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    • Of the cardiovascular studies involving ARBs reported

    2023-09-25

    Of the cardiovascular studies involving ARBs, 3 reported renal outcomes. In the Losartan Intervention For Endpoint study, albuminuria was observed less frequently in the losartan than in the atenolol arm (7% vs. 13%; p=0.002) (5). In the Candesartan Antihypertensive Survival Evaluation in Japan trial, renal events, defined as doubling of serum creatinine or reaching a creatinine of 354 µmol/L or end-stage renal disease did not differ between the candesartan and amlodipine groups (p=0.32) (9). A prespecified analysis in the TRANSCEND study focused on a composite renal endpoint that included doubling of serum creatinine or need for dialysis (14). This outcome was observed in 2.0% of patients taking telmisartan vs. 1.6% taking placebo (HR 1.29, 95% CI 0.87 to 1.89).
    Direct Comparison between ACEIs and ARBs in Patients with Diabetes There were 2 meta-analyses that suggested a potential benefit from ACEIs but not from ARBs on cardiovascular and renal outcomes. The first showed that ACEIs, but not ARBs, reduce all-cause mortality, cardiovascular mortality and major adverse cardiovascular events in patients with Fmoc-Gln(Trt)-OPfp (15). However, most ACEI studies were conducted before 2000, whereas the ARB studies were done more recently. As a consequence, patients in the ARB studies received overall superior cardiovascular protective treatment at baseline, making it harder to show cardiovascular benefit for these drugs. Furthermore, the number of patients taking ARBs was almost half the number of patients taking ACEIs, and failure to demonstrate efficacy might have been related to the studies' power issues. Therefore, results of this meta-analysis should be interpreted with caution. The second meta-analysis showed that ACEIs prevented new onset of diabetic nephropathy, whereas ARBs did not (16). This difference was due to lower incidence of micro- or macroalbuminuria with ACEIs compared to placebo. However, direct comparison of ACEIs to ARBs in the same meta-analysis failed to show any difference between the 2 agents for this outcome. Furthermore, albuminuria is a surrogate marker for more advanced kidney disease, not a hard clinical endpoint. When the effects of both ACEIs and ARBs on doubling serum creatinine or progression to end-stage renal disease were examined, results were similar for both drugs. There were 3 trials that addressed this question in head-to-head comparisons between ACEIs and ARBs. The first of these trials enrolled patients with type 2 diabetes, mild-to-moderate hypertension (diastolic BP <115 mmHg) and albuminuria of 20 to 350 µg/min. Patients were randomized to receive either losartan or enalapril (17). Similar reductions in albuminuria and declines in glomerular filtration rate (GFR) at 1 year were observed in both groups. The Diabetics Exposed to Telmisartan And Enalapril (DETAIL) study examined whether telmisartan was noninferior to enalapril for the preservation of GFR in patients with type 2 diabetes and mild to moderate hypertension (<180/95 mmHg) after at least 3 months of treatment with an ACEI (18). At 5 years, GFR had declined by 17.9 mL/min/1.73 m2 in patients taking telmisartan and by 14.9 mL/min/1.73 m2 in patients taking enalapril (treatment difference of −3 mL/min/1.73 m2, 95% CI −7.6 to 1.6, consistent with a predefined noninferiority cutoff of −10.0 mL/min/1.73 m2). Annual change in proteinuria was similar in both study arms. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) included patients with coronary artery disease, peripheral artery disease, cerebrovascular disease or diabetes mellitus who had evidence of end-organ damage and serum creatinine levels ≤265 µmol/L at baseline (19). Participants were randomized to receive telmisartan, ramipril or both. The primary outcome, a composite of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure, occurred in 16.7% of patients in the telmisartan group and in 16.5% of patients in the ramipril group (HR 1.01, 95% CI 0.94 to 1.09; p=0.83) (19). The renal endpoint of any dialysis, kidney transplantation, doubling of serum creatinine or death from any cause was observed in 13.4% of patients treated with telmisartan and in 13.5% of patients treated with ramipril (HR 1.00, 95% CI 0.92 to 1.09) (20). Telmisartan and ramipril had similar effects on both outcomes in the subgroup of patients with diabetes. More patients taking ramipril than telmisartan discontinued the study's medication (4.5% vs. 1.2%), mainly because of cough or angioedema.