CLINICAL STUDY: CORONARY ARTERY DISEASE
Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease
Benjamin D. Horne, MPHa,
Joseph B. Muhlestein, MD, FACCa,b,
John F. Carlquist, PhDa,b,
Tami L. Bair, BSa,
Troy E. Madsen, BAa,
Noal I. Hart, BSa and
Jeffrey L. Anderson, MD, FACCb
a Cardiovascular Department, LDS Hospital, Salt Lake City, Utah, USA
b University of Utah, Salt Lake City, Utah, USA
Manuscript received February 14, 2000;
revised manuscript received May 8, 2000,
accepted July 11, 2000.
Reprint requests and correspondence: Dr. J. Brent Muhlestein, Department of Cardiology Research, LDS Hospital, 8th Avenue & C Street, Salt Lake City, Utah 84143
ldbmuhle{at}ihc.com
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Abstract
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OBJECTIVES
The joint predictive value of lipid and C-reactive protein (CRP) levels, as well as a possible interaction between statin therapy and CRP, were evaluated for survival after angiographic diagnosis of coronary artery disease (CAD).
BACKGROUND
Hyperlipidemia increases risk of CAD and myocardial infarction. For first myocardial infarction, the combination of lipid and CRP levels may be prognostically more powerful. Although lipid levels are often measured at angiography to guide therapy, their prognostic value is unclear.
METHODS
Blood samples were collected from a prospective cohort of 985 patients diagnosed angiographically with severe CAD (stenosis  70%) and tested for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and CRP levels. Key risk factors, including initiation of statin therapy, were recorded, and subjects were followed for an average of 3.0 years (range: 1.8 to 4.3 years) to assess survival.
RESULTS
Mortality was confirmed for 109 subjects (11%). In multiple variable Cox regression, levels of TC, LDL, HDL and the TC:HDL ratio did not predict survival, but statin therapy was protective (adjusted hazard ratio [HR] = 0.49, p = 0.04). C-reactive protein levels, age, left ventricular ejection fraction and diabetes were also independently predictive. Statins primarily benefited subjects with elevated CRP by eliminating the increased mortality across increasing CRP tertiles (statins: HR = 0.97 per tertile, p-trend = 0.94; no statins: HR = 1.8 per tertile, p-trend < 0.0001).
CONCLUSIONS
Lipid levels drawn at angiography were not predictive of survival in this population, but initiation of statin therapy was associated with improved survival regardless of the lipid levels. The benefit of statin therapy occurred primarily in patients with elevated CRP.
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Abbreviations and Acronyms
| | CAD | = coronary artery disease | | CI | = 95% confidence interval | | CRP | = C-reactive protein | | HDL | = high-density lipoprotein | | HR | = hazard ratio | | LDL | = low-density lipoprotein | | LVEF | = left ventricular ejection fraction | | MI | = myocardial infarction | | TC | = total cholesterol |
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Atherosclerotic cardiovascular disease accounts for nearly half of the deaths in the American population (1). Coronary artery disease (CAD) is responsible for the majority of these deaths. Major established risk factors for the development of CAD include hyperlipidemia, hypertension, smoking, diabetes and a family history of CAD (2,3). Some consider hyperlipidemia to be the most significant modifiable example of these risk factors (4).
Other factors such as inflammation have recently been linked to the risk of CAD. The inflammatory marker C-reactive protein (CRP) has been strongly associated with CAD, coronary ischemia and myocardial infarction (MI) (5–9). Recently, Ridker et al. (10) reported that, taken together, CRP and lipid levels provided a more useful prognostic marker for the assessment of primary CAD risk. This may suggest a connection between hyperlipidemia and inflammation in the pathogenesis of CAD.
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are a class of medications that primarily block mevalonate synthesis, resulting in positive effects on lipid parameters, especially low-density lipoprotein cholesterol (LDL). Clinical trials demonstrate that statins are safe and effective in treating hyperlipidemia and reducing cardiovascular events (11–15). Statins have also been reported to produce nonlipid-lowering benefits, including antithrombotic and anti-inflammatory effects (16,17). However, potential interactions between statin therapy, hyperlipidemia and inflammation in patients with preexisting CAD are unknown.
The purpose of this study was to prospectively evaluate the combined predictive value of lipid and CRP levels on survival among patients with angiographically-defined severe CAD. A second objective was to determine whether statin therapy affected survival for patients with and without elevated CRP.
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Methods
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Study population.
Between August 15, 1994, and February 28, 1997, 1,707 consecutive patients undergoing coronary arteriography at the LDS Hospital (Salt Lake City, Utah) were enrolled in a cardiovascular registry (the Intermountain Heart Study). Patients were of unrestricted age and gender and gave written informed consent for a blood draw at angiography for use in confidential studies approved by the hospital’s institutional review board. In general, patients were residents of Utah, southwestern Idaho or southeastern Wyoming, a population that is primarily of British and Northern European descent. Of these, 985 were found to have severe CAD as defined by one or more 70% stenosis in 1 coronary artery or a primary branch, and these 985 were included in this study.
Follow-up and determination of subject outcomes.
Subjects were followed-up until death or until December 1998. They (or family members, in the case of subject death or disability) were interviewed by telephone survey. Deaths were verified through a national Social Security death index. Subjects unavailable by telephone but not listed in the death index were considered to be alive, thus allowing for 100% assessment of survival.
Determination of lipid levels.
Lipid panels were evaluated by assay on a Vitros 950 (Johnson & Johnson Clinical Diagnostics, Rochester, New York), which measures total cholesterol (TC), triglyceride and high-density lipoprotein (HDL) levels by enzymatic methods and LDL calculated from these. The TC:HDL ratio was computed by dividing TC by the corresponding HDL level.
Determination of CRP.
Testing for CRP was performed using a fluorescence polarization immunoassay (Abbott Diagnostics, Abbott Park, Illinois). Assay validation showed that 95% of healthy individuals had CRP levels <0.5 mg/dl, and 98% had levels <1.0 mg/dl (Abbott Diagnostics, List No. 9550, January 1996). The between-run coefficient of variation of this assay was 4.3% and 2.2% at mean levels of 1.10 mg/dl and 2.94 mg/dl, respectively. For analysis, CRP levels were divided into three tertiles of equal sample size.
Assessment of statin prescription.
Prescription of statins at the time of hospital discharge was determined from a hospital-wide clinical database (18). The database query asked for the prescription of any of the following agents: simvastatin, pravastatin, atorvastatin, lovastatin or fluvastatin. Statin use before hospitalization was not known, and long-term compliance with therapy was not determined. Statin prescription status was available for 889 study subjects; the other 96 were excluded from the statin analysis.
Other variables examined.
Subject demographics, traditional medical risk factors and clinical variables were evaluated to control for confounding factors. These included age, sex, diabetes mellitus, hypertension, smoking, family history of CAD, presenting diagnosis, clinical interventions, number of diseased coronary vessels, renal failure and left ventricular ejection fraction (LVEF). Diabetes was diagnosed by a history of fasting blood sugar greater than 126 mg/dl or a glycosylated hemoglobin >7.5%. Hypertension was defined as a history of a systolic blood pressure >160 mm Hg or a diastolic blood pressure >90 mm Hg. Family history was considered positive if a first-order relative had suffered cardiovascular death, MI or coronary revascularization before age 65. Tobacco use was considered present for active smokers or those with a history of >10 pack-years. The clinical presentation at hospitalization included stable angina (stable exertional symptoms only), unstable angina (progressive symptoms or symptoms at rest) or MI (creatine kinase-MB >6 mg/dl and creatine kinase-MB index >3%). Clinical treatment at hospitalization was categorized as medical therapy (only), percutaneous coronary interventions (including balloon angioplasty, atherectomy or stenting) and coronary artery bypass surgery (CABG). Renal failure was regarded as present if serum creatinine was 2.0 mg/dl.
Statistical considerations.
Survival analysis evaluated the proportional hazards for mortality by Cox regression. The chi-square approximation to the likelihood ratio test was used to examine whether a univariate association with mortality existed for each known or potential risk factor. Subject age, LVEF (generally by contrast ventriculography or by echocardiogram if unavailable) and levels of TC, HDL, LDL and the TC:HDL were entered as continuous variables. C-reactive protein was evaluated as a categorical variable, comparing the third or second tertile to the first.
Multiple variable Cox regression (SPSS, v9.0) was utilized to determine hazard ratios (HR) corrected for possible confounding. The regression model was built by evaluation for significant or near-significant factors (p < 0.10) and for factors confounding those associations. Hazard ratios and 95% confidence intervals (CI) are presented along with two-tailed p values, designating a p value of 0.05 as nominally significant.
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Results
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Patient characteristics.
Table 1 summarizes the overall baseline subject characteristics by statin prescription. Those given statins were younger and more frequently treated with revascularization. The distribution of statin use among the study cohort was 63% simvastatin, 15% atorvastatin, 13% pravastatin, 5% lovastatin and 4% fluvastatin.
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Table 1 Baseline Characteristics of the Study Population Including Percent of Subjects Receiving Prescription of Statins at Hospital Discharge
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Overall, the prevalence of standard cardiovascular risk factors was similar to other populations with known CAD. Table 2 provides the average levels of TC, LDL, HDL, the TC:HDL ratio and CRP. Despite that statins are typically prescribed based on TC and LDL, these were similarly distributed in the statins (ranges: TC = 83 to 445 mg/dl; LDL = 26 to 322 mg/dl) and nonstatins groups (ranges: TC = 85 to 324 mg/dl; LDL= 23 to 269 mg/dl). The tertiles of CRP were: 1) <1.2 mg/dl, 2) 1.2 to 1.7 mg/dl and 3) >1.7 mg/dl. During the follow-up period (mean: 3.0 years, range: 1.8 to 4.3 years), death was confirmed for 109 subjects (11%).
Prediction of survival.
Univariate Cox analyses revealed no association with survival for levels of TC (p = 0.19), LDL (p = 0.30), HDL (p = 0.051) or TC:HDL ratio (p = 0.99). Statin prescription, however, was associated with greatly improved survival (HR = 0.39; CI = [0.20, 0.78], p = 0.002) (Fig. 1). Survival for statin-treated subjects was 95% after an average follow-up of 1,100 days, compared with 87% for those without statins. Other univariate predictors of survival included age, LVEF, diabetes and CRP levels (Table 3).
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Figure 1 Kaplan-Meier survival curve showing the cumulative survival according to statin prescription. In contrast with the findings of the 4S trial, the curve separation occurred between 30 and 40 days after statin prescription. Solid line = statins; dashed line = no statins.
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Multiple variable Cox regression was used to adjust the univariate associations of statins and CRP for other significant or confounding factors. Patient age and index treatments were significantly different based on statin prescription status (Table 1), suggesting possible confounding. In bivariate Cox regression, however, index treatment did not confound statins; this was also found in multiple variable analysis controlling for treatment, statins and other significant factors. In contrast, analysis showed that age somewhat reduced the association of statins with survival; however, statins did retain a significant independent effect. Additionally, although interventional treatment, smoking and number of diseased vessels were each significant univariate predictors of survival, those preliminary associations were eliminated in multiple variable analysis by patient age and LVEF. Levels of TC, LDL, HDL and the TC:HDL ratio remained nonsignificant in multiple variable analysis. The final regression model included statin prescription (HR = 0.49, CI = [0.24, 0.97], p = 0.04) age, LVEF, CRP and diabetes (Table 4).
Statins and CRP.
The predictive value of CRP depended on the status of statin therapy (Fig. 2). For patients not prescribed statins, increasing CRP levels were associated with a graded and markedly increased risk of mortality (test of trend: HR = 1.8 per tertile, p < 0.0001). In contrast, among the statin group this association was eliminated such that patients had similar survival regardless of CRP level (HR = 0.98 per tertile, p = 0.97). These results were unchanged by multiple variable analysis (no statins: HR = 1.8 per tertile, CI = [1.3, 2.3], p < 0.0001; statins: HR = 0.97 per tertile, p = 0.94).
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Figure 2 Percent mortality for statin prescription stratified by CRP levels. For patients receiving statins the risk due to increasing CRP was eliminated. In contrast, among those not prescribed statins, a significant trend toward higher mortality existed across increasing CRP tertiles. CRP = C-reactive protein.
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These differences in CRP-related survival are also illustrated by comparisons of statin status within individual CRP tertiles although the within-tertile comparisons were not statistically significant. Statins reduced death in the third tertile from 18.5% in the nonstatin group to 4.6% in the statin group (adjusted HR = 0.26, CI = [0.06,1.08], p = 0.06). Statins reduced death in the second tertile from 14.9% to 6.3% (adjusted HR = 0.65, p = 0.42) and in the first tertile from 5.8% to 4.9% (adjusted HR = 1.04, p = 0.96).
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Discussion
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Summary of study findings.
Lipid levels, including levels of TC, LDL, HDL and the TC:HDL ratio, did not predict mortality after angiographic CAD diagnosis in this population. As a result joint analysis of CRP and lipid levels was not prognostically useful for secondary risk assessment although its usefulness has been reported for prediction of first MI (10). The cholesterol-lowering statin agents, however, were found to be associated with reduced mortality. Analysis of statin prescription and levels of the inflammatory marker, CRP, showed that the clinical benefit of statin treatment was contained primarily in those patients with elevated CRP.
Cholesterol levels and cardiovascular risk.
Cholesterol level is a major risk factor for the primary development of clinical CAD (2,3) and perhaps the most important among the traditional risk factors (4). Data regarding lipid levels and the prediction of cardiovascular events after the diagnosis of CAD are sparse, but, given the risk associated with lipid levels and the development of CAD, further investigation of the CAD risk after diagnosis is warranted.
Although lipid levels did not predict mortality in this or other secondary prevention studies (19,20), this does not contradict the wealth of data supporting cholesterol as a risk factor for primary development of CAD. Several possible explanations exist. First, our results may suggest that high cholesterol levels do not increase the risk of death once CAD has developed. Death after the establishment of disease may involve different (acute phase) mechanisms that do not depend heavily on processes influenced by lipid levels. Second, once a patient has developed CAD, the lack of association for lipids may indicate that the lipid levels are too high for that particular patient, regardless of whether the absolute lipid levels are above what might be considered a typical at-risk level. If so, lipid-lowering treatment may be warranted. Finally, statins may work through mechanisms unrelated or only indirectly dependent on lowering of plasma lipid levels (i.e., anti-inflammatory effects, lowering of plaque oxidized-LDL, etc.).
Statins and risk.
In multiple clinical trials of cholesterol reduction and event prevention using statin agents, lowering of LDL levels has been shown to protect against first MI, subsequent MI and cardiovascular-related mortality. Several studies found that, in patients with known CAD, statin use decreased the risk of subsequent mortality and coronary events (11,12). Other randomized studies of statins found that patients with average or "normal" lipid levels also benefit from statin use (13–15). Additional evidence indicates that statins slow the progression of CAD in addition to reducing coronary events (21,22).
In this study, among patients with a wide range of lipid levels and with angiographic evidence for CAD, statin prescription was protective against future mortality. This finding is consistent with the randomized clinical trials. Such a benefit, even among patients with "normal" lipid levels, may indicate that a percentage reduction in lipid levels should be the goal for patients after diagnosis, not an absolute reduction from "abnormal" to "normal" levels (23,24).
In addition, it has been proposed that statins may produce beneficial effects other than through their direct plasma lipid-lowering capability (16,17). These benefits may include inhibition of vascular smooth muscle cell proliferation (25–27), prevention of thromboembolism (28–30), improvement of endothelial function (27,31–33) and alteration of the immune (inflammatory) response (16,34). Reduction in plaque oxidized LDL may also be a mechanism of benefit and may be poorly reflected by circulating lipid levels. These proposals are supported by the positive benefit of statins that was found in our study, and this benefit appears regardless of baseline lipid levels.
Interestingly, and in contrast with the findings of the 4S trial (11), the separation in the survival curve began quickly —between 30 and 40 days after initiation of statin therapy. This finding requires further evaluation.
Statins and crp.
Plasma CRP, a nonspecific marker of inflammation, has received much attention as a predictor of risk. Ridker et al. (5) showed it to predict cardiovascular events in a prospective study of presumably healthy physicians. We have found CRP to be associated with CAD and a history of MI and also with mortality after CAD diagnosis in large, angiographically-defined populations (9,35). Ridker et al. (19) have reported results from a retrospective substudy of the CARE trial that are consistent with the findings of our present study. In the CARE trial, patients with elevated CRP at baseline who were randomized to pravastatin experienced a greater reduction in MI or mortality compared with placebo than did those with nonelevated baseline CRP levels.
Our larger, prospective observational study of patients who were angiographically diagnosed with severe CAD confirms the results of the CARE study. Together, they indicate that statins are more beneficial for patients with elevated CRP than in those whose CRP is normal at baseline. Moreover, the reduction in cardiovascular risk due to statins for patients with high CRP may be the result of an actual lowering of CRP levels (30,36,37).
Study strengths and limitations.
This study was a prospective, but observational, evaluation of mortality. The failure to randomize to statins or to use a single statin agent limited the ability of the study to discern between possible differences in the effects of the various statin agents. In addition, the actual statin doses and the patient compliance with therapy were not known. However, inadequate dosing and noncompliance would bias the outcome in favor of the null hypothesis. The benefits found in this study, which are attributed to statins, could be confounded by, or due in part to, selection biases associated with statin use. However, potential confounders were adjusted for by multiple variable Cox regression, including baseline lipid levels and clinical treatment, and the effect of statins remained independently significant.
The use of statins before hospitalization was also not known. This may have produced a bias toward greater significance for statin therapy by predisposing the statin group to a relatively lesser severity of disease. Because statin prescription has not been based on CRP levels in the past, however, the association of CRP and statins to mortality may not be affected.
Baseline CRP levels might have been influenced by myocardial injury (due to MI). However, the presenting clinical status was controlled in the multiple variable analysis and did not alter the overall association of CRP to mortality. Additionally, CRP has been measured by various methods in the literature. We analyzed CRP by tertiles instead of an actual concentration, and, thus, the results are unlikely to relate to the specific CRP measurement method.
The unrandomized, observational nature of this study may be considered to be a strength. This study utilized a design that better approximates real-world actual use in which drug assignment is not randomized, compliance with therapy is not tracked, and patients are not excluded from therapy due to solely study-based criteria. Each of these points increases the generalizability of this study’s results to the overall CAD patient population. At the same time, though, the results also confirm a similar study completed among a randomized study population.
Conclusions.
This study suggests four possible conclusions: 1) although lipid levels are useful in primary prevention, they are not predictive of death when drawn at the time of angiographic CAD diagnosis; 2) prescription of statins for patients who have a broad range of lipid levels and are newly diagnosed with CAD is associated with a reduction in mortality; 3) CRP is a strong predictor of mortality in patients with CAD, as previously described; and 4) statin therapy is particularly beneficial in patients with angiographically-severe CAD whose CRP level is relatively elevated and, thus, statins may exert an anti-inflammatory effect on atherosclerosis.
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Footnotes
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Supported by the LDS Hospital Deseret Foundation, Salt Lake City, Utah.
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R. A.H. Stewart, H. D. White, A. C. Kirby, S. R. Heritier, R. J. Simes, P. J. Nestel, M. J. West, D. M. Colquhoun, A. M. Tonkin, and for the Long-Term Intervention With Pravastatin in
White Blood Cell Count Predicts Reduction in Coronary Heart Disease Mortality With Pravastatin
Circulation,
April 12, 2005;
111(14):
1756 - 1762.
[Abstract]
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L. M. Biasucci
CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Clinical Use of Inflammatory Markers in Patients With Cardiovascular Diseases: A Background Paper
Circulation,
December 21, 2004;
110(25):
e560 - e567.
[Abstract]
[Full Text]
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D. D. Sin, P. Lacy, E. York, and S. F. P. Man
Effects of Fluticasone on Systemic Markers of Inflammation in Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med.,
October 1, 2004;
170(7):
760 - 765.
[Abstract]
[Full Text]
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J. M. Lappe, J. B. Muhlestein, D. L. Lappe, R. S. Badger, T. L. Bair, R. Brockman, T. K. French, L. C. Hofmann, B. D. Horne, S. Kralick-Goldberg, et al.
Improvements in 1-Year Cardiovascular Clinical Outcomes Associated with a Hospital-Based Discharge Medication Program
Ann Intern Med,
September 21, 2004;
141(6):
446 - 453.
[Abstract]
[Full Text]
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H Teragawa, Y Fukuda, K Matsuda, K Ueda, Y Higashi, T Oshima, M Yoshizumi, and K Chayama
Relation between C reactive protein concentrations and coronary microvascular endothelial function
Heart,
July 1, 2004;
90(7):
750 - 754.
[Abstract]
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P. M Ridker and on behalf of the JUPITER Study Group
Rosuvastatin in the Primary Prevention of Cardiovascular Disease Among Patients With Low Levels of Low-Density Lipoprotein Cholesterol and Elevated High-Sensitivity C-Reactive Protein: Rationale and Design of the JUPITER Trial*
Circulation,
November 11, 2003;
108(19):
2292 - 2297.
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A. W. Chan, D. L. Bhatt, D. P. Chew, J. Reginelli, J. P. Schneider, E. J. Topol, and S. G. Ellis
Relation of Inflammation and Benefit of Statins After Percutaneous Coronary Interventions
Circulation,
April 8, 2003;
107(13):
1750 - 1756.
[Abstract]
[Full Text]
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M. S. Beattie, M. G. Shlipak, H. Liu, W. S. Browner, N. B. Schiller, and M. A. Whooley
C-Reactive Protein and Ischemia in Users and Nonusers of {beta}-Blockers and Statins: Data From the Heart and Soul Study
Circulation,
January 21, 2003;
107(2):
245 - 250.
[Abstract]
[Full Text]
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B. D. Horne, J. B. Muhlestein, J. F. Carlquist, T. L. Bair, T. E. Madsen, N. I. Hart, J. L. Anderson, and for the Intermountain Heart Collaborative (IHC) St
Statin Therapy Interacts With Cytomegalovirus Seropositivity and High C-Reactive Protein in Reducing Mortality Among Patients With Angiographically Significant Coronary Disease
Circulation,
January 21, 2003;
107(2):
258 - 263.
[Abstract]
[Full Text]
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C. A. Allen Maycock, J. B. Muhlestein, B. D. Horne, J. F. Carlquist, T. L. Bair, R. R. Pearson, Q. Li, J. L. Anderson, and Intermountain Heart Collaborative Study
Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients
J. Am. Coll. Cardiol.,
November 20, 2002;
40(10):
1777 - 1785.
[Abstract]
[Full Text]
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M. Christ, J. Bauersachs, C. Liebetrau, M. Heck, A. Gunther, and M. Wehling
Glucose Increases Endothelial-Dependent Superoxide Formation in Coronary Arteries by NAD(P)H Oxidase Activation: Attenuation by the 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Atorvastatin
Diabetes,
August 1, 2002;
51(8):
2648 - 2652.
[Abstract]
[Full Text]
[PDF]
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G. J. Blake, P. M. Ridker, and K. M. Kuntz
Projected life-expectancy gains with statin therapy for individuals with elevated c-reactive protein levels
J. Am. Coll. Cardiol.,
July 3, 2002;
40(1):
49 - 55.
[Abstract]
[Full Text]
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D. L. Bhatt and E. J. Topol
Need to Test the Arterial Inflammation Hypothesis
Circulation,
July 2, 2002;
106(1):
136 - 140.
[Full Text]
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D. C. Chan, G. F. Watts, P. H. R. Barrett, L. J. Beilin, and T. A. Mori
Effect of Atorvastatin and Fish Oil on Plasma High-Sensitivity C-Reactive Protein Concentrations in Individuals with Visceral Obesity
Clin. Chem.,
June 1, 2002;
48(6):
877 - 883.
[Abstract]
[Full Text]
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P. Libby, P. M. Ridker, and A. Maseri
Inflammation and Atherosclerosis
Circulation,
March 5, 2002;
105(9):
1135 - 1143.
[Abstract]
[Full Text]
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A. Maseri and D. Cianflone
Inflammation in acute coronary syndromes
Eur. Heart J. Suppl.,
March 1, 2002;
4(suppl_B):
B8 - B13.
[Abstract]
[PDF]
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J. S. Zebrack, J. B. Muhlestein, B. D. Horne, J. L. Anderson, and Intermountain Heart Collaboration Study Group
C-reactive protein and angiographic coronary artery disease: independent and additive predictors of risk in subjects with angina
J. Am. Coll. Cardiol.,
February 20, 2002;
39(4):
632 - 637.
[Abstract]
[Full Text]
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P.M. Ridker
Should statin therapy be considered for patients with elevated C-reactive protein? The need for a definitive clinical trial
Eur. Heart J.,
December 1, 2001;
22(23):
2135 - 2137.
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H. Schmidt and M. Rauchhaus
Ideal weight, body composition and lipid levels: an unresolved dilemma?
J. Am. Coll. Cardiol.,
June 1, 2001;
37(7):
2010 - 2010.
[Full Text]
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R. P. Tracy
Is Visceral Adiposity the "Enemy Within"?
Arterioscler Thromb Vasc Biol,
June 1, 2001;
21(6):
881 - 883.
[Full Text]
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L. K. Heilbronn, M. Noakes, and P. M. Clifton
Energy Restriction and Weight Loss on Very-Low-Fat Diets Reduce C-Reactive Protein Concentrations in Obese, Healthy Women
Arterioscler Thromb Vasc Biol,
June 1, 2001;
21(6):
968 - 970.
[Abstract]
[Full Text]
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Nonlipid Benefits of Statins?
Journal Watch (General),
December 15, 2000;
2000(1215):
2 - 2.
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A. W. Chan, D. L. Bhatt, D. P. Chew, M. J. Quinn, D. J. Moliterno, E. J. Topol, and S. G. Ellis
Early and Sustained Survival Benefit Associated With Statin Therapy at the Time of Percutaneous Coronary Intervention
Circulation,
February 12, 2002;
105(6):
691 - 696.
[Abstract]
[Full Text]
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Abstract
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