Ticagrelor and Aspirin Or Aspirin Alone in Acute Ischemic Stroke Or TIA

The new england journal of medicine

ability of the trial to show a treatment effect. In The editorialist replies: Fernandez-Prado et al. the absence of a plausible hypothesis for treat- raise a couple of excellent points, the first of ment heterogeneity between patients with pro- which is the potential risks of urate-lowering teinuria and those without proteinuria, subgroup therapies. The available urate-lowering medica- analyses are hypothesis-generating at best and tions have potentially serious side effects, includ- should not be overinterpreted.3 ing cardiovascular complications, hypersensitiv- As correctly pointed out by Conway, CKD-FIX ity, and kidney stones,1 and should be used with showed that a large and sustained reduction in caution. On the basis of current data, including serum urate levels could be safely achieved with the PERL trial and CKD-FIX, they are not cur- allopurinol in patients with moderately advanced rently indicated to slow the progression of chronic kidney disease with the use of a care- chronic kidney disease. fully measured dose-escalation strategy. Conway Second, in regard to FEATHER: persons with as well as McCormick et al. point out that the a higher GFR or no proteinuria had a signifi- combined numbers of deaths in CKD-FIX and cantly better GFR at the end of 108 weeks of the PERL trial were greater with allopurinol than febuxostat therapy as compared with placebo. with placebo. Owing to the small number of The placebo group had little change in the GFR events observed for this safety outcome, this during the trial period; nevertheless, the febuxo- finding should be treated as an exploratory re- stat group had a significantly better GFR at the sult only and should not be considered as either end of the trial period.2 A similar observation definitive or a reason to deny urate-lowering was made in a much smaller trial by Sui et al.3 treatment to patients with chronic kidney disease Consequently, given the health and economic and gout. burden of chronic kidney disease, there is still Sunil V. Badve, M.B., B.S., Ph.D. much to be learned about the effect of hyperuri- George Institute for Global Health cemia, especially in younger persons and those Sydney, NSW, Australia with early chronic kidney disease. sbadve@georgeinstitute.org.au Elaine M. Pascoe, M.Biostat. Daniel I. Feig, M.D., Ph.D. David W. Johnson, M.B., B.S., Ph.D. University of Alabama, Birmingham, School of Medicine Birmingham, AL University of Queensland Brisbane, QLD, Australia Since publication of his editorial, the author reports no fur- Since publication of their article, the authors report no further potential conflict of interest. ther potential conflict of interest. 1. Perez-Gomez MV, Bartsch LA, Castillo-Rodriguez E, Fernan- 1. Hsu C-Y, Iribarren C, McCulloch CE, Darbinian J, Go AS. dez-Prado R, Kanbay M, Ortiz A. Potential dangers of serum Risk factors for end-stage renal disease: 25-year follow-up. Arch urate-lowering therapy. Am J Med 2019;132:457-67. Intern Med 2009;169:342-50. 2. Kimura K, Hosoya T, Uchida S, et al. Febuxostat therapy for 2. Tiku A, Badve SV, Johnson DW. Urate-lowering therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: preventing kidney disease progression: are we there yet? Am J a randomized trial. Am J Kidney Dis 2018;72:798-810. Kidney Dis 2018;72:776-8. 3. Siu Y-P, Leung K-T, Tong MK-H, Kwan T-H. Use of allopuri- 3. Fishbane S, Shah HH, Kataria A, Shirazian S, Agarwal R. nol in slowing the progression of renal disease through its Subgroup analyses in nephrology clinical trials. Clin J Am Soc ability to lower serum uric acid level. Am J Kidney Dis 2006;47: Nephrol 2012;7:1872-6. 51-9. DOI: 10.1056/NEJMc2026125 DOI: 10.1056/NEJMc2026125

Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA

To the Editor: In their article describing the lower risk of a composite of stroke or death with- THALES trial, Johnston et al. (July 16 issue)1 re- in 30 days than those who received matching pla- port that among patients with mild-to-moderate cebo plus aspirin. We have several questions. acute noncardioembolic ischemic stroke or tran- First, the trial is described as including patients sient ischemic attack (TIA), those who received with mild-to-moderate stroke with a score of 5 or ticagrelor–aspirin combination therapy had a less on the National Institutes of Health Stroke

1692 n engl j med 383;17 nejm.org October 22, 2020 The New England Journal of Medicine

Scale (NIHSS, ranging from 0 to 42, with higher er NIHSS scores (4 or 5), we describe these strokes scores indicating more severe stroke). However, as moderate. As so defined, patients with moder- some previous studies have defined mild stroke ate strokes constituted 30% of those in the trial as an NIHSS score of less than 8, moderate stroke — a group that has not been included in previous as a score of 8 to 14, and severe stroke as a score trials of clopidogrel–aspirin in acute ischemic of 15 or more.2 Second, in the current trial, ap- stroke or TIA.2,3 Sites in Canada and Mexico were proximately 60% of the patients had an NIHSS the only North American centers that were invit- score of 3 or less, whereas in previous similar ed to participate in the trial, and investigators in trials, 19.8% of strokes were categorized as mild, Canada largely stopped enrolling patients after 30.3% as moderate, and 49.9% as severe on the the publication of the results of the POINT trial, basis of the NIHSS scores.3 Third, North Ameri- which showed that patients with minor ischemic cans constituted only 0.2% of the patients who stroke or high-risk TIA who received a combina- were included in the trial, perhaps because of tion of clopidogrel plus aspirin had a lower risk systems that are well developed for thrombolysis of major ischemic events but a higher risk of ma- (intravenous or endovascular) in this region. The jor hemorrhage at 90 days than those who re- trial highlights the benefits of a combination of ceived aspirin alone.3 This finding did not appear ticagrelor–aspirin therapy in acute ischemic stroke, to affect recruitment rates or characteristics of but certain areas might be further investigated. enrolled patients in other countries. Atul Kaushik, M.D., D.M. The patients who were enrolled in the Surender Deora, M.D., D.M. THALES trial were not expected to represent the Rahul Choudhary, M.D., D.M. full range of patients presenting internationally All India Institute of Medical Sciences with ischemic stroke or TIA. We agree that gen- Jodhpur, India eralization of the findings of the trial to popula- atul_mamc03@yahoo.co.in tions that were not included or that were poorly No potential conflict of interest relevant to this letter was reported. represented requires caution. S. Claiborne Johnston, M.D., Ph.D. 1. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and Dell Medical School at the University of Texas at Austin aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl Austin, TX J Med 2020;383:207-17. clay.johnston@utexas.edu 2. Kvistad CE, Logallo N, Oygarden H, Thomassen L, Waje- Andreassen U, Naess H. Elevated admission blood pressure Pierre Amarenco, M.D. and stroke severity in acute ischemic stroke: the Bergen University of Paris NORSTROKE Study. Cerebrovasc Dis 2013;36:351-4. Paris, France 3. Muchada M, Rubiera M, Rodriguez-Luna D, et al. Baseline National Institutes of Health stroke scale-adjusted time window for the THALES Executive Committee for intravenous tissue-type plasminogen activator in acute ische Since publication of their article, the authors report no fur- mic stroke. Stroke 2014;45:1059-63. ther potential conflict of interest. DOI: 10.1056/NEJMc2027491 1. Fischer U, Baumgartner A, Arnold M, et al. What is a minor stroke? Stroke 2010;41:661-6. 2. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in The authors reply: Although there is no estab- acute minor stroke or transient ischemic attack. N Engl J Med lished definition of mild or minor stroke, many 2013;369:11-9. 3. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and investigators have recommended a cutoff score aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med of 3 or even lower on the NIHSS.1 Since we in- 2018;379:215-25. cluded some patients who had strokes with high- DOI: 10.1056/NEJMc2027491

Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery

To the Editor: In their report on the results of nonmajor orthopedic surgery. Obesity is a risk the PRONOMOS trial, Samama et al. (May 14 is- factor for venous thromboembolism, and the sue)1 state that rivaroxaban was more effective median body-mass index was similar in the two than enoxaparin in the prevention of major ve- groups of patients. However, the dose of enoxa- nous thromboembolism in patients undergoing parin was probably inappropriate for obese pa-

n engl j med 383;17 nejm.org October 22, 2020 1693 The New England Journal of Medicine