Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey

Figures & data

Table 1 Common tools used in cardiovascular risk assessment

Clinical evaluation: history and physical examination

Family history

Global Risk Scoring (FRS, SCORE, Reynolds)

Calculation of lifetime risk

Electrocardiogram (ECG)

Echocardiography

Stress (Exercise) electrocardiography

Myocardial perfusion imaging (MPI)

Stress (Exercise) echocardiography

LDL-C (apolipoprotein B, non-HDL-C)

HDL-C

Lipoprotein “little a” (Lp(a))

Lipoprotein fractionation (VAP, NMR)

hsC-reactive protein (CRP)

Lipoprotein-associated phospholipase A2 (Lp-PLA2)

Coronary angiography

Carotid intima-media thickness using ultrasound (CIMT)

Computed tomography for coronary calcium (CAC)

CT coronary angiography

MRI coronary angiography

Abbreviations: FRS, Framingham Risk Score; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; CT, computerized tomography; MRI, magnetic resonance imaging.

Table 2 Ideal Cardiovascular Health, defined by the American Heart Association, now known as “Life’s Simple 7^™”, is composed of four behaviors and three factors^2,*

Not smoking or quitting over 1 year ago. A body mass index <25 kg/m^2. Exercising at a moderate intensity ≥150 minutes (or 75 minutes at vigorous intensity) each week. Eating a “healthy diet”: adhering to four to five important dietary components sodium intake <1.5 g/day; sugar-sweetened beverage intake <36 oz weekly; ≥4.5 cups of fruits and vegetables/day; ≥three 1 oz servings of fiber-rich whole grains/day; ≥two 3.5 oz servings of oily fish/week. Maintaining total cholesterol (TC) <200 mg/dL. Keeping blood pressure <120/80 mmHg. Keeping fasting blood glucose <100 mg/dL.

Notes:

* Other recommendations include ≥ four servings of nuts, legumes and seeds/week; ≤ less servings of processed meats/week; less than 7% total energy intake as saturated fat.

Table 3 Cardiovascular risk factors as reported in the 2011 Heart and Stroke Foundation Report³⁸

Risk factor	Self-reported perception (% participation)	Actual prevalence (%, estimated)	Not assessed by health care provider (%)	Impact upon life expectancy (years)
Smoking	23	20	37	−13.9
Obesity (age 18 or over)	18	24	Weight: 40% Waist measure: 67%	−4.0
Physically inactive in leisure time	31	48	44	−3.6
High blood pressure	17	19	18	−2.4
Vegetable and fruit intake <5+/day	39	54	52	−1.3

Data from the Heart and Stroke Foundation (HSF) poll of 2000 Canadians performed in December 2010, self-reported from the 2009 Canadian Community Health Survey, or from the 2007–2009 Canadian Health Measures Study.

Table 4 Currently available cardiovascular risk scoring models

Study	Input variables	End point	Region of origin, age, gender	Limitations and comments	Website URL
Framingham Risk Score^Citation146^–^Citation149	Age, sex, BP, smoking, use of HTN meds, TC, HDL-C	All CHD	US, Caucasian volunteers in Mass, M, W, 30–62+ years	Well-studied, classical, user-friendly scoring system in widespread use. Sample size of ≈8500. Poor in Hispanic M, Native-American W, Japanese-American M, in presence of DM2, LVH, severe HTN. Underprediction of 0.43 in high-risk, but overprediction of 2.87 in low-risk populations. Misclassification may result in ineligibility of low risk individuals who may benefit from statins. Recommended by NICE until February, 2010, thereafter defaulted to local preference. See text for details.	http://www.framinghamheartstudy.org/risk/coronary.html
NCEP-ATP III (Framingham)^Citation153,Citation154	Age, sex, sBP, smoking, use of HTN meds, TC, HDL-C	CHD death, nonfatal MI	Universally applicable US, relies upon FRS	Risk algorithm used (2004): High risk: ≥ two risk factors, FRS > 20% or with CHD, DM, PAD, aortic aneurysm, significant or symptomatic carotid artery disease; Moderately high risk: ≥ two risk factors and FRS 10%–20%; Moderate risk: ≥ two risk factors FRS < 10%; Low risk: zero to one risk factor. Misclassification in low risk category may result in denial of statins to persons who might benefit. See text for details. New ATP IV guidelines are scheduled for release in Fall, 2011.	http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm Calculator: http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof ATP IV: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp4/index.htm Compare Joint British Societies Risk 2009: http://www.bhsoc.org/Cardiovascular_Risk_Prediction_Chart.stm and NICE remarks: http://www.nice.org.uk/guidance/CG67
Framingham global CVD^Citation169	Age, sex, sBP, smoking, use of HTN meds, TC, HDL-C, DM	CVD death, stroke, HF, claudication, All CHD	US, Caucasian, M, W, 30–74 years	Caucasian population. Version of FRS to include angina, stroke, PAD, and HF.	http://www.framinghamheartstudy.org/risk/gencardio.html
SCORE^Citation150	Age, sex, smoking, use of HTN meds, TC or TC/HDL, low and high CVD risk	CVD death only	EU, M, W, 40–65 years	Large sample size of ≈205,000 pooled from eleven European countries estimating 10-year risk of initial fatal event only. Regional risk system. Used in European Society of Cardiology guidelines.	http://www.escardio.org/communities/EACPR/toolbox/health-professionals/Pages/SCORE-Risk-Charts.aspx for EU high and low risk regions. Individual countries available at www.HeartScore.org
ASSIGN^Citation152	Age, sex, sBP, TC, HDL-C, FH, social deprivation	CVD death, CHD admission, CABG, PCI	Scotland, M, W, 30–74 years	Based upon a random Scottish sample size of ≈13,300. May overestimate risk. Recommended by the Scottish Intercollegiate Guidelines Network.	http://www.assign-score.com/
QRISK^Citation151	Age, sex, sBP, smoking, use of HTN meds, TC/HDL, FH, BMI, social deprivation	CHD, MI, stroke, TIA	UK, M, W, 35–74 years	Based upon a sample size of 2.29 million (QRISK2). Validated in same UK population used for derivation. Data from general practice registers in UK; not random, but able to be updated continuously. Recommended by NICE guidelines on lipid modification. High potential for UK method of choice.^Citation162	http://www.qrisk.org/ and http://qintervention.org/
PROCAM^Citation155	Age, sex, sBP, smoking, LDL-C, HDL-C, DM	CHD death, nonfatal MI	EU industrial employees, M, W, 20–75 years	Based upon a sample size of ≈30,000 volunteers. Two separate scores calculate major coronary events and cerebral ischemic events. Recommended by the International Task Force for Prevention of Coronary Disease guidelines.	http://www.chd-taskforce.com/pdf/sk_procam_07e.pdf and http://www.assmannstiftung.de/en/procam/procam-risk-scores/procam-health-check/
Reynolds, Women^Citation156	Age, sex, sBP, smoking, TC, HDL-C, CRP, FH, HbA1c if diabetic	CVD death, MI, stroke, revascularization	US, W, 45–80 years	Sample of ≈25,500 predominantly Caucasian W, upper socioeconomic health service employees. Volunteer, self-reported BP, BMI, FH. Data from the Women’s Health Study. Compared to FRS, reclassified 5.8% of women, half to lower risk, half to higher. Lack of external validation; use of non-population based cohort to derive risk estimates.^Citation189 Included in the Canadian Cardiovascular Society Guidelines as an alternative.^Citation190	http://www.reynoldsriskscore.org/
Reynolds, Men^Citation157	Age, sex, sBP, smoking, TC, HDL-C, CRP, FH, HbA1c if diabetic	CVD death, MI, stroke, revascularization	US, M, 45–80 years	Sample size of ≈11,000 predominantly Caucasian M, upper socioeconomic physicians. Volunteer, self-reported BP, BMI, FH. Data from the Physician’s Health Study II.	http://www.reynoldsriskscore.org/

Notes:

+ World Health Organization/International Society of Hypertension (WHO/ISH) risk charts excluding lipid values are not shown; intended for countries with limited access to medical facilities, they are available at http://www.who.int/cardiovascular_diseases/guidelines/Pocket_GL_information/en/index.html. Other risk scores also have predictive potential, such as developed by the Consortium for Southeastern Hypertension Control in COSEHC-11¹⁹¹ with the advantage of data collection directly from electronic medical records.

Abbreviations: All CHD, CHD death; MI, unstable and stable angina; ASSIGN, Assessing Cardiovascular Risk to Scottish Intercollegiate Guidelines Network/SIGN to Assign Preventative Treatment; BMI, Body mass index; BP, Blood pressure; CABG, Coronary artery bypass graft; CHD, Coronary heart disease; CVD, Cardiovascular disease; CRP, C-reactive protein; DM2, Diabetes type 2; FH, Family history; FRS, Framingham risk score; HbA1c, glycosylated hemoglobin; HDL, High-density lipoprotein; HF, Heart failure; HTN, Hypertension; LDL, low-density lipoprotein; LH, Left ventricular hypertrophy; M, Men; Meds, medications; MI, Myocardial infarction; NICE, National Institute for Health and Clinical Excellence, UK; PAD, Peripheral artery disease; PCI, Percutaneous coronary intervention; PROCAM, Prospective Cardiovascular Münster; QRISK, QRESEARCH Cardiovascular Risk Algorithm; SBP, Systolic blood pressure; SCORE, European Systematic COronary Risk Evaluation; TC, Total cholesterol; TIA, Transient ischemic attack; W, Women.

Table 5 Recent statin regression trials using coronary IVUS

Investigators	Type	Statin used	Exam interval	Primary endpoint	Results (mean ± SD)
Petronio et al^Citation270	RCT	Simvastatin	12 months	Plaque volume	−2.5 ± 3.0 mm^3/mm
		Control			1.0 ± 3.0 mm^3/mm
Tani et al^Citation271	RCT	Pravastatin	6 months	% change in plaque volume	−14.4 ± 23%
		Control			1.1 ± 4.6%
ASTEROID^Citation230,Citation242	Not RCT	Rosuvastatin	24 months	Change in PAV	−0.98 ± 3.15%
Takashima et al^Citation272	Not RCT	Pitavastatin	6 months	% change in plaque volume	−10.6 ± 9.4%
		Control			8.1 ± 14.0%
COSMOS^Citation273	Not RCT	Rosuvastatin	18 months	Change in PAV	−5.1 ± 14.1%
JAPAN-ACS^Citation274	RCT	Atorvastatin	8–12 months	% change in plaque volume	−18.1 ± 14.2%
		Pitavastatin			−16.9 ± 13.9%
Hirayama et al^Citation275	Not RCT	Atorvastatin	28 weeks	% change in plaque volume	−9.4 ± 10.3%
			80 weeks		−18.9 ± 14.1%

Abbreviations: RCT, randomized controlled trial; PAV, percent atheroma volume.

Table 6 Outcome improvements with statin therapy in primary prevention found in the Cochrane review²⁹⁸

Outcome	Risk ratio (95% CI)
Total mortality	0.83 (0.73–0.95)
Fatal and nonfatal CHD events	0.72 (0.65–0.79)
Fatal and nonfatal stroke	0.78 (0.65–0.94)

Table 7 Some functions of high-density lipoprotein (HDL)

Participation in reverse cholesterol transport of cholesterol, through the ATP-binding cassette (ABC) transporters and additional mechanisms, is the most important vasculoprotective function. Since peripheral cells cannot metabolize cholesterol, it will accumulate unless carried back to the liver for disposal. Heterogeneous HDL particle subfractions are continuously exchanging moieties and interacting with other lipoproteins, lipolytic enzymes (hepatic and endothelial lipases), and transfer proteins (lecithin:cholesteryl acyltransferase, phospholipid transfer protein). A major feature of HDL remodeling involves transfer of cholesteryl ester from cholesterol-rich HDL in exchange for triglycerides from apolipoprotein B (apoB)–containing cholesterol-acceptor particles.^Citation371 While the atherosclerotic process is affected by cholesterol efflux capacity from cultured macrophage foam cells, this property may be independent of the HDL-C level,^Citation372 related more to its function, ie, quality, rather than quantity.^Citation373 Protection and support of endothelium, through inhibition of monocyte chemotaxis, adhesion molecule expression, and enhanced nitric oxide production.^Citation365 Prevention of LDL oxidation, involving two redox active methionine centers in apoA-I, paraoxonase-1 (PON-1) and paraoxonase-^Citation3,Citation374,Citation375 as well as other component antioxidant enzymes contained in HDL, such as glutathione peroxidase, and platelet activating factor acetylhydrolase). Promotion of efflux of oxidized LDL from macrophages. Antiproliferative actions, particularly reducing apoptosis in macrophages. Anticoagulation, via inhibition of factors Va and VIIa and promotion of urokinase-dependent fibrinolysis. Inhibition of platelet activation and aggregation, which protects the endothelium and inhibits thrombosis. Augmentation of prostacyclin synthesis through activation of cyclooxygenase-2. Stimulation of endothelial cell migration and recruitment of endothelial progenitor cells at sites of endothelial injury. Reduction of inflammatory mediator expression. Participation in the immune system, through component complement proteins.^Citation376 Inhibition of atherogenic remnant particle production, by maintaining VLDL-triglyceride homeostasis. Promotion of glucose uptake and fatty acid oxidation, tempering any rise in insulin resistance, along with upregulation of pancreatic insulin secretion. Mediation of vascular protection ascribed to 17β-estradiol, the most potent endogenous estrogen, via enhanced HDL-induced endothelial nitric oxide synthase 3 activity to increase nitric oxide release.

Table 8 Characteristics of CIMT and CAC by CT

Quality of interest	CIMT (Ultrasound)	CAC scoring (CT)
Area	Intima-media	Calcified lesions
Radiation	None	0.7 mSv for EBT and 3–5 mSv for helical CAC (may vary 10-fold up to 10.5 mSv)
Sensitivity	50 to 70	85
Specificity	60 to 80	75
Hazard ratio for incident CVD event per SD increment change title	1.3	2.1
Reclassification improvement	Unknown	Yes
Discrimination improvement	Uncertain	Yes
Operation simplicity	++	+++
Operation reproducibility	User dependent	Automated
Approximate cost	US $200	US $300–$600
Capitalization and access	Low-within office and research access	High-larger facility access

Abbreviations: CAC, coronary artery calcium; CT, computed tomography; CIMT, carotid intima-media thickness; EBT, electron beam tomography.

Lloyd-JonesDMHongYLabartheDAmerican Heart Association Strategic Planning Task Force and Statistics CommitteeDefining and Setting National Goals for Cardiovascular Health Promotion and Disease Reduction: The American Heart Association’s Strategic Impact Goal Through 2020 and BeyondCirculation2010121458661320089546

 PubMed Web of Science ®Google Scholar

FarzadfarFFinucaneMMDanaeiGon behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Cholesterol)National, regional, and global trends in serum total cholesterol since 1980: systematic analysis of health examination surveys and epidemiological studies with 321 country-years and 3·0 million participantsLancet2011377976557858621295847

 PubMed Web of Science ®Google Scholar

KannelWBMcGeeDGordonTA general cardiovascular risk profile: the Framingham StudyAm J Cardiol19763814651132862

 PubMed Web of Science ®Google Scholar

WilsonPWFD’AgostinoRBLevyDBelangerAMSilbershatzHKannelWBPrediction of coronary heart disease using risk factor categoriesCirculation19989718183718479603539

 PubMed Web of Science ®Google Scholar

Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final reportCirculation2002106253143342112485966

 PubMed Web of Science ®Google Scholar

D’AgostinoRBSrGrundySSullivanLMWilsonPfor the CHD Risk Prediction GroupValidation of the Framingham coronary disease prediction scores. results of a multiple ethnic groups investigationJAMA2001286218018711448281

 PubMed Web of Science ®Google Scholar

D’AgostinoRBSrVasanRSPencinaMJGeneral cardiovascular risk profile for use in primary care: the Framingham Heart StudyCirculation2008117674375318212285

 PubMed Web of Science ®Google Scholar

ConroyRMPyoralaKFitzgeraldAPEstimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE projectEur Heart J20032411987100312788299

 PubMed Web of Science ®Google Scholar

WoodwardMBrindlePTunstall-PedoeHAdding social deprivation and family history to cardiovascular risk assessment: the ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC)Heart200793217217617090561

 PubMed Web of Science ®Google Scholar

Hippisley-CoxJCouplandCVinogradovaYRobsonJMayMBrindlePDerivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort studyBMJ2007335761113614717615182

 PubMed Web of Science ®Google Scholar

DentTHSPredicting the risk of coronary heart disease: I. The use of conventional risk markersAtherosclerosis2010213234535120637467

 PubMed Web of Science ®Google Scholar

AssmannGCullenPSchulteHSimple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the Prospective Cardiovascular Münster (PROCAM) studyCirculation2002105331031511804985

 PubMed Web of Science ®Google Scholar

RidkerPMBuringJERifaiNCookNRDevelopment and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk ScoreJAMA2007297661161917299196

 PubMed Web of Science ®Google Scholar

RohatgiAKKheraAThe Upcoming ATP IV GuidelinesLipid Spin20108469

 Google Scholar

GenestJMcPhersonRFrohlichJ2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult – 2009 recommendationsCan J Cardiol2009251056757919812802

 PubMed Web of Science ®Google Scholar

RidkerPMPaynterNPRifaiNGazianoJMCookNRC-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds risk score for menCirculation2008118222243225118997194

 PubMed Web of Science ®Google Scholar

FerrarioCMMooreMABestermannWJrCOSEHC global vascular risk management quality improvement program: rationale and designVasc Health Risk Manag201061135114521931496

 PubMedGoogle Scholar

PetronioASAmorosoGLimbrunoUSimvastatin does not inhibit intimal hyperplasia and restenosis but promotes plaque regression in normocholesterolemic patients undergoing coronary stenting: a randomized study with intravascular ultrasoundAm Heart J2005149352052615864242

 PubMed Web of Science ®Google Scholar

TaniSWatanabeIAnazawaTEffect of pravastatin on malondialdehyde-modified low-density lipoprotein levels and coronary plaque regression as determined by three-dimensional intravascular ultrasoundAm J Cardiol20059681089109416214443

 PubMed Web of Science ®Google Scholar

NissenSENichollsSJSipahiIEffect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trialJAMA2006295131556156516533939

 PubMed Web of Science ®Google Scholar

BallantyneCMRaichlenJSNichollsSASTEROID InvestigatorsEffect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burdenCirculation2008117192458246618378607

 PubMed Web of Science ®Google Scholar

TakashimaHOzakiYYasukawaTImpact of lipid-lowering therapy with pitavastatin, a new HMG-CoA reductase inhibitor, on regression of coronary atherosclerotic plaqueCirc J200771111678168417965484

 PubMed Web of Science ®Google Scholar

TakayamaTHiroTYamagishiMEffect of rosuvastatin on coronary atheroma in stable coronary artery disease: multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS)Circ J200973112110211719801853

 PubMed Web of Science ®Google Scholar

HiroTKimuraTMorimotoTEffect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intra-vascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study)J Am Coll Cardiol200954429330219608026

 PubMed Web of Science ®Google Scholar

HirayamaASaitoSUedaYQualitative and quantitative changes in coronary plaque associated with atorvastatin therapyCirc J200973471872519225206

 PubMed Web of Science ®Google Scholar

TaylorFWardKMooreTHMStatins for the primary prevention of cardiovascular diseaseCochrane Database Syst Rev20111CD00481621249663

 PubMed Web of Science ®Google Scholar

MassonDJiangXCLagrostLTallARThe role of plasma lipid transfer proteins in lipoprotein metabolism and atherogenesisJ Lipid Res200950SupplS201S20619023137

 PubMed Web of Science ®Google Scholar

KheraAVCuchelMMargarita de la Llera-MoyaCholesterol efflux capacity, high-density lipoprotein function, and atherosclerosisN Engl J Med2011364212713521226578

 PubMed Web of Science ®Google Scholar

HeineckeJHDL and Cardiovascular-Disease risk – time for a new approach?N Engl J Med2011364217017121226584

 PubMed Web of Science ®Google Scholar

VaisarTPennathurSGreenPSShotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDLJ Clin Invest2007117374675617332893

 PubMed Web of Science ®Google Scholar

KonesRPhillipsJHPrevention of Heart Cell DeathYuPNGoodwinJFProgress In Cardiology4Philadelphia, PALea and Febiger1975199224

 Google Scholar

RosenblatMAviramMParaoxonases role in the prevention of cardiovascular diseasesBiofactors20093519810419319852

 PubMed Web of Science ®Google Scholar

GetzGSReardonCAParaoxonase, a cardioprotective enzyme: continuing issuesCurr Opin Lipidol200415326126715166781

 PubMed Web of Science ®Google Scholar

AndersenRVWittrupHHTybjaerg-HansenASteffensenRSchnohrPNordestgaardBGHepatic lipase mutations, elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease: the Copenhagen City Heart StudyJ Am Coll Cardiol200341111972198212798568

 PubMed Web of Science ®Google Scholar