FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2891690505> ?p ?o ?g. }

• W2891690505 endingPage "1223" @default.
• W2891690505 startingPage "1221" @default.
• W2891690505 abstract "HomeCirculationVol. 138, No. 12Pioglitazone Use After Stroke Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPioglitazone Use After StrokeStory of Hearts, Minds, and Bones Jesse Dawson, BSc (hons), MBChB (hons), MD Jesse DawsonJesse Dawson Jesse Dawson, BSc (hons), MBChB (hons), MD, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, & Life Sciences, Room M0.05, Office Block, University of Glasgow, Glasgow G51 4TF, UK. Email E-mail Address: [email protected] Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, & Life Sciences, University of Glasgow, Glasgow, UK. Search for more papers by this author Originally published17 Sep 2018https://doi.org/10.1161/CIRCULATIONAHA.118.036147Circulation. 2018;138:1221–1223This article is a commentary on the followingHeart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With PioglitazoneArticle, see p 1210Approximately one-quarter of people with stroke will suffer recurrence within a 4-year period.1 Recurrence risk is increased in people with cardiovascular risk factors such as hypertension and also in people with insulin resistance,2 which may affect as many as 50% of people with ischemic stroke.3 Although the rate of recurrence is highest within the first few weeks after a first stroke,4 most recurrent strokes occur many years later, leaving substantial potential for secondary prevention.5 Although recurrent stroke is the most common second vascular event, people with stroke are also at risk of future myocardial infarction.If only there were a cheap, widely available drug that, when added to guideline-based preventative treatment, could remove up to one-quarter of this risk. Well, actually, there is. The IRIS trial (Insulin Resistance After Ischemic Stroke) showed that people with insulin resistance (but no diabetes mellitus) and recent ischemic stroke or transient ischemic attack treated with pioglitazone had a lower risk of myocardial infarction and recurrent stroke than people treated with placebo.6 In relative terms, the treatment effect was similar to both antiplatelet and high-dose lipid-lowering therapy.7 It is odd, then, that uptake of pioglitazone use after stroke has been limited. This is largely because of the fear of side effects. Pioglitazone, a thiazolidinedione, has been reported to increase risk of weight gain, bone fracture, and heart failure, all of particular concern in stroke survivors. The combination of stroke and heart failure is associated with poor outcome,8 stroke survivors are already at increased risk of fracture,9 and weight gain will impact on mobility and is associated with increased risk of recurrence.10Young and colleagues,11 in this issue of Circulation, report a post hoc analysis of heart failure in the IRIS trial. No excess of heart failure serious adverse events with pioglitazone was reported in IRIS, but there was an increase in ankle edema. In this more granular analysis of heart failure outcomes, Young and colleagues11 explored whether certain people were more at risk of pioglitazone-associated heart failure. They confirmed no overall excess of any confirmed heart failure, hospitalized heart failure, or nonhospitalized heart failure with pioglitazone. This finding was consistent across 7 individual heart failure risk factors and across the range of a combined heart failure risk score. One treatment interaction was significant: pioglitazone treatment was associated with increased risk of heart failure in people with a baseline HbA1c level of 6.5% to 6.9%, although the effect estimate lacked precision. It is important to note that this level of HbA1c would now denote diabetes mellitus but did not at the start of the IRIS trial. This finding is consistent with a subgroup analysis of people with previous stroke in the PROactive trial (PROspective Pioglitazone Clinical Trial in Macrovascular Events).12 This trial demonstrated a reduction in total recurrent stroke with pioglitazone, and although there was no statistically significant difference, the rate of heart failure requiring hospitalization was ≈50% higher (6.4% with pioglitazone compared with 4% with placebo; P=0.09). By comparison, the rate of heart failure was low in the IRIS trial (1.5%) in pioglitazone-treated participants.There are many potential reasons for this difference in heart failure risk. First, baseline characteristics and risk factors for heart failure differed in people with previous stroke in the PROactive and IRIS trials. PROactive participants had diabetes mellitus, and HbA1c levels were higher. Baseline blood pressure was higher, as were rates of coexisting coronary disease, and baseline cardiovascular medications differed. Participants in the IRIS trial were highly selected. There was a low rate of atrial fibrillation and coexisting cardiac disease, blood pressure was well controlled, and the majority of participants had no disability after stroke. Second, it is possible that in people with stroke and no diabetes mellitus, the mechanism of incident heart failure is predominantly through the occurrence of myocardial infarction, which pioglitazone reduces, and that the mechanism of incident heart failure differs in people with diabetes mellitus. It is perhaps more important to note that the IRIS investigators followed a rigorous protocol designed to minimize heart failure risk, including dedicated weight gain, edema and breathlessness surveys, and dose reduction or cessation if concerns were noted. Twenty percent of pioglitazone-treated participants either stopped or discontinued the study drug, and pioglitazone-treated participants were less likely to be on a full dose of drug than participants treated with placebo. Typically such high attrition from a study drug would be concerning, but here it likely reflects an appropriate and rigorous approach to risk management.The practical message from this study is clear. Pioglitazone use after stroke will not increase heart failure risk if people with diabetes mellitus, defined as having an HbA1c level of >6.5%, are not treated and if there is a rigorous approach to early identification of heart failure, weight gain, and edema followed by appropriate dose change. This is reassuring, but the potential implications are wider. The critical question is whether these data will persuade clinicians to begin to use pioglitazone in people with insulin resistance and ischemic stroke. At present, this scenario is unlikely. The main clinical concern from the IRIS trial was not heart failure but weight gain and fracture. Young and colleagues11 correctly highlight that the benefits on cardiovascular outcomes need to be weighed against the risk of fracture and weight gain. The absolute risk of fracture in IRIS was increased by 2% and the risk of weight gain >4.5 kg by ≈20%.There is a clear need to optimize the risk-benefit ratio for pioglitazone use after stroke. Otherwise we could miss out on the proven and clinically important benefits. The success in eliminating the excess risk of heart failure in IRIS gives cause for hope. Could the risk of fracture and weight gain be mitigated by a similarly rigorous approach to early identification and dose review? There are many potential strategies to explore, including falls risk assessment, prescribed exercise, calcium and vitamin D supplementation or bisphosphonate use, and patient selection through DEXA (dual-energy X-ray absoptiometry) scanning. Other analyses from the IRIS group demonstrate the potential for better patient selection: people with higher than median risk of stroke or myocardial infarction had an absolute risk reduction for stroke or myocardial infarction after pioglitazone of more than double that of people with lower risk.13 These participants also had a higher risk of fracture, particularly those with aphasia or previous stroke. Other recent studies have shown that side effects from thiazolidinediones use, such as weight gain and edema, are more common in females with obesity.14 Taken together, these findings demonstrate the potential for risk prediction algorithms to be developed to help support clinicians with the difficult decision of whether to use pioglitazone after stroke.Understanding the implications of a large ground-breaking clinical trial often takes time. The IRIS trial, where pioglitazone gave with one hand and took with the other, is no different. However, with thoughtful analysis and further study, it finally feels like we are reaching a point where we can identify people most suitable for pioglitazone use.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circJesse Dawson, BSc (hons), MBChB (hons), MD, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, & Life Sciences, Room M0.05, Office Block, University of Glasgow, Glasgow G51 4TF, UK. Email jesse.[email protected]ac.ukReferences1. Mohan KM, Wolfe CD, Rudd AG, Heuschmann PU, Kolominsky-Rabas PL, Grieve AP. Risk and cumulative risk of stroke recurrence: a systematic review and meta-analysis.Stroke. 2011; 42:1489–1494. doi: 10.1161/STROKEAHA.110.602615LinkGoogle Scholar2. Hishinuma A, Majima M, Kurabayashi H. Is insulin resistance related to recurrence of stroke or incident of ischemic heart disease in patients with stroke? A preliminary report.J Stroke Cerebrovasc Dis. 2009; 18:294–297. doi: 10.1016/j.jstrokecerebrovasdis.2008.11.017CrossrefMedlineGoogle Scholar3. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Shulman GI, McVeety JC, Horwitz RI. Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke.Neurology. 2003; 60:1447–1451.CrossrefMedlineGoogle Scholar4. Marnane M, Ni Chroinin D, Callaly E, Sheehan OC, Merwick A, Hannon N, Horgan G, Kyne L, Moroney J, McCormack PM, Dolan E, Duggan J, Williams D, Crispino-O’Connell G, Kelly PJ. Stroke recurrence within the time window recommended for carotid endarterectomy.Neurology. 2011; 77:738–743. doi: 10.1212/WNL.0b013e31822b00cfCrossrefMedlineGoogle Scholar5. Amarenco P, Lavallée PC, Monteiro Tavares L, Labreuche J, Albers GW, Abboud H, Anticoli S, Audebert H, Bornstein NM, Caplan LR, Correia M, Donnan GA, Ferro JM, Gongora-Rivera F, Heide W, Hennerici MG, Kelly PJ, Král M, Lin HF, Molina C, Park JM, Purroy F, Rothwell PM, Segura T, Školoudík D, Steg PG, Touboul PJ, Uchiyama S, Vicaut É, Wang Y, Wong LKS; TIAregistry.org Investigators. Five-year risk of stroke after TIA or minor ischemic stroke.N Engl J Med. 2018; 378:2182–2190. doi: 10.1056/NEJMoa1802712CrossrefMedlineGoogle Scholar6. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O’Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack.N Engl J Med. 2016; 374:1321–1331. doi: 10.1056/NEJMoa1506930CrossrefMedlineGoogle Scholar7. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack.N Engl J Med. 2006; 355:549–559.CrossrefMedlineGoogle Scholar8. Haeusler KG, Laufs U, Endres M. Chronic heart failure and ischemic stroke.Stroke. 2011; 42:2977–2982. doi: 10.1161/STROKEAHA.111.628479LinkGoogle Scholar9. Kanis J, Oden A, Johnell O. Acute and long-term increase in fracture risk after hospitalization for stroke.Stroke. 2001; 32:702–706.LinkGoogle Scholar10. Strazullo P, D’Elia L, Cairella G, Garbagnati F, Cappuccio FP, Scalfi L. Excess body weight and incidence of stroke.Stroke. 2010; 41:418–426.LinkGoogle Scholar11. Young LH, Viscoli CM, Schwartz GG, Inzucchi SE, Curtis JP, Gorman MJ, Furie KL, Conwit R, Spatz ES, Lovejoy A, Abbott JD, Jacoby DL, Kolansky DM, Ling FS, Pfau SE, Kernan WN; On behalf of the IRIS Investigators. Heart failure after ischemic stroke or transient ischemic attack in insulin-resistant patients without diabetes mellitus treated with pioglitazone.Circulation. 2018; 138:1210–1220. doi: 10.1161/CIRCULATIONAHA.118.034763LinkGoogle Scholar12. Wilcox R, Bousser MG, Betteridge DJ, Schernthaner G, Pirags V, Kupfer S, Dormandy J; PROactive Investigators. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04).Stroke. 2007; 38:865–873. doi: 10.1161/01.STR.0000257974.06317.49LinkGoogle Scholar13. Kernan WN, Viscoli CM, Dearborn JL, Kent DM, Conwit R, Fayad P, Furie KL, Gorman M, Guarino PD, Inzucchi SE, Stuart A, Young LH; Insulin Resistance Intervention After Stroke (IRIS) Trial Investigators. Targeting pioglitazone hydrochloride therapy after stroke or transient ischemic attack according to pretreatment risk for stroke or myocardial infarction.JAMA Neurol. 2017; 74:1319–1327. doi: 10.1001/jamaneurol.2017.2136CrossrefMedlineGoogle Scholar14. Dennis JM, Henley WE, Weedon MN, Lonergan M, Rodgers LR, Jones AG, Hamilton WT, Sattar N, Janmohamed S, Holman RR, Pearson EE, Shields BM, Hattersley AT. Sex and BMI alter the benefits and risks of sulfonylureas and thiazolidinediones in type 2 diabetes: A framework for evaluating stratification using routine clinical and individual trial data.Diabetes Care. 2018; dc180344.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bicciato G, Arnold M, Gebhardt A and Katan M (2021) Precision medicine in secondary prevention of ischemic stroke: how may blood-based biomarkers help in clinical routine? An expert opinion, Current Opinion in Neurology, 10.1097/WCO.0000000000001011, 35:1, (45-54), Online publication date: 1-Feb-2022. Krinock M and Singhal N (2021) Diabetes, stroke, and neuroresilience: looking beyond hyperglycemia, Annals of the New York Academy of Sciences, 10.1111/nyas.14583, 1495:1, (78-98), Online publication date: 1-Jul-2021. Related articlesHeart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With PioglitazoneLawrence H. Young, et al. Circulation. 2018;138:1210-1220 September 18, 2018Vol 138, Issue 12 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.036147PMID: 30354440 Originally publishedSeptember 17, 2018 KeywordsEditorialsheart failureinsulin resistancestrokePDF download Advertisement" @default.
• W2891690505 created "2018-09-27" @default.
• W2891690505 creator A5066328545 @default.
• W2891690505 date "2018-09-18" @default.
• W2891690505 modified "2023-10-04" @default.
• W2891690505 title "Pioglitazone Use After Stroke" @default.
• W2891690505 cites W1546258268 @default.
• W2891690505 cites W2008497553 @default.
• W2891690505 cites W2022311922 @default.
• W2891690505 cites W2026598525 @default.
• W2891690505 cites W2070083361 @default.
• W2891690505 cites W2101688816 @default.
• W2891690505 cites W2113338934 @default.
• W2891690505 cites W2131044251 @default.
• W2891690505 cites W2274836352 @default.
• W2891690505 cites W2756069235 @default.
• W2891690505 cites W2803337349 @default.
• W2891690505 cites W2892013022 @default.
• W2891690505 doi "https://doi.org/10.1161/circulationaha.118.036147" @default.
• W2891690505 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30354440" @default.
• W2891690505 hasPublicationYear "2018" @default.
• W2891690505 type Work @default.
• W2891690505 sameAs 2891690505 @default.
• W2891690505 citedByCount "4" @default.
• W2891690505 countsByYear W28916905052021 @default.
• W2891690505 countsByYear W28916905052023 @default.
• W2891690505 crossrefType "journal-article" @default.
• W2891690505 hasAuthorship W2891690505A5066328545 @default.
• W2891690505 hasBestOaLocation W28916905051 @default.
• W2891690505 hasConcept C126322002 @default.
• W2891690505 hasConcept C127413603 @default.
• W2891690505 hasConcept C134018914 @default.
• W2891690505 hasConcept C164705383 @default.
• W2891690505 hasConcept C2777180221 @default.
• W2891690505 hasConcept C2778384471 @default.
• W2891690505 hasConcept C2780645631 @default.
• W2891690505 hasConcept C555293320 @default.
• W2891690505 hasConcept C71924100 @default.
• W2891690505 hasConcept C78519656 @default.
• W2891690505 hasConceptScore W2891690505C126322002 @default.
• W2891690505 hasConceptScore W2891690505C127413603 @default.
• W2891690505 hasConceptScore W2891690505C134018914 @default.
• W2891690505 hasConceptScore W2891690505C164705383 @default.
• W2891690505 hasConceptScore W2891690505C2777180221 @default.
• W2891690505 hasConceptScore W2891690505C2778384471 @default.
• W2891690505 hasConceptScore W2891690505C2780645631 @default.
• W2891690505 hasConceptScore W2891690505C555293320 @default.
• W2891690505 hasConceptScore W2891690505C71924100 @default.
• W2891690505 hasConceptScore W2891690505C78519656 @default.
• W2891690505 hasIssue "12" @default.
• W2891690505 hasLocation W28916905051 @default.
• W2891690505 hasLocation W28916905052 @default.
• W2891690505 hasOpenAccess W2891690505 @default.
• W2891690505 hasPrimaryLocation W28916905051 @default.
• W2891690505 hasRelatedWork W1986410768 @default.
• W2891690505 hasRelatedWork W2033522292 @default.
• W2891690505 hasRelatedWork W2042938358 @default.
• W2891690505 hasRelatedWork W2046264850 @default.
• W2891690505 hasRelatedWork W2115946307 @default.
• W2891690505 hasRelatedWork W2121496639 @default.
• W2891690505 hasRelatedWork W2163547766 @default.
• W2891690505 hasRelatedWork W2412747875 @default.
• W2891690505 hasRelatedWork W2981672174 @default.
• W2891690505 hasRelatedWork W8919293 @default.
• W2891690505 hasVolume "138" @default.
• W2891690505 isParatext "false" @default.
• W2891690505 isRetracted "false" @default.
• W2891690505 magId "2891690505" @default.
• W2891690505 workType "article" @default.