讨 论
尽管替米沙坦组主要终点事件（心血管死亡、心肌梗死、卒中或因心力衰竭入院）较安慰剂组少，但差异无统计学意义。然而，HOPE研究中替米沙坦组到达次要终点（心血管死亡、心肌梗死和卒中）者少于安慰剂组。最近PRoFESS试验（近期卒中后患者应用替米沙坦和安慰剂的比较研究，历时2.5年[15]）也得出了类似结果。两个试验的联合分析显示替米沙坦显著减少心血管死亡、心肌梗死、卒中，然而对因心力衰竭入院两个试验均无此效。但按时间分层分析后发现，两个试验中替米沙坦对前6个月心血管死亡、心肌梗死、卒中的复合终点均无影响，而对6个月后终点有显著影响。这些分析提示ARB的益处延迟6~12个月后才出现，并可能需要几年时间才能显示其全部益处。
出人意料且令人困惑的是，在PRoFESS和TRANSCEND两试验中均未见替米沙坦对因心力衰竭入院的作用，而HOPE试验显示ACEI能显著减少心力衰竭[17]，HOPE试验、PEACE（用ACE预防事件）试验[18]和EUROPA（培哚普利减少稳定性冠心病心脏事件欧洲试验）[19]的联合分析也显示ACEI显著减少因心力衰竭入院[3]。PRoFESS和TRANSCEND研究中发现替米沙坦未能明显减少因心力衰竭入院，这与ONTARGET的研究结论相一致[7]，后者因心力衰竭入院的人数雷米普利组为354例（4.1%），替米沙坦组为394例（4.6%）（RR1.12，95%CI 0.97~1.29）。这些结果提出了替米沙坦预防心力衰竭的作用是否弱于ACEI的疑问。然而，已有针对低射血分数和心功能NYHA分级Ⅱ~Ⅳ级的心力衰竭患者[8]、严重高血压和左室肥厚的患者[10]，或高血压患者对比使用ARB和氨氯地平[20]的研究显示其他ARB可以减少因心力衰竭入院。与之前诸多ARB药物试验相比，本研究纳入的患者没有左室收缩功能障碍（心力衰竭是排除指标），极少数左室肥厚。TRANSCEND试验对照组中心力衰竭风险非常低（网络表格），导致心力衰竭获益的阙如也是可能的。例如，因心力衰竭入院中并不存在显著差异（HOPE试验安慰剂组为每年0.84%，TRANSCEND试验安慰剂组为每年0.96%）[17]，而HOPE试验中安慰剂组每年任何心力衰竭的发生率为2.40％，而本试验中仅为1.49％。在这样的情况下，囊括高危患者的HOPE和PROGRESS[21]试验中雷米普利和培哚普利降低心力衰竭风险，却对DREAM[22]和ADVANCE研究[12]中低危心力衰竭患者无同样效果是值得关注的。当心力衰竭绝对风险较低时，ACEI和ARB不降低心力衰竭发病率也是可能的。相较于HOPE试验（安慰剂组每年事件发生率3.06%），TRANSCEND试验中心肌梗死的发生率较低（每年1.09%）。因而，纳入TRANSCEND研究的人群本身心力衰竭的风险低于HOPE研究人群也是可能的。TRANSCEND试验女性比例约为40%，而ONTARGET试验及之前的ACEI试验女性比例约为25%。TRANSCEND试验中女性未从替米沙坦中明显获益，而HOPE试验男女获益相似。TRANSCEND试验受试对象他汀类药物的使用比例高于以往大多数试验，但TRANSCEND试验及以往试验中服用和未服用他汀的患者的预后是一致的。基于以上分析， TRANSCEND试验研究人群的特征与ONTRAGET及以往的试验人群可能不一样。随机分组后的安慰剂组使用利尿剂和β受体阻断剂比例高于替米沙坦组，这可能掩盖了心力衰竭。最后心力衰竭减少偶然性亦不能除外。
本研究的结果及ONTARGET试验替米沙坦和雷米普利对心肌梗死的相似作用（已证明二者减少此类事件发生），能解除关于ARB可能不减少心肌梗死的疑虑[23]。减少心肌梗死的结果与心力衰竭中坎地沙坦和安慰剂的对比研究结果一致[24]。在TRANSCEND试验（和安慰剂对比）、ONTARGET试验[11]（和ACEI对比）及LIFE研究[10]（和β受体阻断剂对比）中可一致观察到较低的卒中率，提示ARB对脑血管事件有独特益处，但仅据此尚不能定论。
TRANSCEND试验中， 纳入的是不耐受ACEI的患者。尽管如此，坚持使用替米沙坦的比例高于安慰剂，这显示替米沙坦具有良好的耐受性。事实上，即使患者服用ACEI曾有神经血管性水肿和其他副作用也可服用替米沙坦。本研究中较大比例患者接受了降脂药物、抗血小板药物和其他降压药物治疗。此外，与替米沙坦组相比，安慰剂组中更多的患者接受了额外降压治疗，这可能缩小了两组间血压的差异。因而，两组间血压存在适度差异。对适度血压差异的校正未影响TRANSCEND和PRoFESS试验对心血管死亡、心肌梗死及卒中事件的评价，这提示替米沙坦的获益很大比例上独立于血压降低。HOPE研究（雷米普利）[1]和LIFE研究（氯沙坦）[10]已有类似发现。
人们会设想延长替米沙坦治疗时间是否获益更多。PRoFESS[15]、HOPE[1]和LIFE[10]研究的结论支持此可能性，即随机分组后前6~12个月没有或获益很少，以后却可能显现。数个降压试验[25]及降脂试验[26-27]已发现此种延迟的获益。获益的延迟可能是由于通过降压或降脂减缓血管壁的动脉粥样硬化进程，这可能需要数月或数年。而且，即便在随访5年的研究中，治疗到事件的平均时间（假设风险一致）也仅为2.5年。再者，随着如增加他汀类药物和降压药物使用等背景治疗的改进，增加新药获益可能更多，但所需时间可能更长。上述结论提示预防血管事件（现有治疗基础上）的新干预试验应寻求更多获益（例如，RR10%~15%），并应适当延长试验时间以充分观察全部获益。此外，降脂试验[27-28]或ACEI试验[28]结束数年后持续的获益提示一旦血管壁的生物进程被顺利改善，获益将持续存在。
与既往ACEI或ARB试验[29]相比，本试验替米沙坦对糖尿病发病率的作用似乎较小。然而之前的研究中糖尿病并非预设终点[30]，纳入的研究对象囊括了RAAS系统（肾素-血管紧张素-醛固酮系统）严重亢进的患者，如心力衰竭患者[31]，与之对比的是β受体阻断剂或利尿剂[32-33]，且许多研究中血糖未被系统地检测，诊断也仅依据临床资料。仅有的一个前瞻性评价此问题的研究（DREAM）[22]发现，雷米普利预防糖尿病仅有9%的获益，且无显著性意义，这与本研究结果一致。
虽然替米沙坦对不耐受ACEI人群主要终点的作用无统计学意义，对次要终点间差异的解释也需谨慎，但与安慰剂相比，替米沙坦仍能减少HOPE研究的终点事件。而且，ONTARGET试验显示替米沙坦不劣于雷米普利，在PRoFESS试验中亦见事件减少的趋势。联合TRANSCEND和PRoFESS试验结果对此终点的一项预设分析结论是有统计学意义的，尤其在延长治疗时间的情况下（表5）。此外，替米沙坦减少由大血管和微血管事件及因心血管因素入院组成的复合终点事件（亦用于ADVANCE研究），再次展示了其临床益处。这些数据显示在其他标准治疗的基础上，加用替米沙坦能适中地增加获益。基于其耐受性及对心血管事件终点的作用，替米沙坦可作为不耐受ACEI的血管疾病或高危糖尿病患者治疗的候选药物。
Lancet 2008; 372: 1174–83
（徐绍鹏 译）
Acknowledgments:
The study was supported by a grant from Boehringer Ingelheim. S Yusuf was supported by the Heart and Stroke Foundation of Ontario, and a Senior Scientist Award from the Canadian Institutes of Health Research. We thank Judy Lindeman for secretarial assistance.
TRANSCEND Investigators
SWriting group: S Yusuf, K Teo, C Anderson, J Pogue, L Dyal, I Copland,
H Schumacher, G Dagenais, P Sleight.
Steering committee: S Yusuf *(chair and principal investigator),
P Sleight*, C Anderson*, K Teo*, I Copland*, B Ramos†, L Richardson*,
J Murphy*, M Haehl*, L Hilbrich†, R Svaerd*, K Martin†, D Murwin*,
T Meinicke†, A Schlosser*, G Schmidt†, R Creek*, H Schumacher*,
M Distel†, B Aubert, J Pogue, L Dyal, R Schmieder, T Unger, R Asmar,
G Mancia, R Diaz, E Paolasso, L Piegas, A Avezum G Dagenais,
E Cardona Munoz, J Probstfi eld, M Weber, J Young, R Fagard, P Jansky,
J Mallion, J Mann, M Böhm, B Eber, N B Karatzas, M Keltai, B Trimarco,
P Verdecchia, A Maggioni, F W A Verheugt, N J Holwerda,
L Ceremuzynski, A Budaj, R Ferreira, I Chazova, L Rydén, T L Svendsen,
K Metsärinne, K Dickstein, G Fodor, P Commerford, J Redon,
T R Luescher, A Oto, A Binbrek, A Parkhomenko, G Jennings, L S Liu,
C M Yu, A L Dans, R Shah, J-H Kim, J-H Chen, S Chaithiraphan
(*current members of the operations committee, †previous members of
the operations committee).
Correspondence to:
Dr Salim Yusuf, Population Health Research Institute, Hamilton Health Sciences and McMasterUniversity, 237 Barton Street East, Hamilton, ON, CanadaL8L 2X2(e-mail: yusufs@mcmaster.ca)
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