Newly Diagnosed and Previously Known Diabetes Mellitus and 1-Year Outcomes of Acute Myocardial Infarction

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1 Newly Diagnosed and Previously Known Mellitus and 1-Year Outcomes of Acute Myocardial Infarction The Valsartan in Acute Myocardial Infarction (VALIANT) Trial David Aguilar, MD; Scott D. Solomon, MD; Lars Køber, MD, DSc; Jean-Lucien Rouleau, MD; Hicham Skali, MD; John J.V. McMurray, MD; Gary S. Francis, MD; Marc Henis, MD; Christopher M. O Connor, MD; Rafael Diaz, MD; Yuri N. Belenkov, MD, PhD; Sergei Varshavsky, MD; Jeffrey D. Leimberger, PhD; Eric J. Velazquez, MD; Robert M. Califf, MD; Marc A. Pfeffer, MD, PhD Background A prior diagnosis of diabetes mellitus is associated with adverse outcomes after acute myocardial infarction (MI), but the risk associated with a new diagnosis of diabetes in this setting has not been well defined. Methods and Results We assessed the risk of death and major cardiovascular events associated with previously known and newly diagnosed diabetes by studying patients with acute MI enrolled in the VALsartan In Acute myocardial infarction (VALIANT) trial. Patients were grouped by diabetic status: previously known diabetes (insulin use or diagnosis of diabetes before MI, n 3400, 23%); newly diagnosed diabetes (use of diabetic therapy or diabetes diagnosed at randomization [median 4.9 d after infarction], but no known diabetes at presentation, n 580, 4%); or no diabetes (n ). Patients with newly diagnosed diabetes were younger and had fewer comorbid conditions than did patients with previously known diabetes. At 1 year after enrollment, patients with previously known and newly diagnosed diabetes had similarly increased adjusted risks of mortality (hazard ratio [HR] 1.43; 95% confidence interval [CI], 1.29 to 1.59 and HR, 1.50; 95% CI, 1.21 to 1.85, respectively) and cardiovascular events (HR, 1.37; 95% CI, 1.27 to 1.48 and HR, 1.34; 95% CI, 1.14 to 1.56). Conclusions mellitus, whether newly diagnosed or previously known, is associated with poorer long-term outcomes after MI in high-risk patients. The poor prognosis of patients with newly diagnosed diabetes, despite having baseline characteristics similar to those of patients without diabetes, supports the idea that metabolic abnormalities contribute to their adverse outcomes. (Circulation. 2004;110: ) Key Words: myocardial infarction prognosis diabetes mellitus heart failure The increasing prevalence of type 2 diabetes mellitus will have important cardiovascular consequences, given that diabetes is a major risk factor for the development of atherosclerotic disease. 1 Approximately 20% to 30% of patients with an acute myocardial infarction (MI) have a previous diagnosis of diabetes. 2 4 These patients are at increased risk of both short-term and long-term cardiovascular events after MI. 2 5 Most of the studies that have quantified the adverse outcomes of diabetic patients with MI have been limited to patients with a known diagnosis of diabetes at the time of infarction. During the early days after an MI, physicians often diagnose new cases of diabetes, although it is unclear whether this relates to stress hyperglycemia or to the discovery of previously unrecognized diabetes in the population. The characteristics and prognosis of these patients with a new diagnosis of diabetes at the time of MI have been less well defined. We used the VALsartan In Acute myocardial infarction (VALIANT) trial to characterize further the effect of previously known and newly diagnosed diabetes on 1-year mortality and major cardiovascular events in patients with heart failure and/or left ventricular systolic dysfunction after MI. Methods Patient Population The VALIANT trial was a multinational, randomized trial comparing the effects of valsartan, captopril, or their combination in the Received January 29, 2004; revision received April 29, 2004; accepted May 18, From the University of Texas Health Science Center, Houston (D.A.); Brigham and Women s Hospital, Boston, Mass (S.D.S., H.S., M.A.P.); Rigshospitalet, Copenhagen, Denmark (L.K.); Toronto Hospital, Toronto, Ontario, Canada (J.L.R.); University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); The Cleveland Clinic Foundation, Cleveland, Ohio (G.S.F.); Medical Pharmaceutical Consultants, Randolph, NJ (M.H.); Duke Clinical Research Institute, Durham, NC (C.M.O., J.D.L., E.J.V, R.M.C.); Estudios Cardiologicos Latinoamerica, Santa Fe, Argentina (R.D.); Cardiology Research Institute, Moscow, Russia (Y.N.B.); and the CPR/Research Institute of Cardiology, St. Petersburg, Russia (S.V.). Correspondence and reprint requests to Dr David Aguilar, Cardiovascular Division, University of Texas Health Science Center, 6431 Fannin, MSB 1.246, Houston, TX david.aguilar@uth.tmc.edu 2004 American Heart Association, Inc. Circulation is available at DOI: /01.CIR F2 1572

2 Aguilar et al Prognosis of Patients With in VALIANT 1573 Figure 1. VALIANT study design. treatment of acute MI complicated by either clinical or radiological signs of heart failure or evidence of left ventricular systolic dysfunction or both. Patients were at least 18 years old and demonstrated symptoms of MI for at least 12 h but not 10 d. The exclusion criteria included cardiogenic shock, a serum creatinine level 2.5 mg/dl, known intolerance of or a contraindication for angiotensinconverting enzyme inhibitors or angiotensin receptor antagonists, and other serious diseases that could severely limit life expectancy. Details of the protocol and results of the main trial have been published. 6,7 Diabetic status was assessed at presentation with MI and again at randomization into VALIANT (a median of 4.9 d after symptom onset). Investigators were asked whether patients had a known history of diabetes before the qualifying MI, referring to a recorded history of diabetes managed with diet, insulin, or oral medications. Patients with a history of diabetes or insulin use before the qualifying MI were defined as having previously known diabetes. At randomization, investigators were asked whether patients had developed diabetes from the time of MI to randomization and whether they had received insulin or oral hypoglycemic agents within 24 h before randomization. If the investigator answered yes to either of these questions and the patient did not have previously known diabetes at presentation, then the patient was considered to have newly diagnosed diabetes. The remaining participants in the study were considered not to have diabetes (Figure 1). Outcomes The primary outcomes were the risks of death and major cardiovascular events within 1 year after MI. Suspected adverse cardiac events were identified by the primary investigator and were independently confirmed by the Clinical Endpoint Center. Reinfarction was confirmed in the presence of increased cardiac enzymes and typical clinical presentation or electrocardiographic changes that were consistent with MI. Heart failure was defined as an unplanned presentation for new or worsening heart failure requiring an overnight stay or admission to a healthcare facility in which the patient received intravenous inotropic, diuretic, or vasodilator therapy. Stroke was defined as a focal neurological deficit lasting 24 h or resulting in death that was presumed to be related to stroke. Resuscitated sudden cardiac arrest was defined as sudden death or cardiac arrest requiring cardioversion, defibrillation, or cardiopulmonary resuscitation. A composite cardiovascular outcome was defined as the occurrence of cardiovascular death, reinfarction, heart failure, resuscitated sudden death, and stroke. Data Analysis Continuous variables are presented as means with standard deviations unless otherwise specified. Differences in baseline demographics between groups were ascertained using Wilcoxon rank-sum tests for continuous variables and Pearson 2 tests for categorical and ordinal data. Two-sided values of P 0.01 were considered significant. Cox proportional-hazards models were used to assess the relations between diabetic status and the outcome of interest. Both unadjusted and multivariable adjusted hazard ratios are presented. From 70 candidate variables collected at randomization, both backward elimination and stepwise selection were used to identify independent predictors of the outcome. The multivariable model for mortality included the main effects of the following variables: age, heart rate, and systolic and diastolic blood pressures; Killip classification; anterior MI; new left bundle-branch block; thrombolytic therapy, primary percutaneous intervention, or -blocker use with qualifying MI; history of heart failure, previous MI, stroke, dyslipidemia, stable angina, hypertension, or alcohol abuse; previous unstable angina; trial enrollment in the United States; weight; current smoking; serum creatinine; atrial fibrillation, heart failure, hypertension, renal insufficiency, cardiac catheterization, percutaneous coronary intervention, or coronary artery bypass graft surgery after the qualifying MI; and study treatment assignment. The multivariable model for the composite cardiovascular outcome included similar variables, with the exception of US enrollment and -blocker use with qualifying MI and the addition of gender, race, previous hospitalization, and history of peripheral vascular disease or transient cerebral ischemic event. Log-rank tests were used to compare event curves for mortality, cardiovascular death, reinfarction, heart failure, stroke, and the composite outcome of cardiovascular death, heart failure, reinfarction, stroke, or cardiac arrest with resuscitation. Results VALIANT enrolled patients with acute MI complicated by heart failure or left ventricular systolic dysfunction or both. Of these patients, 3400 had previously known diabetes at the time of MI (23%), 580 received a new diagnosis of diabetes between the time of MI and randomization (4%), had no diabetes (73%), and 4 patients lacked the data necessary for classification. Clinical Characteristics Characteristics at baseline and at randomization are described in Table 1. Baseline demographics were similar between patients with newly diagnosed diabetes and patients without diabetes, except for body mass index. In contrast, patients with previously known diabetes were older and presented with more comorbid cardiovascular conditions than did either patients with newly diagnosed diabetes or patients without diabetes. Patients with previously known diabetes were more likely to have a non Q-wave MI and had lower creatine kinase levels than both patients with newly diagnosed diabetes and patients without diabetes. The initial therapy for MI was similar between patients with newly diagnosed diabetes and those without diabetes. In contrast, patients with previously known diabetes were less likely to receive aspirin, -blockers, thrombolytic therapy, or primary percutaneous coronary intervention than were patients without diabetes. They also were less likely to receive -blockers and fibrinolytic therapy than were patients with newly diagnosed diabetes. At randomization, patients with newly diagnosed or previously known diabetes had a faster heart rate and more often had a higher Killip classification than did patients without diabetes. Patients with previously known diabetes also had a slightly lower ejection fraction than did patients without

3 1574 Circulation September 21, 2004 TABLE 1. Clinical Characteristics Characteristic Previously Known (n 3400) Newly Diagnosed (n 580) No (n ) Baseline demographics Age, y * Female, % 40.6* Body mass index, kg/m * * Current cigarette smoking, % 19.3* Hypertension, % 70.4* Dyslipidemia, % 42.6* Peripheral vascular disease, % 15.3* Angina pectoris, % 44.7* Previous MI, % 34.7* Previous heart failure, % 22.5* Previous stroke, % 9.3* Previous percutaneous coronary intervention, % 10.4* Previous bypass surgery, % 11.5* Initial therapy for infarction, % Aspirin 86.9* Platelet glycoprotein IIb/IIIa inhibitor Blocker 54.2* Fibrinolytic agent 26.0* Primary percutaneous coronary intervention 12.5* Non Q-wave MI, % 39.9* Creatine kinase level ( ULN) * Heart rate, bpm * * Systolic blood pressure, mm Hg * Diastolic blood pressure, mm Hg Killip class I, % 76.4* 75.4* 70.4 Ejection fraction * Median days to randomization 5.1 (3.1, 7.3)* 5.0 (3.0, 7.3) 4.8 (3.0, 7.1) Medications at randomization, % Aspirin 90.2* Blocker 65.5* Calcium channel blocker 12.5* HMG-CoA reductase inhibitor 37.1* Insulin 48.5* 38.4* 0 Oral hypoglycemic agent 47.3* 19.5* 0 Treatment assignment, % Captopril Valsartan Combination Data expressed as mean (SD), median (25th, 75th percentiles), or percentage. ULN indicates upper limit of normal. *P 0.01 compared with patients without diabetes. P 0.01 compared with patients with newly diagnosed diabetes. Data available for 77% of patients. diabetes and a higher systolic blood pressure than did patients with newly diagnosed diabetes and those without diabetes. Medications, with the exception of diabetic therapy, did not differ between patients with newly diagnosed diabetes and those without diabetes. In contrast, patients with previously known diabetes were more likely to receive calcium channel blockers and HMG-CoA reductase inhibitors but were less likely to receive aspirin and -blockers than were patients without diabetes. Patients with previously known diabetes also were more likely to receive calcium channel blockers, insulin, and oral hypoglycemic therapy than those with newly diagnosed diabetes.

4 Aguilar et al Prognosis of Patients With in VALIANT 1575 Figure 2. Kaplan-Meier curves for mortality at 1 year by diabetic status. P 0.43 for previous vs new diabetes diagnosis, P for previous vs no diabetes diagnosis, P for new vs no diabetes diagnosis. Mortality By 1 year, 602 patients with previously known diabetes (17.7%), 94 patients with new diagnoses of diabetes (16.2%), and 1169 patients without diabetes (10.9%) had died. Despite similarities in characteristics between patients with newly diagnosed diabetes and those without diabetes, the rate of death was greater in patients with newly diagnosed diabetes and was similar to the rate in patients with previously known diabetes (Figure 2). The 1-year mortality rate for patients with newly diagnosed diabetes was similar whether they were or were not receiving diabetic therapy within 24 h of randomization (15.7% versus 16.8%, respectively; P 0.71). After adjustment for baseline differences, patients with either previously known or newly diagnosed diabetes maintained a higher risk of death as compared with patients without diabetes (Table 2). Nonfatal Events The occurrences of nonfatal adverse cardiovascular events are described in Figure 3. Patients with previously known diabetes and those with newly diagnosed diabetes had higher rates of the composite cardiovascular outcome than those without diabetes (Figure 4). Similar to total mortality, the adjusted risk for the composite cardiovascular end point in patients with newly diagnosed diabetes was similar to the risk TABLE 2. Primary Outcomes of patients with previously known diabetes (Table 2). The incidence of the composite cardiovascular outcome also was similar between patients with newly diagnosed diabetes who were or were not receiving diabetic therapy within 24 h of randomization (30% versus 28.2%, respectively; P 0.64). Discussion In the large VALIANT cohort of high-risk patients with acute MI, 23% had a history of diabetes mellitus at the time of MI. Another 4% were newly diagnosed with diabetes in the early phase of the index infarction. The presence of either previously known or newly diagnosed diabetes was a significant independent predictor of mortality and adverse cardiovascular events at 1 year after MI. Patients with acute MI and a history of diabetes have poorer outcomes than such patients without diabetes, 2 5,8 a finding confirmed in the present study. As in other studies, previously known diabetic patients in VALIANT were more likely to be older and female and to have more comorbid conditions than patients without diabetes. Despite having smaller MIs, as measured by creatine kinase levels, patients with diabetes also were more likely to have a greater degree of heart failure in conjunction with and in the first year after MI. Outcome Previously Known (n 3400) Newly Diagnosed (n 580) No (n ) Deaths, n (%) 602 (17.7) 94 (16.2) 1169 (10.9) Unadjusted HR (95% CI) 1.68 ( ) 1.54 ( ) 1.00 Adjusted HR (95% CI)* 1.43 ( ) 1.50 ( ) 1.00 Cardiovascular composite, n (%) 1217 (35.8) 169 (29.1) 2413 (22.5) Unadjusted HR (95% CI) 1.71 ( ) 1.36 ( ) 1.00 Adjusted HR (95% CI)* 1.37 ( ) 1.34 ( ) 1.00 *Text describes multivariable models.

5 1576 Circulation September 21, 2004 Figure 3. Kaplan-Meier estimates of secondary outcomes at 1 year by diabetic status. *P 0.01 vs patients without diabetes, P 0.01 for previously known diabetes vs newly diagnosed diabetes patients. Multiple mechanisms have been implicated in the increased number of adverse outcomes in patients with diabetes. These mechanisms include an abnormal metabolic response to ischemia with inefficient energy use and accumulation of deleterious oxygen-free radicals, 9 greater endothelial dysfunction, 10 and abnormalities of thrombosis and fibrinolysis. 11 Patients with diabetes are known to have a greater burden of atherosclerotic disease, with more diffuse and more multivessel coronary artery disease. 5,12 The presence of a diabetic cardiomyopathy may lead to greater degrees of heart failure. 8 Finally, although they derive similar therapeutic benefit, patients with diabetes have been demonstrated to be less likely to undergo thrombolysis 13 or receive -blocker therapy 14,15 than were patients without diabetes, a finding seen in the present study. In our study, the 4% of patients who received a new diagnosis of diabetes during the early phase of acute MI displayed an increased risk of death and adverse cardiovascular events. It is important to consider this hazard in light of the differences that may exist in the group of patients with newly diagnosed diabetes. Because no uniform definition was specified and no blood glucose values were available for review, new cases of diabetes were diagnosed by individual physician assessments. Given this likely heterogeneity, as well as difficulties establishing a new diagnosis of diabetes in the early post-mi setting, 16 patients with newly diagnosed diabetes likely composed a spectrum of patients from those with true unrecognized diabetes to those without diabetes but with stress hyperglycemia. Population-based studies and recent analyses of patients who were referred for cardiac catheterization 20,21 have shown that the prevalence of previously unrecognized diabetes may range from one third to one half of the people with diabetes in the population studied and that the presence of unrecognized diabetes is associated with an increased risk of death. 19,20,22 Overall, in studies in which survivors of an acute MI have undergone oral glucose tolerance testing, fasting blood glucose testing 2 to 3 months after MI, or both, the prevalence of undiagnosed diabetes has been estimated at 4% to 6%, 16,23,24 although a recent prospective study using oral glucose testing after acute MI demonstrated a prevalence of unrecognized diabetes and impaired glucose tolerance of 31% and 35%, respectively. 25 It is important to note that patients with newly diagnosed diabetes have been shown to have a significantly increased risk for coronary artery disease. 21 Additionally, vascular wall abnormalities have been demonstrated in patients before the onset of diabetes mellitus. 26 A significant proportion of patients with acute MI have hyperglycemia at presentation, a significant risk factor for adverse outcomes in both diabetic 27,28 and nondiabetic patients. 27,29 The mechanisms underlying the adverse association between hyperglycemia and acute MI are not fully understood, but multiple hypotheses have been proposed. Hyperglycemia may simply be a marker of stress hormones, which occur because of a catecholamine response to more extensive infarction or more severe heart failure. In our study, patients with newly diagnosed diabetes and previously known Figure 4. Kaplan-Meier curves for composite outcome of cardiovascular mortality/morbidity at 1 year by diabetic status. P for previous vs new diabetes diagnosis; P for previous vs no diabetes diagnosis; P for new vs no diabetes diagnosis. Composite cardiovascular outcome included cardiovascular death, reinfarction, heart failure, resuscitated sudden death, and stroke.

6 Aguilar et al Prognosis of Patients With in VALIANT 1577 diabetes had similar heart rates and Killip classifications, suggesting that heart rate and degree of heart failure with infarction, both markers for deranged hemodynamics, may be common components between the two groups. In addition to being a marker of stress hormone response, hyperglycemia may contribute directly to adverse outcomes. Acute hyperglycemia has been linked to impaired endothelial function, 30 reduced collateral coronary blood flow, 31 and, after reperfusion therapy for acute MI, increased microvascular dysfunction. 32 Acute hyperglycemia also may increase thrombus formation; blood glucose levels have been shown to independently predict plateletdependent thrombosis. 33 Finally, hyperglycemia may itself be a marker for the degree of insulin resistance or insulin deficiency at the time of the acute MI and the subsequent associated metabolic consequences. The present study has several limitations. As noted, blood glucose values were not available to allow a direct correlation of hyperglycemia with adverse outcomes. The lack of blood glucose levels and a uniform definition for diabetes likely led to some heterogeneity in the group with newly diagnosed diabetes. Also, individuals who were diagnosed with diabetes after randomization into the trial would not be captured in this analysis. Finally, these analyses were limited to those high-risk patients who fulfilled criteria for entry into the VALIANT trial. Conclusion As anticipated, patients with previously known diabetes had increased risks of death and major cardiovascular events at 1 year after MI. More important, the adjusted risks of death and major cardiac events associated with newly diagnosed diabetes were similar to those of patients with previously known diabetes, although the demographic characteristics and initial management of MI of patients with newly diagnosed diabetes were more similar to those of patients without diabetes. The poorer outcomes of patients with newly diagnosed diabetes, a diagnosis likely based on the presence of hyperglycemia, support the hypothesis that metabolic abnormalities early after MI contribute to the adverse outcomes. Although it is often difficult to confirm a diagnosis of diabetes early after MI, this study underscores the importance of screening for diabetes after MI to identify a group of patients who are at high risk for adverse outcomes and deserve particular medical attention to lower their risk. Disclosure Dr Henis is a former employee of Novartis Pharmaceuticals Corporation. Drs Solomon, Rouleau, Francis, Velazquez, and Califf have served as consultants and/or received honoraria from Novartis. Dr McMurray has served as a consultant and/or received honoraria from Novartis, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr Pfeffer receives honoraria/educational/research grants or serves as a consultant for AstraZeneca, Aventis, Bristol-Myers Squibb, Mitsubishi, Novartis, and Pfizer. The Brigham & Women s Hospital has been awarded patents related to the use of inhibitors of the renin-angiotensin system in selected survivors of MI; Dr Pfeffer is among the coinventors. The licensing agreements with Abbott Laboratories and Novartis are not linked to sales. Acknowledgment The VALIANT study was supported by Novartis Pharmaceuticals Corporation. References 1. mellitus: a major risk factor for cardiovascular disease. 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