Blaha, Michael J

Blumenthal, Roger S

Budoff, Matthew J

Dardari, Zeina A

Guerci, Alan D

Nasir, Khurram

Pollack, Simcha

Reichek, Nathaniel

eScholarship - University of California

UCLAUCLA Previously Published WorksTitleImpact of C-Reactive Protein and Coronary Artery Calcium on Benefit Observed With AtorvastatinPermalinkhttps://escholarship.org/uc/item/34t033xsJournalJournal of the American College of Cardiology, 71(21)ISSN0735-1097AuthorsBlaha, Michael JNasir, KhurramBudoff, Matthew Jet al.Publication Date2018-05-01DOI10.1016/j.jacc.2018.03.478 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaJ O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 1 , N O . 2 1 , 2 0 1 8I S S N 0 7 3 5 - 1 0 9 7 / $ 3 6 . 0 0LettersImpact of C-ReactiveProtein and CoronaryArtery Calcium onBenefit ObservedWith AtorvastatinControversy persists regarding the optimal strategyfor allocating statins in primary prevention, withcontinued interest in a biomarker-guided approach.An effective biomarker in this setting might signaleither improved relative risk reduction (effect modi-fication) or greater absolute risk reduction (viaimproved risk prediction) with statin therapy.High-sensitivity C-reactive protein (hsCRP), amarker of inflammation, and coronary artery calcium(CAC), a marker of coronary plaque burden, haveemerged as leading candidates. For example, theJUPITER (Justification for the Use of Statins in Pri-mary Prevention: An Intervention Trial EvaluatingRosuvastatin) trial showed that patients withhsCRP $2 clearly benefit from rosuvastatin, althoughsubsequent studies have suggested similar benefitwith hsCRP <2 (1). Prior studies have confirmed statinbenefit in coronary disease, although doubt has beencast because certain patients likely to have high CAC—such as those with end-stage renal disease—do notbenefit from statins (1).We sought to compare the impact of hsCRP andCAC on statin benefit in the only large randomizedcontrolled trial with each biomarker measured atbaseline. The single-center St. Francis Heart Study,with an overall biomarker-driven design similar tothat of the JUPITER trial (1), randomized asymptom-atic patients with elevated CAC (>80th percentile forage and sex) to atorvastatin 20 mg and vitamin CþEversus placebo (1,2). A total of 1,003 patients werefollowed for mean 4.3 years for the primary majoradverse cardiovascular events (MACE) outcome, in-clusive of myocardial infraction, stroke, cardiovas-cular death, coronary revascularization, or peripheralarterial surgery. The study launched in 1996, was firstreported in 2005 (2), with a study population of meanage 59  6 years, with 74% men and median Fra-mingham Risk Score of 11%. Median baseline hsCRP(n ¼ 960) and CAC were 2.07 mg/l and 371 Agatstonunits, respectively, with biomarker values balancedacross treatment groups (p ¼ 0.68 and p ¼ 0.80,respectively). There were 85 MACE events in follow-up, 34 (6.9%) in the treatment group and 51 (9.9%)in the placebo group, consistent with a non–statistically significant benefit in the atorvastatin-containing arm (hazard ratio: 0.67; p ¼ 0.08).Our goal was to compare the benefit of therapyacross a priori defined baseline hsCRP (<1, 1 to2, $2 mg/l) and CAC (1 to 100, 101 to 400, >400)groups. We conducted additional analyses usinghsCRP $2 mg/l and CAC >100 as binary cutpoints.Both the relative risk reduction and the absolute riskreduction per 100 patient-years were computed foreach marker. In addition, an interaction term wastested, calculated as the log-transformed biomarker(continuous)  treatment assignment.The complete results are shown in Figure 1. Thehazard ratios for treatment benefit across hsCRP groupstrended higher with increasing hsCRP, pointing towardless benefit with higher hsCRP, although the interac-tion term was nonsignificant (p ¼ 0.76). The absoluterisk reduction was similar across hsCRP groups,consistent with poor to fair discrimination of risk.In contrast, the hazard ratio for treatment benefitacross CAC groups trended lower with higher CAC,suggesting possible greater benefit with higher CAC,with a borderline but nonstatistically significantinteraction term (p ¼ 0.08). Absolute risk reductionwas markedly larger with higher CAC, consistent withstrong predictive value of CAC.Direct comparison of annualized absolute benefitin patients with hsCRP $2 mg/l versus CAC >400 was0.33 versus 1.54 events reduced per 100 patient-years,translating to an estimated 5-year number needed totreat of 61 versus 13. The 5-year number needed totreat of CAC >100 was 24. Results were unchangedafter excluding 10 (12%) events occurring within90 days of randomization.These results, although limited by statistical po-wer, do not support the previous hypotheses that: 1)hsCRP signals selective benefit from statins; or 2) CACsignals selective failure to benefit from statins. Thesignal that patients with higher CAC may obtain agreater relative benefit from treatment (weakevidence for positive effect modification [p ¼ 0.08])FIGURE 1 Relative and Absolute Treatment Benefit Across hsCRP and CAC GroupsAtorvastatin SuperiorSubgroup EventshsCRP <1hsCRP 1-2hsCRP ≥217 / 24920 / 21942 / 492HR (95% CI)0.58 (0.22 - 1.6)0.50 (0.20 - 1.25)0.86 (0.47 - 1.58)10.89 (0.41 - 1.9)0.58 (0.34 - 1.00)CAC 1-100by CACby hsCRPCAC 100-400CAC >4000 / 10426 / 43455 / 465OverallAtorvastatin Inferior0.1 0.5 1 1.5Biomarker*Statin Treatment Interaction Terms:hsCRP (continuous) p = 0.76CAC (continuous) p = 0.085-year NNT:CAC > 100 = 24CAC > 400 = 13hsCRP ≥2 mg/L = 612Placebo Event RatePer 100 person-years0 1 2 3 4                             (Left) Gray triangles ¼ point estimates, orange lines ¼ 95% confidence intervals (CIs). (Right) Gray circles ¼ placebo event rates, and dotted horizontallines extending to the left ¼ absolute benefit (events reduced per 100 patient-years) with treatment. CAC ¼ coronary artery calcium; HR ¼ hazard ratio;hsCRP ¼ high-sensitivity C-reactive protein; NNT ¼ number needed to treat.Letters J A C C V O L . 7 1 , N O . 2 1 , 2 0 1 8M A Y 2 9 , 2 0 1 8 : 2 4 8 7 – 9 42488is intriguing, yet should be considered purely hy-pothesis generating. Unfortunately, baseline CAC hasnot been measured in any other statin randomizedcontrolled trials, so confirmation would require ade novo clinical trial.Limitations of this analysis include: 1) thehypothesis-generating nature of this secondary anal-ysis; inclusion of revascularization endpoints in theprimary MACE endpoint (although median time fromCAC to randomization was already 63 days, limitingimpact of CAC knowledge on outcomes); 2) theinsufficient power for hard event-only analysis andfor drawing strong conclusions of effect modification;and 3) the complicated intervention of the St. FrancisHeart Study, which included a protocol for statin de-escalation, concomitant use of vitamin antioxidants,and aspirin therapy for all patients.In the absence of any available strong evidencefor effect modification, statins are perhaps bestallocated by baseline risk (and therefore expectedabsolute benefit), consistent with 2013 AmericanCollege of Cardiology/American Heart Associationguidelines. In this regard, evidence from multipleprior studies, as well as the present study, point topotential superiority of using CAC for allocatingstatins (1,2).*Michael J. Blaha, MD, MPHKhurram Nasir, MD, MPHMatthew J. Budoff, MDZeina A. Dardari, MPHRoger S. Blumenthal, MDSimcha Pollack, PhDNathaniel Reichek, MDAlan D. Guerci, MD*Johns Hopkins Ciccarone Center for thePrevention of Heart DiseaseBlalock 524D1, JHH600 North Wolfe StreetBaltimore, Maryland 21287E-mail: mblaha1@jhmi.eduhttps://doi.org/10.1016/j.jacc.2018.03.478 2018 by the American College of Cardiology Foundation. Published by Elsevier.Please note: Dr. Budoff has received grant support from General Electric and theNational Institutes of Health. All other authors have reported that they have norelationships relevant to the contents of this paper to disclose.R EF E RENCE S1. KimJ,McEvoy JW,Nasir K, et al. Critical reviewofhigh-sensitivity CRP andCACfor guidance of statin allocation: head-to-head comparison of the JUPITER andSt. Francis Heart Trials. Circ Cardiovasc Qual Outcomes 2014;7:315–22.2. Arad Y, Spadaro LA, Roth M, Newstein D, Guerci AD. Treatment ofasymptomatic adults with elevated CAC scores with atorvastatin, vitamin C,and vitamin E: the St. Francis Heart Study randomized clinical trial. J Am CollCardiol 2005;46:166–72.

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Impact of C-Reactive Protein and Coronary Artery Calcium on Benefit Observed With&nbsp;Atorvastatin

Impact of C-Reactive Protein and Coronary Artery Calcium on Benefit Observed With Atorvastatin.

Impact of C-Reactive Protein and Coronary Artery Calcium on Benefit Observed With Atorvastatin.

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