Fluvastatin : Clinical and Safety Profiledr. Sutikno TanuwidjojoBagian Kardiologi dan Kedokteran VaskularFK. UNDIP / RSUP Dr. Kariadi

Global Disease Mortality 2002Mortality (millions)World Health Organization. The World Health Report 2003: Shaping the Future. 2003.Cardiovascular diseaseMalignant neoplasmsInjuriesRespiratory infectionsCOPD and asthmaHIV/AIDSPerinatal conditionsDigestive diseasesDiarrhoeal diseasesTuberculosisChildhood diseasesMalariaDiabetes

Death from Cardiovascular Causes, Worldwide, in 1990 and Estimated for 2020

Atherothrombosis* Is theLeading Cause of Death Worldwide1*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.1The World Health Report 2001. Geneva. WHO. 2001.22.319.312.69.796.3051015202530Atherothrombosis*Infectious DiseaseCancerInjuriesPulmonary DiseaseAIDSCauses of Mortality (%)

ACS: Tip of the Atherothrombotic IcebergACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. Adapted from Goldstein JA. J Am Coll Cardiol. 2002;39:1464-1467.ClinicalSubclinicalAcute Plaque Rupture ACS (UA/NSTEMI/STEMI)32 million heart attacks and strokes per year

The relations of lifestyle, established and novel risk factors, and cardiovascular disease(Mozaffarian et all, 2008)

Gotto AM Jr et al. Circulation. 1990;81:1721-1733. Castelli WP. Am J Med. 1984;76:4-12.Framingham Study (n=5209)Multiple Risk Factor Intervention Trial (MRFIT) (n=361,662)Each 1% increase in total cholesterol level was associated with a 2% increase in CHD risk Each 1% reduction in total cholesterol level resulted in a 2% decrease in CHD riskSerum cholesterol (mg/dL)Individuals with elevated LDL-C are at increased risk of CHD

The commonest instruments of suicide are a knife and forkMartin Fischer

Relative Risk for CHD (Log Scale)Fig. Log-linear relationship between LDL-C levels and relative risk for CHD.This relationship is consistent with a large body of epidemiological data anddata available from clinical trials of LDL- lowering therapy. These data suggest that for every 30 mg/dl change in LDL-C, the relative risk for CHD is changedin proportion by about 30%. The relative risk is set at 1.0 for LDL-C = 40 mg/dlRELATIONSHIP BETWEEN LDL-C AND RELATIVE RISK FOR CHD THE LOWER THE BETTER40701001301601903.72.92.21.71.31.0??Grundy et al. NCEP Report. Circulation 2004; 110: 227-239

According to NCEP ATP III Guidelines, Most Adults Have Elevated Levels of LDL-CNearly 74% of US adults have LDL-C levels 2.6 mmol/L 100 mg/dLBorderline high 3.3-4.1 mmol/L (130-159 mg/dL)High 4.1-4.9 mmol/L (160-189 mg/dL)Very high 4.9 mmol/L (190 mg/dL)Near or above optimal 2.6-3.3 mmol/L (100-129 mg/dL)Optimal

LDL-C (mg/dL)HDL-C (mg/dL)Risk of CHD.Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. American Journal of Medicine. 1977;62:707-14.

Cholesterol and atherosclerosisLDL-C is strongly associated with an increased risk of atherosclerosis and CVD eventsHDL-C has a protective effect for the risk of atherosclerosis and CHD.1% decrease in LDL-C reduces CHD risk by 1%1 1% change in HDL-C associated with 1-3% reduction in CHD risk2-51.Grundy SM et al. Circulation. 2004; 110: 22739. 2.Gordon DJ, Probstfield JL, Garrison JD et al. Circulation 1989; 79: 8-15. 3.Boden W. American Journal of Cardiology 2000; 86 (suppl): 19L-22L. 4.Manninen V, Elo O, Frick MH et al. JAMA 1988; 260:641-651. 5.Rubins HB, Robins S, Collins D et al. N Engl J Med 1999; 341:410-418

MenWomenn=5,127Triglyceride Level, mg/dL50100150200250300350400Relative Risk00.511.522.53Castelli WP. Epidemiology of triglycerides: a view from Framingham American Journal of Cardiology. 1992;70:3H-9H.

Serum Triglycerides as a Risk Factor for Cardiovascular Diseases in the Asia-Pacific Region

Asia Pacific Cohort Studies Collaboration*Methods and ResultsWe performed an individual participant data meta-analysis of prospective studies conducted in the Asia-Pacific region. Cox models were applied to the combined data from 26 studies to estimate the overall and region-, sex-, and age-specific hazard ratios for major cardiovascular diseases by fifths of triglyceride values. During 796 671 person-years of follow-up among 96 224 individuals, 670 and 667 deaths as a result of coronary heart disease (CHD) and stroke, respectively, were recorded. After adjustment for major cardiovascular risk factors, participants grouped in the highest fifth of triglyceride levels had a 70% (95% CI, 47 to 96) greater risk of CHD death, an 80% (95% CI, 49 to 119) higher risk of fatal or nonfatal CHD, and a 50% (95% CI, 29% to 76%) increased risk of fatal or nonfatal stroke compared with those belonging to the lowest fifth. The association between triglycerides and CHD death was similar across subgroups defined by ethnicity, age, and sex.ConclusionsSerum triglycerides are an important and independent predictor of CHD and stroke risk in the Asia-Pacific region. These results may have clinical implications for cardiovascular risk prediction and the use of lipid-lowering therapy.(Circulation. 2004;110:2678-2686.)

Triglyceride-mediated pathways and coronary disease:collaborative analysis of 101 studiesMethods We assessed the 1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent diff erences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 279 million person-years at risk). We analysed 1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.Findings The minor allele frequency of 1131T>C was 8% (95% CI 79). 1131T>C was not signifi cantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean diff erence per C allele 35% [95% CI 2646]; 0053 mmol/L [00390068]), lower apolipoprotein AI (13% [0323]; 0023 g/L [00050041]), and higher apolipoprotein B (32% [1351]; 0027 g/L [00110043]). By contrast, for every C allele inherited, mean triglyceride concentration was 160% (95% CI 129187), or 025 mmol/L (020029), higher (p=44102). The odds ratio for coronary heart disease was 118 (95% CI 111126; p=2610) per C allele, which was concordant with the hazard ratio of 110 (95% CI 108112) per 16% higher triglyceride concentration recorded in prospective studies. 1131T>C was signifi cantly associated with higher VLDL particle concentration (mean diff erence per C allele 122 nmol/L [95% CI 77167]; p=9310) and smaller HDL particle size (014 nm [008020]; p=7010), factors that could mediate the eff ects of triglyceride.Interpretation These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.Lancet 2010; 375: 163439Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration*

NCEP ATP III: LDL-C Goals (2004 proposed modifications) *Therapeutic option 70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/LGrundy SM et al. Circulation 2004;110:227239.Existing LDL-C goalsProposed LDL-C goals

Odds ratio adj for age, sex, smokeYusuf S, et al. Lancet. 2004;364(9438):93752

INTERHEART: Risk of AMI Associated with Risk Factors

LDL-C achieved mg/dL (mmol/L)WOSCOPS PlaceboAFCAPS - PlaceboASCOT - PlaceboAFCAPS - RxWOSCOPS - RxASCOT - Rx4S - RxHPS - PlaceboLIPID - Rx4S - PlaceboCARE - RxLIPID - PlaceboCARE - PlaceboHPS - Rx05101520253040(1.0)60(1.6)80(2.1)100(2.6)120(3.1)140(3.6)160(4.1)180(4.7)Event rate (%)6 Secondary Prevention Primary Prevention200(5.2)PROVE-IT - PRAPROVE-IT ATVAdapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279LaRosa JC et al. N Engl J Med 2005;352:1425-1435TNT ATV10TNT ATV80Effect of Lowering LDL-C on CHD Events in Statin Trials Lower is BetterNCEP 2004NCEP 2001Eur Joint 2003AHA/ACC Update2006

4Ssimva-WOSCOPSprava-CAREprava-LIPIDprava-AF/TEXCAPS lova-HPSsimva-PROSPERprava-ASCOTatorva-CARDSatorva-TNTatorva-Statins Have Revolutionised CVD Risk ManagementAll drugs in class 2050% Relative Risk Reduction

In primary and secondary prevention

In men and women

4085 years of age

In diabetics, hypertensives, smokersLower LDL-C is better

AHA/ACC guidelinesfor patients with CHD*,2

(Liao, 2002)Isoprenoid intermediates of cholesterol modulate many cellular processesAcetyl-CoA + Acetoacetyl-CoAHMG-CoAHMG-CoAreductaseStatinsMevalonateXp13-kinase/protein kinase Akt eNOSBMP-2/bone formationAngiogenesisCellular growthProliferationDolicholHaemUbiquinoneRasFarnesyl-PPSqualeneGeranylgeranyl-PPCholesterolLipoproteinVitamin DBile acidsSteroid hormoneseNOSs, t-PARhoARac1Cdc42ActincytoskeletonNAD(P)H oxidaseOxidative stressProliferationand migrationPAI-1, ET-1

Effects of Statin on HMG-CoA Reductase InhibitionStatins TXA2 t-PA TXA2 Macrophage Growth Rac1 RhoA ET-1 AT1 Receptor MMPs TF hs-CRP Adhesion Molecule ROS NOPlateletActivationThromboticEffectPlaqueStabilityVascularInflammationSMCHypertrophyEndothelialDysfunctionSMCProliferationVasoconstriction Hypertension AtherosclerosisCardiovascularDiseases

Efficacy & Safety of Cholesterol Lowering Treatment:(Prospective meta analysis of data from 90056 participants in 14 randomised trials of statin)Cholesterol Treatment Trialists (CTT) Collaborators, Lancet 2005;366:1267-78

Proportional effects on major vascular events per mmol/L LDL-cholesterol reduction0.51.01.5Treatment betterControl betterEffect p

Timing of Benefit in Statin Trials Meta-analysis of 14 Studies (90,056 Subjects)0.51.01.5Treatment betterControl betterTrend test for major vascular events: =13.9; P=0002CTTC. Baigent C et al; Lancet 2005

Reduction in rate of first major coronary events per each 39 mg/dL reduction in LDL-C*ResidualRiskAtherogenicdyslipidemia

Metabolicsyndrome

Diabetes

Hypertension

SmokingDefining Residual CVD Risk in Patients With Dyslipidemia23%*Cholesterol Treatment Trialists (CTT) Collaborators. Lancet. 2005;366:1267-1278.

Cholesterol Treatment Trialist (CTT) Collaboration -2010

2-3 mmol/L reduction of LDL-C would reduce risk of occlusive vascular event by 40-50% CTT-2010 Messages

CTT-2010 MessagesThis meta-analysis further confirms the lower is better hypothesis for LDL-CThere was no indication that intensive lowering of LDL-C resulted in increased risk of haemorrhagic stroke, cancer or non-vascular mortalityGreater reductions in LDL-C can be achieved safely with regimens that involve newer, more potent statins

Putting Statin Risks and Benefits into ContextComparing with other risksDRUGS

How Do We Choose Statin ?EfficacyEffect on atherosclerosisLDL-C loweringHDL-C raisingTriglyceride loweringSafety Low drug interaction potentialGood tolerabilityFlexibility/Conveniencelack of need for dose adjustment in different patient groupstaken at any time of day with or without foodCost-effectivenessMore patients reaching guideline goals at same or lower priceFewer events

Least-squares means (SE) for percent change in lipid parameters from baseline to week 24 (Ballantyne, et all; 2001)

Ballantyne et al, 2004

Fluvastatin: Clinical and Safety ProfileRandomised, placebo-controlled trials of fluvastatin with primary or secondary clinical endpointsCorsini et all, 2002

Fluvastatin Reduces Cardiac Mortality in Patients with Coronary Heart DiseaseBallantyne et al, 2004

Ballantyne et al, 2004

Ballantyne et al, 2004

Statins and risk of incident diabetes: a collaborativemeta-analysis of randomised statin trialsMethods We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis.Findings We identified 13 statin trials with 91140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 109; 95% CI 102117), with little heterogeneity (I=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150852) patients with statins for 4 years resulted in one extra case of diabetes.Interpretation Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change.Sattar, et all; Lancet 2010; 375: 73542

Statins and New-Onset Diabetes: A Retrospective Longitudinal Cohort StudyBackground: Statins have been linked to new-onset diabetes (NOD); however, the effect of statins on the development of NOD in patients with hypertension and dyslipidemia has not been well studied.Objective: The goal of this study was to investigate the association between statins and NOD.Methods: This was a retrospective cohort study performed by using data from claim forms provided to the central regional branch of the Bureau of National Health Insurance in Taiwan from July 2006 to December 2009. Prescriptions for statins before the index date were retrieved from a prescription database. We estimated the hazards ratios (HRs) of NOD associated with statin use. Nondiabetic subjects served as the reference group.Results: A total of 1360 (8.5%) NOD cases were identified among 16,027 patients with hypertension and dyslipidemia during the study period.Ma et all, 2012

Cox univariate analysis of incidence of hazards ratios (HRs) with 95% CIs adjusted for age, sex, concomitant medication usage, and mean dose for patients with new-onset diabetes (NOD) according to prescriptions for statins.

Ma et all, 2012

Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trialsMethods: We systematically studied 199,721 participants in 92 placebo-controlled and active-comparator trials comparing atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin in participants with, or at risk of developing, cardiovascular disease. We performed pairwise and network meta-analyses for major coronary events and all-cause mortality outcomes, taking into account the dose differences across trials.Results: There were only a few trials that evaluated fluvastatin. Most frequent comparisons occurred between pravastatin and placebo, atorvastatin and placebo, and rosuvastatin and atorvastatin. Across all populations, statins were significantly more effective than control in reducing all-cause mortality (OR 0.87, 95% credible interval 0.820.92) and major coronary events (OR 0.69, 95% CI 0.640.75). In terms of reducing major coronary events, atorvastatin (OR 0.66, 95% CI 0.480.94) and fluvastatin (OR 0.59, 95% CI 0.360.95) were significantly more effective than rosuvastatin at comparable doses. In participants with cardiovascular disease, statins significantly reduced deaths (OR 0.82, 95% CI 0.750.90) and major coronary events (OR 0.69, 95% CI 0.620.77). Atorvastatin was significantly more effective than pravastatin (OR 0.65, 95% CI 0.430.99) and simvastatin (OR 0.68, 95% CI 0.380.98) for secondary prevention of major coronary events. In primary prevention, statins significantly reduced deaths (OR 0.91, 95% CI 0.830.99) and major coronary events (OR 0.69, 95% CI 0.610.79) with no differences among individual statins. Across all populations, atorvastatin (80%), fluvastatin (79%), and simvastatin (62%) had the highest overall probability of being the best treatment in terms of both outcomes. Higher doses of atorvastatin and fluvastatin had the highest number of significant differences in preventing major coronary events compared with other statins. No significant heterogeneity or inconsistency was detected.Conclusions: Statins significantly reduce the incidence of all-cause mortality and major coronary events as compared to control in both secondary and primary prevention. This analysis provides evidence for potential differences between individual statins, which are not fully explained by their low-density lipoprotein cholesterol-reducing effects. The observed differences between statins should be investigated in future prospective studies.Naci et al, European Journal of Preventive Cardiology 2013

Network of eligible pairwise comparisons for (A) all-cause mortality and (B) major coronary events in placebo-controlled and active-comparator trials of participants with and without prior coronary heart disease at baseline (overall population). Connecting lines indicate the direct pairwise comparison between two treatments (knumber of pairwise comparisons; Noverall number of participants; odds ratios and 95% confidence intervals are given). Arrows depict the direction of comparison (e.g. atorvastatin vs.control). Supplementary Figures S1 (all-cause mortality) and S2 (major coronary events) provide separate network diagrams for secondary and primary prevention populations. A total of 93 out of 101 comparisons are shown in these network diagrams as eight trials compared the same statin (high vs. low dose comparisons), which are not depicted in this figure.Naci et al, 2013

Efficacy & Safety of Cholesterol Lowering TreatmentStatin therapy can safely reduce the 5 yr incidence of major coronary events, coronary revascularization & stroke by about one fifth per mmol/L reduction in LDL Chol (irrespective of initial lipid profile & the absolute reduction in LDL Chol achieved) (1)This findings reinforce the need to consider prolonged statin treatment with substantial LDL Chol reduction in all patients at high risk of any type of major vascular eventsThere was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 23 mmol/L would reduce risk by about 4050%. (2) The potential hazards of lowering LDL cholesterol with these statin regimens seemed to be extremely small in relation to the clear benefits in many circumstances.No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 097, 95% CI 092103; p=03) or on cancer incidence (RR 100, 95% CI 096104; p=09), even at low LDL cholesterol concentrations. (2)Cholesterol Treatment Trialists (CTT) Collaborators, Lancet 2005;366:1267-78Cholesterol Treatment Trialists (CTT) Collaborators, Lancet 2010; 376: 167081

*ALT >3 x ULN on 2 successive occasionsStatin Tolerability and Safety Liver EffectsElevations in liver transaminase levels are infrequent but recognised complication of treatment with statins*Before statin therapy:Liver function tests recommendedCaution in patients who consume excessive quantities of alcohol and/or have a history of liver diseaseContraindicated in patients with active liver disease

Myalgia: Muscle symptoms reported by the patientMyopathy: Muscle symptoms with CK elevation >10x ULNRhabdomyolysis: Widespread muscle injury with CK >10x ULN and accompanying organ (renal) damage. Myoglobinuria/emia featureSome Definitions

Pelaporan kasus Rhabdomyolisis Fatal pada semua Statin yang ada di Market USARhabdomyolisis pada Fluvastatin paling rendahLovaPravaSimvaFluvaAtorvaCerivaDate approved8/8710/9112/9112/9312/966/97Fatal cases of rhabdomyolysis*193140631No. of prescriptions (millions)99.281.411637.41409.8Reporting rate (per 1 million Rx)0.190.040.1200.043.16* Cases reported to the FDA Adverse Event Reporting System through June 2001. Data are through May 2001 and are from the National Prescription Audit Plus, excluding the Long Term Care Channel. Number of cases divided by the number of prescriptions. Note the reporting rate is not the incidence rate.Staffa JA et al. N Engl J Med. 2002;346:539-540.

02040608010012003/99-08/9909/99-02/0003/00-08/0009/00-02/0103/01-08/0109/01-02/0203/02-08/0209/02-02/0303/03-08/0309/03-02/0403/04-08/0409/04-02/0503/05-08/0503/03-08/0309/03-02/0403/04-08/0409/04-02/0503/05-08/0509/05-02/06cerivastatinfluvastatinatorvastatinlovastatinpravastatinsimvastatinezetimiberosuvastatin rosuvastatin AZ global databaseReporting rate per 1,000,000 US prescriptions**Reporting Rates of Rhabdomyolysiswith Lipid-modifying TherapySemiannual Reporting Rates for All Reports of RhabdomyolysisUS Reports* (AERS database)Rosuvastatin Worldwide Reports (AZ global database)Reporting rate per 1,000,000 rosuvastatin prescriptions worldwide*All spontaneous reports including expedited, periodic and direct reports. **US reporting rates based on FDA Adverse Events Reporting System made available through Freedom of Information Act divided by US prescribing data supplied by IMS to the end of August 2005.

Cerivastatin reports received after September 1, 2001, are excluded.

Global reporting rate for rosuvastatin based on spontaneous report counts of rhabdomyolysis within AstraZeneca global drug safety database divided by estimated worldwide prescriptions to end February 2006. Total prescriptions based on IMS data from US, Canada, UK, France, Italy and The Netherlands; rest of world prescriptions based on actual sales calculations.Update: 1 June 2006Due to a change in the way AERS reports are recorded, AERS data corresponding to the period March to August 2005 differs from previous data as it may include non-US reports and those of clinical trial origin. For this reason, the data corresponding to this period is plotted as a dotted line.

SummaryFluvastatin represents a choice for:patients needing moderate LDL-cholesterol reductions to achieve LDL-cholesterol goals; patients requiring combination therapy with other lipid-lowering agents;patients taking multiple medications that place them at high risk for drug interactions during statin therapy; andhigh-risk patient populations, including patients who have undergone coronary intervention procedures and patients with renal disease.Statins significantly reduce the incidence of all-cause mortality and major coronary events as compared to control in both secondary and primary prevention.

According to 2002 mortality figures compiled for the World Health Organizations (WHO) World Health Report 2003: Shaping the Future, cardiovascular diseases (CVD) (mainly ischemic heart disease and stroke) were the leading global cause of death, accounting for approximately 16.6 million deaths, followed by cancer (7.1 million deaths), intentional and unintentional injuries (5.2 million), upper and lower respiratory infection (3.8 million), chronic obstructive pulmonary disease (COPD) and asthma (2.9 million), and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (2.8 million). Reference1. World Health Organization. The World Health Report 2003: Shaping the Future. Geneva, Switzerland: World Health Organization; 2003.**ReferencesThe World Health Report 2001. Geneva: WHO; 2001.Atherothrombosis is the underlying condition that results in events leading to myocardial infarction, ischemic stroke, and vascular death. As such, the leading cause of death of the estimated 55,694,000 people worldwide who died in 2000 was atherothrombosis, manifested as cardiovascular disease, ischemic heart disease and stroke (52% of deaths). Other main causes of death wereAIDS (5%) pulmonary disease (6%)injuries (9%)cancer (12%)violent death (12%)infectious diseases (19%) Atherothrombosis (29%) **Acute coronary syndromesincluding unstable angina, nonSTsegment elevation myocardial infarction and STelevation myocardial infarctionshare a common underlying pathophysiologic link of plaque rupture.Goldstein reviewed data that support the concept of plaque instability in many patients as a pan-coronary process, reflecting systemic inflammatory and metabolic factors that destabilize plaques in several locationsnot only those containing culprit lesionsand are responsible for acute ischemic events.Many ulcerated plaques are not sufficiently disrupted to be detected angiographically and patients who are likely to have unstable coronary artery disease have lipid-rich inflamed vulnerable plaques that have yet to ulcerate and rupture. Goldstein suggested, (t)herefore, angiographic documentation of plaque rupture undoubtedly represents only the, tip of the iceberg, of plaque instability.

ReferencesGoldstein JA. Angiographic plaque complexity: the tip of the unstable plaque iceberg. J Am CollCardiol. 2002;39:1464-1467.*Low density lipoprotein cholesterol (LDL-C) is the primary therapeutic target of CVD prevention guidelines, partly because data from epidemiological and observational studies have demonstrated that individuals with elevated levels of low-density cholesterol (LDL-C) are at increased risk of CHD.1,2

1. Gotto AM Jr et al. Circulation. 1990;81:1721-1733.2. Castelli WP. Am J Med. 1984;76:4-12.

***The majority of adults in the United States have LDL-C levels of 100 mg/dL, the level defined as optimal by the NCEP ATP III guidelines. The estimated number of adults within each LDL-C classification is as follows:Very high (4.9 mmol/L [190 mg/dL]): 8,824,000High (4.1-4.9 mmol/L [160-189 mg/dL]): 21,445,000Borderline high (3.3-4.1 mmol/L [130-159 mg/dL]): 48,751,000Near or above optimal (2.6-3.3 mmol/L [100-129 mg/dL]): 57,381,000Optimal (