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Question(SECONDARY PREVENTION Q's) What is the effectiveness and cost effectiveness of giving Nicotinic acids versus giving placebo, to improve outcome in individuals with established CVD?

Grading:1+Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
Reference number 5177
Clofibrate and niacin in coronary heart disease
1975JAMA231 4pgs 360 381
Study Type:Randomised Controlled Trial
Patient CharacteristicsInclusion criteria: Post MI men aged 30 to 64 years (at least 3 months post infarction). Exclusion criteria: Patients with cardiac failure which required treatment with digoxin and/or diuretics. Patients with diabetes mellitus. Concomitant drug therapy: Not detailed.
InterventionsClofibrate, 1.8 g once daily, 1103 patients. Niacin, 3 g once daily, 1119 patients.
ComparisonsPlacebo: 2789 patients.
Study Length5 years (all surviving patients in the study for at least 54 months).
OutcomesPrimary: All cause mortality. Secondary: Individual components of all cause mortality, nonfatal MI, coronary death or nonfatal MI, definite pulmonary embolism (fatal or nonfatal), definite or suspected fatal or nonfatal pulmonary embolism or thrombo-phlebitis, fatal or nonfatal stroke or intermittent cerebral ischaemic attack, any definite or suspected fatal or nonfatal cardiovascular event.
Effect
FundingNat. Heart and Lung Inst.
ConclusionsResults were analysed using the z test (comparison of 2 means of large groups). A z value of greater than 1.96 or less than −1.96 usually is considered significant (P < 0.05). However, the authors noted that for long term RCT it is more appropriate to consider z values > 2.58 or z < − 2.58, (P < 0.01) or even z values > 2.81 or z < −2.81, (P < 0.005) as significant. A negative z value denotes an event rate in a drug group that is lower than the placebo group. Clofibrate versus placebo: Primary outcome: All cause mortality: 221/1103 (20.0%) Clofibrate versus 583/2789 (20.9%) placebo, z = 0.60, not significant. Secondary outcomes: All cardiovascular mortality: 191/1103 (17.3%) Clofibrate versus 528/2789 (18.8%) placebo, z = −1.17, not significant. Mortality cause unknown: 7/1103 (0.6%) Clofibrate versus 13/2789 (0.5%) placebo, z = 1.27, not significant. Coronary heart disease mortality: 156/1103 (14.1%) Clofibrate versus 452/2789 (16.2%) placebo, z = −1.60, not significant. Sudden cardiovascular death: 93/1103 (8.4%) Clofibrate versus 269/2789 (9.6%) placebo, −1.17, not significant. All cancer deaths: 7/1103 (0.6%) Clofibrate versus 16/2789 (0.6%) placebo, z = 0.22, not significant. Other non cardiovascular death: 16/1103 (1.5%) Clofibrate versus 26/2789 (0.9%) placebo, z = 1.41, not significant. Non fatal MI: 128/1103 (11.6%) Clofibrate versus 339/2789 (12.2%) placebo, z = −0.48, not significant. Coronary death or nonfatal MI: 263/1103 (23.8%) Clofibrate versus 731/2789 (26.2%) placebo, z = −1.53, not significant. Definite pulmonary embolism (fatal or nonfatal): 20/1103 (1.8%) Clofibrate versus 30/2789 (1.1%) placebo, z = 1.84, not significant. Definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis: 57/1103 (5.2%) Clofibrate versus 91/2789 (3.3%) placebo, z = 2.80, significant (P < 0.01). Fatal or nonfatal stroke or intermittent cerebral ischaemic attack: 117/1103 (10.6%) Clofibrate versus 271/2789 (9.7%) placebo, z = 0.84, not significant. Any definite or suspected fatal or nonfatal cardiovascular event: 929/1103 (84.2%) Clofibrate versus 2251/2789 (80.7%) placebo, z = 2.56, significant (P < 0.01). Niacin versus placebo: Primary outcome: All cause mortality:237/1103 (21.2%) Clofibrate versus 583/2789 (20.9%) placebo, z = 0.19, not significant. Secondary outcomes: All cardiovascular mortality: 210/1103 (18.9%) Niacin versus 528/2789 (18.8%) placebo, z = −1.12, not significant. Mortality cause unknown: 3/1103 (0.3%) Niacin versus 13/2789 (0.5%) placebo, z = −0.88, not significant. Coronary heart disease mortality: 178/1103 (15.9%) Niacin versus 452/2789 (16.2%) placebo, z = −1.23, not significant. Sudden cardiovascular death: 118/1103 (10.5%) Niacin versus 269/2789 (9.6%) placebo, 0.85, not significant. All cancer deaths: 7/1103 (0.6%) Niacin versus 16/2789 (0.6%) placebo, z = 0.19, not significant. Other non cardiovascular death: 17/1103 (1.5%) Niacin versus 26/2789 (0.9%) placebo, z = 1.59, not significant. Non fatal MI: 100/1103 (8.9%) Niacin versus 339/2789 (12.2%) placebo, z = −2.88, significant (P < 0.005). Coronary death or nonfatal MI: 255/1103 (22.8%) Niacin versus 731/2789 (26.2%) placebo, z = −2.23, significant (P < 0.01). Definite pulmonary embolism (fatal or nonfatal): 11/1103 (1.0%) Niacin versus 30/2789 (1.1%) placebo, z = −0.26, not significant. Definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis: 44/1103 (3.9%) Niacin versus 91/2789 (3.3%) placebo, z = 1.04, not significant. Fatal or nonfatal stroke or intermittent cerebral ischaemic attack: 86/1103 (7.7%) Niacin versus 271/2789 (9.7%) placebo, z = −1.99, not significant. Any definite or suspected fatal or nonfatal cardiovascular event: 875/1103 (78.2%) Niacin versus 2251/2789 (80.7%) placebo, z = −1.78, not significant. Plasma lipid values: Clofibrate: Mean decrease of cholesterol levels (after correcting for lipid changes in the placebo group) = 16.3 mg/100 ml, mean decrease of 6.5% from baseline level. Mean decrease of triglyceride levels (after correcting for lipid changes in the placebo group) = 1.5 mEq/100 ml, mean decrease of 22.3% from baseline level. Clofibrate: Mean decrease of cholesterol levels (after correcting for lipid changes in the placebo group) = 16.3 mg/dl (0.34 mmol/l), mean decrease of 6.5% from baseline level. Mean decrease of triglyceride levels (after correcting for lipid changes in the placebo group) = 1.5 mEq/100 ml, mean decrease of 22.3% from baseline level. Niacin: Mean decrease of cholesterol levels (after correcting for lipid changes in the placebo group) = 26.2 mg/100 ml (0.67 mmol/l),, mean decrease of 9.9% from baseline level. Mean decrease of triglyceride levels (after correcting for lipid changes in the placebo group) = 1.8 mEq/l, mean decrease of 26.1% from baseline level. Side Effects Clofibrate: Decreased libido or potentia: 150/1065 (14.1%) Clofibrate versus 269/2695 (10.0%) placebo, z = 3.60, P < 0.005. Increase in appetite: 56/1065 (5.3%) Clofibrate versus 84/2695 (3.1%) placebo, z = 3.60, P < 0.005. Niacin: Combination of diarrhoea, nausea, vomiting, black tarry stools, stomach pain: 230/1065 (21.4%) Niacin versus 385/2695 (14.3%) placebo, z = 5.36, P < 0.005. Flushing: 987/1065 (92.0%) Niacin versus 115/2695 (14.3%) placebo, z = 53.42, P < 0.005. Itching of skin: 525/1065 (48.9%) Niacin versus 167/2695 (6.2%) placebo, z = 30.53, P < 0.005. Urticaria: 77/1065 (7.2%) Niacin versus 40/2695 (1.5%) placebo, z = 9.09, P < 0.005. Other type of rash: 212/1065 (19.8%) Niacin versus 159/2695 (5.9%) placebo, z = 12.94, P < 0.005. Pain or burning when urinating: 103/1065 (9.6%) Niacin versus 32/2695 (1.2%) placebo, z = 3.68, P < 0.005. Decrease in appetite:44/1065 (4.1%) Niacin versus 40/2695 (1.5%) placebo, z = 4.81, P < 0.005. Unexpected weight loss: 29/1065 (2.7%) Niacin versus 24/2695 (0.3%) placebo, z = 4.14, P < 0.005. Excessive sweating: 36/1065 (3.4%) Niacin versus 49/2695 (1.8%) placebo, z = 2.95, P < 0.005.
Quality+

From: Appendix D, Clinical Evidence Extractions

Cover of Lipid Modification
Lipid Modification: Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease [Internet].
NICE Clinical Guidelines, No. 67.
National Collaborating Centre for Primary Care (UK).
Copyright © 2008, Royal College of General Practitioners.

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