A randomized trial of the beta-adrenergic antagonist carvedilol in chronic kidney disease

INTERVENTION: Eligible patients with CKD stage 3, 4 and 5 were enrolled in a parallel, open‐label, placebo controlled, randomized treatment protocol. During a run‐in phase of about one month, all patients received 1.25 mg of carvedilol two times a day in order to determine which patients were unable to tolerate low doses of carvedilol. The patients were requested to visit their doctors every two weeks for their medical checks. Patients who could not tolerate such a dose were excluded from this trial. Remaining patients were then randomly assigned to receive either placebo or carvedilol by 1:1 stratified randomization. They continued their background treatment for renoprotection. During the titration period, the dose of carvedilol was doubled at one‐month interval and then increased to a target dose of 10 mg twice a day. When the dose increase was not tolerated for the appearance of adverse reactions such as symptomatic fatigue, HR <50 beats/min or arterial hypotension (BP <90/60 mm Hg), it was temporarily halved, then again increased at same interval. The final dose of carvedilol was individually titrated. At the end of the up‐titration phase, the therapy with carvedilol or placebo was maintained to the end of this study of three years. Antihypertensive agents with dihydropyridine calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists and others was maintained, although the dosage was adjusted according to the clinical conditions of the patient or to the appearance of side effects possibly related to these drugs. First agent to consider was dihydropyridine calcium channel blockers, while the RAAS blockers were last agent to adjust. A total experimental period was 2.5 years. The same protocol was followed for patients allocated to the placebo group. CONDITION: Chronic kidney disease at stage of 3, 4 and 5 PRIMARY OUTCOME: A combined renal outcome of a doubling of serum creatinine concentration and/or end‐stage renal disease SECONDARY OUTCOME: 1) estimated glomerular filtration rate; 2) dairy proteinuria excretion; 3) blood pressure, heart rate; 4) cardiovascular events; 5) cardiac ultrasound; 6) blood neurohormones, hANP, and BNP levels INCLUSION CRITERIA: Age 18 ‐ 70 years, chronic kidney disease stage 3, 4 and 5, as defined by the Japanese Society of Nephrology (JSN), standard renoprotective treatment recommended by the JSN committee, their physical status and laboratory results maintained with variation of less than 30% during at least three consecutive measurements, for a minimum of 3 months after the first consultation, without evidence of urinary‐tract infection or overt heart failure (New York Heart Association [NYHA] class III‐IV) and acute cardiovascular acidents; and no history of allergic reaction to drugs, especially beta‐adrenergic antagonists.