Xue Hao, Lu Zhuang, Tang Wen Lu, Pang Lu Wei, Wang Gan Mi, Wong Gavin W K, Wright James M
Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, China, 201203.
Cochrane Database Syst Rev. 2015 Jan 11;1:CD008170. doi: 10.1002/14651858.CD008170.pub2.
Renin-angiotensin system (RAS) inhibitors are widely prescribed for treatment of hypertension, especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for hypertension in both diabetic and non-diabetic patients, the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear.
To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension.
We searched the Cochrane Hypertension Group's Specialised Register, MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to November 19, 2014 and the Cochrane Central Register of Controlled Trials (CENTRAL) up to October 19, 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Cochrane Hypertension Group's Specialised Register.
We included randomized, active-controlled, double-blinded studies with at least six months follow-up in people with primary elevated blood pressure (≥130/85 mmHg), which compared first-line RAS inhibitors with other first-line antihypertensive drug classes and reported morbidity and mortality or blood pressure outcomes. Patients with proven secondary hypertension were excluded.
Two authors independently selected the included trials, evaluated the risk of bias and entered the data for analysis.
We included 42 studies, involving 65,733 participants, with a mean age of 66 years. Much of the evidence for our key outcomes is dominated by a small number of large studies at a low risk of bias for most sources of bias. Imbalances in the added second-line antihypertensive drugs in some of the studies were important enough for us to downgrade the quality of the evidence.Primary outcomes were all-cause death, fatal and non-fatal stroke, fatal and non-fatal myocardial infarction (MI), fatal and non-fatal congestive heart failure (CHF) requiring hospitalization, total cardiovascular (CV) events (consisted of fatal and non-fatal stroke, fatal and non-fatal MI and fatal and non-fatal CHF requiring hospitalizations), and ESRF. Secondary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).Compared with first-line calcium channel blockers (CCBs), we found moderate quality evidence that first-line RAS inhibitors decreased heart failure (HF) (35,143 participants in 5 RCTs, RR 0.83, 95% CI 0.77 to 0.90, ARR 1.2%), and moderate quality evidence that they increased stroke (34,673 participants in 4 RCTs, RR 1.19, 95% CI 1.08 to 1.32, ARI 0.7%). They had similar effects on all-cause death (35,226 participants in 5 RCTs, RR 1.03, 95% CI 0.98 to 1.09; moderate quality evidence), total CV events (35,223 participants in 6 RCTs, RR 0.98, 95% CI 0.93 to 1.02; moderate quality evidence), total MI (35,043 participants in 5 RCTs, RR 1.01, 95% CI 0.93 to 1.09; moderate quality evidence). The results for ESRF do not exclude potentially important differences (19,551 participants in 4 RCTs, RR 0.88, 95% CI 0.74 to 1.05; low quality evidence).Compared with first-line thiazides, we found moderate quality evidence that first-line RAS inhibitors increased HF (24,309 participants in 1 RCT, RR 1.19, 95% CI 1.07 to 1.31, ARI 1.0%), and increased stroke (24,309 participants in 1 RCT, RR 1.14, 95% CI 1.02 to 1.28, ARI 0.6%). They had similar effects on all-cause death (24,309 participants in 1 RCT, RR 1.00, 95% CI 0.94 to 1.07; moderate quality evidence), total CV events (24,379 participants in 2 RCTs, RR 1.05, 95% CI 1.00 to 1.11; moderate quality evidence), and total MI (24,379 participants in 2 RCTs, RR 0.93, 95% CI 0.86 to 1.01; moderate quality evidence). Results for ESRF do not exclude potentially important differences (24,309 participants in 1 RCT, RR 1.10, 95% CI 0.88 to 1.37; low quality evidence).Compared with first-line beta-blockers, we found low quality evidence that first-line RAS inhibitors decreased total CV events (9239 participants in 2 RCTs, RR 0.88, 95% CI 0.80 to 0.98, ARR 1.7%), and low quality evidence that they decreased stroke (9193 participants in 1 RCT, RR 0.75, 95% CI 0.63 to 0.88, ARR 1.7% ). Our analyses do not exclude potentially important differences between first-line RAS inhibitors and beta-blockers on all-cause death (9193 participants in 1 RCT, RR 0.89, 95% CI 0.78 to 1.01; low quality evidence), HF (9193 participants in 1 RCT, RR 0.95, 95% CI 0.76 to 1.18; low quality evidence), and total MI (9239 participants in 2 RCTs, RR 1.05, 95% CI 0.86 to 1.27; low quality evidence).Blood pressure comparisons between RAS inhibitors and other classes showed either no differences or small differences that did not necessarily correlate with the differences in the morbidity outcomes.In the protocol, we identified non-fatal serious adverse events (SAE) as a primary outcome. However, when we extracted the data from included studies, none of them reported total SAE in a manner that could be used in the review. Therefore, there is no information about SAE in the review.
AUTHORS' CONCLUSIONS: We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to other first-line antihypertensive agents. First-line thiazides caused less HF and stroke than first-line RAS inhibitors. The quality of the evidence comparing first-line beta-blockers and first-line RAS inhibitors was low and the lower risk of total CV events and stroke seen with RAS inhibitors may change with the publication of additional trials. Compared with first-line CCBs, first-line RAS inhibitors reduced HF but increased stroke. The magnitude of the reduction in HF exceeded the increase in stroke. The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes.
肾素 - 血管紧张素系统（RAS）抑制剂被广泛用于治疗高血压，尤其是糖尿病患者，基于其在降低糖尿病肾病以及心血管发病率和死亡率方面的假定优势。尽管血管紧张素转换酶（ACE）抑制剂和血管紧张素受体阻滞剂（ARB）在糖尿病和非糖尿病高血压患者中广泛使用，但与其他抗高血压药物类别相比，RAS抑制剂的疗效和安全性仍不明确。
评估一线RAS抑制剂与其他一线抗高血压药物相比，对高血压患者的益处和危害。
我们检索了Cochrane高血压组专业注册库、MEDLINE、MEDLINE在研数据库、EMBASE和ClinicalTrials.gov，检索截至2014年11月19日的随机对照试验，以及截至2014年10月19日的Cochrane对照试验中央注册库（CENTRAL）。检索世界卫生组织国际临床试验注册平台（ICTRP）以纳入Cochrane高血压组专业注册库。
我们纳入了对原发性血压升高（≥130/85 mmHg）人群进行的至少六个月随访的随机、活性药物对照、双盲研究，这些研究比较了一线RAS抑制剂与其他一线抗高血压药物类别，并报告了发病率、死亡率或血压结果。排除已证实为继发性高血压的患者。
两位作者独立选择纳入的试验，评估偏倚风险并录入数据进行分析。
我们纳入了42项研究，涉及65733名参与者，平均年龄为66岁。对于我们的关键结局，大部分证据由少数大型研究主导，这些研究在大多数偏倚来源方面偏倚风险较低。一些研究中添加的二线抗高血压药物的不平衡对我们来说足够重要，以至于我们降低了证据的质量。主要结局为全因死亡、致命和非致命性卒中、致命和非致命性心肌梗死（MI）、需要住院治疗的致命和非致命性充血性心力衰竭（CHF）、总心血管（CV）事件（包括致命和非致命性卒中、致命和非致命性MI以及需要住院治疗的致命和非致命性CHF）和终末期肾病（ESRF）。次要结局为收缩压（SBP）、舒张压（DBP）和心率（HR）。与一线钙通道阻滞剂（CCB）相比，我们发现中等质量证据表明一线RAS抑制剂可降低心力衰竭（HF）（5项随机对照试验中的35143名参与者，RR 0.83，95%CI 0.77至0.90，绝对风险降低率（ARR）1.2%），中等质量证据表明其会增加卒中（4项随机对照试验中的34673名参与者，RR 1.19，95%CI 1.08至1.32，归因风险增加率（ARI）0.7%）。它们对全因死亡（5项随机对照试验中的35226名参与者，RR 1.03，95%CI 0.98至1.09；中等质量证据）、总CV事件（6项随机对照试验中的35223名参与者，RR 0.98，95%CI 0.93至1.02；中等质量证据）、总MI（5项随机对照试验中的35043名参与者，RR 1.01，95%CI 0.93至1.09；中等质量证据）有相似影响。ESRF的结果不排除潜在的重要差异（4项随机对照试验中的19551名参与者，RR 0.88，95%CI 0.74至1.05；低质量证据）。与一线噻嗪类药物相比，我们发现中等质量证据表明一线RAS抑制剂会增加HF（1项随机对照试验中的24309名参与者，RR 1.19，95%CI 1.07至1.31，ARI 1.0%），并增加卒中（1项随机对照试验中的24309名参与者，RR 1.14，95%CI 1.02至1.28，ARI 0.6%）。它们对全因死亡（1项随机对照试验中的24309名参与者，RR 1.00，95%CI 0.94至1.07；中等质量证据）、总CV事件（2项随机对照试验中的24379名参与者，RR 1.05，95%CI 1.00至1.11；中等质量证据）和总MI（2项随机对照试验中的24379名参与者，RR 0.93，95%CI 0.86至1.01；中等质量证据）有相似影响。ESRF的结果不排除潜在的重要差异（1项随机对照试验中的24309名参与者，RR 1.10，95%CI 0.88至1.37；低质量证据）。与一线β受体阻滞剂相比，我们发现低质量证据表明一线RAS抑制剂可降低总CV事件（2项随机对照试验中的9239名参与者，RR 0.88，95%CI 0.80至0.98，ARR 1.7%），低质量证据表明其可降低卒中（1项随机对照试验中的9193名参与者，RR 0.75，95%CI 至0.88，ARR 1.7%）。我们的分析不排除一线RAS抑制剂与β受体阻滞剂在全因死亡（1项随机对照试验中的9193名参与者，RR 0.89，95%CI 0.78至1.01；低质量证据）、HF（1项随机对照试验中的9193名参与者，RR 0.95，95%CI 0.76至1.18；低质量证据）和总MI（2项随机对照试验中的9239名参与者，RR 1.05，95%CI 0.86至1.27；低质量证据）方面的潜在重要差异。RAS抑制剂与其他类别之间的血压比较显示无差异或差异很小，且这些差异不一定与发病率结局的差异相关。在方案中，我们将非致命性严重不良事件（SAE）确定为主要结局。然而，当我们从纳入的研究中提取数据时，没有一项研究以可用于综述的方式报告总SAE。因此，综述中没有关于SAE的信息。
我们发现主要为中等质量的证据表明，一线RAS抑制剂与其他一线抗高血压药物相比，全因死亡率相似。一线噻嗪类药物引起的HF和卒中比一线RAS抑制剂少。比较一线β受体阻滞剂和一线RAS抑制剂的证据质量较低，随着更多试验的发表，RAS抑制剂所见的总CV事件和卒中较低风险可能会改变。与一线CCB相比，一线RAS抑制剂降低了HF但增加了卒中。HF降低的幅度超过了卒中增加的幅度。不同类别药物在血压影响上的微小差异与主要结局的差异无关。
