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Impact of Combination evidence-Based 1 Medical therapy on Mortality Following 1 Infarction in elderly Patients Myocardial CME
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edgar lik-Wui Tay, MBBS; Mark chan, MBBS; Virlynn Tan, MSc; ling ling Sim, MSc; huay-cheem Tan, MBBS; yeo Tiong cheng, MBBS
From the Cardiac Department, National University Hospital, Singapore Address for correspondence: Edgar Lik-Wui Tay, MBBS, 5 Lower Kent Ridge Road, Level 3, Main Building, National University Hospital, Singapore 119074 E-mail: edgartay1@rediffmail.com Manuscript received June 6, 2007; accepted June 25, 2007

Antiplatelet drugs, b-blockers, statins, and angiotensinogen-converting enzyme inhibitors reduce mortality following myocardial infarction (MI). The data on the impact of combination evidencebased medications on mortality following acute MI in elderly patients are limited. In this study, 5529 patients with MI admitted between January 2000 and December 2003 were assessed. Based on discharge use of evidence-based medications, the patients were divided into those using 0, 1, 2, 3, or 4 medications. The impact of medications on 1-year mortality was assessed for patients younger than 75 years and 75 years and older. Mean age of the patients was 6313 years (71% male). The unadjusted 1-year mortality post-MI was 18.3% and 52.7% for young and elderly patients, respectively. Compared with patients with 0 medications, the adjusted odds ratio for 1-year mortality was lower in patients with 1, 2, 3, and 4 medications in both groups. Use of combination evidence-based medications was independently associated with lower 1-year post-MI mortality irrespective of age. (Am J Geriatr Cardiol. 2008;17:2126) 2008 Le Jacq

t is well-established that age is a negative predictor of outcome after acute myocardial infarction (AMI). The elderly population makes up a significant proportion of the patients who present with AMI, and, more importantly, they account for >60% of AMI-related deaths. Agents such as antiplatelet therapies, b-blockers, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers, (ARBs) and lipid-lowering agents have been shown to reduce mortality post-AMI. Many of these clinical trials have excluded such patients, however. There has thus been limited data on the impact of such agents on elderly patients. There have been a few observational studies or post hoc analyses showing that individual agents have a positive impact on outcomes. Also, there have been data to suggest that the underutilization of

such agents adversely affects the survival of these patients. We sought to find out whether the combination of such evidence-based therapies post-AMI would confer similar benefit in elderly patients.

Methods

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Participants. We identified 5529 consecutive patients with confirmed myocardial infarction admitted to 2 major public hospitals in Singapore between January 2000 and December 2003. All patients were identified by their admission or discharge diagnosis. The diagnosis of AMI was based on the presence of 2 out of 3 of the following criteria: symptoms suggestive of acute coronary insufficiency, electrocardiographic changes, and elevated cardiac biomarkers. The World Health Organization criteria were used because the data for the study were collected prior to the redefinition of AMI.1

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The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Table I. Baseline Characteristics of the Study Patients

Mean age, y Smoking Male sex diabetes hypertension Mean hemoglobin, g/dla dyslipidemia Mean ldl cholesterol, mmol/la STeMi Prior aMi Prior coronary bypass graft chronic kidney disease Mean Gfr, ml/min/1.73 m2a Percutaneous coronary intervention coronary bypass graft Killip class i ii iii iV
a

Group 1, <75 y (n=4311) 57.7910.70 1487 (42.8) 3331 (77.3) 1587 (36.8) 2347 (54.4) 13.982.9 1571 (36.4%) 3.741.1 2612 (60.6) 529 (12.3) 104 (2.4) 1177 (27.3) 80.4322.2 1387 (32.2) 173 (4) 602 (60.5) 913 (21.2) 339 (7.9) 453 (10.5)

Group 2, 75 y (n=1218) 81.425.31 174 (14.3) 597 (49.0) 494 (40.6) 784 (84.4) 12.982.3 285 (23.4) 3.461.2 576 (47.3) 211 (17.3) 39 (3.2) 760 (62.4) 54.3129.4 76 (6.4) 7 (0.6) 462 (37.9) 340 (27.9) 189 (15.5) 227 (18.6)

P Value <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01 <.01

no. of medications <.01 0 197 (4.6) 137 (11.2) 1 312 (7.2) 248 (20.4) 2 669 (15.5) 300 (24.6) 3 1565 (36.3) 312 (25.6) 4 1568 (36.4) 221 (18.1) abbreviations: aMi, acute myocardial infarction; Gfr, glomerular filtration rate; ldl, low-density lipoprotein; STeMi, ST-segment elevation myocardial infarction. data are expressed as no. (%) unless otherwise indicated. a Mean Sd.

data Collection. Clinical, demographic, treatment, and outcome data were collected prospectively and entered into a dedicated myocardial infarction registry database by trained medical personnel. Definitions were based on the recommendations by the American College of Cardiology data standards committee. Besides demographic variables, the other information collected included comorbidities such as smoking, diabetes mellitus, hyperlipidemia, and hypertension. In addition, a history of heart disease (angina, heart failure, myocardial infarction) or revascularization, such as coronary artery bypass grafting or percutaneous coronary intervention, was also recorded. Twelve-lead electrocardiographic changes and initial laboratory data were assessed. Data describing patient management for the acute event such as percutaneous coronary intervention or coronary artery bypass grafting were also entered. Our
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primary interest, which was the discharge use of antiplatelet agents, b-blockers, ACEIs or ARBs, and lipid-lowering agents, was assessed at discharge. Mortality data at 1-year follow-up were obtained for 100% of the patients from medical chart reviews or phone call interviews. statistical Analysis. Baseline characteristics were summarized into frequencies and percentages for categorical variables and means and SD for continuous variables. The patients were divided into 2 groups based on their age at admission (those younger than 75 years and those 75 years and older). The patients were further subdivided into those who had used 0, 1, 2, 3, and 4 medications at discharge (antiplatelet agents, b-blockers, ACEIs or ARBs, and lipid-lowering agents). A multivariate logistic regression model was used for 1-year mortality, adjusting for baseline differences in

The aMerican JoUrnal of GeriaTric cardioloGy 2008 Vol. 17 no. 1

The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

No. of medications 1 2 3 4

OR, 95% CI 0.28, 0.160.50 0.10, 0.060.17 0.05, 0.030.09 0.03, 0.020.06

0 Lower mortality

2 Higher mortality

Figure 1. Odds ratio (OR) of 1-year mortality with respect to number of medications used in the younger cohort. P<.01 in all groups. CI indicates confidence interval.

demographics, comorbidities, and interventions. All analyses were performed using the SPSS statistical program (SPSS Inc, Chicago, IL). The baseline characteristics of the patients are shown in Table I. The mean age was 5710.7 years and 81.425.3 years in the young and the elderly, respectively. There were more men in the younger cohort. This sex distribution is consistent across other studies in the elderly. Not surprisingly, there were significantly more comorbidities in the elderly patients. In particular, there were more elderly patients with diabetes mellitus (41% vs 37%) and hypertension (84% vs 54%). We also assessed the mean hemoglobin levels of the 2 groups, and this measure was found to be lower in the elderly patients (12.9 vs 13.9 g/dL). Using the Modification of Diet in Renal Disease estimation of glomerular filtration rate, the elderly had a very large proportion of chronic kidney disease (62% vs 27%). The mean glomerular filtration rate was 80 mL/min/1.73 m2 and 54 mL/min/1.73 m2 for the younger and elderly patients, respectively. The clinical presentation of the patients in the different age groups also differed. The elderly population presented more often with nonSTsegment elevation myocardial infarction, compared with the younger cohort, and was more often associated with higher Killip class heart

Results

failure. With regard to intervention, the management of the elderly patients appeared to be more conservative. Percutaneous coronary intervention was performed in only 6.4% of the older patients compared with 32% of those younger than 75 years. This was also true for coronary artery bypass grafting. The discharge use of antiplatelet agents, b-blockers, ACEIs or ARBs, and lipid-lowering agents was 74%, 60%, 73%, and 87%, respectively, in the younger patients. The rates of usage were less in the elderly at 49%, 52%, 45%, and 74%, respectively (Table II). The unadjusted 1-year mortality postmyocardial infarction was 18.3% and 52.7% for young and elderly patients, respectively. To adjust for baseline characteristics, a logistic regression was performed. Compared with patients with 0 medication, the adjusted odds ratio for 1-year mortality was lower in patients with 1, 2, 3, and 4 medications in both groups (Figures 1 and 2).These results were adjusted for age, sex, race, smoking, dyslipidemia, hypertension, diabetes mellitus, history of AMI, prior percutaneous coronary intervention/coronary artery bypass grafting, revascularization, and Killip class. There was no significant interaction between the number of medications used and age.

dIsCussIon

Cardiovascular disease remains a significant problem and ranks as the second most common cause

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The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

No. of medications 1 2 3 4 0 Lower mortality 1

OR, 95% CI 0.44, 0.220.87 0.18, 0.090.35 0.16, 0.080.31 0.10, 0.050.21 2 Higher mortality

Figure 2. Odds ratio (OR) of 1-year mortality with respect to number of medications used in the elderly cohort. P<.01 in all groups. CI indicates confidence interval.

of death in Singapore. The elderly population makes up a significant proportion of our patients, similar to other aging societies. Age is a strong predictor of markedly increased mortality postAMI. There are worsened short-term2 as well as long-term3 outcomes. This is likely due to multiple factors that include important comorbidities, more extensive coronary artery disease, and impaired left ventricular systolic and diastolic function. Other mechanisms that have been suggested include less catecholamine responsiveness, blunted ischemic preconditioning,4 lack of collateral coronary vessel formation,5 and reduced agerelated tolerance of myocardial ischemia. Factors that increase longer-term mortality (eg, frailty, heart failure, peripheral vascular disease, diabetes, and renal insufficiency) are more common in the older population and largely explain the high 1-year mortality after AMI. Several evidence-based medications have been shown to decrease 1-year mortality in patients post-AMI, but several of these clinical trials have excluded the elderly. Antiplatelet agents such as aspirin have improved outcomes post-AMI in landmark AMI trials.6 There has been a reluctance in prescribing this agent in the elderly because of a possible increased risk of bleeding or formation of peptic ulcers.7 The underutilization of this agent has been associated with less favorable outcomes.8 Other agents (eg, the adenosine diphosphate receptor inhibitor clopidogrel) have shown benefit as well. Clopidogrel when added to acetylsalicylic acid resulted in an 18.4% risk reduction

of death, nonfatal myocardial infarction, or stroke in patients with acute coronary syndrome.9 The risk reduction was present even in those who were older than 75 years. Again, in the elderly subgroup, there is an increased risk of excess major bleeding, however (excess major bleeding from clopidogrel in patients younger than 65 years, 0.4%; in those aged 6574 years, 1.3%; and in those aged 75 years or older, 1.9%). The use of ACEIs or ARBs has been limited in the elderly population. ACEI use post-AMI in the setting of left ventricular systolic dysfunction has been shown irrespective of age. A recently presented study also showed the benefits of perindopril on preventing cardiac remodeling postmyocardial infarction.10 The use of ACEIs in the elderly has been tardy. This is likely due to the presence of associated comorbidities such as renal impairment or hypotension. b-Blockers have also been shown to improve outcomes in the elderly with AMI, as reported in a study that revealed how the underutilization of b-blockers resulted in worse outcomes.11 With regard to the use of statins, 2 major trials have illustrated the effectiveness of low-density lipoprotein cholesterol lowering for secondary prevention of ischemic heart disease in the elderly.12,13 Despite the findings of these trials, there has be a trend toward the underutilization of statins in the elderly. Possible reasons include a concern over reduced hepatic function and skeletal mass in the elderly coupled with the high likelihood of polypharmacy, which may predispose these patients to more adverse effects. In

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The elderly and Myocardial infarcTion

The aMerican JoUrnal of GeriaTric cardioloGy 2008 Vol. 17 no. 1

The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

Table II. Frequency of Types of Medications

Group 1, <75 y (n=4311) Group 2, 75 y (n=1218) Types of MedicaTions b-Blockers 3175 (73.6) 597 (49.0) aceis/arBs 2566 (59.5) 627 (51.5) 3125 (72.5) 547 (44.9) lipid-lowering agentsa b 3751 (87.0) 897 (73.6) antiplatelet drugs abbreviations: acei, angiotensin-converting enzyme inhibitor; arB, angiotensin receptor blocker. data are expressed as no. (%). aincludes 3-hydroxy-3-methylglutaryl coenzyme a inhibitors and fibrates. bincludes thienopyridines.

the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),14 there was also a concern for neoplasia risk. Because of the above concerns, there has been a significant underutilization of evidenced-based therapies in the elderly. A recently coined term, the treatment-risk paradox,15 aptly describes this. Our study aimed to assess how the combination of evidence-based agents would affect the elderly population. As expected, there were significantly more comorbidities in the elderly group. After adjustment for such comorbidities, the use of more evidence-based medications on discharge was associated with improved 1-year outcomes. These findings give us further impetus to confirm these results in prospective randomized trials. It would also give physicians confidence in the use of these medications in the treatment of elderly patients. There are several limitations in this study. This was an analysis of a registry of patients with confirmed myocardial infarction admitted to 2 public hospitals. The retrospective nature and the fact that the results are based on 2 centers are obvious limitations. The management of the patients was entirely left to the discretion of the primary physician. As such, there could have been selection bias in terms of interventional and medical therapy given to the patients. This reflects real-world practice, however, and we were interested to know the impact of combination evidence-based medications in the real world. We have also tried to correct for baseline differences by using multivariate analysis, a commonly used method to approach registry data. We were, however, unable to fully assess the relative importance of the individual agents or whether certain combinations of drugs were superior to other combinations; doing so would have resulted in multiple subgroup comparisons and very small numbers in each group. This would perhaps be better evaluated in a larger future cohort of patients.

There also remains a possibility that the nonprescription of drugs may reflect a sicker population; this would account for the increased mortality in this group of patients. We have considered specifically the effect of differences in measures such as low-density lipoprotein cholesterol and hemoglobin levels as well as Killip class differences, because these variables may potentially affect the prescription patterns in these 2 distinct populations. It would have been ideal to have the transthoracic echocardiographic ejection fraction data for all patients. Unfortunately, transthoracic echocardiography was not performed in all patients; as such, this could not be factored into the final analysis. The use of ACEIs or b-blockers in these patients was largely based on clinical judgment. We, therefore, used Killip class as a surrogate of heart failure severity. The inclusion of these variables in the multivariate model did not change the outcomes of the study, however. We were also unable to individually assess the reasons for administering or withholding evidence-based therapies because of specific comorbidities (eg, if aspirin was administered less often because of increased bleeding risk), as this would have required larger cohorts and separate analyses and would have been best addressed with prospective randomized trials. We therefore cannot fully ascribe the increase in mortality purely to undertreatment and ignore the fact that some of the prescription patterns may reflect different and potentially more severe comorbidities.

ConClusIons

Patients with advanced age have a significantly worse outcome after AMI. We found that the use of combination evidence-based medications was independently associated with lower 1-year postmyocardial infarction mortality. Further prospective clinical trials should be performed to corroborate these findings and establish the individual benefits of such agents.

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The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.

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8 Frilling B, Schiele R, Gitt AK, et al. Too little aspirin for

secondary prevention after acute myocardial infarction in patients at high risk for cardiovascular events: results from the MITRA study. Am Heart J. 2004;148:306311. Yusuf S, Mehta SR, Zhao F, et al. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation. 2003;107:966972. Ferrari R. Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) Study. Arch Intern Med. 2006;166:659666. Soumerai SB, McLaughlin TJ, Spiegelman D, et al. Adverse outcomes of underuse of beta-blockers in elderly survivors of acute myocardial infarction. JAMA. 1997;277:115121. Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterollowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation. 1997;96:42114218. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:10011009. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:16231630. Ko DT, Mamdani M, Alter DA. Lipid-lowering therapy with statins in high-risk elderly patients: the treatment-risk paradox. JAMA. 2004;291:18641870. Instant CME Credit www.ash-us.org/highlights

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The elderly and Myocardial infarcTion The aMerican JoUrnal of GeriaTric cardioloGy 2008 Vol. 17 no. 1
The American Journal of Geriatric Cardiology (ISSN 1076-7460) is published bimonthly (Jan., March, May, July, Sept., Nov.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at BHarkinson@bos.blackwellpublishing.com or 781-388-8511.