CON6ESTlVE HEART FAtLURE
Renal Function in Severe Congestive Heart Failure During Treatment with Enalapril (the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] Trial) Susanne Ljungman, MD, John Kjekshus, MD, and Karl Swedberg, MD, for the CONSENSUS Trial Group The effect on renal function of long-term troatmerit with either enafapril (n = 123) or placebo (n = 120) in addftfon to conventional therapy was studied in a randomized trial In patients wfth severe congestke heart failure (New York Heart Association functional class IV; the Cooperative North Scandhuwian Enakpril Survival Study). Enalaprtl was administered in a dose of 2.5 to 40 mg/day. Yhe analysts was restrkted to the first 6 months of treatment. Yhere was an average initial increase of 10 to 15% (10 to 20 junofllfter) irrespective of basetfne serum creatinine wfthin the first 3 weeks of enalapril treatment, whereafter mean serum creattnine remained on a similar level during the ffrst 6 months. Enafapril was wefl-tokrated by most patients, and serum creathdne was reduced in 24%. Serum creatbtine increased by >lOO% in 13 patknts (11%) in the enataprtl group (mainly as a consequence of intercurrent disease or severe hypotenskn, and usually transkntly) and in 4 (3%) in the ptacebo group. The maxhnal increase in serum creathtine in the enakprfl group was inversety correlated to the dtastogc blood pressure (p = 0.006) at basetine and to the mean diastotk and systdk bkod pressures measured at the time of the maxhnal increase in serum creatfnlne (p = 0.0001). According to multivariate regressfon analysis, the maximal increase in serum creatfnine was also slightly influenced by the dose of furosemide taken. Yhe development of hypotenston emerged as the strongest factor expkhdng an abnormal i-se in serum creathdne. Patients wfth marked reduction of baseli~ glomerular filtration rate had an increased rislc of developing hypotenston. Ther&re , low beginning doses of analapril and monttorfng of bkod pressure and serum creatinine are recommended in patients with severe heart failure, especially in those with marked reductfon of gtomerular ffttraFrom the Department of Nephrology, Sahlgrenska Hospital, and the Department of Medicine, Ostra Hospital, University of Gothenburg, Gothenburg, Sweden; and the Department of Medicine, Baerum Hospital, Flaerum, Norway. This work was supported by a grant from Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey. Manuscript received October 15,199 1; revised manuscript received April 27, 1992, and accepted May 1. Address for reprints: Susanne Ljungman, MD, Department of Nephrology, Sahlgrenska Hospital, S-413 45 Gothenburg, Sweden.
tfon rate and in those expected to have an excessive stimulation of the renin-angtotendn system. (Am J Cardid 1992;70:47S467)
he reduction in systolic function in heart failure activates neurohormonal mechanisms that in mild heart failure may have some compensatory or supportive role, but in severe congestive heart failure have definite adverse effects on vital organs such as the myocardium and the kidney. Therefore, treatment modalities to improve the prognosis should directly or indirectly influence these neurohormonal mechanisms. Treatment with angiotensin-converting enzyme (ACE) inhibitors has emerged as an important regimen in this context.1-3 In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), we could demonstrate that the addition of enalapril to conventional therapy in severe congestive heart failure significantly improved survival and functional classification symptomatology. Thus, the 6-month mortality (primary object) in the placebo group (calculated by life-table analysis) was 48% and the corresponding figure in the enalapril group was 29%. The prognosis for patients with a baseline serum creatinine level higher than the median value (123 pmol/liter) was better after enalapril treatment than for those whose serum creatinine levels were less than the median value.3 The activation of the renin-angiotensin-aldosterone system in severe congestive heart failure has important implications for renal function and supports the glomerular filtration rate by preferential constriction by angiotensin II of the efferent arteriole.4 Therefore, ACE inhibition may decrease the glomerular filtration rate if its maintenance is strongly dependent on constriction of the efferent arteriole. This may occur in patients with marked reduction of renal perfusion pressure and excessive stimulation of the renin-angiotensin system.5-6More knowledge of the factors influencing the renal function in heart failure during ACE inhibition may make it possible to avoid clinically significant reduction of renal function at the initiation of and during continued treatment with ACE inhibitors in patients with chronic congestive heart failure. The aim of this analysis of the CONSENSUS was to study the long-term effects of enalapril treatment on renal function and to identify risk factors for deteriora-
T
RENAL
FUNCTION
IN HEART
FAILURE
479
tion of renal function in patients with severe congestive heart failure. MerHODS The study design of the CONSENSUS, as well as the inclusion and exclusion criteria, was previously rep~rted.~ The study began in April 1985 and stopped in December 1986. It included 253 patients (mean age 70 years, range 36 to 91) with severe congestive heart failure in New York Heart Association functional class IV who were randomized at 35 Scandinavian centers in a double-blind fashion to placebo (n = 126) or enalapril (n = 127) in addition to conventional therapy. Patients with serum creatinine >300 Fmol/liter were not included. Coronary artery disease was the cause of congestive heart failure in 73%. All patients were receiving diuretics (mean furosemide dose 210 mg), 94% digitalis and 50% vasodilators, usually isosorbide dinitrate (mean dose 62 mg). ACE inhibitors were not permitted. The treatment dose of enalapril/placebo was 2.5 to 40 mg daily. The maintenance dose was obtained after titration during the initial 3 weeks. Treatment began with 5 mg twice daiiy, with weekly increments to 10 and 20 mg twice daily if the patient did not have symptoms of hypotension or other side effects. The maximal dose was 40 mg/day. Early in the trial, the occurrence of symptomatic hypotension in some patients led to a revision of the protocol after 67 patients had been randomly assigned. Patients considered at high risk for hypotension (serum sodium
Renal Function in Severe Congestive Heart Failure During Treatment with Enalapril (the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] Trial) Susanne Ljungman, MD, John Kjekshus, MD, and Karl Swedberg, MD, for the CONSENSUS Trial Group The effect on renal function of long-term troatmerit with either enafapril (n = 123) or placebo (n = 120) in addftfon to conventional therapy was studied in a randomized trial In patients wfth severe congestke heart failure (New York Heart Association functional class IV; the Cooperative North Scandhuwian Enakpril Survival Study). Enalaprtl was administered in a dose of 2.5 to 40 mg/day. Yhe analysts was restrkted to the first 6 months of treatment. Yhere was an average initial increase of 10 to 15% (10 to 20 junofllfter) irrespective of basetfne serum creatinine wfthin the first 3 weeks of enalapril treatment, whereafter mean serum creattnine remained on a similar level during the ffrst 6 months. Enafapril was wefl-tokrated by most patients, and serum creathdne was reduced in 24%. Serum creatbtine increased by >lOO% in 13 patknts (11%) in the enataprtl group (mainly as a consequence of intercurrent disease or severe hypotenskn, and usually transkntly) and in 4 (3%) in the ptacebo group. The maxhnal increase in serum creathtine in the enakprfl group was inversety correlated to the dtastogc blood pressure (p = 0.006) at basetine and to the mean diastotk and systdk bkod pressures measured at the time of the maxhnal increase in serum creatfnlne (p = 0.0001). According to multivariate regressfon analysis, the maximal increase in serum creatfnine was also slightly influenced by the dose of furosemide taken. Yhe development of hypotenston emerged as the strongest factor expkhdng an abnormal i-se in serum creathdne. Patients wfth marked reduction of baseli~ glomerular filtration rate had an increased rislc of developing hypotenston. Ther&re , low beginning doses of analapril and monttorfng of bkod pressure and serum creatinine are recommended in patients with severe heart failure, especially in those with marked reductfon of gtomerular ffttraFrom the Department of Nephrology, Sahlgrenska Hospital, and the Department of Medicine, Ostra Hospital, University of Gothenburg, Gothenburg, Sweden; and the Department of Medicine, Baerum Hospital, Flaerum, Norway. This work was supported by a grant from Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey. Manuscript received October 15,199 1; revised manuscript received April 27, 1992, and accepted May 1. Address for reprints: Susanne Ljungman, MD, Department of Nephrology, Sahlgrenska Hospital, S-413 45 Gothenburg, Sweden.
tfon rate and in those expected to have an excessive stimulation of the renin-angtotendn system. (Am J Cardid 1992;70:47S467)
he reduction in systolic function in heart failure activates neurohormonal mechanisms that in mild heart failure may have some compensatory or supportive role, but in severe congestive heart failure have definite adverse effects on vital organs such as the myocardium and the kidney. Therefore, treatment modalities to improve the prognosis should directly or indirectly influence these neurohormonal mechanisms. Treatment with angiotensin-converting enzyme (ACE) inhibitors has emerged as an important regimen in this context.1-3 In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), we could demonstrate that the addition of enalapril to conventional therapy in severe congestive heart failure significantly improved survival and functional classification symptomatology. Thus, the 6-month mortality (primary object) in the placebo group (calculated by life-table analysis) was 48% and the corresponding figure in the enalapril group was 29%. The prognosis for patients with a baseline serum creatinine level higher than the median value (123 pmol/liter) was better after enalapril treatment than for those whose serum creatinine levels were less than the median value.3 The activation of the renin-angiotensin-aldosterone system in severe congestive heart failure has important implications for renal function and supports the glomerular filtration rate by preferential constriction by angiotensin II of the efferent arteriole.4 Therefore, ACE inhibition may decrease the glomerular filtration rate if its maintenance is strongly dependent on constriction of the efferent arteriole. This may occur in patients with marked reduction of renal perfusion pressure and excessive stimulation of the renin-angiotensin system.5-6More knowledge of the factors influencing the renal function in heart failure during ACE inhibition may make it possible to avoid clinically significant reduction of renal function at the initiation of and during continued treatment with ACE inhibitors in patients with chronic congestive heart failure. The aim of this analysis of the CONSENSUS was to study the long-term effects of enalapril treatment on renal function and to identify risk factors for deteriora-
T
RENAL
FUNCTION
IN HEART
FAILURE
479
tion of renal function in patients with severe congestive heart failure. MerHODS The study design of the CONSENSUS, as well as the inclusion and exclusion criteria, was previously rep~rted.~ The study began in April 1985 and stopped in December 1986. It included 253 patients (mean age 70 years, range 36 to 91) with severe congestive heart failure in New York Heart Association functional class IV who were randomized at 35 Scandinavian centers in a double-blind fashion to placebo (n = 126) or enalapril (n = 127) in addition to conventional therapy. Patients with serum creatinine >300 Fmol/liter were not included. Coronary artery disease was the cause of congestive heart failure in 73%. All patients were receiving diuretics (mean furosemide dose 210 mg), 94% digitalis and 50% vasodilators, usually isosorbide dinitrate (mean dose 62 mg). ACE inhibitors were not permitted. The treatment dose of enalapril/placebo was 2.5 to 40 mg daily. The maintenance dose was obtained after titration during the initial 3 weeks. Treatment began with 5 mg twice daiiy, with weekly increments to 10 and 20 mg twice daily if the patient did not have symptoms of hypotension or other side effects. The maximal dose was 40 mg/day. Early in the trial, the occurrence of symptomatic hypotension in some patients led to a revision of the protocol after 67 patients had been randomly assigned. Patients considered at high risk for hypotension (serum sodium
