Study of Patients Intolerant of Converting Enzyme Inhibitors - SPICE

Description:

Candesartan cilexetil in CHF patients with perceived ACE inhibitor intolerance.

Hypothesis:

To assess the tolerability of candesartan cilexetil in CHF patients with perceived ACE inhibitor tolerance.

Study Design

Study Design:

Patients Screened: 280
Patients Enrolled: 270
NYHA Class: class II, placebo=47.3%, candesartan=57.0%; class III, placebo=49.5%, candesarta
Mean Follow Up: 12 weeks
Mean Patient Age: not reported
Female: 31
Mean Ejection Fraction: Baseline median EF - placebo=29%, candesartan=26%

Patient Populations:

Perceived intolerance to ACE inhibitors Ejection fraction < 35% NYHA class II-IV Age > 21

Exclusions:

Current treatment with ACE inhibitor, potassium-sparing diuretic, or investigational agent Hyperkalemia induced by use of an ACE inhibitor Renal insufficiency Cr > 2.5 mg/dl Unstable angina, cardiac surgery, myocardial infarction, or PTCA within previous 30 days Stroke or TIA in previous 3 months Uncontrolled hypertension Known renal artery stenosis or renal transplantation Pregnancy Obstructive valvular heart disease, constrictive pericarditis, or any noncardiac illness that limited expected survival to less than 2 years

Primary Endpoints:

Tolerability, defined as the percentage of the randomized population completing the 12-week, double-blind, treatment period with the study drug at the 4-, 8-, or 16-mg level.

Secondary Endpoints:

Major cardiovascular clinical events during 12 week therapy: death, worsening of CHF, hospitalization, acute MI, sustained symptomatic hypotension and composite of death or hospitalization for worsening CHF. Quality-of-life evaluation including the Minnesota Living with Heart Failure questionnaire and the SF-36 Health Survey. Functional status assessed by a 6-minute walking test during the 12th week of treatment. Change in NYHA functional class.

Drug/Procedures Used:

Candesartan cilexetil for 12 weeks vs. placebo Initial dose candesartan 4 mg; after 2 weeks the dose was titrated to 8 mg and after 4 weeks to 16 mg

Concomitant Medications:

Other than the randomized treatment assigned, all medical therapy and other management decisions were left to the discretion of the treating physician.

Principal Findings:

Of patients randomized to candesartan the discontinuation rate was 4.1% higher than the placebo arm (82.7% completed the 12-week period of therapy vs 86.8% p=NS). Frequencies of death and morbidity were not significantly different between the candesartan and placebo groups (death 3.4% vs 3.3%; worsening heart failure 8.4% vs 13.2%; myocardial infarction 2.8% vs 5.5%; all-cause hospitalization 12.8% vs18.7%; and death or hospitalization for heart failure 11.7% vs 14.3%). Symptomatic hypotension occurred more frequently with candesartan (5.0% vs 0%, p=0.03). There was no overall difference in change in NYHA functional class between the candesartan and the placebo arms (no change in class, 84% with candesartan vs 75% with placebo, p=NS).

Interpretation:

The benefits of ACE inhibition in CHF are well documented, but are limited by adverse effects, including cough and azotemia. The angiotensin II antagonists appear to be promising new agents for this patient population. The SPICE trial showed that patients with CHF and previous ACE inhibitor intolerance can tolerate candesartan, suggesting that intolerance of ACE inhibitors is primarily mediated through effects other than those of angiotensin. ACE inhibitor intolerance effects 5%-10% of patients with heart failure.

References:

Am Heart J 2000;139:609-617.

Clinical Topics: Heart Failure and Cardiomyopathies, Novel Agents, Acute Heart Failure

Keywords: Biphenyl Compounds, Azotemia, Myocardial Infarction, Angiotensin II Type 1 Receptor Blockers, Benzimidazoles, Heart Failure, Hypotension, Tetrazoles, Cough


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