Cardiovascular and Renal Outcomes With Telmisartan, Ramipril, or Both in People at High Renal Risk

Abstract

dual therapy did not reduce cardiovascular or renal outcomes compared with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers alone. Previous controlled trials with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have demonstrated greater cardiovascular and renal benefit in people with renal risk. We hypothesized that dual therapy would be more effective than monotherapy in patients with low glomerular filtration rate and elevated albuminuria. Methods and Results-Post hoc analysis was performed of renal subgroups of dual therapy versus monotherapy for the ONTARGET study and angiotensin receptor blocker versus placebo for the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND). The studies featured hazard ratios by subgroups and Cox regression models with factors for treatment, subgroup, and interactions. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure, and the main renal outcome was the composite of chronic dialysis or doubling of creatinine. In ONTARGET, there was no cardiovascular or renal benefit from dual over monotherapy in any subgroup, even with low glomerular filtration rate and/or elevated albuminuria. In TRANSCEND, in the comparison of angiotensin receptor blocker with placebo, there was a significant interaction for the main renal outcome (Pϭ0.01) in the direction of harm for patients with normoalbuminuria (0.37 versus 0.16 events per 100 patient-years; hazard ratio, 2.35; confidence interval, 1.33 to 4.15) but a trend to benefit with microalbuminuria (0.52 versus 0.89 events per 100 patient-years; hazard ratio, 0.60; confidence interval, 0.25 to 1.46) and macroalbuminuria (1.57 versus 2.60 events per 100 patient-years; hazard ratio, 0.71; confidence interval, 0.21 to 2.44). Key Words: albuminuria Ⅲ cardiovascular outcomes Ⅲ dialysis Ⅲ mortality Ⅲ renal insufficiency C hronic kidney disease is associated with accelerated cardiovascular disease. 1 For example, in post-myocardial infarction patients with estimated glomerular filtration rate (eGFR) Ͻ60 but Ͼ45 mL/min per 1.73 m 2 , total mortality was 25% higher 2 than with an eGFR Ͼ60 mL/min per 1.73 m 2 , and after an acute coronary artery syndrome, a fall in GFR also was associated with worse cardiovascular outcomes. 3 Blockade of the renin-angiotensin-aldosterone system (RAAS) is associated with less renal progression 4 and therefore potentially with better cardiovascular outcomes. Indeed, RAAS blockade with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) in patients with cardiovascular risk and a low eGFR significantly lowered the risk for cardiovascular mortality. 5,6 More intense inhibition of the RAAS with an ACE inhibitor and an ARB ("dual therapy") reduced albuminuria to a greater extent than either drug alone, but major cardiovascular or renal end points were not examined. 7 Conclusions-This Ed...

Determinants and Changes Associated with Aldosterone Breakthrough after Angiotensin II Receptor Blockade in Patients with Type 2 Diabetes with Overt Nephropathy

“…Long-term studies are required to test whether prevention of aldosterone breakthrough by cautious dual ACEI/ARB blockade in specific patient populations (29,30) or aldosterone inhibitors (31) would lead to improved nephroprotection. …”

ONTARGET still OFF-TARGET?

“…19 Surprisingly, the authors did not find any protective effects of dual therapy on hard renal and cardiovascular outcomes. Important within this context is the question of what dual therapy did to blood pressure and albuminuria.…”

“…18 In the current issue of Circulation, Tobe et al report on the TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) trial, in which the ARB telmisartan is compared to placebo in patients intolerant to ACEi. 19 They demonstrate greater treatment effects on renal outcomes in patients with GFR below 60 mL/min and micro-or macroalbuminuria. Interestingly, in patients with normoalbuminuria, telmisartan had no beneficial effect, and it increased the risk of renal events compared with placebo.…”

Referral to sub-specialists: who have the most to gain from early specialist intervention among patients with markers of renal disease?

“…Moreover, the risk of cardiovascular comorbidities has not differed significantly between treatment and placebo (LE Ia, Ib). [22][23][24][25][26] It has been shown that 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) significantly reduce the risk of death, stroke or coronary disease in hyperlipidemic patients with impaired GFR, but no large trials have reported outcome data for albuminuric subjects. [27][28][29][30] b blockers reduce the risk of mortality, myocardial infarction and heart failure (chronic heart failure) in patients with CKD.…”