他汀用于心血管疾病一级预防_诸俊仁.ppt

1、他汀用于心血管疾病一级预防的时代到了吗 ?,诸骏仁,复旦大学中山医院,WOS : NEJM 1995; 333 : 1301-1307 CARE : NEJM 1996; 335 : 1001-1009 LIPID : NEJM 1998; 339: 1349-1357 4S : Lancet 1994; 344 : 1383-1389 TexCAPS: JAMA 1998; 279: 1615-1622,经典他汀临床试验,CARE n=4,159 TC 5.4 mmol/l,LIPID n=9,014 TC 5.6 mmol/l,WOS n=6,595 TC 7.0 mmol/l,4S n=

2、4,444 TC 6.8 mmol/l,有冠心病 高胆固醇,有冠心病 正常胆固醇,无冠心病 高胆固醇,TexCAPS n=6,605 TC 5.7 mmol/l,无冠心病 低 HDL,二级预防,一级预防,他汀在二级预防心血管病、临床事件、死亡中的作用已经确立，但对其在心血管事件的一级预防中的作用尚知之甚少,Abramson J, Wright J. Lancet 2007; 369-168-169.,2007,血脂指南是否都是循证的？,“最近一版的美国指南是2001年的，将推荐用他汀的美国人由1300万增加到3600万，他们大多数还没有发生冠心病，但估计处于发生冠心病的危险轻度增高。为支持在妇

3、女和65岁以上的人用他汀作冠心病一级预防，指南分别引用了7项和5项随机临床试验。但是，其中没有一项提供这种证据”,Abramson J, Wright J. Lancet 2007; 369-168-169.,Abramson J, Wright J. Lancet 2007; 369-168-169.,推荐他汀用于一级预防被质疑,*两项试验报告,基于分析 8项随机临床试验比较他汀与安慰剂 在危险增加的人群一级预防,他汀不宜用于任何年龄妇女和69岁以上男性！,若只考虑心血管事件, 他汀使结局减低到统计学显著意义的程度 ，然而，绝对危险减低 1.5% 是小的。这意味着必须平均 67人 治疗5年才

4、防止1起事件。 上述获益仅限于年龄30-69岁间的高危男人. 试验汇总中将近11000名妇女他汀未减少冠心病事件，69岁以上男或女性(n=3239)也然如此。,争辩,Abramson J, Wright J. Lancet 2007; 369-168-169.,分歧何来?,假设问题 当今指南均基于以下假设: 心血管危险为连续体 二级预防中收益的证据可以延伸到一级预防人群 心血管危险能被准确预测 分析的方法学问题 二级预防与一级预防试验混合分析,Abramson J, Wright J. Lancet 2007; 369-168-169.,2008,用他汀治疗作心血管死亡和事件一级预防 6500

5、0病人联网荟萃分析,随机影响荟萃分析: 心血管病死亡率,Mills EJ, et al. JACC 2008:52;1769-1781,随机影响荟萃分析：全因死亡率,Mills EJ, et al. JACC 2008:52;1769-1781,汇集估算: 二级结局,Mills EJ, et al. JACC 2008:52;1769-1781,结论: 他汀在心血管病的一级预防显然起作用,2009,在无确立的心血管病但有心血管危险因素者的他汀获益： 随机对照临床试验的荟萃分析,Brugts JJ,et al.BMJ 2009;338:b2376,Brugts JJ,et al. BMJ 200

6、9;338:b2376,以前知道什么What is already known 他汀在确有心血管病病人（二级预防）有效，但获益 是否适用于一级预防 则未知 研究对他汀用在处于比较低危的人所提供的回答莫衷 一是 他汀在65岁以上人和糖尿病人群亚组的效果有争议,现在提示什么What is suggested now 他汀在无确立心血管病的病人改善生存率、减低主要 心血管和脑血管事件在临床上设定的年龄、性别、和糖尿病的组群他汀的 疗效无差别处于心血管病危险增高的人不应否认他汀应用的相对 获益,Brugts JJ,et al. BMJ 2009;338:b2376,荟萃分析的受限分析中纳入了临床有心血

7、管病的病人(6%) 包括的临床试验间他汀的品种和剂量各异 包括的临床试验代表着临床上危险水平不 等的参试者,Brugts JJ,et al. BMJ 2009;338:b2376,一级预防他汀试验的比较,一级预防他汀试验的比较,何人何时应该用他汀作一级预防? For whom and when should statin be used in primary prevention?,ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapy in Different Risk Categories and Proposed Modifi

8、cations Based on Recent Clinical Trial Evidence,Grundy, S. et al., Circulation 2004;110:227-39.,不同危险人群TLC和药物治疗的目标和切点 (ATP III 2004),不同危险人群TLC和药物治疗的目标和切点 (中国指南),极高危冠心病+ 1)急性冠脉综合征 2)糖尿病,Chinese Guidelines for Prevention and Management of Dyslipidemia in Adults,2007,Japan Atherosclerosis Society Guidel

9、ine for Diagnosis and Prevention of Atherosclerotic Cardiovascular Disease for Japanese,J Athroscler Thromb 2007:14;209-214,日本动脉粥样硬化学会日本人诊断和 预防粥样硬化性心血管病指南,无确立的粥样硬化心血管病但有心血管病危险因素且血脂水平相对较高者是合理的用他汀作一级预防的对象,他汀治疗与发生2型糖尿病的危险:一项荟萃分析, Analysis of 6 trials with WOSCOPS added Decrease of DM risk RR 1.0695%CI

10、0.93-1.25 Hetrogeneity significant WOSCOPS Decrease of DM risk RR 0.795%CI 0.5-0.99,Diabetes Care. 2009(Oct);32(10):1941-3,Rainathak SN,Kumbhani DI,Crandall J,Barzilai N,Alderman M,Ridker PM, Analysis of 5 trials(HPS,LIPID,ASCOT,JUPITER,CORONA) 57593 patients mean FU 3.9 years 2082 incident DM Incre

11、ase of DM risk RR 1.1395%CI 1.03-1,23 No heterogeneity across trials,结论: 虽然他汀治疗大大降低血管性风险,包括有糖尿病或有 糖尿病危险者,但他汀治疗与间发 糖尿病的关系仍未明,估测危险是重要的!,危险因素,主要, 独立的危险因素 吸烟 高血压 血脂异常 高LDL- c 低HDL-c 早发冠心病家族史 年龄 (男 45岁;女55岁) 生活习惯危险因素 肥胖(BMI 30) 体力活动少 致粥样硬化饮食,发展中危险因素 Lp(a) 同型半胱胺酸 促栓因素 促炎因素 空腹血糖高 亚临床粥样硬化,ATP III,2001,“.” 当

12、前,对以下各点尚不明确: 什么人应筛查 hs-CRP?, 如果升高,什么人应该治疗? 筛查所有人群或以危险人群为目标是否合算?,CRP在一级预防时危险评估中的地位,CRP对血管炎症非特异性,N=90,N=35,N=35,Data on file; diaDexus, Inc.,生物标志物的生物变异性比较,Data on file; diaDexus, Inc.,炎性标志物,Ridker PM, et al, Circulation. 1998 Ridker PM, et al. New Engl J Med. 1997 Ridker PM, et al, Circ. 2001,4. Carpe

13、nter Keri LH, et al. FEBS Lett. 2001 5. Macphee CH, et al. Expert Opin Ther Targets. 2002 6. Packard CH, et al. New Engl J Med. 2000,Design: 1. Carried out a genome-wide association (n=17967) and replication study (n=13615) to identify genetic loci associated with plasma CRP concentrations. 2.Carrie

14、d out a Mendelian randomization study of most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28112 cases and 100823 controls, to investigate the association of CRP variants with coronary heart disease. 3.Compared

15、 our finding with that predicted from meta-analysis of observa- tional studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, selected the most closely associated SNP for testing against coronary heart disease among 14365 cases and 32069 controls. Re

16、sults:Mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease 结论: CRP基因型的冠心病危险作用与CRP血中水平之间缺乏一致性说明CRP与冠心病之间无因果关系,基因位点和CRP水平的相关同冠心病的危险,hsCRP在心血管病一级预防中有何作用?,hsCRP是一种炎症的标志物,敏感度高而特异性差.迄今 为止未有hsCRP作为血管性炎症特异标志物的证据. 如hsCRP增高,只有除外其他炎症病因方可考虑心血管 相关的意义,因此在人群中

17、普遍用作筛选并不值得. hsCRP作为一种炎症的参考标志物,不是治疗的靶的. 如已有其他心血管危险因素存在,hsCRP的增高有支持 价值.,老年人研究,研究发现最大的获益集中于占32%的随机时年龄为70岁 或70岁略高者,这些病人构成一级终点的49%.,研究提供强力证据不要忽略他汀对老年人的获益,JUPITER in the elderly,胆固醇增高对相对危险的影响随年龄降低.40岁心脏病人 LDL-C下降 40-mg/dL使心血管事件下降56%,但在70岁者 同样幅度LDL-C改变仅下降17%. JUPITER研究中老年人复合一级终点减低39%,少于非老年人.但5年预防一级终点NNT为19

18、,在年轻人为29人;预防一次一级终点NNT为29,在年轻人为55,JUPITER,耐受性和安全数据,Rosuvastatin placebo p value (n=9801) (n=9801) 不良事件(%) 任何 SAE 15.2 15.5 0.60 肌无力,肌痛 16.0 15.4 0.34 肌病 0.1 0.1 0.82 肌溶 0.1 0.1 - 新肿瘤 3.4 3.5 0.51 肿瘤死亡 0.4 0.7 0.02 胃肠病案 19.7 19.2 0.43 肾疾病 6.0 5.4 0.08 出血 2.9 3.1 0.45 肝病案 2.4 2.1 0.13 其他事件(%) 新发糖尿病* 3.

19、0 2.4 0.01 出血性卒中 0.1 0.1 0.44 *医师报告新诊断糖尿病,Ridker P et al. N Eng J Med 2008;359:2195,他汀与发生 2型糖尿病: 荟萃分析, Analysis of 6 trials with WOSCOPS added Decrease of DM risk RR 1.0695%CI 0.93-1.25 Hetrogeneity significant WOSCOPS Decrease of DM risk RR 0.795%CI 0.5-0.99,Diabetes Care. 2009(Oct);32(10):1941-3,R

20、ainathak SN,Kumbhani DI,Crandall J,Barzilai N,Alderman M,Ridker PM, Analysis of 5 trials(HPS,LIPID,ASCOT,JUPITER,CORONA) 57593 patients mean FU 3.9 years 2082 incident DM Increase of DM risk RR 1.1395%CI 1.03-1,23 No heterogeneity across trials,结论: 虽然他汀治疗大大减低血管危险,包括已有糖尿病或有糖尿病危险者, 但她汀与间发糖尿病之间的关系仍然未明.

21、,Michos ED et al. J Am Coll Cardiol 2009; 53:931-935.,Population estimate meeting the JUPITER study eligibility (in millions),Statins for the Primary Prevention of CHD: Has the Time Arrived ?,Zhu Jun Ren Zhong Shan Hospital Fudan University,WOS : NEJM 1995; 333 : 1301-1307 CARE : NEJM 1996; 335 : 10

22、01-1009 LIPID : NEJM 1998; 339: 1349-1357 4S : Lancet 1994; 344 : 1383-1389 TexCAPS: JAMA 1998; 279: 1615-1622,Classic statin clinical trials,CARE n=4,159 TC 5.4 mmol/l,LIPID n=9,014 TC 5.6 mmol/l,WOS n=6,595 TC 7.0 mmol/l,4S n=4,444 TC 6.8 mmol/l,With CHD high cholesterol,With CHD normal cholestero

23、l,Without CHD high cholesterol,TexCAPS n=6,605 TC 5.7 mmol/l,Without CHD low HDL,Secondary prevention,Primary prevention,The role of statin is well established for secondary prevention of cardiovascular diseases, clinical events and mortality, little is known of their role in primary cardiovascular

24、event prevention,Abramson J, Wright J. Lancet 2007; 369-168-169.,2007,“The last major revision of the US guidelines, in 2001, increased the number of Americans for whom statins are recommended from 13 million to 36 million, most of whom do not yet have but are estimated to be at moderately elevated

25、risk of developing coronary heart disease. In support of statin therapy for the primary prevention of this disease in women and people aged over 65 years, the guidelines cite seven and nine randomized trials, respectively. Yet not one of the studies provides such evidence.”,Abramson J, Wright J. Lan

26、cet 2007; 369-168-169.,Abramson J, Wright J. Lancet 2007; 369-168-169.,Recommendation of statins in primary prevention questioned,*Reported in two trials only,Based on analysis of 8 RCT compared statin and placebo in primary prevention populations at increased risk,Statin should not be used in women

27、 of any age and men aged over 69 years,When only cardiovascular events were considered, statins reduced this outcome to a statistically significant degree; however, the absolute risk reduction of 1.5% was small. This would mean 67 people have to be treated for five years to prevent one event. This b

28、enefit might be confined to high-risk men between the ages of 30 and 69. Statins did not reduce coronary heart disease events in the almost 11000 women in pooled trials, nor in men and women older than 69 (n=3239).,Arguments,Abramson J, Wright J. Lancet 2007; 369-168-169.,Why the disagreement?,Probl

29、ems in assumptions Current guidelines are based on the assumptions: Cardiovascular risk is a continuum Evidence of benefits in secondary prevention can be extrapolated to primary prevention populations Cardiovascular risk can be accurately predicted Problems in methodology of analysis Mixed analysis

30、 of trials of statins for secondary prevention and for primary prevention,Abramson J, Wright J. Lancet 2007; 369-168-169.,2008,Random effects meta-analysis: All cause mortality,Mills EJ, et al. JACC 2008:52;1769-1781,Pooled estimate: Secondary outcomes,Mills EJ, et al. JACC 2008:52;1769-1781,Conclus

31、ion: Statin have a clear role in primary prevention of CVD,Random effect meta-analysis: cardiovascular mortality,Mills EJ, et al. JACC 2008:52;1769-1781,2009,Brugts JJ,et al.BMJ 2009;338:b2376,Brugts JJ,et al. BMJ 2009;338:b2376,What is already known Statins are effective in patients with establishe

32、d cardiovascular disease (secondary prevention) but whether the benefits apply to primary prevention is unknown Research has provided ambiguous answers on statin use in people at relatively lower risk The efficacy of statins in subgoups of people aged more than 65,women, and those with diabetes is d

33、ebated,What is suggested now Statins improve survival and reduce the risk of major cardiovascular and cerebrovascular events in people without established cardiovascular diseaseNo significant differences in treatment effect of statins were observed in clinically defined groups of age, sex, and diabe

34、tes statusPeople at increased risk of cardiovascular disease should not be denied the relative benefits of long term statin use,Brugts JJ,et al. BMJ 2009;338:b2376,Limitations of meta-analysisThree trials in the analysis had recruited patients with clinical cardiovascular disease(6%)The dose and typ

35、e of statins differed between included trialsThe included trials represented participants with a clinically heterogenous level of risk,Brugts JJ,et al. BMJ 2009;338:b2376,Comparison of statin trials in primary prevention,Comparison of statin trials for primary prevention,For whom and when should sta

36、tin be used in primary prevention?,ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapy in Different Risk Categories and Proposed Modifications Based on Recent Clinical Trial Evidence,Grundy, S. et al., Circulation 2004;110:227-39.,Goals and Cutpoints for TLC and Drug Therapy in Different Risk

37、 Categories (Chinese Guidelines),Very high riskischemic heart disease(CHD)+ 1)Acute coronary syndrome 2)diabetes mellitus,Chinese Guidelines for Prevention and Management of Dyslipidemia in Adults,2007,Japan Atherosclerosis Society Guideline for Diagnosis and Prevention of Atherosclerotic Cardiovasc

38、ular Disease for Japanese,J Athroscler Thromb 2007:14;209-214,Those have no established atherosclerotic cardiovascular diseases but have cardiovascular disease risk factors and at relatively high lipid levels are reasonable candidates for primary prevention with statins,Estimating risk is important!

39、,Risk Factors,Major, independent risk factors Cigarette smoking Hypertension Dyslipidemia High LDL cholesterol Low HDL cholesterol Family history of premature CHD Age (men 45 yrs; women 55 yrs) Life-habit risk factors Obesity (BMI 30) Physical inactivity Atherogenic diet,Emerging risk factors Lipopr

40、otein (a) Homocysteine Prothrombotic factors Proinflammatory factors Impaired fasting glucose Subclinical atherosclerosis,ATP III,2001,. Currently, it is not clear who should be screened for hs-CRP?, if it is elevated, who should be treated? whether screening all persons or targeting populations at

41、risk would be cost-effective?,What is the role of CRP in risk assessment for primary prevention,CRP is nonspecific to vascular inflammation,N=90,N=35,N=35,Data on file; diaDexus, Inc.,Comparison of biovariability of markers,Data on file; diaDexus, Inc.,2,Inflammatory markers,Ridker PM, et al, Circul

42、ation. 1998 Ridker PM, et al. New Engl J Med. 1997 Ridker PM, et al, Circ. 2001,4. Carpenter Keri LH, et al. FEBS Lett. 2001 5. Macphee CH, et al. Expert Opin Ther Targets. 2002 6. Packard CH, et al. New Engl J Med. 2000,Design: 1. Carried out a genome-wide association (n=17967) and replication stud

43、y (n=13615) to identify genetic loci associated with plasma CRP concentrations. 2.Carried out a Mendelian randomization study of most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28112 cases and 100823 controls

44、, to investigate the association of CRP variants with coronary heart disease. 3.Compared our finding with that predicted from meta-analysis of observa- tional studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, selected the most closely associated

45、 SNP for testing against coronary heart disease among 14365 cases and 32069 controls. Results:Mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease Conclusion: Lack of concordance between the effect of coronary artery disease risk of CRP genotyp

46、es and CRP levels argues against a causal association of CRP and coronary artery disease,What is the role of hsCRP in primary CVD prevention,hsCRP is a marker for inflammation with high sensitivity but low specificity as far as CVD is concerned. Up to the present no evidence was obtained to show hsC

47、RP as the specific marker of vascular inflammation. In case of increased hsCRP,it become significant for CVD only after excluding other inflammatory etiology, therefore it is not cost-effective in screening in the general population. As a reference marker of inflammation, hsCRP is not the target of

48、treatment.,in the elderly,The trial found a huge benefit is focusing on the 32% of the population who were 70 years old and older at randomization. Those 32% had 49% of the primary end points.,It provides strong evidence for not depriving elderly patients the benefits of statins,JUPITER in the elder

49、ly,The relative risks of elevated cholesterol levels decline with increasing age. A meta-analysis showed that an approximate 40-mg/dL reduction in LDL cholesterol in a patient 40 years old with heart disease results in roughly a 56% reduction in risk of cardiovascular events, whereas the same LDL reduction in a patient 70 years old results