Schwartz, Ronald G.

Wexler, Orren

English

Via Medica Journals

www.cardiologyjournal.org 195EDITORIALCardiology Journal2009, Vol. 16, No. 3, pp. 195–XXXCopyright © 2009 Via MedicaISSN 1897–5593Address for correspondence: Orren Wexler, University of Rochester, School of Medicine and Dentistry,601 Elmwood Avenue, Box 679-N, Rochester, NY 14642, USA, e-mail: orren_wexler@urmc.rochester.edu;ronald_schwartz@urmc.rochester.eduPost-infarction risk is higher with low LDL?Pondering global risk, treatment bias andthe nature of outcome eventsOrren Wexler1, Ronald G. Schwartz21University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA2Cardiology Division, Department of Medicine, University of Rochester Schoolof Medicine and Dentistry, Rochester, NY, USAArticle p. 227In this issue of Cardiology Journal Al-Mallahet al. [1] report the seemingly counter-intuitiveresult that lower LDL levels (£ 105 mg/dL) atpresentation of non-ST elevation myocardial infarc-tion (NSTEMI) predict worse outcomes than higherLDL levels (> 105 mg/dL). In this retrospectivestudy of 517 patients at a tertiary care center,patients with LDL > 105 mg/dL had half the three--year mortality event rate (7.1%) that was observedfor patients with LDL £ 105 mg/dL (14.8%). The two--fold increased risk for patients with lower LDL re-mained significant even after adjustment for race, priormyocardial infarction, hypertension, diabetes, prioraspirin, lipid lowering and beta-blocker therapy,diastolic blood pressure, and admission HDL level.At first glance, one might infer that this studycalls into question our understanding of LDL asa significant risk factor for the development of co-ronary artery disease and morbid cardiovascularevents. If these results are correct, the studywould furthermore appear to raise a question of thevalue of our usual practice of targeting LDLlowering as the cornerstone of primary and secon-dary prevention efforts. However, the evidence forLDL involvement in atheroma formation, its roleas a major risk factor for morbid cardiovascularoutcomes, and its value as a treatment target inknown or suspected cardiovascular disease are veryfirmly established. What then accounts for theunexpected results of the current study?Patient selection in this study appears to haveresulted in a study population at high risk ofsubsequent non-cardiac mortality. Table 5 demon-strates non-cardiac etiologies which account for theexcess subsequent events in the low LDL group.The low LDL group had higher six-month (10 vs.5%) and three-year (15 vs. 7%) all-cause mortalityrates, while no difference was noted in major ad-verse coronary events (24 vs. 21%) at six monthfollow-up. The inclusion of “all cause mortality” inthe definition of major adverse coronary events bythe authors is perplexing and problematic in under-standing the results of this study. Explanations areneeded for non-cardiac related deaths in patientswith low LDL at the presentation of NSTEMI aswell as the composition of endpoints in “majoradverse cardiac events” which included all causemortality. One potential explanation is that the lowLDL group, which had twice the rate of peripheralarterial disease (PAD) (10 vs. 4%; p = 0.02), mayhave been associated with deaths caused by com-plications from PAD, vascular surgery, anesthesia,or sepsis. Another possibility is the low LDL co-hort may have had a greater percentage of patientswith pro-thrombotic and atherogenic conditionssuch as renal failure and malignancy that contribu-ted to the development of NSTEMI and causeda non-cardiac related death. These co-morbid con-ditions were not identified for analysis, and theirattributable risk remains unstudied.The classification of the etiology of deaths byclinical assessment is problematic. Discrepancyexists in 20% of cases between the cause of death196Cardiology Journal 2009, Vol. 16, No. 3www.cardiologyjournal.orgdetermined clinically compared with post-mortemexamination [2]. In the current study many cardiacrelated events may not have been correctlyidentified.  Thus, explanations for excess risk inpatients in the lower LDL group require conside-ration of the possibility that cardiovascular eventsmay not have been correctly identified.The cardiac risk profiles of the low and highLDL groups clearly differ and lead to the conclu-sion that the lower LDL group was at greater expec-ted cardiac event risk. Table 1 shows that low LDLgroup had an 8% excess of previous myocardial in-farction, 11% excess of patients with diabetes, andan 11% excess of hypertension. The reasons whythe low LDL group was loaded with greater coro-nary artery disease risk remain unclear. Perhaps themost striking omission in this study is the lack ofsmoking rate data in the methods and results sectionsin the two LDL groups, and the unsubstantiatedstatement in the Figure legend that smoking wasadjusted for in the survival analysis.The excess risk of the lower LDL group is notapparent from the other lipid data shown in Table 2.For example, despite a 6% lower HDL level in thelow LDL group, mean total cholesterol to HDL(C:H) ratios (3.71 vs. 4.7) appears lower in thelower LDL group. Whether inflammatory biomarkersmight have identified higher risk in this lower LDLgroup with substantially greater PAD prevalenceremains unknown. In support of this possibility isthe demonstration of the incremental value ofhs-CRP levels in assessment of cardiovasculardisease events in patients with normal levels of LDL[3]. Recently, the Jupiter trial demonstratedsubstantial reduction of cardiovascular events withaggressive treatment of patients with elevations ofhs-C-reactive protein despite normal LDL levels[4]. Information about conditions associated withelevation of inflammatory biomarkers such as familyhistory, metabolic syndrome, larger waist to hipratios, and hs-C-reactive protein levels would havefurther enhanced our understanding of the vascularand non-vascular risks of these two LDL groupsunder study.In summary this article reported patients witha lower mean LDL (£ 105 mg/dL) who had higherall-cause mortality rates at 6-months and three-years compared to patients with higher mean LDL(> 105 mg/dL). Clearly, global risk equations canbe employed to compare the cardiovascular risk inmany populations (e.g., www.heartdecision.org). Tothe extent all cause mortality in this vasculopathicpopulation reflects non-vascular events that may ormay not have been correctly identified by etiology,global risk and treatment bias remain considerationsto help us understand the paradoxical results of thecurrent study.References1. Al-Mallah MH, Hatahet H, Cavalcante JL, Sanjaya K. Lowadmission LDL-cholesterol is associated with increased 3-yearall-cause mortality in patients with non ST segment elevationmyocardial infarction. Cardiol J, 2009; 16: 227–233.2. Tai DYH, El-Bilbeisi H, Tewari S, Mascha EJ, Wiedemann HP,Arroliga AC. A study of consecutive Autopsies in the ICU. Chest,2001; 119: 530–536.3. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison ofC-reactive protein and low-density lipoprotein cholesterol lev-els in the prediction of first myocardial events. New Engl J Med,2002; 347: 1557–1565.4. Ridker PM, Danielson E, Fonseca FAH et al. Rosuvastatin toprevent vascular events in men and women with elevatedC-reactive protein. New Engl J Med, 2008; 359: 2195–2207.

Post-infarction risk is higher with low LDL? Pondering global risk, treatment bias and the nature of outcome events

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Post-infarction risk is higher with low LDL? Pondering global risk, treatment bias and the nature of outcome events

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