Title: C-Reactive Protein Concentration and Risk of Coronary Heart Disease, Stroke, and Mortality: An Individual Participant Meta-Analysis
Topic: Prevention/Vascular
Date Posted: 12/21/2009 8:00:00 PM
Author(s): The Emerging Risk Factors Collaboration.
Citation: Lancet 2009;Dec 22:[Epub ahead of print].
Clinical Trial: No
Study Question: What is the association of C-reactive protein (CRP) concentration and risk of vascular and nonvascular outcomes, and is the relationship causal?
Methods: A collaborative study using meta-analysis was conducted between investigators of 54 prospective studies of cardiovascular risk factors who provided individual subject data regarding CRP and outcomes. The cohort included 160,309 people without a history of vascular disease (i.e., 1.31 million person-years at risk, 27,769 fatal or nonfatal disease outcomes). Within-study regression analyses were adjusted for within-person variation in risk factor levels. The primary outcome was coronary heart disease (CHD) (i.e. first-ever myocardial infarction or fatal CHD), with subsidiary analyses of stroke by subtype, death from vascular disease, and aggregate of nonvascular death.
Results: Loge CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischemic vascular disease and nonvascular mortality. Significant increases in risk ratios (RRs) were found for CHD per 1-standard deviation higher loge CRP concentration (threefold higher) RR 1.63 when initially adjusted for age and sex only, and RR 1.37 when adjusted further for conventional risk factors; 1.44 and 1.27 for ischemic stroke; 1.71 and 1.55 for vascular mortality; and 1.55 and 1.54 for nonvascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 for CHD; 1.32 for ischemic stroke; 1.34 for vascular mortality; and 1.34 for nonvascular mortality.
Conclusions: CRP concentration has continuous associations with the risk of CHD, ischemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. Associations with ischemic vascular disease depend considerably on conventional risk factors and other markers of inflammation.
Perspective: There is debate about the clinical utility of CRP for risk assessment in cardiovascular disease as well as whether it is a causal relationship or simply a biomarker of risk. This study adds to the abundant literature supporting CRP as a risk marker for cardiovascular events and mortality. And the JUPITER trial provided clinical evidence that it may be useful to risk stratify persons with relatively normal lipid profiles for deciding statin therapy. CRP binds to low-density lipoprotein, and is found in atherosclerotic plaque, suggesting causality. However, this study showing attenuation of attributable risk when corrected for fibrinogen, and recent studies showing no relationship between genetic polymorphisms associated with a higher level of CRP and cardiovascular disease imply that CRP is a risk marker, but not a risk factor for cardiovascular events. And the important saga continues. Melvyn Rubenfire, M.D., F.A.C.C.
Title: Association of Circulating Cholesteryl Ester Transfer Protein Activity With Incidence of Cardiovascular Disease in the Community
Topic: Prevention/Vascular
Date Posted: 12/16/2009
Author(s): Vasan RS, Pencina MJ, Robins SJ, et al.
Citation: Circulation 2009;120:2414-2420.
Clinical Trial: No
Study Question: What is the relationship between plasma cholesteryl ester transfer protein (CETP) activity and the incidence of cardiovascular disease (CVD)?
Methods: Plasma CETP activity was measured in 1978 Framingham Heart Study participants (mean age, 51 years; 54% women) who attended a routine examination from 1987 to 1990 and were free of CVD. On follow-up (mean, 15.1 years), 320 participants experienced a first CVD event (fatal or nonfatal coronary heart disease, cerebrovascular disease, peripheral vascular disease, or heart failure).
Results: In multivariable analyses adjusted for standard risk factors including high-density lipoprotein (HDL) cholesterol, plasma CETP activity was related inversely to the incidence of CVD events (hazard ratio [HR] for activity, at or above the median of 0.72; 95% confidence interval, 0.57-0.90; p = 0.004 [compared with below median]; HR per standard deviation increment, 0.86; 95% confidence interval, 0.76-0.97; p = 0.01). The inverse association of CETP activity with CVD incidence remained robust in time-dependent models updating standard risk factors every 4 years, and was maintained in analyses of incident “hard” CVD events (myocardial infarction, stroke, or heart failure).
Conclusions: In this prospective investigation of a community-based sample, lower plasma CETP activity was associated with greater CVD risk. These observations, if confirmed, challenge the concept that CETP inhibition may lower CVD risk.
Perspective: Although HDL levels are inversely related to the risk of CVD, pharmacologic strategies designed to raise HDL based on CETP inhibition have not produced beneficial vascular effects, and may even be harmful. Whether these adverse effects are due to off-target drug effects or to the mechanism of raising HDL is unclear and will be addressed in future clinical trials with other CETP inhibitors. Studies addressing relationships between genetic CETP abnormalities and circulating CETP concentrations with CVD have been controversial. The current study adds important prospective data to this controversial area and suggests CETP inhibitors will not have beneficial effects on CVD events, and may lead to harm. Daniel T. Eitzman, M.D., F.A.C.C.
Title: Total Cardiovascular Disease Burden: Comparing Intensive With Moderate Statin Therapy: Insights From the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) Trial
Topic: Prevention/Vascular
Date Posted: 12/11/2009 9:00:00 AM
Author(s): Tikkanen MJ, Szarek M, Fayyad R, et al., on behalf of the IDEAL Investigators.
Citation: J Am Coll Cardiol 2009;54:2353-2357.
Clinical Trial: No
Study Question: What is the comparative treatment efficacy of high-dose atorvastatin and usual-dose simvastatin for the prevention of events subsequent to the first event?
Methods: This was a post-hoc analysis of the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial, aimed to assess the comparative treatment efficacy of two statin regimens for the events beyond the first, using the broadest secondary endpoint (any cardiovascular disease [CVD]), consisting of the primary endpoint (coronary heart disease death, nonfatal myocardial infarction, and resuscitated cardiac arrest) plus the following: stroke, revascularization, hospitalization for unstable angina pectoris, hospitalization for congestive heart failure, and peripheral artery disease. The Wei, Lin, and Weissfeld method allows the analysis of repeated occurrence of events of the same type or of entirely different natures; it regards the recurrence times as multivariate event (failure) times, and models the marginal (individual) distribution for each event with the Cox proportional hazards model.
Results: In the IDEAL trial, compared with patients taking simvastatin 20-40 mg daily, patients receiving atorvastatin 80 mg daily had their relative risk of a first cardiovascular event reduced by 17% (p < 0.0001), of a second by 24% (p < 0.0001), of a third by 19% (p = 0.035), of a fourth by 24% (p = 0.058), and of a fifth by 28% (p = 0.117).
Conclusions: The authors concluded that intensive statin therapy continues to be more effective than standard statin therapy, even beyond the first event.
Perspective: This study explored the possibility that new information concerning treatment efficacy of intensive statin therapy compared with standard statin therapy could be gained by analysis of repeated occurrences (after the first event) of different types of CV events. The method allowed analysis of not only time to first CV event, but also time to second, third, fourth, and fifth events. The study results indicate that intensive statin therapy continued to be more effective than standard statin therapy even beyond the first event. This analysis provides new insights into the treatment of patients experiencing repeated occurrences of CVD and suggests that especially for such patients, intensive statin therapy is preferable to standard therapy. Debabrata Mukherjee, M.D., F.A.C.C.