Mega clinical trials which have shaped the RAS intervention clinical practice

Abstract

Following extensive clinical research, drugs affecting the renin–angiotensin system have been used for the treatment of patients with congestive heart failure, myocardial infarction, hypertension, diabetic nephropathy, chronic renal failure and for reducing the risk of developing major cardiovascular (CV) events. This review examines all mega trials (those involving >1000 patients) and smaller pivotal trials involving angiotensin-converting enzyme inhibitors (ACE-Is; 25 mega trials) and angiotensin receptor blockers (ARBs; 27 mega trials) to provide perspective on the huge database of evidence that has accumulated on the use of these drugs. Our review demonstrates that ACE-Is and ARBs are generally as effective as conventional therapies in the treatment of hypertension, but offer additional cardioprotective benefits in patients with heart failure, and in those who have experienced myocardial infarction. Also, both ACE-Is and ARBs are capable of renal protection in addition to their blood-pressure-lowering effects. Although ACE-Is and ARBs provide major benefits to CV patients, doubts remain over the concept of blood-pressure-independent CV protection offered by both classes of drugs. ACE-Is and ARBs appear to be equally effective with respect to morbidity and mortality endpoints, but ARBs are better tolerated. Considering the available evidence, the combined use of an ACE-I and ARB should be avoided and full doses of either ACE-I or ARB should be aimed for as evidence suggests they provide a greater prognostic benefit.

Introduction and the evolution of renin–angiotensin system drugs

The renin–angiotensin system (RAS) has emerged as the crucial regulatory system for the maintenance of arterial blood pressure (BP), and fluid and electrolyte homeostasis [Atlas, 2007; Seva Pessoa et al. 2013]. Experimental and clinical evidence has demonstrated that the RAS plays a role in the development of hypertension and cardiovascular (CV) disease [Hsueh and Wyne, 2011], fuelling intense research efforts to develop drugs with RAS-modifying capabilities [Paulis and Unger, 2010; Oparil and Schmieder, 2015].

The first drug to specifically target the RAS was teprotide, a synthetic nonapeptide-converting enzyme inhibitor which decreases BP via inhibition of the conversion of angiotensin I to angiotensin II [Cushman et al. 1973]. The first angiotensin-converting enzyme inhibitor (ACE-I) to be used in clinical practice, captopril, became available in 1981 and since then, considerable progress has been made in the development of this class of drugs, which are now used widely in the treatment of several CV and renal indications. Angiotensin receptor blockers (ARBs) were subsequently developed, specifically antagonizing the binding of angiotensin II to the angiotensin II type 1 (AT₁) receptor. These came into clinical use in the mid-1990s, several years after ACE-Is, offering another treatment choice to target the RAS but with increased selectivity and improved tolerability [Smith, 2002]. More recent interventions include direct renin inhibitors [Liu et al. 2014; Ozaki et al. 2014] such as aliskiren and mineralocorticoid receptor antagonists [Rossi and Maiolino, 2014], together with newer strategies including aldosterone synthase inhibitors [Namsolleck and Unger, 2014] and angiotensin II type 2 receptor stimulators [Dhande et al. 2015].

As with many new discoveries, both overoptimistic expectations and unfounded rejection of ACE-Is and ARBs have emerged. Almost 35 years after the introduction of the first ACE-I, and more than 20 years after ARBs became available, it is worth looking back at the clinical evidence from RAS intervention studies to examine how these results have shaped treatment strategies in modern medicine. For the purposes of this review, we have focused on large-scale or mega trials including >1000 patients, in addition to some smaller seminal trials that are crucial to our understanding of the clinical success that both the ACE-Is and ARBs have achieved.

Overview and key findings of pivotal and mega trials with ACE-Is

A summary of mega trials with ACE-Is and key results are given in Table 1 and a chronology of mega trials with ACE-Is is given in Figure 1.

Table 1.

Mega trials with ACE-Is and key results.

Study	Study involving ACE-I	Year published	Patients randomized	Key result
Congestive heart failure
SOLVD [The SOLVD Investigators, 1991]	Studies of Left Ventricular Dysfunction	1991	2569	Enalapril reduced mortality and hospitalizations in patients with low ejection fractions
SOLVD 2 [Konstam et al. 1992]	Studies of Left Ventricular Dysfunction 2	1992	4228	Enalapril reduced incidence of heart failure and hospitalizations in patients with asymptomatic left ventricular dysfunction
ATLAS [Ryden et al. 2000]	Assessment of Treatment with Lisinopril and Survival	2000	3164	Higher doses of lisinopril more effective than lower doses
Post-MI
CONSENSUS II [Sigurdsson and Swedberg, 1994]	Cooperative New Scandinavian Enalapril Survival Study II	1994	6090	Enalapril, started with an intravenous infusion within 24 hours after onset of MI (continued by oral treatment) without an effect on mortality
SAVE [Pfeffer et al. 1992]	Survival and Ventricular Enlargement Study	1992	2231	Captopril started between 3 and 16 days after MI effective (mortality and morbidity ↓)
AIRE [The AIRE Investigators, 1993]	Acute Infarction Ramipril Efficacy Study	1993	2006	Ramipril started between 3 and 9 days after MI effective (mortality ↓)
GISSI-3 [GISSI-3 Study Group, 1994]	Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico 3	1994	18,895	Lisinopril, started within 24 h after MI, effective (mortality and severe ventricular dysfunction ↓)
SMILE [Borghi and Ambrosioni, 1995]	Survival of MI Long-term Evaluation Study	1995	1556	Zofenopril improved both short-term and long-term outcome when started within 24 hours after acute anterior MI
TRACE [Kober et al. 1995]	Trandolapril Cardiac Evaluation Study	1995	1749	Trandolapril started between day 3 and day 7 after MI in patients with reduced left ventricular function is effective (mortality, mortality from CV causes, sudden death, and development of severe heart failure ↓)
ISIS-4 [ISIS-4 Collaborative Group, 1995]	Fourth International Study of Infarct Survival	1995	58,050	Captopril was effective in reducing 5-week mortality. The benefit appeared to be larger in certain higher-risk groups. The survival advantage appeared to be maintained in the longer term
SMILE-2 [Borghi et al. 2003]	Survival of Myocardial Infarction Long-term Evaluation-2	2003	1024	Both zofenopril and lisinopril are well tolerated and associated with a low rate of severe hypotension when dose-titrated in thrombolyzed patients with acute MI
Hypertension
CAPPP [Hansson et al. 1999]	Captopril Prevention Project	1999	10,985	Captopril and conventional treatment (beta-blocker, diuretics) did not differ in efficacy in preventing CV morbidity and mortality
STOP-Hypertension 2 [Dahlof et al. 1993]	Swedish Trial in Old Patients with Hypertension 2	1993	6614	Old and new antihypertensive drugs (including enalapril and lisinopril) were similar in prevention of CV mortality or major events
ALLHAT [Collaborative Research Group, 2002]	Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial	2002	33,357	No significant difference between lisinopril and chlorthalidone for the primary outcome (fatal or nonfatal MI), mortality or for the secondary combined outcome
ANBP 2 [Doggrell, 2003]	Australian National BP Study 2	2003	6083	Initiation of antihypertensive treatment involving ACE-Is in older subjects, particularly men, appears to lead to better outcomes than treatment with diuretic agents
ASCOT BPLA [Dahlof et al. 2005]	Anglo-Scandinavian Cardiac Outcomes Trial-BP-Lowering Arm	2005	19,257	Amlodipine-based regimen (plus perindopril) lowered BP more effectively and prevented more CV events and induced less diabetes than atenolol-based regimen (plus bendroflumethiazide)
HYVET [Beckett et al. 2008]	Hypertension in the Very Elderly Trial	2008	3845	Antihypertensive treatment with indapamide, in 73.4% of patients with additional perindopril, in persons 80 years of age or older is beneficial (versus placebo)
ACCOMPLISH [Jamerson et al. 2008]	Avoiding CV Events through Combination Therapy in Patients Living with Systolic Hypertension	2008	11,506	Benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing CV events
High cardiovascular risk
HOPE [Yusuf et al. 2000]	Heart Outcomes Prevention Evaluation Study	2000	9297	Ramipril significantly reduces the rates of death, MI, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure
EUROPA [Fox and Investigators, 2003]	European Trial on Reduction of Cardiac events with Perindopril in Stable Coronary artery Disease	2003	12,218	Perindopril significantly improved outcome among patients with stable coronary heart disease without apparent heart failure
PEACE [Braunwald et al. 2004]	Prevention of Events with ACE Inhibition Trial	2004	8290	In patients with stable coronary heart disease and preserved left ventricular function who are receiving standard therapy and in whom the rate of CV events is lower than in previous trials of ACE-Is in patients with vascular disease, there is no evidence that the addition of trandolapril provides further benefit
Diabetes and diabetic nephropathy
MICRO-HOPE [HOPE Study Investigators, 2000]	Heart Outcomes Prevention Evaluation Study (Diabetes Subgroup)	2000	3577	Ramipril was beneficial for CV events and overt nephropathy in people with diabetes
BENEDICT [Remuzzi et al. 2006]	Bergamo Nephrologic Diabetes Complications Trial	2004	1204	In subjects with type 2 diabetes and hypertension but with normo-albuminuria, the use of trandolapril alone or plus verapamil decreased the incidence of microalbuminuria to a similar extent
ADVANCE [Chalmers et al. 2006]	Action in Diabetes and Vascular Disease	2006	11,140	A fixed combination of perindopril and indapamide versus placebo to patients with type 2 diabetes reduced the risks of major vascular events, including death
Stroke
PROGRESS [PROGRESS Collaborative Group, 2001]	Perindopril Protection against Recurrent Stroke Study	2001	6105	BP-lowering with perindopril (plus indapamide) versus placebo reduced the risk of stroke among both hypertensive and non-hypertensive individuals with a history of stroke or transient ischemic attack (within the past 5 years)

ACE-I, angiotensin converting enzyme inhibitor; BP, blood pressure; CV, cardiovascular; MI, myocardial infarction.

Figure 1.

Chronology of mega trials with ACE-Is (>1000 patients).

A total of 25 mega trials with the use of ACE-Is have been published containing over 244,000 patients.

ACE-I, angiotensin-converting enzyme inhibitor; MI, myocardial infarction; CV, cardiovascular.

Congestive heart failure

Great optimism surrounding the use of RAS intervention drugs was initially stimulated following a small single study involving 253 patients. The first randomized clinical trial designed to specifically investigate the effects of an ACE-I, enalapril, on mortality in severe congestive heart failure (New York Heart Association [NYHA] functional class IV) was the ‘Co-operative North Scandinavian Enalapril Survival Study’ (CONSENSUS) I in 1987 [The Consensus Trial Study Group, 1987]. In this pivotal study, adding enalapril to patients’ conventional treatment regimens reduced mortality by 40% at 6 months versus placebo (p = 0.002) and by 27% (p = 0.003) by the end of the 12-month study period. These data set the foundation for two larger-scale investigations into the role of ACE-Is in patients with congestive heart failure, the ‘Studies of Left Ventricular Dysfunction’ (SOLVD) 1 and 2, confirming a prognostic benefit of such treatment [The SOLVD Investigators, 1991; Konstam et al. 1992].

An analysis from another large-scale study, the ‘Assessment of Treatment with Lisinopril and Survival’ (ATLAS) study, which included a total of 3164 patients with chronic heart failure (CHF) at high CV risk, suggested that the effects of an ACE-I in patients with congestive heart failure may be dose-dependent [Ryden et al. 2000]. In this study, treatment with high-dose versus low-dose lisinopril led to a trend towards reduced risk of all-cause mortality and significantly reduced hospitalizations.

From the clinical data available it became obvious, however, that the magnitude of the morbidity and mortality benefit of ACE-Is in congestive heart failure was clearly dependent on the clinical severity of the disease being treated.

Post-myocardial infarction

The first mega trial in patients with left ventricular dysfunction following MI was the ‘Survival And Ventricular Enlargement’ (SAVE) trial in which the cardioprotective effects of the ACE-I, captopril, were investigated [Pfeffer et al. 1992]. Patients who received long-term captopril versus placebo experienced a lower incidence of mortality and morbidity due to reduced CV events. To date, several large-scale clinical studies [Gruppo Italiano Per Lo Studio Della Sopravvivenza Nell’infarto Miocardico, 1994; Pfeffer et al. 1992; ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group, 1995; Ambrosioni et al. 1995; Kober et al. 1995] have supported the prognostic benefit of ACE-Is in patients post MI (Figure 1).

One study, CONSENSUS II, did not demonstrate a benefit of using an ACE-I in patients with MI, but this may have been due to methodological differences; in this trial, treatment was started with an intravenous infusion of the ACE-I within 24 hours after MI, and patients were observed for a relatively short period of 6 months [Sigurdsson and Swedberg, 1994]. This finding somewhat contrasts with the results of the GISSI-3 (‘Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico’) trial in which lisinopril treatment also started within 24 hours after the onset of MI and was associated with a 12% reduction in mortality after 6 weeks [Gruppo Italiano Per Lo Studio Della Sopravvivenza Nell’infarto Miocardico, 1994]. Also, in the ‘Fourth International Study of Infarct Survival’ (ISIS-4) trial, captopril was given within 24 hours of the onset of suspected acute MI and reduced mortality was seen after 5 weeks of treatment [ISIS-4 Collaborative Group, 1995]. In both of these studies, however, the ACE-I was given orally with a low starting dose to avoid hypotensive complications in the unstable initial phase of MI.

Hypertension

Interestingly, the first study to investigate an ACE-I, captopril, in hypertension, the ‘Captopril Prevention Project’ (CAPPP), was published 18 years after the first ACE-I became available [Hansson et al. 1999]. In this study, captopril and conventional treatment with diuretics and beta-blockers did not differ in their ability to prevent CV morbidity and mortality. Subsequent studies were also unable to establish a prognostic benefit of ACE inhibition compared with other treatment options [Dahlof et al. 1993; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002] (Figure 1).

From a review of published data from large-scale studies, only the ‘Australian National Blood Pressure’ (ANBP) 2 trial [Doggrell, 2003] demonstrated that initiation of antihypertensive treatment involving an ACE-I in older subjects, particularly men, lead to better outcomes than treatment with diuretic agents, despite similar reductions in BP.

A more recent study with an ACE-I, the ‘Hypertension in the Very Elderly Trial’ (HYVET) showed that in patients of 80 years and older, treatment with a thiazide-like diuretic (indapamide) plus perindopril in about three quarters of patients pretreated with indapamide was associated with a 21% reduction in mortality and marked improvements in various morbidity endpoints [Beckett et al. 2008]. However, it remains unclear whether the dramatic prognostic effect with such treatment is due to marked BP-lowering or a treatment-specific effect.

In the ‘Anglo-Scandinavian Cardiac Outcomes Trial’ (ASCOT-BPLA), patients were either treated with an amlodipine-based regimen in which the ACE-I perindopril was added, or an atenolol-based regimen in which bendroflumethiazide was added [Dahlof et al. 2005]. By the end of the trial, as intended by design, most patients (78%, 14,974 of 19,242) were taking at least two antihypertensive agents. In this study, amlodipine [a calcium channel blocker (CCB)] plus perindopril was more effective in lowering BP (the average difference throughout the trial was 2.7/1.9 mmHg), prevented more major CV events, and induced less diabetes than the atenolol-based regimen.

Finally, in the study ‘Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension’ (ACCOMPLISH), combination therapy of benazepril plus amlodipine was superior to a combination of benazepril plus hydrochlorothiazide in reducing CV events in patients with hypertension who were at high risk of such events [Jamerson et al. 2008].

Thus, while little evidence points to a superiority of ACE inhibition versus other treatment options in the treatment of hypertension, combination therapy using a CCB plus an ACE-I was superior to a beta-blocker plus a diuretic and the addition of a CCB on top of an ACE-I appears to be superior to adding a diuretic.

High cardiovascular risk

The effects of ACE inhibition were investigated in patients at high CV risk in three mega trials; ‘Heart Outcomes Prevention Evaluation’ (HOPE) [Yusuf et al. 2000], ‘European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease’ (EUROPA) [Fox and EUROPA Investigators, 2003] and ‘Prevention of Events with Angiotensin Converting Enzyme Inhibition’ (PEACE) [Braunwald et al. 2004]. In the HOPE trial, over 9000 high-risk patients with vascular disease or diabetes, 47% of who had hypertension, were randomised to receive ramipril or placebo over a 5-year period. Death, MI and stroke were significantly reduced in ramipril-treated patients, but only minor changes in office BP were observed (−3/−2 mmHg). However, these results must be interpreted cautiously as further analysis from a small HOPE substudy, in which ambulatory BP was monitored over a 24-hour period, found significant differences in systolic and diastolic BP throughout the day [Svensson et al. 2001]. Thus, 24-hour ambulatory BP was significantly reduced in ramipril-treated subjects (−10/−4 mmHg, p = 0.03), mainly because of a more pronounced BP-lowering effect at night (−17/−8 mmHg, p < 0.001). As the study drugs were taken at night in the HOPE trial, the effects on CV morbidity and mortality seen with ramipril in this patient group may, to a larger extent than initially ascribed, relate to effects on BP patterns over the 24-hour period.

In the EUROPA trial (perindopril versus placebo) [Fox and EUROPA Investigators, 2003] the average BP difference during double-blind treatment with perindopril was −5/−2 mmHg. This study showed no effect on total or CV mortality, but the combined primary endpoint of CV mortality, nonfatal MI, and resuscitated cardiac arrest was significantly reduced by 20%.

Finally, in the PEACE trial (trandolapril versus placebo) [Braunwald et al. 2004], which included patients with stable coronary heart disease and preserved left ventricular function, no benefit in terms of death from CV causes, MI, or coronary revascularization could be observed in spite of a significant difference in BP of −3/−1 mmHg in actively treated subjects. However, the patients enrolled in this study had a lower rate of CV events than in the two previously mentioned trials involving ACE-Is (HOPE and EUROPA) [Yusuf et al. 2000; Fox and EUROPA Investigators, 2003].

Taken together, these three studies do not provide convincing evidence that ACE inhibition in patients at high CV risk, but without impaired cardiac function, is associated with a BP-independent prognostic benefit.

Diabetes and diabetic nephropathy

The renal-protective effects of the ACE-I captopril were investigated in a pivotal trial involving 409 patients with diabetic nephropathy who had type I diabetes, proteinuria and a serum creatinine concentration of ⩽2.5 mg/dl [Lewis et al. 1993]. During a median follow up of 3 years, treatment with captopril reduced the risk of the combined endpoint (death, dialysis and transplantation) by 50%, thereby demonstrating for the first time renal protection in this patient group. This renal protective effect was significantly more pronounced than could be expected by BP control alone and soon after led to the indication of captopril treatment in insulin-dependent diabetic patients with diabetic nephropathy.

The ‘Bergamo Nephrologic Diabetes Complication Trial’ (BENEDICT) included 1204 patients with type 2 diabetes, arterial hypertension, normoalbuminuria, and normal renal function, and was designed to assess the efficacy of the ACE-I trandolapril, the CCB verapamil, and a combination of trandolapril plus verapamil, compared with placebo in the prevention of microalbuminuria [Remuzzi et al. 2006]. The results showed that diabetic nephropathy can be prevented by ACE inhibition and the benefits observed were not enhanced by adding the CCB. Thus, the advantage of ACE-Is over other agents in hypertensive patients with type 2 diabetes includes a protective effect on the kidney against the development of microalbuminuria, which is an early marker of diabetic renal disease.

Stroke

The ‘Perindopril Protection against Recurrent Stroke Study’ (PROGRESS) included 6105 hypertensive and nonhypertensive individuals who had a history of stroke or transient ischaemic attack within the past 5 years [PROGRESS Collaborative Group, 2001]. This study was designed to investigate whether the BP-lowering effect of perindopril (plus indapamide) versus placebo reduced the risk of stroke. The results showed that BP was reduced by 9/4 mmHg over 4 years of follow up in the perindopril (plus indapamide) group compared with placebo, and there was a relative risk reduction for stroke of 28% (p < 0.0001) together with improvements of other CV endpoints. However, single-drug therapy with perindopril alone in 42% of patients reduced BP by 5/3 mmHg and had no discernible effect on stroke risk. In patients receiving perindopril plus indapamide, BP was reduced by 12/5 mmHg and stroke risk was markedly reduced.

Thus, the secondary preventive effect of active treatment in PROGRESS cannot be related to the ACE-I but is most likely secondary to the effective BP lowering achieved by combination therapy.

Overall, and despite the limitations mentioned above, ACE inhibition has revolutionized CV and renal therapy. When the entire ACE-I mega trial data are taken into consideration, it can be concluded that these treatments are generally as effective as conventional therapies in the treatment of hypertension, but offer further cardio-protective benefits in patients with heart failure and post-MI. They have also proven to be renal protective in both type 1 and 2 diabetic patients.

Overview and key findings of pivotal and mega trials with ARBs

A summary of mega trials with ARBs and key results is given in Table 2 and a chronology of mega trials with ARBs is given in Figure 2.

Table 2.

Mega trials with ARBs and key results.

Study	Study involving ARB	Year published	Patients randomized	Key result
Congestive heart failure
ELITE II [Pitt et al. 2000]	Losartan Heart Failure Survival Study 2	2000	3152	Losartan versus captopril. No differences in all-cause mortality, sudden death or resuscitated arrests between the two treatment groups.
Val-Heft [Cohn et al. 2001]	Valsartan Heart Failure Trial	2001	5010	Valsartan modestly improved morbidity but not mortality in the entire group (93% of patients already treated with an ACE-I). In the small subgroup of patients not on an ACE-I (7%) there was a marked reduction in mortality and morbidity.
CHARM [Pfeffer et al. 2003a; Granger et al. 2003; McMurray et al. 2003; Yusuf et al. 2003]	Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity	2004	7601	CHARM Overall. Candesartan reduced CV death and hospital admission for CHF. CHARM Added. Candesartan reduced CV death and hospital admission for CHF. CHARM Preserved. Candesartan had a moderate impact in preventing admissions for CHF among patients with LVEF higher than 40%. CHARM Alternative. Candesartan markedly reduced CV mortality and morbidity in patients who are intolerant to ACE-Is.
HEAAL [Konstam et al. 2009]	Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan Study	2009	1919	Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with reduced left-ventricular ejection fraction and intolerance to ACE-Is compared with losartan 50 mg daily.
I-PRESERVE [Massie et al. 2008]	Irbesartan in Heart Failure with Preserved Ejection Fraction Study	2008	4128	Irbesartan did not improve the outcomes of patients with heart failure and a preserved LVEF (ejection fraction of ⩾45%).
SUPPORT [Sakata et al. 2015]	Supplemental Benefit of an ARB in Hypertensive Patients with Stable Heart Failure using Olmesartan Trial	2015	1147	Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with ACE-I and/or beta-blockers. The triple combination therapy with olmesartan, ACE-I and beta-blockers was associated with increased adverse cardiac events.
Post-myocardial infarction
OPTIMAAL [Dickstein et al. 2002]	Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan	2002	5477	Losartan 50 mg once daily versus captopril 50 mg three times daily. Nonsignificant difference in total mortality in favour of captopril.
VALIANT [Pfeffer et al. 2003b]	Valsartan in Acute MI Trial	2003	14,703	Valsartan is as effective as captopril in patients who are at high risk for CV events after MI. Combining valsartan with captopril increased the rate of AEs without improving survival.
Hypertension
LIFE [Dahlof et al. 2002]	Losartan Intervention for Endpoint Reduction Study	2002	9198	Losartan prevents more CV morbidity and death than atenolol for a similar reduction in BP and is better tolerated.
SCOPE [Lithell et al. 2003]	Study on Cognition and Prognosis in the Elderly	2003	4964	In elderly hypertensive patients, a slightly more effective BP reduction during candesartan-based therapy compared with control therapy was associated with a marked reduction in non-fatal stroke.
VALUE [Julius et al. 2004]	Valsartan Antihypertensive Long-term use Evaluation	2004	15,245	Valsartan-based versus amlodipine-based treatment. No difference in the primary endpoint defined as a composite of cardiac mortality and morbidity.
E-COST [Suzuki et al. 2005]	Efficacy of Candesartan on Outcome in Saitama Trial	2005	2048	Candesartan-based antihypertensive treatment was superior to conventional treatment for reducing the risk of stroke and MI in Japanese hypertensive patients, especially in patients with a past history of CV disease.
CASE-J [Ogihara et al. 2008]	Candesartan Antihypertensive Survival Evaluation in Japan	2008	4728	Candesartan and amlodipine equally reduced the incidence of CV events.
HIJ-CREATE [Kasanuki et al. 2009]	Heart Institute of Japan Candesartan Randomised Trial for Evaluation in Coronary Artery Disease	2009	2049	Patients with coronary artery disease and hypertension were assigned to either candesartan-based or non-ARB-based pharmacotherapy including ACE-I. There was no difference in major CV events.
OSCAR [Ogawa et al. 2012]	Olmesartan and Calcium Antagonists Randomised Study	2012	1164	Olmesartan 20 mg plus CCB combination lowered BP more effective than olmesartan 40 mg and reduced the incidence of primary endpoints more than the high-dose ARB.
COLM [Ogihara et al. 2014]	Combinations of Olmesartan Study	2014	5141	Japanese hypertensive patients were randomised to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. There was no significant difference in CV events.
High cardiovascular risk*
ONTARGET The ONTARGET Investigators Group, 2008	Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial	2004	17,044	Telmisartan was equivalent to ramipril in patients with CV disease or high-risk diabetes.
TRANSCEND [Yusuf et al. 2008b]	Telmisartan Randomised Assessment Study in ACE-I Intolerant Subjects with CV Disease	2008	5926	Patients intolerant to ACE-Is with CV disease or diabetes with end-organ damage received telmisartan 80 mg/day or placebo. BP was lower in the telmisartan group than in the placebo group (−4.0/−2.2 mmHg). The composite of CV death, MI, stroke, or hospitalization for heart failure (primary endpoint) was not different between the two groups.
ACTIVE I [ACTIVE I Investigators, 2011]	Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of CV Events	2011	9016	In patients with atrial fibrillation, irbesartan versus placebo reduced BP (−2.9/−1.9 mmHg) but did not reduce CV events in patients with atrial fibrillation.
Diabetes† and/or diabetic nephropathy
RENAAL [Brenner et al. 2001]	Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study	2001	1513	Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy.
IDNT [Lewis et al. 2001]	Irbesartan Diabetic Nephropathy Trial	2000	1715	Irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in BP.
NAVIGATOR [The NAVIGATOR Study Group, 2010]	Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research Study	2010	9306	Among patients with impaired glucose tolerance and CV disease or risk factors, valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of CV events.
ROADMAP [Ritz et al. 2010]	Randomised Olmesartan and Diabetes Microalbuminuria Prevention Trial	2010	4449	Olmesartan was associated with a delayed onset of microalbuminuria.
NEPHRON-D [Fried et al. 2013]	Nephropathy in Diabetes Study	2013	1448	Combination therapy with an ACE-I and an ARB was associated with an increased risk of AEs among patients with diabetic nephropathy.
Stroke
MOSES [Schrader et al. 2005]	Morbidity and Mortality after Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention Study	2005	1405	Hypertensive patients with a cerebral event during the last 24 months were randomised to eprosartan or nitrendipine. In the absence of differences in BP more CV and cerebrovascular events occurred in nitrendipine-treated patients.
PRoFESS [Diener et al. 2008]	Prevention Regimen for Effectively Avoiding Second Strokes	2008	20,332	Therapy with telmisartan versus placebo initiated soon after an ischaemic stroke and continued for 2.5 years lowered BP (−3.8/−2.0 mmHg) but did not significantly lower the rate of recurrent stroke, major CV events, or diabetes.
SCAST [Sandset et al. 2011]	Scandinavian Acute Stroke Trial	2011	2029	There was no indication that careful BP-lowering treatment with the ARB candesartan is beneficial in patients with acute stroke and raised BP. If anything, the evidence suggested a harmful effect.

^*Includes atrial fibrillation.

^†Includes people with impaired glucose tolerance (IGT).

ACE-I, angiotensin-converting enzyme inhibitor; AE, adverse event; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CHF, congestive heart failure; CV, cardiovascular; MI, myocardial infarction.

Figure 2.

Chronology of mega trials with ARBs (>1000 patients).

A total of 27 mega trials with ARBs have been recorded, enrolling over 161,000 patients.

ARB, angiotensin receptor blocker; MI, myocardial infarction; CV, cardiovascular.

Congestive heart failure

As was the case with ACE-Is, a small study in patients with congestive heart failure initially stimulated interest in the use of ARBs in CV indications, and also prompted optimism that ARBs would be the superior approach to block the RAS compared with ACE-Is. In the ‘Evaluation of Losartan in the Elderly’ (ELITE) trial, the ARB losartan 50 mg once daily was compared with the ACE-I captopril 50 mg three times daily in 722 patients with heart failure above 65 years of age [Pitt et al. 1997]. The primary endpoint was a measure of renal safety, a persisting increase in serum creatinine of 0.3 mg/dl or more, and the secondary endpoint was a composite of death and/or hospitalizations for heart failure. An unexpected 32% reduction in death and/or hospital admission for heart failure was found in patients treated with losartan, a risk reduction that was mainly due to a 46% decrease in all-cause mortality. In addition, losartan was better tolerated than captopril and thus fewer patients discontinued losartan therapy due to adverse events (12.2% versus 20.8% for captopril, p = 0.002).

These positive results prompted a large-scale follow-on study, the ELITE II trial, in which the effects on morbidity and mortality in heart failure patients treated with losartan (n = 1578) and captopril (n = 1574) were evaluated [Pitt et al. 2000]. The results, however, did not confirm the initial finding of the ELITE study; there were no significant differences in all-cause mortality, sudden death or resuscitated arrests between the two treatment groups. Losartan was, however, better tolerated than captopril. It was therefore concluded that an ARB may be a useful treatment option if an ACE-I is poorly tolerated. One weakness of the ELITE II study design was the treatment doses used; a relatively low dose of losartan (50 mg taken once daily) versus a full dose of captopril (50 mg taken three times daily). This was addressed in the ‘Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan’ (HEAAL) trial where 3846 patients with heart failure were randomized to receive low-dose (50 mg) or high-dose (150 mg) losartan [Konstam et al. 2009]. The primary combined endpoint, admission for heart failure and mortality rate, significantly favoured the high-dose group, mainly due to reduced hospital admissions, but no difference in mortality was observed.

In the ‘Valsartan Heart Failure Trial’ (Val-Heft) a small morbidity benefit was demonstrated in 5010 patients with heart failure of NYHA class II, III, or IV, 93% of whom were already pretreated with an ACE-I [Cohn et al. 2001]. However, in a post hoc analysis of the small patient subgroup (7%) which was not being treated with an ACE-I, there was a 44.0% reduction in the combined endpoint of mortality and morbidity and a 33.1% reduction in mortality.

In the ‘Candesartan in Heart Failure Assessment of Mortality and Morbidity’ (CHARM) program [Pfeffer et al. 2003a] three distinct types of heart failure patients (n = 7601) were randomized to treatment with the ARB candesartan or placebo: patients with left-ventricular ejection fraction (LVEF) ⩽40% who were not receiving an ACE-I because of intolerance (CHARM Alternative) [Granger et al. 2003] or who were currently receiving an ACE-I (CHARM Added) [McMurray et al. 2003], and patients with LVEF >40% (CHARM Preserved) [Yusuf et al. 2003]. In the CHARM Alternative trial candesartan reduced CV mortality and morbidity and this was also observed, albeit to a lesser extent, in CHARM Added. Thus, both Val-Heft and CHARM Added give some support to adding an ARB on top of an ACE-I in patients with congestive heart failure. However, serious questions remain with respect to dual RAS blockade in such patients. Thus, in Val-Heft, the small subgroup of patients without ACE-I pre-treatment may have impacted the overall results and in both studies ACE-I pre-treatment may have been dosed too low to reach the maximum effect of this treatment option.

In the more recent ‘Supplemental Benefit of an ARB in Hypertensive Patients with Stable Heart Failure Using Olmesartan’ (SUPPORT) trial, additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with an ACE-I, beta-blockers or both during a median observation period of 4.4 years [Sakata et al. 2015]. Furthermore, subgroup analyses suggested that the triple combination therapy with olmesartan, ACE-Is and beta-blockers was associated with increased adverse cardiac events and renal dysfunction. However, the small number of patients included in the study (olmesartan, n = 578; control, n = 569) with even lower numbers in the mentioned subgroups should be noted.

Finally, both CHARM Preserved and the ‘Irbesartan in Heart Failure with Preserved Ejection Fraction’ (I-PRESERVE) [Massie et al. 2008] studies with irbesartan demonstrated that an ARB does not reduce total or CV mortality of patients with heart failure and a preserved LVEF. However, in CHARM Preserved, fewer patients in the candesartan group than in the placebo group were admitted to hospital for CHF.

From the results of these mega trials, it appears that ARBs and ACE-Is are equally effective in patients with congestive heart failure with respect to mortality or morbidity endpoints. However, ARBs are better tolerated than ACE-Is. ARBs have no or little effect in patients with preserved LVEF. Considering the available evidence, the combined use of an ACE-I and an ARB should be discouraged and full doses of either ACE-I or ARB appear to provide a greater prognostic benefit and should thus be aimed for.

Post-myocardial infarction

In the ‘Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan’ (OPTIMAAL) 5477 patients with acute MI were randomized to either 50 mg of losartan once daily or 50 mg of captopril three times daily and followed for a mean observation period of 2.7 years [Dickstein et al. 2002]. There was a trend towards reduced mortality and also several morbidity endpoints in favour of the ACE-I. However, as with the ELITE II trial [Pitt et al. 2000] in patients with congestive heart failure, the low dose of losartan used in comparison with a full dose of the ACE-I should be noted.

In the ‘Valsartan in Acute Myocardial Infarction’ (VALIANT) trial, 14,703 patients were randomly assigned to additional therapy of valsartan (160 mg of valsartan twice daily), or captopril (50 mg three times daily), or valsartan plus captopril (80 mg of valsartan twice daily plus 50 mg of captopril three times daily) 0.5–10 days post-MI [Pfeffer et al. 2003b]. The primary endpoint of death from any cause was almost identical in each of the three groups indicating treatment with valsartan was as effective as captopril in patients following MI. Combining the two agents, however, increased the rate of adverse events without improving survival.

Hypertension

In the ‘Losartan Intervention for Endpoint Reduction in Hypertension’ (LIFE) trial antihypertensive therapy based on the ARB losartan was compared to treatment based on the beta-blocker atenolol [Dahlof et al. 2002]. Over 9000 patients with essential hypertension and left ventricular hypertrophy were followed for at least 4 years. In the presence of comparable BP lowering in the two treatment arms, an adjusted risk reduction difference of 13% (p = 0.021) in the primary composite endpoint (CV morbidity and death) in favour of losartan was observed. The superiority of losartan on the combined endpoint was almost completely due to a marked reduction in fatal and nonfatal strokes (adjusted risk reduction of 25%, p = 0.001). In addition, new onset diabetes was also markedly reduced by 25% (p < 0.001) in losartan-treated versus atenolol-treated patients.

The superiority of losartan-based treatment in the LIFE trial could, at least in part, be due to the choice of the comparator drug atenolol since several analyses have shown a weaker cardioprotective and cerebroprotective effect of various beta-blockers, including atenolol, compared with other antihypertensive agents in the treatment of hypertension [Carlberg et al. 2004; Bradley et al. 2006; Bangalore et al. 2008]. In contrast, a more recent meta-analysis demonstrated that all classes of blood pressure lowering drugs had a similar effect in reducing cardiac events. Furthermore, the observed lesser effect of beta-blockers on stroke rested on comparator trials with calcium channel blockers. Exclusion of the results of these trials weakened the evidence favouring a disadvantage of beta-blockers over the three other classes included in the meta-analysis (thiazide-diuretics, ACE-Is and ARBs) (relative risk 1.11, 0.86–1.44; p =0.40) [Law et al. 2009]. In addition, other intervention trials with an ACE-I or a CCB could not demonstrate differences against beta-blocker- and diuretic-based therapy on such endpoints. Therefore, the possibility remains that in LIFE [Dahlof et al. 2002], the ARB losartan exhibited a BP-independent cerebroprotective effect.

The ‘Valsartan Antihypertensive Long-term Use Evaluation’ (VALUE) trial compared valsartan and the CCB amlodipine in 15,245 patients aged ⩾50 years with treated or untreated hypertension and high risk of cardiac events [Julius et al. 2004]. BP was more effectively lowered in amlodipine-treated patients and this accounted for some differences in cause-specific outcomes. However, the main outcome of cardiac morbidity and mortality did not differ between the treatment groups. As in other trials, the rate of new onset diabetes was significantly lower in valsartan (−23%; p < 0.0001) as compared with amlodipine-treated patients.

In a small study randomizing only 809 patients, the ‘Trial of Preventing Hypertension’ (TROPHY), early treatment of prehypertension was investigated to see if disease progression could be prevented or delayed [Julius et al. 2006]. Patients with repeated measurements of systolic pressure of 130–139 mmHg and diastolic pressure of 85–89 mmHg were randomly assigned to the ARB candesartan (n = 409) or placebo (n = 400) and followed up for 4 years. After the first 2 years, hypertension developed in 154 patients taking placebo versus 53 in the candesartan group (relative risk reduction of 66.3%, p < 0.001). Thus, treating prehypertension with an ARB is able to lower the risk of incident hypertension and could be a viable treatment option in certain patients.

Taken together, with the exception of the LIFE trial using a beta-blocker-based strategy as a comparator, the available intervention studies are unable to demonstrate BP-independent differences in hard morbidity and mortality endpoints with the use of ARBs in hypertension. However, similar to the use of ACE-Is, there seems to be a lower rate of new onset diabetes.

High cardiovascular risk

In the ‘Ongoing Telmisartan Alone or in Combination with Ramipril Global Endpoint Trial’ (ONTARGET), the use of the ARB telmisartan alone, the ACE-I ramipril alone, and the combination of telmisartan and ramipril was examined in over 25,000 high-risk patients, 69% of whom had hypertension [The ONTARGET Investigators, 2008]. The comparator for telmisartan was 10 mg of ramipril, which was the same dose claimed to have BP-independent CV protective benefits in the HOPE trial [Yusuf et al. 2000]. The primary endpoint was a combination of CV death, nonfatal MI, stroke, and hospitalizations for heart failure. Telmisartan was slightly more effective than ramipril in reducing BP (0.9/0.6 mmHg). Results showed telmisartan was as effective as ramipril in high-risk patients, but combining the two agents increased safety concerns.

The understanding of these results depends entirely on the interpretation of the HOPE study results. If a BP-independent effect of ramipril accounts for the clinical efficacy of ramipril in HOPE, this BP-independent effect must consequently also be ascribed to the ARB telmisartan. However, as is also suggested from the meta-analyses of the hypertension intervention trials with many high-risk patients, in which no BP-independent effect was demonstrated with the use of ACE-Is or ARBs, BP lowering may be the main driving force of cardioprotection in the HOPE study. In that case, the appropriate conclusion is that similar BP lowering of ramipril and telmisartan resulted in comparable clinical efficacy in the ONTARGET trial [The ONTARGET Investigators, 2008].

In a study similar to ONTARGET, patients with high CV risk intolerant to ACE-Is were randomized to telmisartan 80 mg/day (n = 2954) or placebo (n = 2972) in the ‘Telmisartan Randomised Assessment Study in ACE-I Intolerant Subjects with Cardiovascular Disease’ (TRANSCEND) [Yusuf et al. 2008b]. The primary outcome was the composite of CV death, MI, stroke, or hospitalization for heart failure. Mean BP was lower in the telmisartan than in the placebo group throughout the study (weighted mean difference between groups 4.0/2.2 mmHg). However, no difference in the primary endpoint between the two treatment groups could be noted despite the marked BP difference in favour of telmisartan.

Taken together, the available evidence sheds some serious doubts about the concept of BP-independent CV protection by an ACE-I or ARB.

Diabetes and diabetic nephropathy

The ‘Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan’ (RENAAL) trial was the first of several designed to investigate renal protective effects of an ARB [Brenner et al. 2001]. A total of 1513 patients with type 2 diabetes and nephropathy were randomized to receive losartan (100 mg once daily) or placebo in addition to conventional antihypertensive treatments. The primary endpoint was doubling of the baseline serum creatinine concentration, end-stage renal disease, or death. Losartan conferred significant renal benefits in these patients as fewer patients reached the primary endpoint in the losartan versus the placebo group (p = 0.02). The benefit exceeded that attributable to changes in BP. Data from a further three trials, ‘Irbesartan Diabetic Nephropathy Trial’ (IDNT) [Lewis et al. 2001], ‘Irbesartan in Patients with type 2 Diabetes and Microalbuminuria’ (IRMA) 2 [Parving et al. 2001; Persson et al. 2006] and ‘Microalbuminuria Reduction with Valsartan’ (MARVAL) [Viberti et al. 2002] also suggested that an ARB improved the prognosis of patients with type 2 diabetes and diabetic nephropathy.

Based on the evidence from these four trials and from Lewis and colleagues [Lewis et al. 1993] (in which captopril reduced the risk of the combined endpoint [death, dialysis and transplantation] by 50%), several guidelines at this time recommended different treatment regimens for patients with type 1 diabetic nephropathy (ACE-I) and for patients with type 2 diabetic nephropathy (ARB) [Strippoli et al. 2004]. However, one small trial, ‘Diabetics Exposed to Telmisartan and Enalapril’ (DETAIL), compared ACE-I and ARB use in a group of 250 patients with type 2 diabetes and early nephropathy [Barnett et al. 2004]. Over the 5-year treatment period, there was no difference between the two drug classes on glomerular filtration rate (GFR). There was also no difference in the secondary endpoints of annual changes in GFR, serum creatinine level, urinary albumin excretion, BP, rates of end-stage renal disease, CV events, and the rate of death from all causes. These findings prompted changes in treatment guidelines, which no longer recommend different treatments for type 1 and type 2 diabetic nephropathy.

Stroke

Drug treatment of hypertension has been suggested to represent a main factor underlying the decline in stroke incidence and mortality observed over the past decades [Lackland et al. 2014]. In order to investigate whether differences between drug classes exist with respect to cerebroprotection three studies have investigated the effect of ARBs in patients after a cerebrovascular event. In the ‘Morbidity and Mortality after Stroke’ (MOSES) trial [Schrader et al. 2005], 1405 hypertensive patients with a cerebral event during the last 24 months were randomized to treatment with either eprosartan or nitrendipine. Both treatments reduced BP to a similar extent. However, the combined primary endpoint was significantly lower in eprosartan as compared with nitrendipine treated patients which was largely due to a significant reduction in cerebrovascular events (p = 0.03). This is in contrast to the findings from the ‘Prevention Regimen for Effectively Avoiding Second Strokes’ (PROFESS) trial [Yusuf et al. 2008a]. In this study, therapy with telmisartan versus placebo was initiated soon after an ischaemic stroke and continued for 2.5 years in 20,332 patients. While BP was lowered in the telmisartan group (−3.8/−2.0 mmHg), the use of this ARB did not significantly reduce the rate of recurrent stroke, major CV events, or diabetes compared with placebo. The ‘Scandinavian Acute Stroke Trial’ (SCAST) [Hornslien et al. 2015] in 2029 patients and a follow up period of 6 months also failed to show a benefit for BP-lowering treatment with candesartan in 1256 patients treated in the acute phase of stroke and may suggest even a harmful effect. On the basis of all of the three studies in patients post stroke, a specific, BP independent CV or cerebroprotective effect of an ARB seems unlikely.

Conclusions

ACE-Is and ARBs have significantly improved the treatment of patients with congestive heart failure, following MI and with chronic renal disease. The question of whether ACE-Is and ARBs provide BP-independent CV protection in high-risk patients (without heart failure) remains inconclusive. The evidence of superior effectiveness versus other therapeutics in patients with hypertension is low, with only one ACE-I study (versus diuretic; ANBP 2) [Doggrell, 2003] showing a slight improvement in CV prognosis, particularly in men. Likewise, only one study with an ARB (LIFE) [Dahlof et al. 2002] has demonstrated superiority over beta-blocker-based treatment because of enhanced protection from stroke. However, whether ARBs generally offer improved cerebrovascular protection also remains a matter of debate. On the background of this clinical trial evidence, the relevance of the lower rate of new-onset diabetes with ACE-Is and ARBs, as compared with other antihypertensive therapies, is still unclear. Finally, ARBs provide improved safety and tolerability versus ACE-Is.