This study challenges conventional wisdom that patients with more coronary heart disease (CHD) risk factors have worse outcomes following their first MI. We found that patients with multiple CHD risk factors presented much earlier in life with MI and had lower hospital mortality than patients with fewer or no risk factors. We confirmed that the high prevalence of risk factor exposure in patients with MI was consistent with the prior literature. In summary, we report an unexpected and possibly controversial association that, like all observational findings, should be considered hypothesis-generating and further explored in terms of health care provided to patients who reach the hospital alive with first MI

Santulli, Gaetano

English

Columbia University Academic Commons

LETTERSCoronary Heart Disease Risk Factors andMortalityTo the Editor: Dr Canto and colleagues1 found that hospi-tal mortality increased as the number of cardiovascular riskfactors declined. This inverse relationship is perplexing andthe potential explanations discussed by the authors appearnot completely satisfactory.The authors just considered the number of risk factors,whereas the severity of each factor was not evaluated. Bloodpressure, plasma glucose, and lipids are continuous, not dis-creet, variables that exert a dose-dependent effect on car-diovascular risk.2 It would be of interest to see the resultsof the analysis conducted considering these parameters,which also would help to clarify the still controversial as-sociation of themetabolic syndrome andmortality aftermyo-cardial infarction (MI).3It also would be interesting to know if the inverse corre-lation is still present after correction for one of themost im-portant predictors of mortality after acute coronary syn-drome,4 the baseline infarct size.Last, traditional cardiovascular risk factors do not fullyexplain the pathophysiological process of atherothrombo-sis in acute ischemic heart disease. Several studies have iden-tified a series of emerging biomarkers reflecting thrombo-sis, inflammation, and oxidative stress.5 Do the authors haveany data about this issue?Gaetano Santulli, MDAuthor Affiliation: Columbia University Medical Center, New York, New York(gs2620@columbia.edu).Conflict of Interest Disclosures: The author has completed and submitted the ICMJEForm for Disclosure of Potential Conflicts of Interest and none were reported.1. Canto JG, Kiefe CI, Rogers WJ, et al; NRMI Investigators. Number of coronaryheart disease risk factors and mortality in patients with first myocardial infarction.JAMA. 2011;306(19):2120-2127.2. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk pro-file for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743-753.3. Petersen JL, Yow E, AlJaroudi W, et al. Metabolic syndrome is not associatedwith increased mortality or cardiovascular risk in nondiabetic patients with a newdiagnosis of coronary artery disease. Circ Cardiovasc Qual Outcomes. 2010;3(2):165-172.4. Wu E, Ortiz JT, Tejedor P, et al. Infarct size by contrast enhanced cardiac mag-netic resonance is a stronger predictor of outcomes than left ventricular ejectionfraction or end-systolic volume index: prospective cohort study. Heart. 2008;94(6):730-736.5. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction offirst major cardiovascular events and death. N Engl J Med. 2006;355(25):2631-2639.To the Editor: The study by Dr Canto and colleagues1provides an example of an epidemiological phenomenonthat deserves wider recognition. Differential selectionfrom an underlying population cohort into a study dataset can reverse the direction of observed associations,making a deleterious factor appear protective. It is well-known that conditioning on a variable that is affected byboth an exposure and outcome can produce a distortionknown as selection bias.2 Admission into the analysisdata set in this study was a function of both the exposure(number of cardiovascular risk factors) and the outcome(all-cause, in-hospital, or 30-day mortality) becausedeaths occurring before hospitalization and patients withexisting cardiovascular disease diagnoses were excluded.Approximately 30% of MIs lead to death prior to hospi-talization.3 In the study, 75% of those who were admittedto the hospital after their MI were excluded (1.62 millionof 2.16 million; Figure 1 in the article).The combined effect of these 2 selection mechanismsmeans that individuals with more cardiovascular risk fac-tors were more likely to be excluded. If an increased num-ber of risk factors accelerate mortality so that more eventsoccur in the prehospital window rather than during hospi-talization or 30-day follow-up, risk factors will appear to beprotective.4 The study results are therefore understandablein terms of selection bias and require no elaborate specu-lation about pathophysiological processes1 or “novel but as-yet uncharacterized and deadly CVD [cardiovascular dis-ease] risk factors.”5Hailey R. Banack, MASam Harper, PhDJay S. Kaufman, PhDAuthor Affiliations: Department of Epidemiology, Biostatistics, and OccupationalHealth, McGill University, Toronto, Ontario, Canada (hailey.banack@mail.mcgill.ca).Conflict of Interest Disclosures: The authors have completed and submitted theICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Harper reportedreceiving a grant to his institution from Fonds de recherche´ du Que´bec-Sante´. DrKaufman reported holding an endowed chair from the federal government ofCanada. Ms Banack reported no disclosures.1. Canto JG, Kiefe CI, Rogers WJ, et al; NRMI Investigators. Number of coronaryheart disease risk factors and mortality in patients with first myocardial infarction.JAMA. 2011;306(19):2120-2127.2. Herna´n MA, Herna´ndez-Dı´az S, Robins JM. A structural approach to selectionbias. Epidemiology. 2004;15(5):615-625.3. Chambless L, Keil U, Dobson A, et al; WHO MONICA Project. Population ver-sus clinical view of case fatality from acute coronary heart disease: results fromthe WHO MONICA Project 1985-1990. Circulation. 1997;96(11):3849-3859.GUIDELINES FOR LETTERS. Letters discussing a recent JAMA article shouldbe submitted within 4 weeks of the article’s publication in print. Letters receivedafter 4 weeks will rarely be considered. Letters should not exceed 400 words oftext and 5 references and may have no more than 3 authors. Letters reportingoriginal research should not exceed 600 words of text and 6 references and mayhave no more than 5 authors. They may include up to 2 tables or figures but on-line supplementary material is not allowed. All letters should include a word count.Letters must not duplicate other material published or submitted for publication.Letters not meeting these specifications are generally not considered. Letters willbe published at the discretion of the editors and are subject to abridgement andediting. Further instructions can be found at http://jama.com/instructions. A signedstatement for authorship criteria and responsibility, financial disclosure, copyrighttransfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Con-flicts of Interest are required before publication. Letters should be submitted viathe JAMA online submission and review system at http://manuscripts.jama.com(note: do not include “www” before the URL). For technical assistance, pleasecontact jama-letters@jama-archives.org.Letters Section Editor: Jody W. Zylke, MD, Senior Editor.©2012 American Medical Association. All rights reserved. JAMA, March 21, 2012—Vol 307, No. 11 1137Downloaded From: http://jama.jamanetwork.com/ by a Columbia University User  on 05/22/20124. Flanders WD, Klein M. Properties of 2 counterfactual effect definitions of a pointexposure. Epidemiology. 2007;18(4):453-460.5. Peterson ED, Gaziano JM. Cardiology in 2011—amazing opportunities, hugechallenges. JAMA. 2011;306(19):2158-2159.In Reply: Our study challenges conventional wisdom thatpatients with more coronary heart disease (CHD) risk fac-tors haveworse outcomes following their firstMI.We foundthat patients withmultiple CHD risk factors presentedmuchearlier in life withMI and had lower hospital mortality thanpatients with fewer or no risk factors. We confirmed thatthe high prevalence of risk factor exposure in patients withMI was consistent with the prior literature.Dr Santulli seeks additional information that may en-hance our study, such as the influence of a dose-dependenteffect of CHD risk factors, presence of the metabolic syn-drome, other novel risk markers, and infarct size. Unfortu-nately, these factors were not available in the National Reg-istry ofMyocardial Infarction. Although baseline infarct sizewas not recorded, the finding of an inverse relationship be-tween the number of CHD risk factors and mortality wasconsistently observed among patients with low-, interme-diate-, and high-risk features using 2 well-validated mea-sures of infarct severity (Killip classification and TIMI RiskIndex).Ms Banack and colleagues suggest that bias in the selec-tion of our study cohort could have reversed the directionof observed associations, making a deleterious factor ap-pear protective. An MI cohort with no previous cardiovas-cular disease represents amore uniform population to studygiven the differences inmanagement and treatment after ath-erosclerosis is manifest. Excluding patients with previouscardiovascular disease simply presents findings generaliz-able only to patients without previous disease. When ouranalysis was rerun using only an MI cohort with previouscardiovascular disease (N=630 210), our results did notchange appreciably (TABLE).Banack et al also raise the possibility that patients withmultiple CHD risk factors might have died disproportion-ately before hospitalization. This is merely speculative.No prior study has examined the relationship betweenthe number of CHD risk factors and mortality amongpatients with suspected MI who died prior to hospitalarrival, perhaps due to the challenges of confirming MI inthe prehospital setting.In the discussion of our findings, we devoted 4 para-graphs to methodological issues that may have limited gen-eralizability and inferences of causality, including risk fac-tor misclassification, bias with case ascertainment, residualconfounding, healthy survivor bias, and index event bias.1Index event bias (also known as reverse epidemiology orcollider stratification bias) may affect research that exam-ines disease progression and severity when there are mul-tiple risk factors for progression or for severity that are alsorisk factors for having the disease in the first place.1We alsopresent biologically plausible alternative interpretations ofour findings, including receipt of more aggressive treat-ments and follow-up care among patientswithmultipleCHDrisk factors.In summary, we report an unexpected and possibly con-troversial association that, like all observational findings,should be considered hypothesis-generating and further ex-plored in terms of health care provided to patients who reachthe hospital alive with first MI.John G. Canto, MD, MSPHCatarina I. Kiefe, MD, PhDPhilip Greenland, MDAuthor Affiliations: Center for Cardiovascular Prevention, Research and Educa-tion, Watson Clinic LLP, Lakeland, Florida (Dr Canto) (jcanto@watsonclinic.com);Department of Quantitative Health Sciences, University of Massachusetts Medi-cal School, Worcester (Dr Kiefe); and Clinical and Translational Sciences Institute,Northwestern University, Chicago, Illinois (Dr Greenland).Conflict of Interest Disclosures: The authors have completed and submitted theICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Kiefe and Green-land reported receiving grants from the National Institutes of Health. Dr Green-land also reported being a consultant to the University of Pennsylvania, Ohio StateUniversity, and the National Heart, Lung, and Blood Institute; and receiving pay-ment for lectures from the National Institutes of Health and several universities.Dr Canto reported no disclosures.1. Dahabreh IJ, Kent DM. Index event bias as an explanation for the paradoxesof recurrence risk research. JAMA. 2011;305(8):822-823.Urinary SodiumExcretion andCardiovascular EventsTo the Editor: Dr O’Donnell and colleagues, in their studyon urinary sodium excretion and risk of cardiovascularevents,1 reached the counterintuitive conclusion that so-dium restriction increased the risk of cardiovascular events,which runs counter to the consistent evidence that, in in-dividuals with hypertension, decreased sodium intake re-duces blood pressure and improves the effectiveness of treat-ment with antihypertensive agents.2-4Table. Crude Hospital Mortality of Patients With Myocardial Infarction (MI) and Previous Cardiovascular DiseaseaNo. of Risk Factors at Presentationb0 1 2 3 4 5No. (%)MI (N = 630 210) 83 978 (13.3) 195 238 (31.0) 205 224 (32.6) 111 384 (17.7) 30 893 (4.9) 3493 (0.6)Crude hospital mortality 15 790 (18.8) 30 825 (15.8) 25 894 (12.6) 10 336 (9.3) 2293 (7.4) 220 (6.3)aData are from the National Registry of Myocardial Infarction, 1994-2006. Excluded patients without prior cardiovascular disease, those who had been transferred, and those withmissing data.bFive major risk factors: smoking, diabetes, dyslipidemia, hypertension, and family history of coronary heart disease.LETTERS1138 JAMA, March 21, 2012—Vol 307, No. 11 ©2012 American Medical Association. All rights reserved.Downloaded From: http://jama.jamanetwork.com/ by a Columbia University User  on 05/22/2012

Coronary heart disease risk factors and mortality

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Coronary heart disease risk factors and mortality

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