Clinical and Echocardiographic Characteristics and ...

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Jan 5, 2017 - peptidase-4 inhibitors)4-6 and others may decrease the risk (the sodium glucose cotransporter 2 inhibitor empagliflozin).7 Three GLP-1 agonist ...

10.1161/CIRCULATIONAHA.116.024593

Clinical and Echocardiographic Characteristics and Cardiovascular Outcomes According to Diabetes Status in Patients with Heart Failure and Preserved Ejection Fraction. A Report from the Irbesartan in Heart Failure with Preserved Ejection Fraction Trial (I-Preserve) Running Title: Kristensen et al.; Diabetes in HFpEF

Søren L. Kristensen, MD, PhD1,2; Ulrik M. Mogensen, MD, PhD1,2; Pardeep S. Jhund, MD, PhD1; Mark C. Petrie MB ChB1; David Preiss, MD, PhD3; Downloaded from http://circ.ahajournals.org/ by guest on January 5, 2017

Sithu Win, MD4; Lars Køber, MD, DMSc2; Robert S. McKelvie, MD PhD5; Michael R. Zile, MD6; Inder S. Anand, MD, DPhil (Oxon.)7; Michel Komajda, MD8; John S. Gottdiener, MD9; Peter E. Carson, MD10; John J.V. McMurray, McMurray y, MD1

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BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK; Department Depa De part pa rtme rt m nt ooff Cardiology, Rigshospitalet Un University niversity Hospital, Copenhagen, Cop o enhagen, Denmark; 3 Clinical C linical al Trial Triall Service Unit and Epidemiological Epidemiologi gical Studies Unit, Unnit, Nuffield N ffield Department of Nu Population Populat tioon Health, Hea ealt lth, h, University Unive ive verrsitty of Oxford, Oxf xford, d U UK; K; 4Ma Mayo y Clinic, yo Cli linnicc, Rochester,MN; Roc oche oc hester ter er,MN M ; MN 6 5 Western West We s ern Univ University, ver e sitty, Lo L London, ndon on, ON, Canada; on Cana nada; Ra Ralph Ralp ph H. Johnsons Joh ohns nsoons Veterans ns V teraans Affairs Ve Affairs M Medical ed dical Cen Center enter 7 andd Me M Medical dical Un Univ University verssitty off So S South outh Ca Caro Carolina, olliina, Cha C Charleston, harllesston on, SC;; D on Division ivvission of of Cardiology, Cardiolo Ca ogy, University Univerrsiity y off M Minnesota, inneeso sota ta, Mi M Minneapolis, nnea nn eapo poli lis, li s MN MN;; 8Un Université Univ iver iv ersi er s té t P Paris a is 6 an ar andd Ho H Hospital spit sp i al P it Pitié-Salpétrière, i iéé-Sa it Salp Sa lp pét étri rièr èrre, P Paris, aris ar iss, France; 9University of Maryland Medical Center, Center Baltimore, Baltimore MD; 10Georgetown University and Washington DC Veterans Affairs Medical Center, Washington DC 2

Address for Correspondence: John JV McMurray, MD Institute of Cardiovascular and Medical Sciences, BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, G12 8TA United Kingdom Tel: +44 141 330 3479 Fax: +44 141 330 6955 Email: [email protected] Journal Subject Terms: Diabetes, Type 2; Heart Failure; Echocardiography; Clinical Studies

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Abstract

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Background—In patients with HF and preserved ejection fraction (HFpEF), little is known about the characteristics of and outcomes in those with and without diabetes. Methods—We examined clinical and echocardiographic characteristics and outcomes in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), according to history of diabetes. Cox regression models were used to estimate hazard ratios (HR) for cardiovascular outcomes adjusted for known predictors, including age, sex, natriuretic peptides, and comorbidity. Echocardiographic data were available in 745 patients and were additionally adjusted for in supplementary analyses. Results—Overall, 1134 of 4128 patients (27%) had diabetes. Compared to those without diabetes, they were more likely to have a history of myocardial infarction (28% vs. 22%), higher BMI (31kg/m2 vs. 29kg/m2), worse Minnesota living with HF score (48 vs. 40), higher median NT-proBNP concentration (403 vs 320 pg/ml; all p14 (p=0.001) suggesting significantly more diastolic dysfunction among patients with diabetes.18 E/A was also higher among patients with diabetes (1.18±0.97 vs 1.00±0.65, p=0.01). Left atrial area was greater (24±6 vs. 23±6 cm2, p=0.003), as were the proportion of individuals with an enlarged left atrium (75 vs. 66%, P=0.02), all compared to patients without diabetes. Clinical Outcomes The unadjusted rates of the composite endpoint of cardiovascular death and HF hospitalization and all-cause mortality were higher in patients with diabetes (Table 3 and Figure 1 and 2).

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Over a median of 4.1 years of follow-up, the composite endpoint occurred in 391 of patients (34%) with diabetes compared with 662 of those without (22%), with event rates per 100 person years of 10.2 and 5.7, respectively. After adjustments for known predictive variables (see Methods), the hazard ratio (HR) for patients with diabetes, compared to those without, was 1.75 (95% CI 1.49-2.05). Competing risk analyses gave comparable results (Supplementary Appendix Table 2). The pattern of higher risk associated with diabetes (HR 1.79 [1.28-2.51] for the composite endpoint) was also seen in the echocardiography subgroup, although this risk was no Downloaded from http://circ.ahajournals.org/ by guest on January 5, 2017

longer statistically significant (HR 1.45 [0.82-2.59]) after further adjustment for echocardiographic variables (see Methods and Table 4) possibly due to the smaller sample size. The results of the sensitivity analyses of the models that included echocardio echocardiographic ogrrap aphi hicc data hi data showed howed similar results. Diabetes was associated with higher rates of all-cause death, as well as cardiovascular death and non-cardiovascular nonn-ccardiovasccular a death. ar dea e th ea h. The The elevated e ev el evat a ed d rrisks isks of the these hese ooutcomes utco ut co ome m s pers ppersisted ers r is i te ted after affte terr ad adju adjustments justme ju ment me ntss for nt for known know own prognostic ow prognoost stic variables varria iabless (Table (Table 3). ) Mode Mode ooff de death eathh according acco ac c rdin co rdd ng to the presence preeseence orr absence abssence off diabetes is depicted d picted de d in Ta T Table ble 5. Pump failure faiilure and sudden cardiac de ddeath ath were more frequent in patients with diabetes, whereas rates of fatal myocardial infarction and stroke were similar. HF hospitalization occurred in 253 patients (22%) with diabetes, compared to 408 patients (14%) without diabetes, yielding event rates per 100 person-years of 6.6 and 3.5, giving a diabetes/no diabetes adjusted hazard ratio of 1.77 (1.45-2.16). When repeat HF hospitalizations were included, 708 admissions occurred in those with diabetes and 468 in individuals without diabetes, resulting in event rates per 100 person-years of 9.3 and 5.7, respectively. The number and rates of admission to hospital for any reason, and for cardiovascular and non-cardiovascular reasons separately, were also higher in individuals with diabetes compared to those without

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(Table 3). Results stratified by use/non-use of insulin treatment in patients with diabetes are shown in Supplementary Table 3, which displays a step-wise worsening, with the highest risk in patients with diabetes who were insulin-treated. Adverse events Serious adverse events and drug discontinuation due to adverse events (excluding death) are listed in Supplementary Appendix Table 4. Overall, serious adverse events were rare, but increased potassium, chronic kidney disease and cough were more prevalent in patients with Downloaded from http://circ.ahajournals.org/ by guest on January 5, 2017

diabetes (all p-values45% (285 of the 987 patients had diabetes).7 In the Olmsted county epidemiological study, diabetes was

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independently predictive of death (and cardiovascular death) in a community heart failure cohort, irrespective of ejection fraction.21 However, unlike in these earlier trials we were able to adjust outcomes for NT proBNP levels. Despite adjustment for NT-proBNP as well as other prognostic variables, patients with diabetes were 1.5 to 2.0 times as likely to have an adverse clinical outcome. In contrast, we found that after additional adjustment for LV end-systolic volume, LV mass, E/e’, and left atrial area in the echocardiographic subgroup, the risk associated with diabetes was no longer statistically significant (Table 4), possibly due either to the smaller Downloaded from http://circ.ahajournals.org/ by guest on January 5, 2017

sample size of the echocardiographic subgroup or because adverse LV remodelling is an important mediator of the risk associated with diabetes. The excess risk associated with diabetes was seen for each off death and heart failure hospitalization and was apparent for bo both th cardiovascular and non-cardiovascular death i.e. there was no specific type of event that seemed too be particularly increased in patients with diabetes. Adjustment for echocardiographic findings did not no attenuate attenuat atee the at th he risk riisk of of no nonnon-CV n-CV nCV out outcomes. utcomes. s s. Our stu study udy d hhas as a num number mber of limi limitations. itaations.. T The hee an analyses nal alys ysees w ys were eree rretrospective etroospe peective ctt rath rather her th than han pre-planned. d Th he diagnosis of diabetes was iinvestigator-reported nvestigator-reported and not standardised. Al A though h The Although similar to that in DIG and CHARM trials, the prevalence of diabetes in I-Preserve was lower than in most more recent trials, presumably reflecting the steadily increasing prevalence of diabetes.2, 22 The small numbers of events in those with echocardiographic data may have led to “overfitting” of the model, although sensitivity analyses found similar results after removing variables from the model. Finally, patient selection in clinical trials limits the external validity of findings when extrapolating to a typical community population. In summary, among patients with HFpEF, those with diabetes have more signs of congestion, worse quality of life, higher NT-proBNP levels, greater structural and functional

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echocardiographic abnormalities and worse outcomes than those without diabetes. Further investigation is needed to determine the mediators of the adverse impact of diabetes on outcomes in HFpEF, and whether they are modifiable.

Sources of Funding Dr. Kristensen is supported by a Postdoctoral grant from the Danish Independent Research Council, and a Research Fellowship from the Heart Failure Association of the European Society Downloaded from http://circ.ahajournals.org/ by guest on January 5, 2017

of Cardiology (ESC).

Disclosures Drs. Kristensen, Preiss, Anand and Gottdiener reports no relevant conflicts of interests. Dr. Komajd Komajda j a is on the speakers bureau for Bristol-Myers Squibb, Sanofi, AstraZeneca, Menarini, Menarini MSD, MS SD, D and Servier Servi vierr aand vi ndd iiss consultant c nssul co ulta tant ta nt forr Servier Servier e and er nd Amgen. Amg mgen mg en. Dr en D Mogensen Mog o en ense s n reports repo re port po rtss speakers rt spea e ke ea kers r fees rs fee e s steering committee member from m Novo Nordisk Noord rdissk and an nd MSD. MS SD. Dr. Køber Købe ber has received receeiv re ved d honoraria hon o orraria aass stee eering ng commi m ttee mi ee membe ber from AstraZe AstraZeneca. Z neca. Dr D JJhund hund reports consultin consulting i g andd speakers fees fr ffrom om N Novartis ovartis and research h funding from Boehringer Ingelheim. Dr. Petrie reports speakers fees from Astellas, AstraZeneca, Bayer, Takeda, Boerhinger Ingelheim, Novartis, Roche, GlaxoSmithKline. Dr. Zile reports consultant fees from Amgen, A-Z, Bayer, Bristol Myers Squibb, Capricor, Corvia, Eli Lilly, Giliad, Ironwood, Medtronic, Merck, Novartis, St. Jude Medical and research support from NHLBI, VA, DOD, Medtronic and Novartis. Dr. McMurray´s employer, University of Glasgow, has received fees for his consulting or trial committee work with Abbvie, Amgen, AstraZeneca/Medimmune, Bayer, Bristol Myers Squibb, DalCor, GlaxoSmithKline, Merck, Novartis, Resverlogix, Sanofi-Aventis and Stealth Therapeutics.

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References

Downloaded from http://circ.ahajournals.org/ by guest on January 5, 2017

1. Aguilar D, Deswal A, Ramasubbu K, Mann DL and Bozkurt B. Comparison of patients with heart failure and preserved left ventricular ejection fraction among those with versus without diabetes mellitus. Am J Cardiol. 2010;105:373-7. 2. MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, Solomon SD, Granger CB, Swedberg K, Yusuf S, Pfeffer MA, McMurray JJ and Investigators C. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J. 2008;29:1377-85. 3. Seferovic PM and Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J. 2015;36:1718-27, 1727a-1727c. 4. McGuire DK, Van de Werf F, Armstrong PW, Standl E, Koglin J, Green JB, Bethel MA, Cornel JH, Lopes RD, Halvorsen S, Ambrosio G, Buse JB, Josse RG, Lachin JM, Pencina MJ, Garg J, Lokhnygina Y, Holman RR, Peterson ED and Trial Evaluating Cardiovascular Outcomes With Sitagliptin Study G. Association Between Sitagliptin Use and Heart Failure Hospitalization and Related Outcomes in Type 2 Diabetes Mellitus: Secondary Analysis of a Randomized C ca Trial. a . JJAMA Ca diol. 2016;1:126-35. 0 6; : 6 35. Clinical Cardiol. 5. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fl lecck PR PR,, Mehta Meht Me ha Fleck CR, Kupfer S, Wilson C, Lam H, White WB and Investigators E. Heart failure and nd m mortality orrta tali lity li ty outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-76. 6. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, Udell JA, Mosenzon O,, Im K K,, Umez-Eronini AA, Pollack P PS, Frederich Mose enz nzon on O S, Hirshberg B, Fr F ed derich R, Lewis BS, McGuire Davidson PG, Bhatt Committee S-TS Heart McGu Guire DK, D Gu avi vidson vi on JJ,, St Steg eg P G, Bha hatt DL,, C ommiitttee S om - S and -T and Investigators*. In nve v stig igat ig a or at ors* s . He s* H artt ar failure, saxagliptin, and mellitus: observations SAVOR-TIMI fail lure, saxagliptin n, an nd ddiabetes iab bet e es mel ellitu el tus: obser ervaatiions ns from m tthe he SA SAVO OR--TI TIMI 553 3 randomized r nddomizzed ra trial. Circulation. 2014;130:1579-88. riaal. l Circulatio ionn. 2014;130 io 0:1 1579-88. Fitchett Lachin Hantel S,, Salsali 7. Fitch ch het ettt D,, Zinman Zin nman B, Wanner Wan nne ner C, Lac achhin JM ac JM, Ha H nttel S Saals l al a i A, A, Johansen Joh ohanse senn OE, se OE E, Woerle Woeerlle UC, Inzucchi E-ROt. failure with HJ, Broedl U C, Inzucch hi SE and investigators E -RO ROt. Heart fai ilure outcomes wi ith empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37:1526-34. 8. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Solomon SD, Tardif JC and Investigators E. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373:2247-57. 9. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB, Committee LS and Investigators LT. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375:311-22. 10. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J and Vilsbøll T. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2016;375:1834-1844. 11. Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, Mann DL, Whellan DJ, Kiernan MS, Felker GM, McNulty SE, Anstrom KJ, Shah MR, Braunwald E, Cappola TP and Network NHFCR. Effects of Liraglutide on Clinical Stability Among Patients 16

10.1161/CIRCULATIONAHA.116.024593

Downloaded from http://circ.ahajournals.org/ by guest on January 5, 2017

With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016;316:500-8. 12. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE and Investigators E-RO. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373:2117-28. 13. Zile MR, Gottdiener JS, Hetzel SJ, McMurray JJ, Komajda M, McKelvie R, Baicu CF, Massie BM, Carson PE and Investigators IP. Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation. 2011;124:2491-501. 14. Carson P, Massie BM, McKelvie R, McMurray J, Komajda M, Zile M, Ptaszynska A, Frangin G and Investigators I-P. The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial: Rationale and design. Journal of Cardiac Failure. 2005;11:576585. 15. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A and Investigators IP. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-67. 16. Komajda M, Carson PE, Hetzel S, McKelvie R, McMurray J, Ptaszynska A, Zile MR, Demets associated with ou outcome e e s D aand d Massie ass e BM.. Factors ac o s assoc a ed w co e in heart ea failure a u e with w ppreserved ese ved ejection fraction: findings from the Irbesartan in Heart Failure with Preserved Ejec Ejection Fraction ecti tion ti on F raact ctio ion io Study (I-PRESERVE). Circ Heart Fail. 2011;4:27-35. 17. Fine JP and Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of the American Statistical Association. 1999;94:496-509. Nagueh 18. Nagu g eh SF, Smiseth OA, Appleton CP, Byrd BF, 3rd, Dokainish H, Edvardsen T, Flachskampf Gillebert Lancellotti Flachs hska hs kamp ka mpff FA mp FA, Gi G llebert TC, Klein AL, Lancello lotti P, Marino P, P Ohh JK, JK, Popescu BA and Waggoner Recommendations Evaluation Left Ventricular Diastolic Function Wa agg ggoner AD. D R ecom ec mme mend n at atio ions io ns for for tthe h Eva he alu uattio on of L eftt Ve ef Ven ntri ntri r cu c la lar Di ias asto to oli licc Fu unc ncti tion ti on bby y Echocardiography: Update American Society Echocardiography Ech hocardiographyy: Ann Up U daate from m th tthee Amer riccan nS ociiety off Echo oc hocarddiogr graaphy aand gr nd tthe hee European Association Imaging. Echocardiogr. 2016;29:277-314. Euro roope p an Assoc ociaati oc tionn ooff Cardiovascular Caardiovascular ar Imag ging.. J Am SSoc oc E choc ocarddiog oggr. 2016;2 29:27 277-3144. 19. Lindman VG, Mann McNulty L nddma Li man BR, BR Davila-Roman D vilaa-R Da -Rom om man V G, M annn DL an DL, Mc M Nuult ltyy S, S Semigran Sem emig igrann MJ, M , Lewis MJ Lew Le wiss GD, GD, de las Fuentes L, Josephh SM, MM. Cardiovascular SM Vader J, Hernandez Hernanddez AF AF andd Redfield M M. Cardi diovascular phenotype in i HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol. 2014;64:541-9. 20. Mohammed SF, Borlaug BA, Roger VL, Mirzoyev SA, Rodeheffer RJ, Chirinos JA and Redfield MM. Comorbidity and ventricular and vascular structure and function in heart failure with preserved ejection fraction: a community-based study. Circ Heart Fail. 2012;5:710-9. 21. Henkel DM, Redfield MM, Weston SA, Gerber Y and Roger VL. Death in heart failure: a community perspective. Circ Heart Fail. 2008;1:91-7. 22. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM and Investigators T. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-92.

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Table 1. Baseline Characteristics stratified by presence of diabetes in I-Preserve

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Age, mean – years >/=65 years >/=75 years Female sex, no. (%) Race, no (%): Caucasian Black Other Ejection fraction Body mass index Underweight (

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