Mega clinical trials which have shaped the RAS intervention clinical practice

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.

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.