hospitalization, atrial fibrillation hospitalization, cardiovascular (CV) death, and all-cause mortality was assessed using Cox proportional hazards models. The dose-response relationship between xanthine oxidase inhibitor use and adverse CV outcomes were also determined. Results A total of 44,111 patients were included for each group, and all baseline covariates were well matched. Febuxostat users were at a significantly higher risk for HF hospitalization (hazard ratio [HR], 1.22; 95% CI, 1.13-1.33), atrial fibrillation hospitalization (HR, 1.19; 95% CI, 1.05-1.36), and CV death (HR, 1.19; 95% CI, 1.03-1.36) than allopurinol users, whereas no difference was found for the major adverse cardiac events composite endpoint, venous thromboembolism, myocardial infarction, ischemic stroke, and all-cause mortality. The elevated risk of HF hospitalization was consistent throughout the primary and sensitivity analyses. In addition, febuxostat increased the risk of adverse CV outcomes in a dose-dependent manner. Conclusion The use of febuxostat, compared with allopurinol, was associated with a significantly increased risk of adverse CV events. Higher febuxostat doses had a greater impact. Further studies are needed to investigate the mechanisms linking febuxostat to adverse CV outcomes.
4 (Kang et al)	Eun Ha Kang, Hyon K Choi, Anna Shin, Yun Jong Lee, Eun Bong Lee, Yeong Wook Song, Seoyoung C Kim, Comparative cardiovascular risk of allopurinol versus febuxostat in patients with gout: a nation-wide cohort study, Rheumatology, Volume 58, Issue 12, December 2019, Pages 2122–2129, https://doi.org/10.1093/rheumatology/kez189	Objective. To compare cardiovascular (CV) risk among gout patients initiating allopurinol vs febuxostat. Methods. Using 20022015 Korean National Health Insurance Service data for the entire Korean population, we conducted a cohort study on gout patients initiating allopurinol or febuxostat. The primary outcome was a composite CV end point of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. Secondary outcomes were individual components of the primary outcome, and all-cause mortality. We used propensity score-matching with a 4:1 ratio for allopurinol and febuxostat initiators to control for confounding. Competing risk analyses were done for nonfatal outcomes accounting for deaths. Results. We included 39 640 allopurinol initiators propensity score-matched on 9910 febuxostat initiators. The mean age was 59.1 years and 78.4% were male. The incidence rate per 100 person-years for the primary outcome was 1.89 for allopurinol and 1.84 for febuxostat initiators. The corresponding hazard ratio comparing allopurinol vs febuxostat initiators was 1.09 (95% CI: 0.90, 1.32). No significant difference was found for the secondary outcomes, including all-cause mortality (hazard ratio 0.96; 95% CI: 0.79, 1.16). Subgroup analyses limited to those at high CV risk and to equipotentdose initiators (i.e. allopurinol 5300 mg/day vs febuxostat 540 mg/day) showed similar results. Conclusion. Overall, this large Korean population-based study suggests no difference in the risk of non-fatal CV events and all-cause mortality between allopurinol and febuxostat initiators. These findings are consistent with the recent US Medicare population study, although the current study population consisted of younger Asians.
5 (Zhang et al)	Assessment of Cardiovascular Risk in Older Patients With Gout Initiating Febuxostat Versus Allopurinol MaryAnn Zhang, MD, Daniel H. Solomon, MD, MPH, Rishi J. Desai, PhD, Eun Ha Kang, MD, PhD, Jun Liu, MD, MPH Tuhina Neogi, MD, PhD, and Seoyoung C. Kim, MD, ScD	Background: Hyperuricemia and gout are associated with an increased risk of cardiovascular disease. Xanthine oxidase inhibitors, allopurinol and febuxostat, are the mainstay of urate-lowering treatment for gout and may have different effects on cardiovascular risk in patients with gout. Methods: Using US Medicare claims data (2008–2013), we conducted a cohort study for comparative cardiovascular safety of initiating febuxostat versus allopurinol among patients with gout ≥65 years of age. The primary outcome was a composite end point of hospitalization for myocardial infarction or stroke. Secondary outcomes were individual end points of hospitalization for myocardial infarction, stroke, coronary revascularization, new and recurrent heart failure, and all-cause mortality. We used propensity score matching with a ratio of 1:3 to control for confounding. We estimated incidence rates and hazard ratios for primary and secondary outcomes in the propensity score–matched cohorts of febuxostat and allopurinol initiators. Results: We included 24 936 febuxostat initiators propensity score–matched to 74 808 allopurinol initiators. The median age was 76 years, 52% were male, and 12% had cardiovascular disease at baseline. The incidence rate per 100 person-years for the primary outcome was 3.43 in febuxostat and 3.36 in allopurinol initiators. The hazard ratio for the primary outcome was 1.01 (95% CI, 0.94–1.08) in the febuxostat group compared with the allopurinol group. Risk of secondary outcomes including all-cause mortality was similar in both groups, except for a modestly decreased risk of heart failure exacerbation (hazard ratio, 0.94; 95% CI, 0.91–0.99) in febuxostat initiators. The hazard ratio for all-cause mortality associated with long-term use of febuxostat (>3 years) was 1.25 (95% CI, 0.56–2.80) versus allopurinol. Subgroup and sensitivity analyses consistently showed similar cardiovascular risk in both groups. Conclusions: Among a cohort of 99 744 older Medicare patients with gout, overall there was no difference in the risk of myocardial infarction, stroke, new-onset heart failure, coronary revascularization, or all-cause mortality between patients initiating febuxostat compared with allopurinol. However, there seemed to be a trend toward an increased, albeit not statistically significant, risk for all-cause mortality in patients who used febuxostat for >3 years versus allopurinol for >3 years. The risk of heart failure exacerbation was slightly lower in febuxostat initiators.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
White et al (2018)	RCT	-Multi-center, double blind non-inferiority trial -patients had gout and cardiovascular disease -randomly assigned to receive febuxostat or allopurinol -stratified according to kidney function -6190 patients were randomized and followed for a median of 32 months with a maximum of 85 months	-prespecified noninferiority margin of 1.3 based on the hazard ratio for the primary endpoint -primary endpoint: cardiovascular death, nonfatal MI, nonfatal stroke, unstable angina requiring urgent revascularization	– A primary endpoint event occurred in a total of 335 patients (10.8%) in the febuxostat group and 321 (10.4%) in the allopurinol group. -All cause and cardiovascular mortality were higher in the febuxostat group as compared to the allopurinol group (1.01:1.47). -equal number in both groups discontinued treatment or follow up	-Limitations: large number of patients who discontinued the treatment -Large number of patients who did not complete the follow up. -Discontinued treatment biases the analysis to the null hypothesis, which could have missed significant difference between the groups.
Mackenzie et al (2020)	RCT	-Prospective randomized open label, blinded endpoint, non-inferiority trial of febuxostat vs allopurinol in patients with gout in the UK, Denmark, and Sweden -Eligible for participation: >60 years-old, already receiving allopurinol, and at least 1 cardiac risk factor -Those with a MI, stroke in the past 6 months, significant CHF or renal failure were excluded -first patients were optimized with allopurinol for serum urate <0.356 mmol/L and then randomized to either continue to receive allopurinol or switch to febuxostat -6128 patients were included in this trial	-Composite of hospitalization for non-fatal MI, positive cardiac biomarker ACS, non-fatal stroke, cardiovascular death. -Hazard ratio using Cox proportional hazards model was used to assess for non-inferiority	-For primary endpoint febuxostat was noninferior to allopurinol (1.72 events per 100 patient years vs 2.05 events per 100 patient years). -222 (7.2%) of the febuxostat patient group died, 1720 (57.3%) had a serious adverse event -263 (8.6%) of the allopurinol group died, and 1812 (59.4%) had a serious adverse event -Randomized therapy was discontinued in 973 of the febuxostat group and 503 in the allopurinol group	-no placebo group – patients were taking allopurinol prior, may have had an additive effect
Ching et al (2019)	Retrospective Cohort	-new users of febuxostat and allopurinol between April 2012 and December 2015 were identified using the Taiwan National Health Insurance Research database -groups were 1:1 matched for propensity score, benzbromarone use, renal impairment, time of drug initiation. -44,111 participants were included in each group	-risk of major adverse cardiovascular event (MACE), venous thromboembolism (VTE), heart failure (HF) hospitalizations, atrial fibrillation (AF) hospitalization, cardiovascular death, all cause mortality -Cox proportional hazards model -dose response relationship between xanthine oxidase inhibitor use and CV outcomes were assessed	-Users of febuxostat were at an increased risk for hospitalizations from heart failure, atrial fibrillation and cardiovascular death as compared to allopurinol users. -No difference between the two groups were found with MACE, VTE, MI, ischemic stroke and all cause mortality.	-not a randomized trial is therefore able to have confounding and selection bias -some covariates were not controlled for (serum uric acid, creatinine levels) -analysis was conducted using diagnostic coding, and there could be coding problems -retrospective trial so could only define medication exposure based on pharmacy dispensing of the medication
Kang et al (2019)	Cohort	-2002-2015 Korean National Insurance Service which includes entire Korean population -cohort study of gout patients initiating allopurinol or febuxostat -39,640 allopurinol users were compared to 9910 febuxostat users	-primary outcome: compositive cardiovascular endpoint of MI, stroke, TIA, coronary revascularization -secondary outcome: individual component of primary outcome and all cause mortality	-The primary outcome incidence rate per 100 person-years was 1.89 for allopurinol group and 1.84 for the febuxostat group. -There were no significant differences found on secondary outcomes including all cause mortality	-confounding and selection bias due to lack of randomization process -follow up time with the patients was shorter than some other studies
Zhang et al (2018)	Cohort	-US Medicare claims data between 2008-2013 -patients with gout >65 years of age -24,936 febuxostat users were compared with 74,808 allopurinol users. -median age was 76, 52% male, 12% with baseline cardiovascular disease	-primary outcome: composite end point of hospitalization for MI or stroke. -secondary outcome: individual endpoint  for hospitalization for MI, stroke, coronary revascularization, new and recurrent HF, all cause mortality	-incidence rate for primary outcome per 100-person-years was 3.43 in febuxostat group and 3.36 in allopurinol initiators. -hazard ratio for primary outcome was 1.01 in febuxostat group compared to allopurinol group -secondary outcomes were similar in both groups with the exception of a moderately decreased risk of HF exacerbation in febuxostat users	-misclassification bias may have occurred due to reliance on diagnosis codes -Medicare does not provide data on cause-specific mortality, family history of CVD, severity of gout, use of NSAIDs or aspirin. -mean follow up was 1.2 years, which is not long term -cohort study can lead to selection bias due to lack of randomization

Conclusion(s):
– Briefly summarize the conclusions of each article, then provide an overarching conclusion.

1. White et al: when looking only at cardiovascular adverse events, febuxostat and allopurinol were similar. When it came to all- cause mortality and cardiovascular mortality febuxostat rates were higher than allopurinol.
2. Mackenzie et al: febuxostat is non-inferior to allopurinol therapy when looking specifically at cardiovascular endpoints, long term use is also not associated with an increased risk of death or serious adverse events compared to allopurinol.
3. Ching et al: compared to allopurinol, febuxostat increased the risk of serious adverse cardiovascular events, the higher the dose of febuxostat the greater impact. They concluded further studies are needed to investigate the link between febuxostat and adverse cardiovascular events.
4. Kang et al: that there is no difference in the risk of non fatal CV events and all cause mortality between patients with gout initiated on allopurinol versus febuxostat. This finding was consistent with a recent US Medicare population study.
5. Zhang et al: overall there is no difference in risk of MI, stroke, new onset HF, coronary revascularization, or all-cause mortality in patients initiating febuxostat compared to allopurinol. There is a trend toward a NOT statistically significant increase of all-cause mortality in patients who use febuxostat >3 years vs. allopurinol >3 years. There is a slightly lower risk of HF exacerbation in users of febuxostat.

Overall: Both allopurinol and febuxostat are associated with adverse cardiovascular events, but there is no significant difference between the two. A meta analysis of these randomized control trials should be done in order to determine whether these results are practice changing. UpToDate recommends that despite these trials we continue to prefer allopurinol over febuxostat in the prevention of gout attacks.

Clinical Bottom Line:

Please include an assessment of the following:

– Weight of the evidence – summarize the weaknesses/strengths of the articles and explain how they factored into your clinical bottom line (this may recap what you discussed in the criteria for choosing the articles)

I weighed White et al the strongest because it is a RCT, done in the US. It is a high level of evidence, it had a large number of subjects at 6190. I liked this article because it directly compared the cardiovascular outcome, which was my objective and the subjects had cardiovascular risk factors. Some limitations to this study was patient discontinuation of the trial as well as patients being lost to follow up.  Next I weighed Mackenzie et al, because it was also an RCT, high level of evidence. It also had a number of subjects >6000. I chose this study after White et al because it was done out of the US, but I liked it because it had similar objectives as White et al and its results are used in practice changing guidelines in US practice. Next I weighed Zhang et al, I weighed it after both RCTs since it is a cohort study and lacks the strength of evidence that RCTs have. I weighed it higher than the other two cohort studies because the patient population was in the US. Next I weighed Ching et al, another cohort study because of its large sample size of >44,000 in each group. Finally I weighed Kang et al, I weighed it last of the cohort studies because it was a foreign study (although valuable for understanding other populations) and a smaller sample size than Ching et al, although its sample size was still large, which is why it was a valuable study.  

– Magnitude of any effects

It is hard to conclude the magnitude of any effects given the current data available, as there are no meta analysis. Additionally 4 of the studies came to the similar conclusion that there are significant cardiovascular risks in using either drug, but no significant difference between the two. The exception was Ching et al which concluded that febuxostat has a slightly higher risk, but that more studies with higher levels of evidence are required.

– Clinical significance (not just statistical significance)

Given the current level of evidence it is reasonable to continue to prefer allopurinol over febuxostat regarding cardiovascular safety in patients with gout.

– Any other considerations important in weighing this evidence to guide practice – If the evidence you retrieved was not enough to conclude an answer to the question, discuss what aspects still need to be explored and what the next studies will have to answer/provide (e.g. larger number, higher level of evidence, answer which sub-group benefits, etc.)

I think that studies with higher levels of evidence are still required to have conclusive evidence of cardiovascular safety between febuxostat and allopurinol. There are no available meta-analysis looking at this outcome. A meta-analysis based on several large RCTs is needed. I think more studies with long term follow up would be valuable to clarify this comparison as well.  I think more studies on dose dependent outcomes are also necessary when comparing the two medications, only of the studies I found included that in their outcomes.