A Review of Angiotensin Receptor Blocker-based Therapies at all Levels of Cardiovascular Risk

The renin–angiotensin system (RAS) has a key role in the maintenance of cardiovascular (CV) homeostasis, and water and electrolyte metabolism in healthy subjects.¹ By contrast, the excess of angiotensin II in several diseases represents a pathophysiological mechanism that can promote or even accelerate atherosclerotic processes, cardiac and vascular hypertrophy, and kidney disease.¹ In particular, as has been clearly demonstrated in animal models, the lack of appropriate RAS suppression results in a dramatic acceleration of coronary artery disease, ischaemic renal disease and brain vascular disease, as well as of hypertrophy and fibrosis processes both at the heart and vascular levels.

There are several different mechanisms that can be antagonised by RAS-blocking drugs, which affect the activity of the RAS at different steps of the protein–enzymatic cascade (see Figure 1).² These mechanisms include renin production and release in the juxta-glomerular apparatus, the action of angiotensin-converting enzyme (ACE) in tissues, and the interaction between angiotensin II and the different angiotensin subtype receptors for angiotensin II. The latter mechanism in particular, which is antagonised by angiotensin II receptor blockers (ARBs), has a major role in all pathological activities of angiotensin II, including vasoconstriction, sodium retention, aldosterone release, glomerular filtration, cardiac and vascular hypertrophy, inflammation, fibrosis, oxidation and even proarrhythmic activity.^3,4 Much effort has been put into demonstrating that blocking the angiotensin II receptor type 1 (AT1) subtype receptors through ARB-based therapy has proven benefits in different clinical settings.

Cardiovascular Protection and Renin–Angiotensin System Blockade

The benefits of blocking RAS with ARBs have been extensively and consistently documented. Evidence is available on their benefits on major CV endpoints (e.g., mortality, myocardial infarction and development of congestive heart failure) in several clinical conditions embracing the whole CV continuum, from hypertension,^5,6 hypertension with left ventricular hypertrophy,⁷ high CV risk,^8–10 coronary disease,^11,12 left ventricular dysfunction,^13–16 heart failure with preserved left ventricular function^17,18 and stroke^19–21 to diabetic nephropathy with proteinuria.^22–24 In clinical trials that have involved thousands of patients at high CV risk (which are listed in Table 1), individual ARBs have been tested in patients with different clinical conditions.

It has been systematically shown that there is a benefit to the use of ARBs in terms of CV morbidity and mortality, or at least an equivalence (i.e., non-inferiority) compared to the best available therapy (conventional therapy), which often consists of ACE inhibitors. These randomised clinical trials of ARBs, which began in 1998 and are ongoing, have produced an impressive amount of data covering the whole CV continuum. The latest ones have shown that the benefits obtained with ARBs can be demonstrated even in the earliest stages of renal disease – such as albuminuria – which can be associated with diabetes or hypertension.²⁵ ARBs were the first class of antihypertensive drugs to be shown to reduce primary CV endpoints in the presence of comparable reductions in blood pressure levels obtained with different antihypertensive drug classes or molecules. This was the case, for example, in the Losartan intervention for endpoint reduction in hypertension (LIFE) trial,⁸ in which equivalent reductions of blood pressure were obtained with the ARB losartan 50–100 mg and with the beta-blocker atenolol 50–100 mg. The LIFE trial also showed that the incidence of non-fatal myocardial infarction, non-fatal stroke and CV death as a cumulative endpoint was significantly lower in the group of patients treated with the ARB compared with that observed in the group of patients treated with the beta-blocker. In the same trial, remarkable benefits were observed in the group of patients treated with the ARB compared with the group of patients treated with the beta-blocker, i.e., a reduced incidence of stroke in patients with isolated systolic hypertension,²⁶ new-onset diabetes,²⁷ new-onset atrial fibrillation,²⁸ regression of left ventricular hypertrophy^26,29 and microalbuminuria,^30,31 as well as a dramatic reduction of the risk of stroke in patients with atrial fibrillation.³²

Further studies have confirmed that ARBs can prevent stroke in patients with hypertension. This beneficial effect has been demonstrated in the Morbidity and mortality after stroke – eprosartan compared with nitrendipine for secondary prevention (MOSES) trial,²¹ in the Jikei Heart Study⁵ and, more recently, in the Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET).⁹ The latter showed an equivalence between the ARB telmisartan and the ACE inhibitor ramipril in terms of stroke prevention, although the ARB-based therapy showed a slight trend towards better control of new incidence of stroke.

If one adds, to the findings of the ONTARGET, the results of two other randomised clinical trials of telmisartan – the Telmisartan randomized assessment study in ACE intolerant subjects with cardiovascular disease (TRANSCEND)¹⁰ and the Prevention regimen for effectively avoiding second strokes (PROFESS) trial¹⁹ – the stroke endpoint was significantly reduced compared with placebo (i.e., the best available treatment for patients at high-risk).

Benefits Beyond Blood Pressure Reduction

Beyond their high efficacy in terms of blood pressure reduction and their efficiency in terms of major CV events prevention, ARBs are also very safe drugs. The hypothesis that they could eventually increase the risk of myocardial infarction³³ or cancer³⁴ has been completely ruled out by evidence derived from recently published, large meta-analytical studies that have systematically demonstrated no significant increase in the risk of myocardial infarction³⁵ or cancer³⁶ in patients treated with these drugs. In addition, from a pathophysiological point of view, the possibility of ARBs causing a myocardial infarction or leading to cancer does not hold;³⁷ instead, a beneficial effect could theoretically be expected.³⁵ Currently, ARB-based therapy represents an alternative for the treatment of high-risk individuals and patients with post-myocardial infarction^11,12 or congestive heart failure,^13,38,39 which are the most advanced points in the CV continuum. In the ONTARGET,⁹ the time to primary outcome was comparable in patients treated with the ARB telmisartan and those treated with the ACE inhibitor ramipril, which was confirmed as the gold standard therapy for treating high-risk patients after publication of the Heart outcomes prevention evaluation (HOPE) trial.⁴⁰ Also, telmisartan was noninferior to ramipril for all CV endpoints, including CV death, myocardial infarction, stroke, hospitalisation for heart failure and cumulative death. Finally, ARBs reduce new-onset diabetes, as demonstrated in a recent meta-analysis.⁴¹ They also prevent atrial fibrillation,^42,43 especially in patients who have structural abnormalities of the heart, such as those with left ventricular hypertrophy enrolled in the LIFE trial.²⁸

Conclusion

Randomised clinical trials of ARBs have provided support to evidence-based medicine, which allows to propose the use of the RAS-blocking strategy for the prevention of CV, renal and metabolic disorders. By summarising what has been learnt from those trials in recent years, two conclusions can be reached. First, hard endpoint trials comparing ARB treatment with traditional treatment shows little, if any, superiority of ARBs over any other CV drugs. In these settings, ARBs are consistently confirmed as effective and safe treatment options for patients with any level of CV disease. Second, the fact that ARBs are generally equivalent to other antihypertensive therapies (including ACE inhibitors) but show a better tolerability (including in terms of reduced cough and angiooedema) means that they can be considered as a valid alternative to treatment with ACE inhibitors of most conditions, particularly in high-risk patients. Finally, ARBs combine well with other antihypertensive agents and CV drugs, including aspirin, statins and antidiabetic drugs. They can be combined with low-dose thiazide diuretics or calcium-antagonists (or both) to increase their antihypertensive efficacy. The combination of ARBs with direct renin inhibitors is currently under investigation in several ongoing studies. The combination of ARBs and ACE inhibitors has been observed to benefit patients with congestive heart failure and/or end-stage renal disease, but does not appear to be supported by data from patients with hypertension or from high-risk individuals.