從臨床試驗(yàn)到JNC-PT課件

1、Robert A. Phillips, M.D., Ph.D., F.A.C.C., F.A.H.A.Chairman Department of MedicineLenox Hill HospitalProfessor of Medicine NYU School of Medicine President, Eastern Chapter, American Society of HypertensionFrom clinical trials to JNC 7: Evidence That Will Change PracticeRobert A. Phillips, M.D., Ph.

2、DRecent Clinical Trials in “Uncomplicated Hypertension” that Inform JNC7HOT - Hansson et al., Lancet 1998:351:1755Optimal BP 140/90 mm HgFelodipine based trialRecent Clinical Trials in “UncHOT Study: Risk of a Major CV Event Reduced by 30% (DBP)10095908085Achieved DBP (mm Hg)Optimal DBP reductionHan

3、sson L et al. Lancet. 1998;351:1755-1762Percentriskreduction in major CV events*Fatal and nonfatal MI, stroke, all other CV deaths.HOT Study: Risk of a Major CV HOT Study: Risk of a Major CV Event Reduced by 30% (DBP)170160150130140Achieved SBP (mm Hg)Hansson L et al. Lancet. 1998;351:1755-1762*Fata

4、l and nonfatal MI, stroke, all other CV deaths.Percentriskreductionin majorCV events*Optimal SBP reductionHOT Study: Risk of a Major CV HOT Study Results: Lower is Marginally Better for Non-Diabetic Hypertensives and ASA is GoodThose assigned to 80 mm Hg group had few myocardial infarctions than tho

5、se assigned to 90 mm Hg group2.6 vs. 3.6 events per 1000 patient years (p=0.05)ASA group (one-half of the patients) had 15% few CV events (p=0.05)Hansson et al., Lancet 1998:351:1755HOT Study Results: Lower is MaRecent Clinical Trials in “Uncomplicated Hypertension”STOP-2 - Hansson et al., Lancet, 1

6、999; 354:175156Compared “old” (diuretics and -blockers) vs. “new” (calcium channel blockers and ACE inhibitors) in overall CV outcomesAll had equal ability to prevent CV morbidity or mortality in elderly patients with hypertension. ACE inhibitors prevented more MI and CHF than CCBsINSIGHT - Brown et

7、 al., Lancet, 2000;356:366-72Nifedipine-GITS vs diuretic-based therapy. Equally effective in reducing stroke and total cardiovascular events, Greater incidence of MI and CHF in CCB group. Recent Clinical Trials in “UncRecent Clinical Trials in “Uncomplicated Hypertension”NORDIL - Hansson et al., Lan

8、cet, 2000;356:359-65Diltiazem as effective as diuretic and -blocker therapy in preventing the combined primary endpoint of all stroke, myocardial infarction, and other cardiovascular deathCCB was more effective in reducing stroke. 2nd Australian National BP Study, NEJM, 2003;348:583-592Low risk elde

9、rly populationACE better than diureticSummary:BP reduction in the patient with uncomplicated hypertension is the critical factorWhich drug is better may be a nuance CCB monotherapy appears to be related to more CHFCombinations are usually required Recent Clinical Trials in “UncRecent Clinical Trials

10、 in “Complicated” Hypertension that Inform JNC7HOT - Hansson et al., Lancet 1998:351:1755HOPE - NEJM,2000;342:145-153; Lancet 2000;355:253-259ALLHAT- JAMA 2000 Apr 19;283(15):1967-75RENAAL - Brenner BM, et al. N Engl J Med. 2001;345:861-869.IDNT - Lewis EJ, et al. N Engl J Med. 2001;345:851-860.AASK

11、 AASK Study Group, JAMA, 2002;ALLHAT 2002, JAMA, 2002;288:2981-2997Clinical Summary:In renal disease, blockade of the renin-angiotensin-aldosterone system is beneficialIf multiple risk factors, including diabetes, blood pressure lowering may be most important, diuretics should be part of therapy if

12、possibleRecent Clinical Trials in “ComHOT Study Results: Lower is Definitely Better in Patients with Diabetes and Hypertension 50% reduction in major CV events in those diabetic hypertensives assigned to 80 mm Hg compared to 90 mm Hg groupImpressive, since only 4 mm Hg difference between groups at e

13、nd of studyHansson et al., Lancet 1998:351:1755HOT Study Results: Lower is DeImpact of Randomized Drug Class on Outcomes in AASKAASK Study Group, JAMA. 2002;288:2421-2431Impact of Randomized Drug ClasFollow-up BP by Drug Group(Mean SD)RamiprilAmlodipineMetoprololMAP(mmHg)100 999 8100 9Systolic BP (m

14、mHg) 135 14133 12*135 13Diastolic BP (mmHg) 82 9 81 881 9Summaries include visits after three months and exclude GFR visits* Significant difference between amlodipine and metoprolol groups (p 0.05)AASK Study Group, JAMA. 2002;288:2421-2431Follow-up BP by Drug GroupRamiMain Clinical Composite Outcome

15、Declining GFR Event, ESRD, or Death% with EventsMetoprolol vs. Amlodipine:RR= 20%, p=0.17 Ramipril vs. Amlodipine: RR= 38%, p=0.004 MetoprololRamiprilAmlodipine0510152025303540Follow-up Month06121824303642485460Ramipril vs. MetoprololRR = 22%, p = 0.042RR = Risk Reduction, Adjusting for Baseline Cov

16、ariatesAASK Study Group, JAMA. 2002;288:2421-2431Main Clinical Composite OutcomHard Clinical Endpoint Composite Of ESRD or Death Follow-up MonthMetoprolol vs. Amlodipine:RR = 42%, p = 0.003 Ramipril vs. Amlodipine: RR = 49%, p 300 mg/24 hrsDuring Follow-up by Drug GroupRamipril vs. Metoprolol: p=0.0

17、14Amlodipine vs. Metoprolol: p=0.009Ramipril vs. Amlodipine: p0.001% with Events0102030405060Follow-up Month06121824303642485460Analysis of patients with UP/Cr 0.22 at baselineMetoprololRamiprilAmlodipineAASK Study Group, JAMA. 2002;288:2421-2431% of Patients Reached Urine PrALLHAT: Chlorthalidone G

18、roup had Lowest Average Systolic BPALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.1501451401351300123456Follow-up YearsBlood Pressuremm HgLisinopril Amlodipine ChlorthalidoneBP vs Chlorthalidone at 5 Years+2 mm Hg P.001+0.8 mm Hg P=.03ALLHAT: Chlorthalidone Group hMedication Use and B

19、P Control in ALLHATCushman et al. J Clin Hypertens. 2002;4:393-404.Baseline6 mo1 y3 y5 y1 Drug2 Drugs3 Drugs% Controlled 140/90 mm Hg% PatientsMedication Use and BP Control ALLHAT Primary Endpoint: CHD Death and Nonfatal MIALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.Relative Risk (

20、95% CI)FavorsChlorthalidoneAmlodipine 0.98 (0.90-1.07)0.71.3Lisinopril 0.99 (0.91-1.08)Favors AmlodipineFavors Lisinopril1ALLHAT Primary Endpoint: CHD ALLHAT: Secondary Endpoints: StrokeRelative Risk (95% CI)Favors AmlodipineFavors Lisinopril0.93 (0.82-1.06)1.15 (1.02-1.30)FavorsChlorthalidoneAmlodi

21、pineLisinoprilALLHAT: Secondary Endpoints: SALLHAT: Stroke (Lisinopril vs Chlorthalidone) SubgroupsLisinopril BetterChlorthalidone Better0.512Total Age 65Age 65MenWomenBlackNonblack Diabetic Nondiabetic1.15 (1.02-1.30)1.21 (0.97-1.52)1.13 (0.98-1.30)1.10 (0.94-1.29)1.22 (1.01-1.46)1.40 (1.17-1.68)1.

22、00 (0.85-1.17)1.07 (0.90-1.28)1.23 (1.05-1.44)Relative Risk (95% CI)ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.ALLHAT: Stroke (Lisinopril vs ALLHAT: Secondary Endpoints: Combined CVDRelative Risk (95% CI)1.04 (0.99-1.09)1.10 (1.05-1.16)AmlodipineLisinoprilFavors Amlodipine Favors

23、Chlorthalidone ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.Favors LisinoprilALLHAT: Secondary Endpoints: ALLHAT: Combined CVD (Lisinopril vs Chlorthalidone) Subgroups1.5Total Age 65Age 65MenWomenBlackNonblack Diabetic Nondiabetic1.10 (1.05-1.16)1.05 (0.97-1.15)1.13 (1.06-1.20)1.08

24、(1.02-1.15)1.12 (1.03-1.21)1.19 (1.09-1.30)1.06 (1.00-1.13)1.08 (1.00-1.17)1.12 (1.05-1.19)0.51Lisinopril BetterChlorthalidone BetterRelative Risk (95% CI)ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.ALLHAT: Combined CVD (LisinoprALLHAT: Components of Secondary Endpoints*: Heart Fai

25、lure*Heart failure is a component of combined CVD.ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.1.38 (1.25-1.52)Relative Risk (95% CI)Favors AmlodipineFavors LisinoprilHeart Failure (fatal, nonfatal, hospitalized or treated)1.19 (1.07-1.31)AmlodipineLisinoprilHospitalized/Fatal HF1.3

26、5 (1.21-1.50)1.10 (0.98-1.23)AmlodipineLisinoprilFavors Chlorthalidone 0.52.01ALLHAT: Components of SecondarALLHAT: Heart Failure (Amlodipine vs Chlorthalidone) Subgroups20.51Amlodipine BetterChlorthalidone BetterTotal Age 65Age 65MenWomenBlackNonblack Diabetic Nondiabetic1.38 (1.25-1.52)1.51 (1.25-

27、1.82)1.33 (1.18-1.49)1.41 (1.24-1.61)1.33 (1.14-1.55)1.47 (1.24-1.74)1.33 (1.18-1.51)1.42 (1.23-1.64)1.33 (1.16-1.52)Relative Risk (95% CI)ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.ALLHAT: Heart Failure (AmlodipALLHAT: Heart Failure (Lisinopril vs Chlorthalidone) SubgroupsTotal A

28、ge 65Age 65MenWomenBlackNonblack Diabetic Nondiabetic1.20 (1.09-1.34)1.23 (1.01-1.50)1.20 (1.06-1.35)1.19 (1.03-1.36)1.23 (1.05-1.43)1.32 (1.11-1.58)1.15 (1.01-1.30)1.22 (1.05-1.42)1.20 (1.04-1.38)0.512Lisinopril BetterChlorthalidone BetterRelative Risk (95% CI)ALLHAT Collaborative Research Group. J

29、AMA. 2002;288:2981-2997.ALLHAT: Heart Failure (LisinopALLHAT Summary and ConclusionsThe ALLHAT trial addressed the most typical patient - i.e. the 55 y.o. with another risk factor for CAD, many of whom had prior CVDIt brings therapeutics back to 30 years ago, but with a twist - the chlorthalidone do

30、se was 12.5 mg compared to higher doses used in the 1970s and 1980sAvoids the diuretic-related hypokalemia issues of the 70s and 80sPatients treated with diuretics had lower risk of stroke, heart failure and CHD compared to patients taking lisinoprilALLHAT Collaborative Research Group. JAMA. 2002;28

31、8:2981-2997.ALLHAT Summary and ConclusionsU.S. Department of Health and Human ServicesNational Institutes of HealthNational Heart, Lung, and Blood InstituteThe Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)U.S. Departm

32、ent of National InFor persons over age 50, SBP is a more important than DBP as CVD risk factor.Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range. Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.Those with SBP 120139

33、 mmHg or DBP 8089 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD. New Features and Key MessagesFor persons over age 50, SBP iRisk of hypertension (%)Residual risk of developing hypertension among people with blood pressure 20/10 mmHg abo

34、ve goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.New Features and Key Messages New Features and Key Messages (Continued)The most effective therapy prescribed by the careful clinician will control HTN only if patients are motivated.Motivation improves when pat

35、ients have positive experiences with, and trust in, the clinician.Empathy builds trust and is a potent motivator.The responsible physicians judgment remains paramount.New Features and Key Messages BP Measurement and Clinical Evaluation Classification of BPCVD RiskBenefits of Lowering BPBP Control Ra

36、tesBP Measurement Techniques In-office Ambulatory BP Monitoring Self-measurementPatient Evaluation Laboratory Tests and Other Diagnostic ProceduresBP Measurement and Clinical EBlood Pressure ClassificationNormal120and160or100BP ClassificationSBP mmHgDBP mmHgBlood Pressure ClassificationN*Classificat

37、ion of BP (JNC 6)SystolicDiastolicNormal129139159179 120- 130- 140- 160- 18080-8485-8990-99100-109110High NormalStage 1Stage 2Optimal135/85 mmHg and during sleep 120/75 mmHg.BP drops by 10 to 20% during the night; if not, signals possible increased risk for cardiovascular events.Ambulatory BP Monito

38、ringABPM iApproximately 25% of Hypertensives have WCHStaessen et al.,JAMA 1997;278:1065Approximately 25% of HypertensPatients with White-Coat Hypertension Have Same Probability of Event Free Survival as Normotensives by 7.5 YearsVerdecchia P et al. Hypertension 24:793-801,1994 N=1187, mean age 4515

39、yearsNml. Daytime BP=136/87 for men 135/85 mmHg is generally considered to be hypertensive.Home measurement devices should be checked regularly.Self-Measurement of BPProvidesPatient EvaluationEvaluation of patients with documented HTN has three objectives: Assess lifestyle and identify other CV risk

40、 factors or concomitant disorders that affect prognosis and guide treatment. Reveal identifiable causes of high BP.Assess the presence or absence of target organ damage and CVD. * Start with H & P: complete but CV-focused (fundi, pulses, bruits, etc)Patient EvaluationEvaluation oIdentifiable Causes

41、of Secondary HypertensionSleep apneaDrug-induced or related causesChronic kidney diseasePrimary aldosteronismRenovascular diseaseChronic steroid therapy and Cushings syndromePheochromocytomaCoarctation of the aortaThyroid or parathyroid diseaseIdentifiable Causes of SeconLaboratory TestsRoutine Test

42、s Electrocardiogram Urinalysis Blood glucose, and hematocrit Serum potassium, creatinine, or the corresponding estimated GFR, and calcium Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and triglycerides Optional tests Measurement of urina

43、ry albumin excretion or albumin/creatinine ratio More extensive testing for identifiable causes is not generally indicated unless BP control is not achievedLaboratory TestsRoutine TestsTreatment OverviewGoals of therapyLifestyle modificationPharmacologic treatment Algorithm for treatment of hyperten

44、sion Compelling indications for specific drug classesTreatment OverviewGoals of theGoals of TherapyReduce CVD and renal morbidity and mortality. Treat to BP 140/90 mmHg or BP 50 years of age.Goals of TherapyReduce CVD aLifestyle ModificationModificationApproximate SBP reduction(range)Weight reductio

45、n 520mmHg/10 kg weight lossAdopt DASH eating plan 814 mmHgDietary sodium reduction 28 mmHgPhysical activity 49 mmHgModeration of alcohol consumption 24 mmHgLifestyle ModificationModificaEfficacious Lifestyle Modification Weight:1 kg = 1.6/1.3 mmHgAchieve 15% above ideal Na intake:100 mEq = 5.4/6.5 m

46、mHgAchieve 4-6 g salt / day (70-100 mEq Na)Shopping “smart” EtOH to 30 cc = 1 oz / day whiskey 3 oz, wine 10 oz, beer 24 oz; half in women Exercisedynamic activity 45 min 3-4 times / wkSalt sdmnfabc Salt Efficacious Lifestyle ModificaDASH Diet: Eating Plan*Food group Servings Serving sizes ExamplesG

47、rains & grain 7-8 daily 1 slice bread Whole wheat bread, Englishproducts dry cereal muffins, pita bread, bagels, 1/2C cooked rice, cereals, grits, oatmealVegetables 4-5 daily 1 C raw, leafy Tomatoes, potatoes, carrots, peas, squash, broccoli, leafy 6 oz. Vegetable greens sweet potatoes, beans juiceF

48、ruits 4-5 daily 6 oz fruit juice Apricots, bananas, dates, grapes 1 medium fruit oranges, grapefruit, mangoes melons, peaches, pineapples, prunes, raisins, strawberries,Low-fat or nonfat 2-3 daily 8 oz milk Skim or 1% milk, nonfat or low 1 C yogurt fat yogurt, nonfat or part-skim 1.5 oz cheese chees

49、eMeats, poultry, 2 or 3 oz. cooked meat Lean meats; trim visible fat;fish poultry or fish remove skin from poultry; broilNuts, seeds, 4-5per 1.5 oz. Nuts Almonds, filberts, mixed nutslegumes 2 tbsp seeds peanuts, walnuts, sunflower seed kidney beans, lentils DASH Diet: Eating Plan*Food gr Appel LJ,

50、et al., NEJM 1997;336: 1117-1124DASH Study: 8 week Fruit and Vegetable Rich Diet (4-5 servings each), Low-fat Dairy Foods, and Reduced Total and Saturated Fat, (Combination Diet) Lowers BP in Normotensives and Stage I Hypertensives Appel LJ, et al., NDASH Diet Has Significant Effect on Systolic BP i

51、n Patient with ISHMoore et al., Hypertension, 2001;38:155-158DASH Diet Has Significant EffeAlgorithm for Treatment of HypertensionNot at Goal Blood Pressure (140/90 mmHg) (160 or DBP 100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)Stage 1 Hyperte

52、nsion(SBP 140159 or DBP 9099 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.Without Compelling IndicationsNot at Goal Blood PressureOptimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension speciali

53、st.Algorithm for Treatment of HypCompelling Indications for Individual Drug ClassesCompelling Indication Initial Therapy Options Clinical Trial BasisACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES ACC/AHA Post-MI Guideline, BHAT, SAVE Capricorn, EPHES

54、USALLHAT, HOPE, ANBP2, LIFE, CONVINCE THIAZ, BB, ACEI, ARB, ALDO ANT BB, ACEI, ALDO ANT THIAZ, BB, ACE, CCB Heart failure Postmyocardialinfarction High CAD risk Compelling Indications for InDiabetes Chronic kidney disease Recurrent stroke prevention Compelling Indications for Individual Drug Classes

55、Compelling Indication Initial Therapy Options Clinical Trial BasisNKF-ADA Guideline, UKPDS, ALLHAT NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK PROGRESS THIAZ, BB, ACE, ARB, CCB ACEI, ARB THIAZ + ACEI Diabetes Chronic kidney diseasClassification and Management of BP for adultsBP classifi

56、cation SBP* mmHg DBP* mmHg Lifestyle modification Initial drug therapy Without compelling indication With compelling indicationsNormal 120 and 160 or 100 Yes Two-drug combination for most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). *Treatment determined by highest BP category.Init

57、ial combined therapy should be used cautiously in those at risk for orthostatic hypotension.Treat patients with chronic kidney disease or diabetes to BP goal of 130/80mmHg. Classification and Management UKPDS=United Kingdom Prospective Diabetes Study; MDRD=Modification of Diet in Renal Disease; HOT=

58、Hypertension Optimal Treatment; AASK=African American Study of Kidney Disease; RENAAL=Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT=Irbesartan Diabetic Nephropathy Trial. Hypertension in High-Risk Patients: Number of Agents NeededNumber of BP MedicationsUKPDS (85 mm Hg, diastolic)4321MDRD (92 mm Hg, MAP)HOT (80 mm Hg, diastolic)AASK (92 mm Hg, MAP)RENAAL (140/90 mm Hg)IDNT