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Influence of sex, age and race on coronary and heart failure events in patients with diabetes and post-acute coronary syndrome

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Abstract

Background

Women, older patients and non-White ethnic groups experience a substantial proportion of acute coronary syndromes (ACS), although they have been historically underrepresented in ACS randomized clinical trials (RCTs). To assess the influence of sex, age and race on major adverse cardiovascular events (MACE) and on heart failure events, we studied patients with type 2 diabetes in a large post-ACS trial (EXAMINE).

Methods

Differences in baseline characteristics and the respective composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE) and cardiovascular death or heart failure hospitalization (HF events) were evaluated by subgroups in a cohort of post-ACS patients with diabetes, using unadjusted and adjusted Cox regression modelling.

Results

The EXAMINE trial enrolled 5380 patients with 35% aged > 65, 32% female and 27% non-White. The risk of MACE was higher in non-White compared to White patients after adjustment for potential confounding (HR = 1.35; 95% CI 1.04–1.75), but there were no significant differences by sex and age (HR = 1.03; 95% CI 0.87–1.22 for women; HR = 1.14; 95% CI 0.96–1.35 for patients ≥ 65 years). The risk of HF events was higher in non-White patients (HR = 1.56; 95% CI 1.13–2.14), and in patients aged > 65 (HR = 1.33; 95% CI 1.07–1.66) and nominally so in women (HR = 1.23; 95% CI 0.99–1.52). The additive risk of each demographic factor (women, older age and non-White race) was greater for HF events in comparison with MACE. Moreover, non-White elderly patients consistently had poorer prognosis regardless of sex.

Conclusions

Older adults, women and non-White patients with diabetes who are post-ACS are often underrepresented in RCTs. The risk for HF events was higher in older and non-White patients, with a trend towards significance in women, whereas only non-White patients (and not women and older patients) were at higher risk for MACE. Future trials should enrich enrollment of these persons at risk.

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References

  1. Peters SAE, Huxley RR, Sattar N, Woodward M (2015) Sex differences in the excess risk of cardiovascular diseases associated with type 2 diabetes: potential explanations and clinical implications. Curr Cardiovasc Risk Rep 9:1–7. https://doi.org/10.1007/s12170-015-0462-5

    Article  Google Scholar 

  2. Rossello X, Ferreira JP, McMurray JJ et al (2019) Editor’s choice-impact of insulin-treated diabetes on cardiovascular outcomes following high-risk myocardial infarction. Eur Hear J Acute Cardiovasc Care 8:231–241. https://doi.org/10.1177/2048872618803701

    Article  Google Scholar 

  3. Cosentino F, Grant PJ, Aboyans V et al (2020) 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 41:255–323. https://doi.org/10.1093/eurheartj/ehz486

    Article  PubMed  Google Scholar 

  4. Tahhan AS, Vaduganathan M, Greene SJ et al (2020) Enrollment of older patients, women, and racial/ethnic minority groups in contemporary acute coronary syndrome clinical trials: a systematic review. JAMA Cardiol 5:714–722. https://doi.org/10.1001/jamacardio.2020.0359

    Article  PubMed  Google Scholar 

  5. Scirica BM, Bhatt DL, Braunwald E et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317–1326. https://doi.org/10.1056/NEJMoa1307684

    Article  CAS  PubMed  Google Scholar 

  6. Green JB, Bethel MA, Armstrong PW et al (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373:232–242. https://doi.org/10.1056/NEJMoa1501352

    Article  CAS  PubMed  Google Scholar 

  7. Rosenstock J, Perkovic V, Johansen OE et al (2019) Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the carmelina randomized clinical trial. JAMA 321:69–79. https://doi.org/10.1001/jama.2018.18269

    Article  CAS  PubMed  Google Scholar 

  8. Rosenstock J, Kahn SE, Johansen OE et al (2019) Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA 322:1155–1166. https://doi.org/10.1001/jama.2019.13772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Go Red for Women-American heart association. In: https://www.goredforwomen.org/en/about-go-red-for-women. https://www.goredforwomen.org/en/about-go-red-for-women. Accessed 27 Aug 2020

  10. Women’s heart alliance. https://www.womensheartalliance.org/about/. Accessed 27 Aug 2020

  11. Lüscher TF, Miller VM, Bairey Merz CN, Crea F (2020) Diversity is richness: why data reporting according to sex, age, and ethnicity matters. Eur Heart J 41:3117–3121. https://doi.org/10.1093/eurheartj/ehaa277

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mosca L, Benjamin EJ, Berra K et al (2011) Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American heart association. Circulation 123:1243–1262. https://doi.org/10.1161/CIR.0b013e31820faaf8

    Article  PubMed  PubMed Central  Google Scholar 

  13. Williams B, Mancia G, Spiering W et al (2018) 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 39:3021–3104

    Article  Google Scholar 

  14. Rossello X, Yellon DM (2017) A new era in the management of type 2 diabetes: is cardioprotection at long last a reality? Int J Cardiol 228:198–200. https://doi.org/10.1016/j.ijcard.2016.11.246

    Article  PubMed  Google Scholar 

  15. Kato ET, Silverman MG, Mosenzon O et al (2019) Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 139:2528–2536. https://doi.org/10.1161/CIRCULATIONAHA.119.040130

    Article  CAS  PubMed  Google Scholar 

  16. White WB, Cannon CP, Heller SR et al (2013) Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369:1327–1335. https://doi.org/10.1056/NEJMoa1305889

    Article  CAS  PubMed  Google Scholar 

  17. Zannad F, Cannon CP, Cushman WC et al (2015) Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 385:2067–2076. https://doi.org/10.1016/S0140-6736(14)62225-X

    Article  CAS  PubMed  Google Scholar 

  18. White WB, Bakris GL, Bergenstal RM et al (2011) Examination of cardiovascular outcomes with alogliptin versus standard of care in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J 162:620–626. https://doi.org/10.1016/j.ahj.2011.08.004

    Article  PubMed  Google Scholar 

  19. Hwang Y-C, Morrow DA, Cannon CP et al (2018) High-sensitivity C-reactive protein, low-density lipoprotein cholesterol and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE (examination of cardiovascular outcomes with alogliptin versus standard of care) trial. Diabetes Obes Metab 20:654–659. https://doi.org/10.1111/dom.13136

    Article  CAS  PubMed  Google Scholar 

  20. White WB, Jalil F, Cushman WC et al (2018) Average clinician-measured blood pressures and cardiovascular outcomes in patients with type 2 diabetes mellitus and ischemic heart disease in the EXAMINE trial. J Am Heart Assoc 7:e009114. https://doi.org/10.1161/JAHA.118.009114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cavender MA, White WB, Jarolim P et al (2017) Serial measurement of high-sensitivity troponin I and cardiovascular outcomes in patients with type 2 diabetes mellitus in the EXAMINE trial (examination of cardiovascular outcomes with alogliptin versus standard of care). Circulation 135:1911–1921. https://doi.org/10.1161/CIRCULATIONAHA.116.024632

    Article  CAS  PubMed  Google Scholar 

  22. White WB, Kupfer S, Zannad F et al (2016) Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial. Diabetes Care 39:1267–1273. https://doi.org/10.2337/dc16-0303

    Article  CAS  PubMed  Google Scholar 

  23. Rossello X, Ferreira JP, Pocock SJ et al (2020) Sex differences in mineralocorticoid receptor antagonist trials: a pooled analysis of three large clinical trials. Eur J Heart Fail 22:834–844. https://doi.org/10.1002/ejhf.1740

    Article  CAS  PubMed  Google Scholar 

  24. Rossello X, Ariti C, Pocock SJ et al (2019) Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left-ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials. Clin Res Cardiol 108:477–486. https://doi.org/10.1007/s00392-018-1378-0

    Article  CAS  PubMed  Google Scholar 

  25. Pfeffer MA, Claggett B, Diaz R et al (2015) Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373:2247–2257. https://doi.org/10.1056/NEJMoa1509225

    Article  CAS  PubMed  Google Scholar 

  26. Brown AF, Gregg EW, Stevens MR et al (2005) Race, ethnicity, socioeconomic position, and quality of care for adults with diabetes enrolled in managed care: the translating research into action for diabetes (TRIAD) study. Diabetes Care 28:2864–2870. https://doi.org/10.2337/diacare.28.12.2864

    Article  PubMed  Google Scholar 

  27. Zelniker TA, Wiviott SD, Raz I et al (2019) Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus: systematic review and meta-analysis of cardiovascular outcomes trials. Circulation 139:2022–2031. https://doi.org/10.1161/CIRCULATIONAHA.118.038868

    Article  CAS  PubMed  Google Scholar 

  28. Correa-de-Araujo R, Stevens B, Moy E et al (2006) Gender differences across racial and ethnic groups in the quality of care for acute myocardial infarction and heart failure associated with comorbidities. Women’s Health Issues 16:44–55. https://doi.org/10.1016/j.whi.2005.04.003

    Article  PubMed  Google Scholar 

  29. Correa-de-Araujo R, McDermott K, Moy E (2006) Gender differences across racial and ethnic groups in the quality of care for diabetes. Women’s Health Issues 16:56–65. https://doi.org/10.1016/j.whi.2005.08.003

    Article  PubMed  Google Scholar 

  30. Santema BT, Ouwerkerk W, Tromp J et al (2019) Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study. Lancet 394:1254–1263. https://doi.org/10.1016/s0140-6736(19)31792-1

    Article  CAS  PubMed  Google Scholar 

  31. Ferreira JP, Rossello X, Eschalier R et al (2019) MRAs in elderly HF patients: individual patient-data meta-analysis of RALES, EMPAHSIS-HF, and TOPCAT. JACC Heart Fail 7:1012–1021. https://doi.org/10.1016/j.jchf.2019.08.017

    Article  PubMed  Google Scholar 

  32. Ferreira JP, Girerd N, Rossignol P, Zannad F (2015) Geographic differences in heart failure trials. Eur J Heart Fail 17:893–905. https://doi.org/10.1002/ejhf.326

    Article  PubMed  Google Scholar 

  33. Rosselló X, Huo Y, Pocock S et al (2017) Global geographical variations in ST-segment elevation myocardial infarction management and post-discharge mortality. Int J Cardiol 245:27–34. https://doi.org/10.1016/j.ijcard.2017.07.039

    Article  PubMed  Google Scholar 

  34. Bueno H, Rossello X, Pocock S et al (2018) Regional variations in hospital management and post-discharge mortality in patients with non-ST-segment elevation acute coronary syndrome. Clin Res Cardiol 107:836–844. https://doi.org/10.1007/s00392-018-1254-y

    Article  PubMed  Google Scholar 

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Acknowledgements

The EXAMINE trial was funded by Takeda.

Funding

The EXAMINE trial was funded by Takeda.

Author information

Authors and Affiliations

  1. Cardiology Department, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, Palma, Spain

    Xavier Rossello

  2. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Xavier Rossello

  3. Facultat de Medicina, Universitat de les Illes Balears (UIB), Palma, Illes Balears, Spain

    Xavier Rossello

  4. Centre D’Investigation Clinique-Plurithématique Inserm CIC-P 1433, Inserm U1116, CHRU Nancy hopitaux de Brabois, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Université de Lorraine, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, 4 Rue du Morvan, 54500, Vandoeuvre lès Nancy, France

    João Pedro Ferreira, Zohra Lamiral & Faiez Zannad

  5. Endocrinology and Diabetes Department, Hospital Juaneda Miramar, Palma de Mallorca, Spain

    Francisca Caimari

  6. Division of Cardiology, McGill University Health Centre, Montreal, QC, Canada

    Abhinav Sharma

  7. Cytel Corporation, Cambridge, MA, USA

    Cyrus Mehta

  8. Department of Medicine, American Heart Association Comprehensive Hypertension Center, University of Chicago, Chicago, IL, USA

    George Bakris

  9. Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA

    Christopher P. Cannon

  10. Baim Institute for Clinical Research, Boston, MA, USA

    Christopher P. Cannon

  11. Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT, USA

    William B. White

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  1. Xavier Rossello
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Corresponding author

Correspondence to Faiez Zannad.

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Conflict of interest

XR, JPF, FC, ZL and CM have nothing to disclose. AS has received support from the FRSQ-Junior 1 clinician scientist award, the Alberta Innovates Health Solution Clinician Scientist fellowship, the European Society of Cardiology Young Investigator research grant, and has received support from Roche Diagnostics, Astrazeneca, Boeringer-Ingelheim, Novartis, Servier, Novo-Nordisk, and the Canadian Cardiovascular Society Bayer Vascular award. Dr Ferreira has received consulting fees from Boehringer-Ingelheim. GB reports other from Merck, Novo Nordisk, Vasular Dynamics, Bayer, Ionis, Alnylam, KBP Biosciences, outside the submitted work. CPC reports in calendar years 2018–2020: (1) Research Grants from: Amgen, Boehringer-Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer, and (2) Consulting fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Corvidia, Eli Lilly, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, Rhoshan, Sanofi. WBW reports personal fees from Takeda Millenium Pharmaceuticals, outside the submitted work. FZ reports steering committee personal fees from Applied Therapeutics, Amgen, Bayer, Boehringer, Novartis, Janssen, Cellprothera and CVRx, advisory board personal fees from, AstraZeneca, Vifor Fresenius, Cardior, Cereno pharmaceutical, Corvidia, Merck, Myokardia, NovoNordisk and Owkin, stock options at Cereno and G3Pharmaceutical, and being the founder of the Global Cardiovascular Clinical Trialist Forum.

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The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki.

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Informed consents were obtained from each patient.

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Rossello, X., Ferreira, J.P., Caimari, F. et al. Influence of sex, age and race on coronary and heart failure events in patients with diabetes and post-acute coronary syndrome. Clin Res Cardiol 110, 1612–1624 (2021). https://doi.org/10.1007/s00392-021-01859-2

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  • DOI: https://doi.org/10.1007/s00392-021-01859-2

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