Statin Therapy, LDL Cholesterol, C-Reactive Protein, and Coronary Artery Disease
Steven E. Nissen, M.D., E. Murat Tuzcu, M.D., Paul Schoenhagen, M.D., Tim Crowe, B.S., William J. Sasiela, Ph.D., John Tsai, M.D., John Orazem, Ph.D., Raymond D. Magorien, M.D., Charles O'Shaughnessy, M.D., Peter Ganz, M.D., for the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators
Background Recent trials have demonstrated better outcomes withintensive than with moderate statin treatment. Intensive treatmentproduced greater reductions in both low-density lipoprotein(LDL) cholesterol and C-reactive protein (CRP), suggesting arelationship between these two biomarkers and disease progression.
Methods We performed intravascular ultrasonography in 502 patientswith angiographically documented coronary disease. Patientswere randomly assigned to receive moderate treatment (40 mgof pravastatin orally per day) or intensive treatment (80 mgof atorvastatin orally per day). Ultrasonography was repeatedafter 18 months to measure the progression of atherosclerosis.Lipoprotein and CRP levels were measured at baseline and follow-up.
Results In the group as a whole, the mean LDL cholesterol levelwas reduced from 150.2 mg per deciliter (3.88 mmol per liter)at baseline to 94.5 mg per deciliter (2.44 mmol per liter) at18 months (P<0.001), and the geometric mean CRP level decreasedfrom 2.9 to 2.3 mg per liter (P<0.001). The correlation betweenthe reduction in LDL cholesterol levels and that in CRP levelswas weak but significant in the group as a whole (r=0.13, P=0.005),but not in either treatment group alone. In univariate analyses,the percent change in the levels of LDL cholesterol, CRP, apolipoproteinB-100, and non–high-density lipoprotein cholesterol wererelated to the rate of progression of atherosclerosis. Afteradjustment for the reduction in these lipid levels, the decreasein CRP levels was independently and significantly correlatedwith the rate of progression. Patients with reductions in bothLDL cholesterol and CRP that were greater than the median hadsignificantly slower rates of progression than patients withreductions in both biomarkers that were less than the median(P=0.001).
Conclusions For patients with coronary artery disease, the reducedrate of progression of atherosclerosis associated with intensivestatin treatment, as compared with moderate statin treatment,is significantly related to greater reductions in the levelsof both atherogenic lipoproteins and CRP.
Two recent trials demonstrated that intensive lipid-loweringtherapy with statins improved clinical outcomes1 and reducedthe progression of atherosclerosis.2 Many authorities attributedthe greater benefits of intensive statin therapy, as comparedwith moderate statin therapy, to greater reductions in the levelsof atherogenic lipoproteins, particularly low-density lipoprotein(LDL) cholesterol.3 However, statins have a wide range of biologiceffects in addition to lipid lowering, including reductionsin the levels of C-reactive protein (CRP), a phenomenon commonlytermed a "pleiotropic effect."4,5,6 In both recent comparisons,at the conclusion of the trials, CRP levels were 30 to 40 percentlower after intensive statin therapy than after moderate treatment.4This finding raises a provocative scientific question: Do reductionsin CRP represent an independent factor influencing the benefitsof more intensive statin therapy?
Large observational studies have established a strong relationshipbetween CRP levels and the morbidity and mortality associatedwith coronary disease.7,8,9 However, the precise mechanism underlyingthe association between CRP levels and adverse outcomes remainsincompletely described. Theoretically, by decreasing the levelsof atherogenic lipoproteins, statins could decrease systemicinflammation, thereby reducing CRP levels. An alternative hypothesisproposes that statins have direct antiinflammatory effects,independent of their lipid-lowering capabilities. In this model,CRP plays a more direct role in the pathogenesis of atherosclerosis,and a statin-mediated reduction in inflammation contributesdirectly to reduced disease activity. Because statins decreasethe levels of both LDL cholesterol and CRP, it is difficultto determine whether CRP is an indirect biomarker reflectingthe benefits of statins or a direct participant in atherogenesis.
Intravascular ultrasonography is a useful technique for assessingthe effect of therapies on the vascular wall, providing a preciseand continuous measure of the progression of atherosclerosis.In the Reversal of Atherosclerosis with Aggressive Lipid Lowering(REVERSAL) trial, intensive therapy with 80 mg of atorvastatinper day slowed the progression of atherosclerosis more thandid moderate treatment with 40 mg of pravastatin per day.2 Weapplied statistical methods to examine the relationship betweenthe reductions in LDL cholesterol and CRP levels and the rateof disease progression measured by intravascular ultrasonography.
Methods
Study Design
The institutional review board of each participating centerapproved the protocol, and all patients provided written informedconsent. Intravascular ultrasonography was performed in a singlevessel in patients who had a clinical indication for coronaryangiography and had stenosis of at least 20 percent on angiography.Eligible patients had to have an LDL cholesterol level of 125to 210 mg per deciliter (3.23 to 5.43 mmol per liter) aftera statin-free washout period of 4 to 10 weeks. Patients wererandomly assigned to receive either 40 mg of pravastatin or80 mg of atorvastatin orally daily. The patients and all studypersonnel were unaware of the treatment assignments or the resultsof laboratory measurements.
Intravascular Ultrasonography
Investigators performed intravascular ultrasonography in thelongest and least angulated target vessel that met the inclusioncriteria. After the administration of intracoronary nitroglycerin,the transducer was positioned in the distal vessel and withdrawnat a rate of 0.5 mm per second (the "pullback") with the useof a motor drive. A core laboratory evaluated the image qualityof each ultrasonogram, and only patients whose ultrasonogramsmet prespecified image-quality requirements were eligible forrandomization. After an 18-month treatment period, patientsagain underwent intravascular ultrasonography under identicalconditions. This method of intravascular ultrasonography hasbeen described previously in detail.2,10,11
Core Laboratory Measurements
Personnel who were unaware of the patients' clinical characteristicsand treatment assignments used manual planimetry to measure,on a computer screen, a series of cross-sections of ultrasonographicimages selected exactly 1.0 mm apart along the long axis ofthe vessel. Measurements were performed in accordance with thestandards of the American College of Cardiology and the EuropeanSociety of Cardiology.12 For each cross-section analyzed, theoperator measured the area of the external elastic membraneand the lumen. The accuracy and reproducibility of this methodhave been reported previously.2,13
Calculation of End Points
The average area of atheroma per cross-section was calculatedas follows:
(EEMCSA–LUMENCSA) ÷ n,
where EEMCSA is the cross-sectional area of the external elasticmembrane, LUMENCSA is the cross-sectional area of the lumen,and n is the number of cross-sections in the pullback. To compensatefor pullbacks of differing lengths, the total atheroma volumefor each patient was calculated as the average area of atheromamultiplied by the median number of cross-sections in the pullbacksfor all patients in the study. The efficacy variable "changein normalized total atheroma volume" (TAV) was calculated asTAV18 months–TAVbaseline. The percent atheroma volume(PAV) was calculated with the use of the following formula:
(EEMCSA–LUMENCSA) ÷ EEMCSA x 100.
The efficacy variable "change in PAV" was calculated as PAV18months–PAVbaseline.
Laboratory Tests
A central laboratory performed all biochemical determinations(Medical Research Laboratory, Highland Heights, Ky.).
Statistical Analysis
For continuous variables with a normal distribution, means ±SDare reported. For CRP levels, the geometric means and interquartileranges are reported. Because the ultrasonographic end pointswere not normally distributed, we applied an analysis-of-covariancemodel to rank-transformed data to determine P values. Correlationsbetween variables are described with the use of Spearman rank-correlationcoefficients, and multivariate regression analyses based onrank-transformed data were used to obtain partial correlationcoefficients adjusted for the effects of covariates.14 The ultrasonographicvariable served as the dependent variable; the independent variablesconsisted of the change in CRP coupled with the change in non–high-densitylipoprotein (non-HDL) cholesterol, LDL cholesterol, or apolipoproteinB-100 (apo B-100). For a further description of bivariate relationshipswith ultrasonographic end points, we used the locally weightedscatterplot smoothing (LOWESS) technique.15 This technique isdesigned to produce a smooth fit to the data and reduces theinfluence of extreme outliers. Analyses were performed withthe use of SAS software, version 6.12.
Results
Patient Population
Between June 1999 and September 2001, 502 patients were enrolledat 34 U.S. centers and underwent intravascular ultrasonographyat both baseline and 18 months of follow-up that could be evaluated(249 in the pravastatin group and 253 in the atorvastatin group).The average age was 56 years, 72 percent were men, 89 percentwere white (race was recorded by the study coordinators on thecase-report form), 26 percent were current smokers, 69 percenthad a history of hypertension, and 19 percent had a historyof diabetes.2
Laboratory Findings and Results of Intravascular Ultrasonography
Table 1 summarizes laboratory values at baseline and at thecompletion of the study (18 months) for the entire populationand each treatment group. For all 502 patients, the mean baselineLDL cholesterol level was 150.2 mg per deciliter (3.88 mmolper liter), the non-HDL cholesterol level was 189.6 mg per deciliter(4.90 mmol per liter), and the geometric mean CRP level was2.9 mg per liter. After 18 months of treatment, the mean LDLcholesterol level was 94.5 mg per deciliter (2.44 mmol per liter),the non-HDL cholesterol level was 125.4 mg per deciliter (3.24mmol per liter), and the geometric mean CRP level was 2.3 mgper liter. There were greater reductions in LDL cholesterol,non-HDL cholesterol, and CRP levels in the atorvastatin groupthan in the pravastatin group (P<0.001 for each comparison).2
Table 1. Laboratory Values at Baseline and Follow-up and Change in Values from Baseline.
Table 2 summarizes measures of disease burden as determinedby intravascular ultrasonography at baseline and the completionof the study for the entire population and the two treatmentgroups. Both measures of the progression of atherosclerosis— total atheroma volume and percent atheroma volume —reflected a slower rate of progression in the group that receivedintensive treatment with atorvastatin than in the group thatreceived moderate treatment with pravastatin.
Table 2. Baseline and Follow-up Values for Intravascular Ultrasonographic End Points and Change in Values from Baseline.
Correlation between Reductions in Lipoprotein and CRP
There was a weak but significant correlation between the percentreductions in LDL cholesterol and in CRP levels only for thestudy group as a whole (r=0.13, P=0.005) — not for thepravastatin group alone (r=–0.008, P=0.90) or the atorvastatingroup alone (r=0.09, P=0.17). Changes in other atherogenic lipoproteins,such as apo B-100 and non-HDL cholesterol, had similarly weakcorrelations with the reduction in CRP levels in the regressionanalysis.
Effect of Changes in CRP and Lipids on Progression
Table 3 summarizes the correlations between the changes in thelevels of atherogenic lipoproteins, CRP, and HDL cholesteroland the rate of progression of atherosclerosis for both endpoints assessed by means of intravascular ultrasonography. Univariateanalysis revealed significant correlations between ultrasonographicmeasures of disease progression and laboratory measures of atherogeniclipoproteins, including LDL cholesterol, apo B-100, and non-HDLcholesterol. The percent change in the LDL cholesterol levelhad the closest correlation with progression, with a correlationcoefficient of 0.12 for total atheroma volume (P=0.005) andof 0.14 for percent atheroma volume (P=0.002).
Table 3. Relationships between Changes in Laboratory Measures and Intravascular Ultrasonographic End Points.
The correlations between the reduction in CRP levels and therates of progression on intravascular ultrasonography were alsosignificant and similar in strength to the relationships observedfor the atherogenic lipoproteins. Univariate analysis yieldeda correlation coefficient of 0.11 for both total and percentatheroma volume (P=0.02 and P=0.01, respectively). Most correlationsbetween the rates of progression on ultrasonography and thepercent change in non-HDL cholesterol, LDL cholesterol, andCRP levels remained significant on multivariate analysis butwere weaker than those obtained by univariate analyses (Table 3).
As shown in Figure 1, greater reductions in LDL cholesterollevels were associated with slower rates of progression on intravascularultrasonography. Figure 2 shows this same relationship for thereduction in CRP levels. Patients with the largest reductionsin CRP levels had regression of atheroma, as evidenced by progressionrates of less than zero.
Figure 1. Locally Weighted Smoothed Scatterplots Showing the Relationship between the Change in LDL Cholesterol Levels and the Rate of Progression of Atherosclerosis in the Entire Group of 502 Patients.
In each plot, the solid line represents the point estimates and the upper and lower lines the 95 percent confidence intervals. To convert values for LDL cholesterol to millimoles per liter, multiply by 0.02586.
Figure 2. Locally Weighted Smoothed Scatterplots Showing the Relationship between the Changes in CRP Levels and the Rate of Progression of Atherosclerosis in the Entire Group of 502 Patients.
In each plot, the solid line represents the point estimates and the upper and lower lines the 95 percent confidence intervals.
Table 4 shows the rates of progression of atherosclerosis onultrasonography for subgroups defined according to whether thereductions in LDL cholesterol or CRP levels were greater thanor less than the median decreases. For both efficacy measures,the highest rates of progression were in the subgroup in whichdecreases in both LDL cholesterol and CRP levels were less thanthe median. Significantly lower progression rates were observedin the subgroup with decreases in both LDL cholesterol and CRPlevels that were greater than the median (P=0.001 for both efficacymeasures).
Table 4. Rates of Progression According to the Change in LDL Cholesterol and CRP Levels.
Discussion
Epidemiologic evidence has established a strong relationshipbetween elevated levels of atherogenic lipoproteins, particularlyLDL cholesterol, and the risk of death and complications fromcardiovascular causes. Placebo-controlled trials of statinshave demonstrated that pharmacologic therapies that reduce LDLcholesterol levels also proportionally decrease cardiovascularrisk.16,17,18,19 Accordingly, the clinical benefits of statintherapy have largely been attributed to reductions in the levelsof atherogenic lipoproteins. However, observational studieshave also established a strong relationship between the levelsof CRP, the most stable and reliable laboratory measure of systemicinflammation, and adverse cardiovascular outcomes. Statins havea variety of pleiotropic properties, including their abilityto induce dose-dependent decreases in the levels of CRP andother inflammatory biomarkers.5,6 Since statins reduce the levelsof both LDL cholesterol and CRP, it is difficult to determinethe relative contribution of the reduction in each of thesebiomarkers to the observed clinical benefits.
We sought to close this gap in knowledge by analyzing the correlationamong lipid levels, CRP levels, and the rate of progressionof atherosclerosis, using intravascular ultrasonography to measuredisease progression in patients who were being treated withstatins.2 Intravascular ultrasonography is a useful techniquefor assessing the effect of therapies on the vascular wall,providing a precise and continuous measure of disease progression.20In the REVERSAL trial, intensive therapy with 80 mg of atorvastatinper day slowed the rate of progression of atherosclerosis morethan did moderate treatment with 40 mg of pravastatin per day.Because we studied two different intensities of statin therapy,we evaluated a broad range of reductions in LDL cholesteroland CRP, permitting a post hoc analysis of the relationshipbetween these two biomarkers and the rate of progression ofatherosclerosis across a clinically important range of values.
Correlation analysis revealed that reductions in the levelsof atherogenic lipoproteins were not closely correlated withreductions in CRP levels. There was a weak but significant correlationbetween the reduction in LDL cholesterol levels and the reductionin CRP levels for the overall group of 502 patients (r=0.13,P=0.005), but not in either treatment group alone. These datademonstrate that statin-mediated reductions in CRP are largelyunrelated to the decrease in LDL cholesterol levels. These findingsconfirm the work of other investigators and strongly suggestthat the statin-mediated reduction in CRP is unlikely to bea secondary consequence of a reduction in LDL cholesterol but,rather, is potentially mediated by independent pathways.21
Analysis of the relationship among lipoprotein levels, CRP levels,and the rate of progression of atherosclerosis yielded particularlyinformative results. Reductions in both LDL cholesterol andCRP levels were significantly correlated to the rate of progression.In univariate analyses, both ultrasonographic measures of progression— the change in the normalized total atheroma volume andthe change in percent atheroma volume — correlated significantlywith the reduction in the levels of atherogenic lipoproteins,including LDL cholesterol, non-HDL cholesterol, and apo B-100.The closest correlation was between the LDL cholesterol leveland the percent atheroma volume (r=0.14, P=0.002). However,similar correlations were observed for the relationship betweenthe reduction in CRP levels and the rate of progression on intravascularultrasonography (r=0.11, P=0.01). Substituting non-HDL cholesterolfor LDL cholesterol, to account for the broad range of atherogeniclipoproteins, did not increase the correlation. Since the levelsof both CRP and LDL cholesterol showed relatively weak correlationswith the ultrasonographic end points (r values of 0.11 to 0.14),this analysis demonstrates that biomarkers can account for onlya small fraction of the observed progression rate.
To determine whether the reduction in CRP levels representedan independent factor influencing the progression of atherosclerosis,we adjusted the CRP correlations for the effects of atherogeniclipoproteins. In this multivariate analysis, CRP remained significantin most analyses, regardless of which measure of atherogeniclipoproteins was used — LDL cholesterol, apo B-100, ornon-HDL cholesterol. Patients with reductions in the levelsof both LDL cholesterol and CRP that were greater than the medianreduction had significantly lower progression rates than patientsin whom the reductions were less than the median decrease (P=0.001).These data provide evidence that the reduction in CRP levelsplays an independent role in the beneficial effects of statinson the progression of coronary atherosclerosis.
Since measures of progression reflected by intravascular ultrasonographyare not normally distributed, we used LOWESS methods to illustratethe relationships between the reductions in LDL cholesteroland CRP levels and the rates of progression determined by ultrasonography(Figure 1 and Figure 2). These plots demonstrated a continuousrelationship between the magnitude of reduction in either LDLcholesterol or CRP levels and the rates of progression of atherosclerosisfor both measures of efficacy. Atherosclerosis regressed inpatients with the greatest reduction in CRP levels, but notin those with the greatest reduction in LDL cholesterol levels.Although the data are not provided in this article, LOWESS plotsshowed slower rates of progression in the intensively treatedatorvastatin subgroup across a broad range of reductions inlipids and CRP. The slower rate of progression in the atorvastatingroup for any magnitude of reduction in LDL cholesterol levelscan be partially explained by the additional effects of treatmenton the reduction in CRP levels, just as the differences in theCRP plots can be partially explained by the additional reductionin LDL cholesterol levels effected by atorvastatin therapy.Thus, the effects of the reductions in both LDL cholesteroland CRP levels must be considered to explain the observed differencesin progression between atorvastatin and pravastatin treatment.
Our findings have important implications for understanding thepathogenesis of the progression of atherosclerosis and the mechanismof benefit of statin therapy. The Pravastatin or Atorvastatinand Infection Therapy (PROVE IT) trial demonstrated improvedoutcomes1 and the REVERSAL trial demonstrated reduced ratesof progression of atherosclerosis2 after intensive, as comparedwith moderate, statin therapy. Although a single trial had previouslyshown that the effects of statins are evident within 16 weeks,22the rapidity of the divergence in results between the treatmentgroups in both trials was unexpected.4 In most earlier placebo-controlledtrials, differences between statins and placebo were not evidentfor the first two years after randomization.16,17,18 However,in both the REVERSAL and PROVE IT trials, CRP levels were 30to 40 percent lower at the conclusion of the trial in the intensivelytreated patients than in the group that received moderate treatment,which may explain the magnitude and unexpectedly rapid divergenceof outcomes reported by Ridker et al. elsewhere in this issueof the Journal.23
Our findings are consistent with a variety of experimental observationsthat suggest a direct role for CRP in the pathogenesis of atherosclerosis.CRP renders oxidized LDL more susceptible to uptake by macrophages,induces the expression of vascular-cell adhesion molecules,stimulates the production of tissue factor, and impairs theproduction of nitric oxide.24,25,26,27 Children with elevatedCRP levels have increased carotid intimal medial thickness andreduced vasodilatation mediated by brachial-artery flow.28 Arecent study suggested that the presence of above-average levelsof CRP attenuates the benefits of intensive statin therapy withrespect to the carotid intimal media thickness.29
Evidence of a dual mechanism of benefit for statins —lipid lowering and a reduction in inflammation — has importantimplications for current and future treatment of atherosclerosis.Current guidelines emphasize the use of lipid-lowering therapiesto reach target levels of LDL cholesterol, non-HDL cholesterol,or both. However, individual agents differ in their abilityto reduce the levels of inflammatory biomarkers. Accordingly,our study raises the provocative question of whether the effectsof statins on CRP, as well as LDL cholesterol, should be consideredin decisions regarding therapy.
Our study has important limitations. It is a hypothesis-generatingpost hoc analysis examining the effect of a single inflammatorymarker on disease progression, not morbidity or mortality. Nonetheless,our findings suggest that the level of CRP may ultimately representan important therapeutic target. We do not believe that thesedata are sufficient to recommend routine serial measurementof CRP in order to modulate statin therapy, but further studyis warranted. An ongoing clinical trial is assessing the useof CRP levels to guide therapy in patients who do not have elevatedLDL cholesterol levels.30 Since approaches to the reductionof LDL cholesterol levels that do not involve statins have uncertainantiinflammatory effects, the ability of such therapies to improvethe outcome requires testing in clinical trials.31
Funded by Pfizer.
Dr. Nissen reports having served as a consultant to AstraZeneca,Atherogenics, Lipid Sciences, Wyeth, Novartis, Pfizer, Sankyo,Takeda, Kowa, Sanofi, Novo-Nordisk, Eli Lilly, Kos Pharmaceuticals,GlaxoSmithKline, Forbes Medi-tech, and Merck–ScheringPlough; having served as a lecturer for AstraZeneca and Pfizer;and having received funding from AstraZeneca, Takeda, Sankyo,Pfizer, Atherogenics, and Lipid Sciences for ongoing clinicaltrials. Dr. Tuzcu reports having received lecture fees fromAstraZeneca, Merck, Pfizer, and Takeda and grant support fromPfizer. Mr. Crowe reports owning Pfizer stock. Drs. Sasiela,Tsai, and Orazem are employees of Pfizer. Dr. Magorien reportshaving served as a consultant to Bristol-Myers Squibb and owningstock in Merck. Dr. Ganz reports having served as a consultantfor AstraZeneca and Pfizer and a lecturer for Pfizer.
* The REVERSAL Investigators are listed in the Appendix.
Source Information
From the Cleveland Clinic Foundation, Cleveland (S.E.N., E.M.T., P.S., T.C.); Pfizer, New York (W.J.S., J.T., J.O.); Ohio State University Medical Center, Columbus (R.D.M.); North Ohio Heart Care, Elyria (C.O.); and Brigham and Women's Hospital, Boston (P.G.).
Address reprint requests to Dr. Nissen at the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, or at nissens{at}ccf.org.
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Appendix
In addition to the authors, the following investigators participatedin this study: Wake Forest University, Winston-Salem, N.C.,M. Kutcher; University of Colorado Health Sciences Center, Denver,J. Burchenal; University of Texas–San Antonio, San Antonio,S. Bailey; Heart Institute at Borgess, Kalamazoo, Mich., T.Fischell; University of Florida, Gainesville, R. Kerensky; HeartCare Center, Blue Island, Ill., R. Iaffaldano; University ofChicago, Chicago, J. Lopez; William Beaumont Hospital, RoyalOak, Mich., C. Grines; University of California, San Diego,San Diego, A. DeMaria; UCLA Medical Center for Health Sciences,Los Angeles, J. Tobis; LeBauer Cardiovascular Research Foundation,Greensboro, N.C., B. Brodie; University of Washington MedicalCenter, Seattle, D. Linker; Cedars-Sinai Medical Center, LosAngeles, J. Forrester; University of North Carolina, ChapelHill, S. Smith; Androscoggin Cardiology Research, Auburn, Me.,R. Weiss; Medical College of Ohio, Toledo, C. Cooper; RhodeIsland Hospital, Providence, B. Sharaf; East Carolina University,Greenville, N.C., M. Miller; Buffalo Cardiology and PulmonaryAssociates, Buffalo, N.Y., J. Corbelli; Heart Care Group, Allentown,Pa., J. Kleaveland; University of Arkansas for Medical Sciences,Little Rock, L. Garza; University of Louisville, Louisville,Ky., M. Leesar; Capital Cardiology Associates, Albany, N.Y.,A. DeLago; Cardiology of Georgia–Piedmont Hospital, Atlanta,C. Wickliffe; New England Medical Center, Boston, J. Kuvin;Kramer & Crouse Cardiology, Kansas City, Mo., P. Kramer;Miriam Hospital, Providence, R.I., P. Gordon; Mount Sinai Hospital,New York, S. Sharma; Oklahoma Heart Institute, Tulsa, W. Leimbach;Eastlake Cardiovascular Associates, St. Clair Shores, Mich.,R. Cleary, Jr.; University Hospitals of Cleveland, R. Nair.
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