1、Integrating Aggressive CV Risk Management in Primary Care High prevalence of multiple CV risk factors in US adultsCDC.MMWR.2005;54:113-40.Behavioral Risk Factor Surveillance System,20032 of hypertension,hypercholesterolemia,diabetes,smoking,physical inactivity,obesity40.0%46.2%36.0%39.9%33.0%35.9%27
2、.0%32.9%INTERHEART:Exponential rise in CV disease with added risk factorsOdds ratio for1st MI*(99%CI)6451216122561283284Smk(1)DM(2)HTN(3)ApoB/A1 ratio(4)1+2+3All 4All 4+ObesAll 4+PsAll 9 riskfactors2.92.41.93.313.042.368.5182.9333.7Yusuf S et al.Lancet.2004;364:937-52.Smk=smoking;DM=diabetes;HTN=hyp
3、ertension;Obes=obesity;Ps=psychosocial factors*Plotted on a doubling scale 3-fold 26-foldINTERHEART:Any smoking increases CV riskTeo KK et al.Lancet.2006;368:647-58.*vs never smokedN=27,098 from 52 countries12345678910 1112 1314 1516 1718 1920Odds ratio for first MI*Cigarettes smoked(n/day)Never21-0
4、.751248Lifetime CVD risk estimate and risk factor burden70605040302010050607080906950463656050403020100Men(n=3564)Women(n=4362)Adjusted cumulative incidence of CVD(%)50607080902 Major RFs1 Major RF1 Elevated RF1 Not optimal RFAll optimal RFs705039278Attained age(years)Lloyd-Jones DM et al.Circulatio
5、n.2006;113:791-8.2-fold in higher age groupAdditive risk of age with hypertension+hypercholesterolemiaWong ND et al.Am J Cardiol.2006;98:204-8.NHANES 2001-2002;N=286426.552.743.121.4Clinical manifestations of obesityInsulinresistanceGlucotoxicityLipotoxicity Adiponectin LeptinAtherosclerosisCourtesy
6、 of Selwyn AP,Weissman PN.2006.Type 2 diabetes and glycemic disorders FFAsDyslipidemia Low HDL Small,dense LDL HypertriglyceridemiaHypertensionEndothelial dysfunction/inflammation(hsCRP)Impaired thrombolysis PAI-1Metabolic consequences of visceral obesity Visceral/abdominal obesity Correlates more s
7、trongly with insulin resistance than lower body obesityIs associated with plasma levels of fatty acids and accompanying TG Insulin resistance Altered hepatic fat accumulation and metabolism Dyslipidemia Proinflammatory adipokines(insulin resistance,risk for CV disease)Visceral fat correlates more st
8、rongly with insulin resistance than subcutaneous fatGrundy SM et al.Circulation.2005;112:2735-52.Desprs J-P et al.BMJ.2001;322:716-20.Visceral obesity in CV risk CT scans from men matched for BMI and total body fat White=visceral fat area(VFA);black=subcutaneous fatDesprs J-P.Eur Heart J Suppl.2006;
9、8(suppl B):B4-12.Subcutaneous obesityFat mass:19.8 kgVFA:96 cm2Visceral obesityFat mass:19.8 kgVFA:155 cm2Visceral obesitydrives CV risk progression independent of BMIMeasurement of waist circumference may offer a more useful surrogate marker of visceral adiposity than waist-hip ratioOptimal marker(
10、s)for visceral adiposityDesprs JP et al.BMJ.2001;322:716-720.Measuring waist circumferenceIliac crestCDC Projections 2005 to 2050:Diabetes focus Narayan KMV et al.Diabetes Care.2006;29:2114-6.*Revised projection“appears more alarming than previously estimated”32.1 million new diabetes patients by 20
11、50*174%220%470%423%606%in blacks 75 yr20502005Individuals with diabetes(millions)Diabetes2005-2050(%)Multiple risk factors:Undertreated and poorly controlledWong ND et al.Am J Cardiol.2006;98:204-8.NHANES 2001-2002;n=638 with hypertension and hypercholesterolemiaSudden cardiac death:Too often the fi
12、rst sign of CV diseaseFox CS et al.Circulation.2004;110:522-7.50%of sudden cardiac deaths occur in persons with no CV disease historyCall to actionIdentify all risk factorsBase treatment on global risk assessmentTreat multiple risk factors aggressively CV eventsABCs of multiple risk factor managemen
13、tAAspirinACE inhibitionA1C controlBBP control -blockadeCCholesterol management Control weightDDietDont smokeEExercisePlatelet activationand aggregationHypertensionHyperglycemia/Insulin resistanceDyslipidemiaAdapted from Cohen JD.Lancet.2001;357:972-3.Beckman JA et al.JAMA.2002;287:2570-81.AHA diet a
14、nd lifestyle recommendations Healthy diet Fruits,vegetables,legumes,whole grains,non-fat/low-fat dairy,fish,poultry,limited alcohol intake Physical activity 30 min on most days No smoking Avoid use of and exposure to tobacco productsLichtenstein AH et al.Circulation.2006;114:82-96.CV riskWeight loss
15、 improves CV risk factorsSjstrm L et al.N Engl J Med.2004;351:2683-93.Conventional treatment(n=1660)Gastric surgery(n=1845)*At 2 yearsN=4047 with obesity3-Week diet+exercise regimen yields favorable metabolic changes*P 0.01P 0.05Roberts CK.et al.J Appl Physiol.2006;100:1657-65.U/mLN=31 overweight/ob
16、ese men;weight 8.4 lbsBaseline Follow-upPhysical activity reduces CV and all-cause mortalityFang J et al.Am J Hypertens.2005;18:751-8.N=9791;moderate physical activity vs little or no physical activity0.75(0.531.05)0.76(0.391.49)0.79(0.650.97)All-cause deathCV deathAll-cause deathPrehypertensionCV d
17、eathHypertensionHazard ratio1.51.00.5Normal BP02.0All-cause deathCV death0.79(0.581.09)0.88(0.800.98)0.84(0.730.97)Adjusted HR(95%CI)FavorsexerciseFavorsno exerciseNHANES 1 Epidemiological Follow-up Survey(19711992)Dietary programs can be effective yet difficult to maintainDansinger ML et al.JAMA.20
18、05;293:43-53.N=160 overweight or obese with 1 CV risk factorEmerging strategies in weight control Lifestyle interventions must include both diet and exercise Even moderate weight loss(5%10%)can:Decrease cardiometabolic risk factors Encourage continued health-promoting behaviors and adherence to medi
19、cal therapy Novel approaches to decreasing cardiometabolic risk factors are neededEckel RH et al.Circulation.2006;113:2943-6.Gelfand EV,Cannon CP.J Am Coll Cardiol.2006;47:1919-26.Goals for optimal health AACE.Endocr Pract.2002;8(suppl 1):40-82.Lifestyle intervention Diet Physical activity Smoking c
20、essation Weight controlAggressive management of comorbid conditions*Lipid modifying BP lowering ASA for prevention of vascular events*Dyslipidemia,hypertension,early renal diseaseIntensive glycemic control A1C 6.5%Glucose(mg/dL)Preprandial 110 Postprandial 140Steno-2:Rationale for Target-Driven Beha
21、vior Modification and PolypharmacySteno-2:Goals of intensive pharmacologic strategyTherapyGoalACE inhibitorsAll patients(ARBs,if contraindicated)AspirinAll patients(150 mg/d)BP control130/80 mm HgLipid controlTotal-C 175 mg/dLTriglycerides 150 mg/dLGlucose controlA1C 6.5%Gde P et al.N Engl J Med.200
22、3;348:383-93.Steno-2 results:Better control with intensive therapyGde P et al.N Engl J Med.2003;348:383-93.Conventional therapy(n=80)Intensive therapy(n=80)Follow-up(years)Follow-up(years)0123456785015025035000123456781101301501700SBP(mm Hg)P 0.001Total-C(mg/dL)P 0.001012345678501502503500AlC(%)P 0.
23、001TG(mg/dL)P=0.015012345678579110Steno-2:Multifactorial intervention improves macrovascular outcomesGde P et al.N Engl J Med.2003;348:383-93.*CV death,MI,stroke,revascularization,amputation,PAD surgery;UnadjustedPrimary composite outcome*(%)Follow-up(months)6050403020100ConventionalIntensive0122436
24、4860728496NNT=5Absolute risk reduction=20%53%RRRP=0.01N=160 with type 2 diabetes and microalbuminuriaSteno-2:Intensive intervention improves vascular and neuropathic outcomesGde P et al.N Engl J Med.2003;348:383-93.0.01.02.0NephropathyRetinopathyAutonomicneuropathyPeripheralneuropathyVariableRRPInte
25、nsivebetterConventionalbetter0.390.420.371.090.0030.020.0020.66 Risk of microvascular complications after 4 years was maintained at 8 yearsRelative risk3.0Integrating Antihypertensive Agents in CV Risk ReductionRelation of BP to CV disease is continuousMeta-analysis of 61 observational studies;N=958
26、,074Prospective Studies Collaboration.Lancet.2002;360:1903-13.120 140 160 180Usual SBP(mm Hg)Usual DBP(mm Hg)7090 100 11080Systolic BPDiastolic BPAge at risk(y):80897079606950594049Age at risk(y):808970796069505940492561286432168421025612864321684210IHDmortality(floatingabsoluterisk)*Plotted on a do
27、ubling scaleBPLTTC:Comparison of more-vs less-intensive BP loweringEvents/participants by BP-lowering strategyMore intensiveLess intensiveStroke140/7494261/13,394CHD274/7494348/13,394Major CV events482/8034719/13,948Blood Pressure Lowering Treatment Trialists Collaboration.Lancet.2003;362:1527-35.Me
28、ta-analysis of 4 trials;1998-2002;N=162,3410.61.01.4Relative riskFavorsmore intensiveFavorsless intensiveASCOT-BPLA:Rationale Premise Multiple risk factors markedly increase CV disease severity Standard BP-lowering therapies(diuretics and-blockers)have not been proven to prevent CHD events ASCOT-BPL
29、A compared newer vs older antihypertensive regimens in patients with 3 risk factors Hypothesis Newer,aggressive combination BP-lowering agents will prevent more CV eventsBPLTTC.Arch Intern Med.2005;165:1410-9.Dahlf B et al.Lancet.2005;366:895-906.Anglo-Scandinavian Cardiac Outcomes Trial-Blood Press
30、ure Lowering ArmASCOT-BPLA:Comparison of older vs newer therapy*Plus K supplement if neededBP 160/100 mm Hg(untreated)or BP 140/90 mm Hg(treated)+3 other risk factors N=19,257Amlodipine 510 mg perindopril 48 mgAtenolol 50100 mg bendroflumethiazide 1.252.5 mg*Primary outcome:Nonfatal MI and fatal CHD
31、Follow-up:5.5 yearsRandomizedDouble-blindDahlf B et al.Lancet.2005;366:895-906.ASCOT patient profile Sever PS et al.J Hypertens.2001;19:1139-47.Sever PS et al.Lancet.2003;361:1149-58.Patients with risk factor(%)0102030405060708090100HypertensionAged 55 yearsMaleMicroalbuminuria/proteinuriaSmokerFami
32、ly history of CHDPlasma TC:HDL-C 6Type 2 diabetesECG abnormalitiesLVHPrior cerebrovascular eventsPeripheral vascular diseaseASCOT-BPLA:BP reductions over timeBlood pressure(mm Hg)Atenolol 50100 mg bendroflumethiazide 1.252.5 mg/potassiumAmlodipine 510 mg perindopril 48 mgDahlf B et al.Lancet.2005;36
33、6:895-906.Time(years)1.02.03.04.05.000.51.52.53.54.55.5 BPMean difference=1.9,P 0.000160100080120140160180Mean difference=2.7,P 0.0001Diastolic BP137.7136.179.277.4Systolic BPASCOT-BPLA:Reduction in primary outcome Proportionof events(%)62401234810560Time(years)10%RRRHR 0.90(0.791.02)P=0.1052Atenolo
34、l 50100 mg bendroflumethiazide 1.252.5 mg/potassiumAmlodipine 510 mg perindopril 48 mgDahlf B et al.Lancet.2005;366:895-906.Nonfatal MI and fatal CHDASCOT-BPLA:Additional reductions with amlodipine-based regimenDahlf B et al.Lancet.2005;366:895-906.Secondary endpointsNonfatal MI(excluding silent)7.4
35、 8.5+fatal CHDTotal coronary endpoint14.6 16.8Total CV events and procedures 27.4 32.8 All-cause mortality13.9 15.5 CV mortality4.9 6.5 Fatal/nonfatal stroke6.2 8.1 Fatal/nonfatal HF2.5 3.0 Tertiary endpointsDevelopment of diabetes11.0 15.9 Development of renal impairment7.7 9.1 Rate/1000 patient-ye
36、arsAmlodipine-based(n=9639)Atenolol-based(n=9618)Amlodipine-based betterAtenolol-based better0.500.701.001.452.00Unadjusted hazard ratioP0.05 0.010.0001 0.05 0.001 0.001 NS 0.0001 40%Age 50 yearsCV death,MI,coronary revascularization*or diabetes+1 CV risk factorLVEF=left ventricular ejection fractio
37、nHOPE Study Investigators.N Engl J Med.2000.EUROPA Investigators.Lancet.2003.PEACE Trial Investigators.N Engl J Med.2004.HOPE,EUROPA,PEACE:Concomitant CV therapies at baselineHOPEEUROPAPEACEAntiplatelet agents(%)769291-blockers(%)406260Lipid-lowering agents(%)295870Calcium channel blockers(%)473136D
38、iuretics(%)15913HOPE Study Investigators.N Engl J Med.2000.EUROPA Investigators.Lancet.2003.PEACE Trial Investigators.N Engl J Med.2004.HOPE,EUROPA,PEACE:Primary outcomesHOPEPatients(%)Placebo22%RRP 0.001155100200Ramipril 10 mg2413Time(years)PEACEPlaceboTrandolapril4 mg3020101551234525064%RRP=0.43EU
39、ROPA124100134140PlaceboPerindopril 8 mg8625220%RRP=0.0003RR=risk reductionHOPE,EUROPA,PEACE:Reduction in all-cause mortalityEvents(%)ACEIPlacebo HOPE10.412.2 EUROPA6.16.9 PEACE7.28.1Total7.88.9Favors ACEIFavors placeboOdds ratio(95%CI)Dagenais GR et al.Lancet.2006;368:581-8.0.61.01.4HOPE,EUROPA:Bene
40、fit consistent across ancillary therapyAdapted from Dagenais GR et al.Lancet.2006;368:581-8.1.11.00.50.9Odds ratio(95%CI)AntiplateletsNo antiplateletsLipid-lowering agentsNo lipid-lowering agents-blockersNo -blockersRevascularizationNo revascularizationSubgroupPatients(n)4-year rates in placebo grou
41、ps0.0030.6510.1390.078PInteraction0.60.70.818,3313184948912,02611,32310,19210,39411,12313.217.910.616.413.414.311.516.0ACEI betterACEI worseCV death,nonfatal MI,or strokeHOPE,EUROPA,PEACE:Benefit of ACEIs across broad spectrum of riskDagenais GR et al.Lancet.2006;368:581-8.TrialPatients(n)Annual rat
42、es in placebo groupsOR(95%CI)P-520405301535Odds reduction(%)25100PEACE82902.137(-8 to 19)0.328HOPE total92973.9525(16 to 32)0.0001HOPE lower risk30832.1718(-4 to 35)HOPE med risk31003.5820(3 to 33)HOPE high risk31145.9824(12 to 34)EUROPA total12,2182.6019(8 to 28)0.0007EUROPA lower risk39761.4019(-5
43、 to 38)EUROPA med risk39752.4128(11 to 41)EUROPA high risk39754.0010(-4 to 22)AIRE198622.624(7 to 38)0.0068TRACE174917.025(9 to 33)0.0028SOLVD-P42287.415(2 to 27)0.0252SOLVD-T256913.123(10 to 33)0.0009SAVE22319.820(4 to 33)0.0168CV death,*nonfatal MI or strokeACEI worseACEI better*Or total mortality
44、 in AIRE,TRACE,SOLVD,SAVE trialsACEIs vs ARBs:Comparative effect on stroke,HF,and CHDTurnbull F.15th European Meeting on Hypertension.2005.Adapted by Strauss MH,Hall AS.Circulation.2006;114:838-54.CHD=MI and CV deathBlood Pressure Lowering Treatment Trialists Collaboration meta-analysisN=137,356;21
45、randomized clinical trialsACEIARBStroke-1%(9%to-10%)HF10%(10%to 0%)CHD9%(14%to 3%)Stroke2%(33%to-3%)HF16%(36%to-5%)CHD-7%(7%to-24%)30%030%DecreaseIncreaseStrokeP=0.6HFP=0.4CHDP=0.001RiskRRRACEIs in vascular disease:Conclusions ACEIs reduce mortality,MI,HF,and stroke in patients with vascular disease
46、 with/without LVSD or HF Benefit in addition to antiplatelet agents,-blockers,and lipid-lowering agents Combining ACEIs with these agents provides greatest benefit Benefit in patients across a broad range of risk for CV events Annual rate in placebo groups of 1.4%22.6%Dagenais GR et al.Lancet.2006;3
47、68:581-8.Fox K et al.Eur Heart J.2006;27:2154-7.Consider ACEIs in all patients with vascular disease Assess risk/benefits and tolerability Use doses proven in clinical trialsIntegrating Statinsin CV Risk ReductionStatins reduce all-cause death CTT Collaborators.Lancet.2005;366:1267-78.Cholesterol Tr
48、eatment Trialists Collaboration;N=90,056Cause of death3.40.810.910.950.93Vascular causes:StrokeOther vascularAny vascularAny non-CHD vascular0.60.61.24.72.40.20.11.13.88.59.74.01.20.10.32.45.71.30.70.64.4Nonvascular causes:CancerRespiratory0.831.010.820.890.870.950.88TraumaOther/unknownAny nonvascul
49、arAny deathEvents(%)Treatment betterControlbetter1.51.00.5CHDRelative riskTreatment(n=45,054)Control(n=45,002)Meta-analysis of 14 trialsHPS:Assessing statin benefit in high-risk patientsHPS Collaborative Group.Lancet.2002;360:7-22.Heart Protection StudyTotal-C 135 mg/dL and diabetes,CAD,stroke,PAD,o
50、r treated hypertension(if male,aged 65 years)N=20,536Simvastatin 40 mgFollow-up:5 yearsPrimary outcomes:Mortality(overall analysis)Fatal/nonfatal vascular events(subcategory analysis)PlaceboRandomizedOpen-label Blinded outcomeHPS:Statins confer benefit independent of baseline LDL-C358(21.0%)282(16.4
