As the largest international multicenter clinical study of cardiovascular protection in the world, the ONTARGET study was described as “a model of non-inferiority clinical research” by the New England Journal of Medicine. Numerous previous clinical studies have demonstrated the benefit of ACEIs in reducing cardiovascular events in high-risk populations, and studies have demonstrated the benefit of ARBs, which also act on RAAS, in patients with heart failure and post-infarction left ventricular insufficiency, but are they as beneficial as ACEIs in terms of cardiovascular protection? What is the efficacy and tolerability of ARBs in patients who cannot tolerate ACEIs? These are questions of great interest for which evidence was first obtained in the ONRARGET study. I. ONTARGET Study Methods and Results Introduction The ONTARGET study was a large, multinational, multicenter, randomized, double-blind, parallel, controlled trial with 733 centers in 40 countries, enrolling 31,546 patients (>55 years of age, with coronary artery disease or diabetes combined with other risk factors and no evidence of heart failure). The patients were randomized to ramipril (10 mg/d), telmisartan (80 mg/d), or a combination of both, and were followed for a mean of 56 months to compare the efficacy and safety of the three treatment regimens. Also, patients who could not tolerate ACEI at initial enrollment were entered into the sub-study TRANSCEND and randomized to temisartan (80 mg/d) and placebo control to compare whether temisartan benefited from temisartan 80 mg/d in patients who could not tolerate ACEI and for tolerability issues. The primary endpoint was a composite cardiovascular endpoint consisting of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for congestive heart failure. Secondary endpoints were new diagnosis of congestive heart failure, cardiovascular revascularization, new-onset diabetes, cognitive decline, dementia, new-onset atrial fibrillation, and renal disease. The results of the ONTARGET study showed that telmisartan was non-inferior to ramipril in reducing cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure. The incidence of these cardiovascular events was 16.7% in the telmisartan group compared to 16.5% in the ramipril group, with a relative risk of 1.01 and 95% confidence interval of 0.94-1.09. Also, telmisartan showed better tolerability than ramipril, with 360 patients (4.2%) in the ramipril-treated group discontinuing treatment due to cough compared to 93 in the telmisartan group (1.1 percent). Twenty-five patients (0.3%) in the ramipril group discontinued treatment due to angioneurotic edema, compared with 10 patients (0.1%) in the temisartan group. The combination of the two drugs was not superior to ramipril monotherapy, with the aforementioned cardiovascular event rate of 16.3% in the combination group and a relative risk of 0.99 compared to the ramipril group, with a 95% confidence interval of 0.92-1.07. And the combination of the two drugs increased the incidence of adverse events such as hypotension, syncope and renal insufficiency. The results of the TRANSCEND study showed no significant difference between temisartan and placebo in reducing cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure in patients who could not tolerate ACEI. The incidence of these cardiovascular events was 15.7% in the temisartan group compared to 17% in the placebo group (p=0.216). Patients who were intolerant to ACEI tolerated ARB well, and the most common adverse effect was hypotension, with an incidence of only 0.98% compared with 0.54% in the placebo group. Second, study interpretation and clinical value assessment 1, ACEI and ARB endothelial protection mechanism of action similarities and differences By acting on different sites of the RAAS pathway to block the activation of RAAS, theoretically, ACEI and ARB should produce similar effects, but clinical application did observe the differences in efficacy and adverse effects of these two types of drugs. An increasing number of mechanisms have been used to explain these differences: 1) ARB can only block AT1R, ACEI can attenuate the binding of AngII to both AT1R and AT2R due to reduced AngII production, but the physiological mechanism of AT2R is currently unknown; 2) ACEI inhibits ACE while activating the ACE2-Ang-(1-7)-Mas axis, which can (3) ACEI inhibits the breakdown of bradykinin and other peptides involved in the inflammatory response, and the accumulation of inflammatory mediators stimulates the receptors in the lungs to cause cough, which explains the superior tolerance of ARB over ACEI. 2. ARB = ACEI + NO cough? From the results of the ONTARGET study, the benefit of ARB is not inferior to ACEI and has better tolerability, does it indicate that ARB has challenged the clinical status of ACEI? Let’s review the early studies of ARBs; the ELITE1, ELITE2, and OPTIMAAL studies failed to demonstrate non-inferiority of the results of the comparative study of losartan and captopril, and later clinical trials of ARBs (valsartan, candesartan, and losartan) and placebo controls did not yield evidence particularly favorable to ARBs. So what do we make of the ONTARGET results? Telmisartan, a novel ARB, has a unique property in addition to a long half-life – a partial agonist effect of peroxisome proliferator-activated receptor gamma (PPAR-γ), which allows it to protect multiple pathways through nitric oxide synthase (eNOS), oxidative stress, Rho kinase, etc. vascular endothelial function. This may partially explain the long-term benefit of telmisartan in reducing cardiovascular events. That said, the ONTARGET study does not generalize to all ARBs and only demonstrates a non-inferior effect of temisartan on ramipril. 3. Is there any additional benefit of ACEI + ARB? The most surprising aspect of the ONTARGET study for the investigators was that the combination did not provide more benefit than either single agent and increased hypotension, syncope, hyperkalemia and renal adverse effects. We know that the vasoprotective effects of ACEI and ARB benefit in part from their antihypertensive effects, and it is difficult to understand the lack of additional benefit when the combination group did have a stronger antihypertensive effect than the ramipril group. the explanation given by the ONTARGET investigators was that: 1) the “success” of the patients enrolled in the ONTARGET study with prior use of other drugs “treatment” reduced the clinical value of adequate, dual RAS blockade; 2) the combination of the two drugs may have had some deleterious effects that offset the benefits of the combination. The Canadian Hypertension Education Program (CHEP) does not recommend the combination of drugs in patients without heart failure and renal disease. It should be noted that there is evidence of greater benefit from the combination of the two drugs in patients with severe heart failure and renal disease, and that the two drugs are often used in combination in clinical practice to further reduce proteinuria and delay the progression of renal disease. 4. Is ARB better than placebo for patients who cannot tolerate ACEI? In the TRANSCEND study, for patients who could not tolerate ACEI, there was no significant benefit of telmisartan compared to placebo, but it was well tolerated. This finding is inconsistent with ONTARGET, and there are several possible reasons for the bias in the results: 1) the follow-up period was too short, with a median of 2.5 years; 2) the event rate in the TRANSCEND study was low compared to other clinical trials; 3) previous studies have shown that after a period of ACEI or ARB administration, there is a lingering after-effect of months to years of Patients in the placebo group of the TRANSCEND study were pretreated with an ACEI and the follow-up period was too short for the after-effects to have a significant impact on the outcome of the placebo group. Therefore, the absence of cardiovascular protection with telmisartan compared to placebo cannot be based solely on the TRANSCEND study. In conclusion, the ONTARGET/TRANSCEND study showed that the ARB telmisartan was comparable to the ACEI ramipril in reducing cardiovascular death, myocardial infarction, stroke, and congestive heart failure in patients at high cardiovascular risk, and was better tolerated. For other ARBs, there is no similar evidence. Since ACEI has more clinical evidence and is more widely used in this application, we suggest that for such patients, ACEI should be preferred, and for patients who cannot tolerate ACEI, ARBs such as telmisartan can be considered as an alternative to ACEI.