BRIEF OBSERVATIONS

Serum HomocysteineLevels and Mortality inOutpatients with orwithout Coronary ArteryDisease: An ObservationalStudyMonica Acevedo, MD, Gregory L. Pearce, MS,Donald W. Jacobsen, PhD, Stephen Minor, MD,Dennis L. Sprecher, MD

Observational studies have shown that homocys-teine is an independent predictor of cardiovas-cular events—fatal and nonfatal coronary artery

disease—in several populations (1– 8). The results of pro-spective studies have not been uniform, however.Whereas eight studies (2,5–7,9 –12) reported that homo-cysteine was a predictor of cardiovascular disease, five(13–17) failed to show this association. Most of the stud-ies consisted of large, primarily healthy populations(3– 6) or patients whose homocysteine levels were mea-sured at the time of coronary angiography (9,12) and whowere followed for cardiovascular events. Few studies haveexamined total mortality as the primary endpoint(5–7,9,10,12).

In the present study, we sought to determine whetherhomocysteine is independently associated with totalmortality in a clinical setting that included patients withand without known cardiovascular disease.

METHODS

Our study consisted of all patients in whom we measuredhomocysteine levels at their first consult to our Preven-tive Cardiology and Rehabilitation Unit at the ClevelandClinic Foundation between January 1996 and February2002 (n � 3427). More than 80% of our patients arereferred from other cardiovascular services. The remain-ing patients are referred from internal medicine, familypractices, neurology and obstetrics-gynecology. In ourclinic, patients are assessed routinely for traditional car-diovascular risk factors, as well as for several nontradi-tional risk factors such as homocysteine. Demographic,general medical, and cardiovascular data (including anupdated list of medications) were obtained by question-naire.

PatientsThe sample included patients with or without knowncoronary artery disease who were referred to the clinic

principally for cardiovascular risk factor modification.Coronary artery disease was diagnosed if at least one ofthe following was present: documented myocardial in-farction, stenosis (�50%) in at least one major coronaryartery, history of coronary artery bypass graft surgery, orabnormal stress test results. In the patients who did notreport a history of coronary artery disease and who weretreated at our institution, we corroborated that informa-tion by examining their medical records. When available,cardiovascular diagnostic information was also evalu-ated. Among patients with previous cardiac events, themean (� SD) time to enrollment was 30 � 49 months.No patient was referred to the clinic because of elevatedhomocysteine levels.

On June 30, 2002, the vital status of these patients wasassessed by searching the Social Security AdministrationDeath index database. No information on the specificcause of death was available.

Data CollectionDuring the first visit to the clinic, all patients underwentan examination that included anthropometry (height,weight, waist) and blood pressure. A fasting blood speci-men was obtained for a complete lipid profile and levelsof glucose, creatinine, and homocysteine. Patients wereclassified as someone who had “never smoked,” as a“former smoker,” or as a “current smoker.” Patients wereconsidered to have hypertension if they had a history ofhigh blood pressure (physician diagnosed) and had aresting blood pressure �140/90 mm Hg or were takingantihypertensive medications. Diabetes was diagnosed byasking if the patient was taking an oral hypoglycemicagent or insulin, or rarely, when the patient reported ahistory of diabetes.

The Cleveland Clinic Institutional Review Board ap-proved the Preventive Cardiology database registry usedin this study for the collection and systematic analysis ofpatient data.

Laboratory TestingLevels of fasting total cholesterol, high-density lipopro-tein cholesterol, low-density lipoprotein cholesterol, andtriglycerides were measured in serum after a 12-hour fastand analyzed using enzymatic assays (Hitachi Analyzer,Boehringer Mannheim, Mannheim, Germany) (18). Tri-glyceride values �400 mg/dL were analyzed by beta-quantification. Total fasting serum homocysteine levelwas measured using high-performance liquid chroma-tography (19). Only fresh samples that were drawn at thefirst clinic visit were used. The normal range in our labo-ratory is 3.92 to 17.12 �mol/L.

Statistical AnalysisCox proportional hazards models were used to assessthe univariate associations between homocysteine (byquartiles: �9.4 �mol/L, 9.5 to 11.5 �mol/L, 11.6 to

© 2003 by Excerpta Medica Inc. 0002-9343/03/$–see front matter 685All rights reserved. doi:10.1016/S0002-9343(03)00123-2

14.3 �mol/L, �14.4 �mol/L) and mortality. Hazard ra-tios and 95% confidence intervals were used to compareeach of the upper three quartiles with the lowest quartile.Framingham global risk scores (20) were calculated foreach patient to adjust for traditional risk factors. In addi-tion, the models were adjusted for each Framinghamcomponent individually. Linear contrast statements wereused to test for trends toward increasing mortality acrosshomocysteine quartiles. Interactions between homocys-teine and sex and coronary artery disease were testedbased on a priori clinical concerns about potential differ-ences in associations in these groups. Models were alsoadjusted for serum creatinine level and use of aspirin,vitamin supplements (folic acid, B vitamins, multivita-mins), and statins.

RESULTS

After a mean (� SD) follow-up of 37 � 21 months(range, 2 to 75 months), 119 patients (3.5%) of the 3427patients had died (Table 1). Those who died had higherbaseline homocysteine levels than did those who survived(16.5 � 6.6 �mol/L vs. 12.3 � 4.7 �mol/L, P �0.001). Asignificant graded relation was observed among homo-cysteine quartiles (Table 2). The association between ho-

Table 1. Baseline Characteristics of the Sample (n � 3427)

Characteristic

Number (%), Mean� SD, or Median

(Interquartile Range)

Known coronary artery disease 1818 (53)Age (years)* 56 � 12Female sex* 1154 (34)Smoking* 328 (10)History of hypertension 1748 (51)History of diabetes* 655 (19)Body mass index (kg/m2) 28.8 � 5.2Total serum homocysteine (�mol/L) 12.5 � 4.8Creatinine (mg/dL) 0.9 (0.8–1.1)Total cholesterol (mg/dL)* 232 � 81LDL cholesterol (mg/dL) 131 � 58HDL cholesterol (mg/dL)* 43 � 16Triglycerides (mg/dL) 177 (115–283)Systolic blood pressure (mm Hg)* 132 � 21Diastolic blood pressure (mm Hg)* 79 � 11Framingham Risk Score 6.0 (3.0–9.0)Use of statins 1383 (40)Use of aspirin 2026 (59)Use of multivitamins 1101 (32)Prior myocardial infarction 860 (25)Prior coronary artery bypass graft

surgery798 (23)

* Indicates that the variable is a component of the Framingham RiskScore (18).HDL � high-density lipoprotein; LDL � low-density lipoprotein.

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Homocysteine Levels and Mortality/Acevedo et al

686 June 1, 2003 THE AMERICAN JOURNAL OF MEDICINE� Volume 114

mocysteine level and mortality was consistent regardlessof the adjustment method (Table 2). Similar results wereseen after adjustment for the Framingham Risk Score(Figure).

We found no evidence of an interaction with coronaryartery disease (P for interaction � 0.49) or sex (P forinteraction � 0.23). In an analysis that adjusted for cor-onary artery disease; creatinine level; use of aspirin, vita-min supplements, and statins; and Framingham RiskScores, the hazard ratio for the highest homocysteinequartile (vs. the lowest) was 3.2 (95% confidence interval[CI]: 1.6 to 6.3; P �0.001).

DISCUSSION

The relation between homocysteine and mortality in ourpatients is consistent with previous prospective studies(5–10,12,21). For example, the British United ProvidentAssociation study (5), an observational study in men con-ducted mainly in a primary prevention setting, revealed astrong and graded association between homocysteinequartiles and cardiovascular mortality (relative risk �2.9; 95% CI: 2.0 to 4.1).

In the secondary prevention setting among patientswith known coronary artery disease, two studies (9,12)reported a strong, graded, and independent relation ofbaseline homocysteine with mortality. This similarity

among studies of overall mortality is in contrast with fivelarge prospective cohort studies that used a combinedendpoint of coronary artery disease and cardiovasculardeath (13–17), all of which failed to demonstrate a signif-icant association with homocysteine. The Multiple RiskFactor Intervention Trial (15), for example, did not find asignificant relation between homocysteine quartile andfatal and nonfatal coronary artery disease (hazard ratio �0.82; 95% CI: 0.55 to 1.54).

Elevated homocysteine levels in patients with knowncoronary artery disease may be a consequence of vasculardisease rather than a cause of future cardiovascular out-comes (so-called “reverse causality”) (22,23). However,epidemiologic trials that measured homocysteine valuesa mean of 10 years before observed events have reportedhazard ratios similar to ours (6,7). Furthermore, al-though acute cardiac events may have a short-term effecton homocysteine levels for 6 months (22,23), this mostlikely did not affect our results, because the mean interval(from prior event to measurement) was 2.5 years. In ad-dition, our study did not reveal any significant differencesin the association between homocysteine level and totalmortality by whether or not patients had known coronaryartery disease.

Most studies exploring homocysteine levels and car-diovascular disease included men only (3,5,14,15). A few

Figure. Kaplan-Meier survival curves by homocysteine quartile, adjusted for age, sex, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, diabetes, smoking, and known coronary artery disease. The number of subjects at riskis presented for each 3-month interval.

Homocysteine Levels and Mortality/Acevedo et al

June 1, 2003 THE AMERICAN JOURNAL OF MEDICINE� Volume 114 687

studies specifically addressed mortality in women. Karket al. (7) reported a positive association between homo-cysteine level and mortality among men and women inIsrael, but when women were analyzed separately, the ad-justed association was no longer statistically significant.Ridker et al. (8) reported that homocysteine level was arisk factor for cardiovascular events in postmenopausalwomen, but did not provide mortality data. In our study,the effects of homocysteine on mortality did not vary bysex.

Using mortality as an outcome may have introduced abias towards identifying factors associated with acute andsevere (i.e., fatal) consequences of atherosclerosis, such asthrombosis.

In conclusion, our findings are consistent with thesmall number of studies that suggest an association be-tween serum homocysteine levels and all-cause mortality,regardless of baseline cardiovascular disease.

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14. Chasan-Taber L, Selhub J, Rosenberg IH, et al. A prospective studyof folate and vitamin B6 and risk of myocardial infarction in USphysicians. J Am Coll Nutr. 1996;15:136 –143.

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16. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study ofcoronary heart disease incidence in relation to fasting total homo-cysteine, related genetic polymorphisms, and B vitamins: the Ath-erosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98:204 –210.

17. Fallon U, Ben-Shlomo Y, Elwood P, et al. Homocysteine and coro-nary heart disease in the Caerphilly cohort: a 10 year follow-up.Heart. 2001;85:153–158.

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From the Department of Cardiology (MA, GLP, SM, DLS), Section ofPreventive Cardiology and Rehabilitation, and the Department of CellBiology (DWJ), The Cleveland Clinic Foundation, Cleveland, Ohio.

Requests for reprints should be addressed to Dennis L. Sprecher, MD,Section of Preventive Cardiology and Rehabilitation, The Cleveland ClinicFoundation, 9500 Euclid Avenue, Desk C 51, Cleveland, Ohio 44195, orsprechd@ccf.org

Manuscript submitted November 13, 2001, and accepted in revised formDecember 16, 2002.

Sharps-Related Injuries inHealth Care Workers: ACase-Crossover StudyDavid N. Fisman, MD, MPH,Anthony D. Harris, MD, MPH, Gary S. Sorock, PhD,Murray A. Mittleman, MD, DrPH

Injuries caused by sharp medical devices are commonamong health care workers in the United States. Thebest available data suggest that between 400,000 and

800,000 such injuries occur in hospitals each year (1–3).

Sharps Injuries in Health Care Workers/Fisman et al

688 June 1, 2003 THE AMERICAN JOURNAL OF MEDICINE� Volume 114