ACC公布的临床试验的启示课件

1、Womens Health StudyUse of aspirin for primary prevention COMMIT and CLARITYUse of clopidogrel in acute-MI patientsTNTHigh-dose atorvastatin in stable CHD patients ASCOT-BPLACalcium channel blocker plus ACE inhibitor reduced all-cause mortality and other cardiovascular end points Topics第1页，共50页。Women

2、s Health StudyUse of aspirin for primary prevention第2页，共50页。Womens Health Study: DesignUse of aspirin for primary prevention in women(N Engl J Med 2005: published March 7th)39 876 initially healthy women 45 years of age or olderRandomized to 100 mg of aspirin on alternate days or placebo Monitored f

3、or first major CV event (nonfatal MI, nonfatal stroke, or death from CV causes)10-year follow-up 第3页，共50页。WHS: Cardiovascular end points End pointEvents (n), aspirin(n=19 934)Events (n), placebo (n=19 942)Relative risk pMajor CV event4775220.910.13StrokeMI2211982661930.831.020.040.83Death from CV ca

4、uses1201260.950.68第4页，共50页。WHS: Stroke end points End pointEvents (n), aspirin(n=19 934)Events (n), placebo(n=19 942)Relative risk pStroke2212660.830.04Ischemic1702210.760.009Hemorrhagic51411.240.31Fatal23221.040.90Nonfatal1982440.810.02第5页，共50页。WHS: Ambitious trialGlass half-full vs half-emptyReduc

5、es stroke in a primary- prevention population But does not reduce mortality, which may have been an ambitious end point, in retrospectFerguson第6页，共50页。WHS: Surprising resultsBenefit in stroke and myocardial infarction reduction in women older than 65 yearsYou do have to be at risk to get benefit fro

6、m aspirin.Cannon第7页，共50页。Gender differencesSignificant differences in stroke reduction in the Womens Health Study and the Physicians Health StudyDoes stroke occur earlier in women than it does in men?第8页，共50页。Gender differencesMean ages roughly the same, but different follow-upPhysicians Health Stud

7、y: 5-year follow-upWomens Health Study: 10-year follow-upThese are not apples and apples were comparing.- Ferguson第9页，共50页。WHS: Aspirin doseWe dont know what the right dose of aspirin is right now.- FergusonPhysicians Health Study used 325-mg doseAntithrombotic Trialist Collaboration suggests doses

8、less than 75 mg/day not as effective第10页，共50页。WHS: The guidelines Changing guidelines? No need . . .Aspirin used in primary prevention only when patients risk-factor profile is intermediate based on Framingham risk scoreBut may need to revisit the stroke reduction benefitFuster第11页，共50页。WHS: Who get

9、s aspirin?How low down the risk spectrum do we go?No benefit in younger patientsNeed to categorize women at high risk for stroke to direct aspirin therapy to them Cannon第12页，共50页。WHS: Not change practiceIts telling us what we sort of knew already. Not everybody needs to be taking aspirin.Benefits ti

10、ed to the degree of riskStroke-prevention data need to be teased out furtherFerguson第13页，共50页。COMMITClopidogrel and Metoprolol in Myocardial Infarction TrialCLARITYClopidogrel as Adjunctive Reperfusion Therapy - Thrombolysis in Myocardial Infarction (TIMI) 28第14页，共50页。New data about clopidogrel CLAR

11、ITY(N Engl J Med 2005: published March 9, 2005)3500 patients Clopidogrel improved infarct-related artery patency in MI patients receiving thrombolysis-Reduced occluded arteries by 36%-Reduced death, MI, or recurrent ischemia requiring revascularization at 30 days by 20%第15页，共50页。New data about clopi

12、dogrel COMMIT46 000 patients Addition of clopidogrel in patients with ST-segment-elevation MI with or without thrombolysis-Death/MI/stroke reduced by 9%-Death reduced by 7%第16页，共50页。CLARITY and COMMITThis adds the final piece of the puzzle that clopidogrel is beneficial in ST-segment-elevation MI- C

13、annon第17页，共50页。CLARITY and COMMITSubstantial clinical benefit in keeping vessels openCOMMIT counterintuitive: most of the benefit in patients presenting within first 12 hoursTrend toward benefit in patients also treated with fibrinolyticsFerguson第18页，共50页。MechanismsSame mechanism as aspirin?After 18

14、0 minutes, the arteries open more and stay open because of the combinationPrevention of reocclusion is likely the operative mechanismTwo agents are better than one. Cannon第19页，共50页。CLARITY and COMMITIf you have risk, more antiplatelet therapy provides incremental benefitOpportunity to significantly

15、improve aspirinFerguson第20页，共50页。TNT Treating to New TargetsHigh-dose atorvastatin in stable CHD patients第21页，共50页。TNT: DesignLowering LDL cholesterol levels in stable CHD patients substantially below current guidelines(N Engl J Med 2005: published March 8, 2005)Parallel-group study randomizing 10 0

16、01 patients to atorvastatin 10 mg or 80 mgPatients included were men and women aged 35 years to 75 years with clinically evident CHDPrimary end point was first major CV event (death from CHD, nonfatal MI, nonfatal and fatal stroke, or resuscitation after cardiac arrest)5-year follow-up 第22页，共50页。TNT

17、: LDL cholesterol levels LDL cholesterol levelAtorvastatin 10 mg (n=5006)Atorvastatin 80 mg (n=4995)Mean baseline LDL cholesterol levels (mg/dL)9897Final LDL cholesterol levels (mg/dL)10177第23页，共50页。TNT: Primary efficacy outcomes OutcomeAtorvastatin 10 mg (n=5006)Atorvastatin 80 mg (n=4995)Hazard ra

18、tio(95% CI)pTotal major cardiovascular events (%)10.98.70.78(0.69-0.89)0.001Death from coronary heart disease (%)2.52.00.80(0.61-1.03)0.09Nonfatal MI (%)6.24.90.78(0.66-0.93)0.004Resuscitation after cardiac arrest (%)0.50.50.96(0.56-1.67)0.89Fatal or nonfatal stroke (%)3.12.3 0.75(0.59-0.96)0.02第24页

19、，共50页。TNT: What does it add?PROVE-IT showed that lower is better in ACS patients, but did it apply to stable CHD patients?Yes! Confirms and supports that lower LDL cholesterol is better, but also expands the principle to more than 30 million US patientsCannon第25页，共50页。TNT: What does it add?Baseline

20、LDL cholesterol levels low in TNTNo longer good enough to simply put a statin in the drinking waterLevel of LDL cholesterol matters need to get it down even further than we thought we did第26页，共50页。Is it all about the LDL? Looking down the road to tease out benefitWhat happens when patients are strat

21、ified by LDL cholesterol levels coming into the study?Is it all LDL? What happens above and beyond LDL lowering?Ferguson第27页，共50页。Beyond the guidelines Patient with angina and prior MIGoal to bring LDL cholesterol level to 70 mg/dLDo I start treatment at the maximum 80-mg dose of atorvastatin? Fuste

22、r第28页，共50页。ACS vs stable CHDIn ACS patients, start with a high-dose statin, as PROVE-IT showed benefit emerged after 10 daysIn stable CHD patients, slower titration is an option, but getting control of LDL and CRP is keyCannon第29页，共50页。TNT: Safety issues 1.2% of patients treated with atorvastatin 80

23、 mg had a persistent elevation in alanine aminotransferase, aspartate aminotransferase, or both, compared with 0.2% of patients receiving atorvastatin 10 mg (p160 mm Hg systolic or 100 mm Hg diastolic untreated or 140 mm Hg systolic or 90 mm Hg diastolic despite being on treatment 第37页，共50页。ASCOT-BP

24、LA: DesignAmlodipine (5/10 mg) with or without perindopril (4/8 mg) or Atenolol (50/100 mg) with or without the bendroflumethiazide (1.25-2.5 mg)as well as further treatment as required to reach a target BP 140/90 mm HgRandomized to第38页，共50页。Amlodipine/perindopril vs atenolol/bendroflumethiazideEnd

25、point Hazard ratio95% CIpAll-cause mortality0.860.78-0.960.005Primary end point: nonfatal MI and fatal CHD0.900.78-1.030.12Total coronary end point: primary end point + new-onset angina + fatal and nonfatal heart failure0.860.78-0.960.0048Fatal and nonfatal stroke0.770.66-0.900.0007All CV events and

26、 revascularization procedures0.840.77-0.900.0001CV mortality0.76 0.65-0.910.0017第39页，共50页。ASCOT-BPLA: Results Amlodipine plus an ACE inhibitor vs atenolol plus a diuretic achieved similar blood-pressure control, and yet the results are quite different Fuster第40页，共50页。ASCOT: Targeted therapy My initi

27、al gut reaction was that the results were a little bit of a surprise.The mechanistically targeted therapy more effective than older strategiesMore going on than a simple reduction in blood pressure, but not sure if ACE inhibitor is driving the results Ferguson第41页，共50页。ASCOT: Surprising resultsMy ta

28、ke-away is that calcium-channel blockers are back.Amlodipine plus an ACE inhibitor looks terrific in these patients Shifts the order we start choosing medicinesmoves calcium-channel blockers upCannon第42页，共50页。ASCOT: New onset diabetes with amlodipine/perindopril vs atenolol/ bendroflumethiazide End

29、pointHazard ratio95% CIpNew diabetes mellitus0.680.60-0.770.0001第43页，共50页。ASCOT: Diabetes dataIs the benefit providing a better milieu and a less likelihood for developing diabetes, or is the diabetes driving the negative results for atenolol? My guess is that the diabetes is not the driving force h

30、ere- Ferguson第44页，共50页。ASCOT: Diabetes dataTime for diabetes to translate into excess MI or mortality is longer than the duration of the study But the risk of developing diabetes should be a factor in deciding which therapy to select- Cannon第45页，共50页。Other drug effectsWhen you give a drug to move a parameter, such as b