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Published online October 24, 2007
Diabetes Care 31:363-365, 2008
DOI: 10.2337/dc07-1745
© 2008 by the American Diabetes Association
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Cardiovascular and Metabolic Risk
Original Research

Aspirin and Mortality in Patients With Diabetes Sustaining Acute Coronary Syndrome

Richard M. Cubbon, MBCHB1, Christopher P. Gale, PHD1, Adil Rajwani, MBCHB1, Afroze Abbas, MBCHB1, Christine Morrell, RGNSCM2, Raj Das, MD2, Julian H. Barth, MD3, Peter J. Grant, MD1, Mark T. Kearney, MD1 and Alistair S. Hall, PHD2

1 Leeds Institute of Genetics, Health & Therapeutics, LIGHT Laboratories, University of Leeds, Leeds, U.K
2 British Heart Foundation Heart Research Centre, Jubilee Wing, Leeds General Infirmary, Leeds, U.K
3 Department of Clinical Biochemistry and Immunology, Leeds General Infirmary, Leeds, U.K

Address correspondence and reprint requests to Mark T. Kearney, Leeds Institute of Genetics, Health & Therapeutics, LIGHT Laboratories, University of Leeds, Clarendon Way, Leeds, LS2 9JT, U.K. E-mail: m.t.kearney{at}leeds.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
OBJECTIVE—We sought to compare mortality reduction associated with secondary prevention in patients with and without diabetes after acute coronary syndrome (ACS).

RESEARCH DESIGN AND METHODS—We conducted a cohort study involving 2,499 patients with ACS recruited from 11 U.K. hospitals. Multivariable analysis comparing all-cause mortality risk reduction associated with pharmacologic agents in patients with and without diabetes.

RESULTS—Aspirin was not associated with significant mortality benefit in diabetes sufferers (95% CI 0.50–1.08); nondiabetic patients derived a 48% mortality reduction (P < 0.001). The interaction between diabetes and aspirin use was statistically significant (P = 0.037), indicating that patients with diabetes experience less effective mortality reduction from aspirin use.

CONCLUSIONS—Aspirin, but not other secondary prevention agents, is associated with less effective mortality reduction in patients with diabetes and unstable coronary artery disease.

Abbreviations: ACS, acute coronary syndrome


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
The last decade has witnessed a significant improvement in use of evidence-based therapies and mortality after acute coronary syndromes (ACSs) (1). Outcomes for patients with diabetes may not have improved, despite similar improvements in the adoption of these strategies (2); the reasons for this are unclear. A recent meta-analysis suggested that antiplatelet agents confer less benefit to diabetic patients with stable vascular disease (3). We assessed whether this relationship remained in patients with unstable coronary artery disease.


   RESEARCH DESIGN AND METHODS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
Retrospective analysis of the EMMACE-2 (Evaluation of Methods and Management of Acute Coronary Events-2) study was performed (4) examining outcomes in 2,499 unselected patients with ACS admitted to 11 U.K. hospitals between April and October 2003; all gave informed consent to participate, with ethics committee approval. ACS was diagnosed using established guidelines (5). The U.K. Office of National Statistics provided mortality data (mean 2 years).

Data in multivariable analyses include age, sex, heart failure, cardiovascular disease, chronic renal impairment, ST elevation, biomarker elevation (>0.06 µg/l Troponin I; Beckman Coulter), or creatinine kinase twice the upper reference range in the context of clinical myocardial infarction and provision of reperfusion, revascularization, aspirin, ACE inhibitors, statins, β-blockers, and clopidogrel. Doses were converted to equivalent doses based on the percentage of the maximal dose of other agents within these classes. Chronic renal impairment refers to estimated glomerular filtration rate <30 ml/min per 1.73 m2. Cardiovascular disease is a composite of coronary, cerebral, or peripheral vascular disease. Reperfusion refers to primary angioplasty or thrombolysis and revascularization to in-hospital or planned percutaneous coronary intervention or coronary artery bypass grafting. Secondary prevention agent utilization was assessed at discharge from hospital. Individuals with diabetes were identified using past history documented in the medical records or provision of diabetes-related dietary or pharmacologic intervention during hospitalization.

Statistical analyses were performed using SPSS (version 13.0; SPSS, Chicago, IL). Groups were compared using t tests for continuous data and Pearson's {chi}2 for categorical data. Statistical significance was defined as <0.05. Multivariable analysis using Cox proportional hazards analysis estimated hazard ratios (HRs) of clinical variables listed above in relation to all-cause mortality for cohorts with and without diabetes. Covariates were selected a priori and included in analysis without stepwise removal. Further multivariable analysis involving the entire study cohort included interaction terms between diabetes and drug classes to assess differences in mortality risk reduction related to diabetes status. Missing data resulted in omission of 63 patients.


   RESULTS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
Seventeen percent of patients were diabetic; mean age was 71.5 years and, 58.5% were male, both similar to patients without diabetes. At 2 years, 162 (38.7%) and 543 (26.9%) deaths occurred in patients with and without diabetes, respectively. Patients with diabetes experienced rates of heart failure and chronic renal impairment around twice those of nondiabetic patients (10.2 and 7.9%, respectively). Non–ST segment elevation ACS was more common in diabetic patients (80.8 vs. 71.7%). Aspirin, statin, and clopidogrel use was similar, whereas patients with diabetes were more likely to receive ACE inhibitors and received β-blockers less often. The mean ± SD doses of agents (milligrams) received by patients with and without diabetes, respectively, were 108.9 ± 8.9 and 117.8 ± 4.0 for aspirin (P = 0.07), 31.6 ± 2.4 and 29.6 ± 0.8 for the simvastatin equivalent (P = 0.126), 5.4 ± 0.4 and 4.9 ± 0.2 for the ramipril equivalent (P = 0.017), and 4.5 ± 0.3 and 4.4 ± 0.2 for the bisoprolol equivalent (P = 0.81). Clopidogrel was always prescribed at 75 mg daily.

HRs associated with the use of pharmacologic agents, after accounting for the clinical variables described in RESEARCH DESIGN AND METHODS, are outlined in Fig. 1. Clopidogrel was associated with nonsignificant mortality reduction in patients with and without diabetes (HR 0.86 [95% CI 0.6–1.23] and 0.92 [0.74–1.14], respectively). The interaction between diabetes status and pharmacologic agent use was statistically significant only for aspirin, suggesting that patients with diabetes derive less survival benefit from this agent but comparable benefits from statins, ACE inhibitors, β-blockers, and clopidogrel.


Figure 1
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  		Figure 1— HRs (95% CI) associated with secondary prevention agents in groups with and without diabetes.

 

   CONCLUSIONS—
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
Despite similar dosing regimens, our study suggests aspirin offers less effective mortality reduction post-ACS to patients with diabetes, which contrasts with clopidogrel, statins, β-blockers, and ACE inhibitors. Our observations support the need for more effective antiplatelet strategies to improve outcomes in patients with diabetes and unstable coronary disease. Observational research is criticized for not accounting for bias and unknown confounding factors, though clinical trial data are often poorly representative of real-life practice. However, our work compliments the Anti-Thrombotic Trialists’ meta-analysis of antiplatelet therapy in stable cardiovascular disease (3) by providing similar findings in unstable coronary artery disease. The distinction between stable and unstable vascular diseases is significant though; as such, our observations are important. Further corroborating evidence comes from studies showing enhanced platelet activity in patients with diabetes treated with aspirin (6–8). The other secondary preventative agents in our study were associated with similar magnitudes of risk reduction in patients with and without diabetes. Supporting data again exists suggesting comparable benefits for statins, ACE inhibitors, and clopidogrel in primary and secondary prevention (9–12).

The mechanisms underlying our observations are unclear. One could speculate that aspirin dosing, antiplatelet agent combinations, compliance, or diabetes-specific factors (e.g., hyperglycaemia) may be relevant (13). Further investigation is required to elucidate the impact of diabetes on platelet biology and assess novel therapeutic strategies. In particular, though, further clinical trials of aspirin in patients with diabetes are needed to improve the poor outcomes they continue to experience after ACS.


   Acknowledgments
 
R.M.C., A.R., and A.A. are supported by fellowships from the British Heart foundation. The EMMACE Study was funded with educational grants from Astra Zeneca and Beckman Coulter. All authors declare their independence from the study funders.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 24 October 2007. DOI: 10.2337/dc07-1745.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication September 4, 2007. Accepted for publication October 17, 2007.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. Fox KA, Steg PG, Eagle KA, Goodman SG, Anderson FA Jr, Granger CB, Flather MD, Budaj A, Quill A, Gore JM; GRACE Investigators: Decline in rates of death and heart failure in acute coronary syndromes, 1999–2006. JAMA 297: 1892–1900, 2007[Abstract/Free Full Text]
  2. Cubbon RM, Wheatcroft SB, Grant PJ, Gale CP, Barth JH, Sapsford RJ, Ajjan R, Kearney MT, Hall AS; Evaluation of Methods and Management of Acute Coronary Events Investigators: Temporal trends in mortality of patients with diabetes mellitus suffering acute myocardial infarction: a comparison of over 3000 patients between 1995 and 2003. Eur Heart J 28: 540–545, 2007[Abstract/Free Full Text]
  3. Antithrombotic Trialists’ Collaboration: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324: 71–86, 2002[Abstract/Free Full Text]
  4. Das R, Kilcullen N, Morrell C, Robinson MB, Barth JH, Hall AS; EMMACE-2 (evaluation of methods and management of acute coronary events) Investigators: The British Cardiac Society Working Group definition of myocardial infarction: implications for practice. Heart 92: 21–26, 2006[Abstract/Free Full Text]
  5. Fox KAA, Birkhead J, Wilcox R, Knight C, Barth J; British Cardiac Society Working Group: British Cardiac Society Working Group on the definition of myocardial infarction. Heart 90: 603–609, 2004[Abstract/Free Full Text]
  6. Evangelista V, Totani L, Rotondo S, Lorenzet R, Tognoni G, De Berardis G, Nicolucci A: Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin. Thromb Haemost 93: 8–16, 2005[Medline]
  7. Fateh-Moghadam S, Plöckinger U, Cabeza N, Htun P, Reuter T, Ersel S et al: Prevalence of aspirin resistance in patients with type 2 diabetes. Acta Diabetol 42: 99–103, 2005[Medline]
  8. Watala C, Golanski J, Pluta J, Boncler M, Rozalski M, Luzak B, Kropiwnicka A, Drzewoski J: Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin)–its relation to metabolic control. Thromb Res 113: 101–113, 2004[Medline]
  9. Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355: 253–259, 2000[Medline]
  10. Ahmed S, Cannon CP, Murphy SA, Braunwald E: Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial. Eur Heart J 27: 2323–2329, 2006[Abstract/Free Full Text]
  11. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil W, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH; CARDS Investigators: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364: 685–696, 2004[Medline]
  12. Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ: Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 90: 625–628, 2002[Medline]
  13. Stratmann B, Tschoepe D: Pathobiology and cell interactions of platelets in diabetes. Diabetes Vasc Dis Res 2: 16–23, 2005

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This Article
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Right arrow Articles by Cubbon, R. M.
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