Familial Atherosclerosis Treatment Study - FATS

Description:

Intensive lipid-lowering therapy for CAD progression.

Hypothesis:

Cardiovascular benefits may be related to the degree of reduction in the low-density lipoprotein (LDL) cholesterol level and possibly the degree of increase in the high-density lipoprotein (HDL) cholesterol level.

Study Design

Study Design:

Patients Screened: 364
Patients Enrolled: 146
Female: 0

Patient Populations:

Men <62 years of age
Elevated apolipoprotein B (>125 mg/dL, approximately the 88th percentile for a 47-year-old man)
Evidence of coronary atherosclerosis on a baseline arteriogram
>1 lesion occluding 50% or more of the diameter of the artery or 3 lesions causing at least 30% stenosis
Family history of coronary artery disease (CAD) that suggested a heritable risk if an early cardiovascular event (angina, myocardial infarction, sudden death, stroke, or claudication occurring before the age of 56 in men or before the age of 70 in women) had taken place in at least 20% of the first-degree relatives of the patient's mother or father who had reached middle age (defined for this purpose as 45 years of age for men and 55 for women)

Exclusions:

Completed or scheduled revascularization procedure
Diabetes
Severe hypertension
Cancer
Liver, thyroid, or kidney disease

Primary Endpoints:

Measure of change in the severity of disease in the proximal coronary arteries, as assessed by quantitative arteriography

Drug/Procedures Used:

Colestipol, initially 5g tid with meals then increased to 10g tid after 10 days (unless side effects); niacin, initially 125 mg bid and gradually increased to 500mg qid (with meals and at bedtime) at one month and 1 g qid at two months (if the LDL cholesterol level did not fall below 3.1 mmol/L [120 mg/dL] after three months, the dose of niacin was increased to 1.5 g [3 tablets] qid, but no further); lovastatin, initially 20 mg bid (in the morning and at bedtime) and if the LDL cholesterol level did not fall below 3.1 mmol/L (120 mg/dL) after three months, the dose of lovastatin was increased to 40 mg bid

Concomitant Medications:

Psyllium hydrophic mucilloid

Principal Findings:

The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes, -7 and +5 percent, respectively), but more substantially among patients treated with lovastatin and colestipol (-46 and +15 percent) or niacin and colestipol (-2 and +43 percent).

In the conventional-therapy group, 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent. By comparison, progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent), and regression was more frequent (lovastatin and colestipol, 32 percent; niacin and colestipol, 39 percent; P less than 0.005).

Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure, and an increase in HDL cholesterol correlated independently with regression of coronary lesions.

Clinical events (death, myocardial infarction, or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy, as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment, 0.27; 95 percent confidence interval, 0.10 to 0.77).

After the original FATS angiographic trial ended in 1989, patients in the active therapy group were given the option of remaining on triple therapy for additional long-term follow-up. Eight-year follow-up is now available for 60 patients who chose to remain on this 3-drug regimen, plus an additional 15 patients who discontinued this regimen a mean of 2.4 years after the extended follow-up period began. The extended, observational follow-up data were analyzed on an intention-to-treat basis and compared to 101 patients in the placebo control group who continued to receive usual care following the conclusion of the original FATS trial. Both groups were well-matched at baseline.

Compared to usual care, triple therapy in the extended follow-up period was associated with a significantly greater reduction in total cholesterol (-90 mg/dL vs. -20 mg/dL, p<0.001) and low-density lipoprotein (LDL) cholesterol (-88 mg/dL vs -21 mg/dL, p<0.001). Triglycerides were comparable in both groups at baseline, rose steadily during usual care, and fell 32% during triple therapy (p<0.001). High-density lipoprotein (HDL) levels were comparable at baseline, too, rose slightly during usual care, but increased 30% during triple therapy (p<0.001).

Freedom from cardiovascular death or nonfatal myocardial infarction was greater in the triple-therapy group vs. usual care (94% vs. 81%, p=0.03), demonstrating a 68% reduction in this primary endpoint over 10 years. Kaplan-Meier estimates of total mortality also favored the triple-therapy group (1.3% vs. 19.8%) at 10 years; this is a 93% relative reduction which is highly significant (p=0.001).

Interpretation:

In men with coronary artery disease who were at high risk for cardiovascular events, intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions, increased the frequency of regression, and reduced the incidence of cardiovascular events. The extended follow-up data support the hypothesis that plaque stability is maintained during prolonged intensive lipid therapy. Triple therapy provides dramatic LDL lowering, and has predictably favorable effects on HDL, HDL-2, triglycerides, and LDL particle size distribution. The long-term reductions in total mortality are encouraging, although interpretations of these data are tempered by the limitations of observational analyses.

References:

1. N Engl J Med 1990;323:1289-1298. Final result
2. Circulation 1998;98(Suppl I):I-635. Extended follow-up

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Risk, Coronary Artery Disease, Kaplan-Meier Estimate, Myocardial Infarction, Stroke, Follow-Up Studies, Multivariate Analysis, Cholesterol, LDL, Lovastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Death, Sudden, Blood Pressure, Constriction, Pathologic, Particle Size, Intention to Treat Analysis, Colestipol, Cholesterol, HDL, Niacin, Confidence Intervals, Triglycerides, Lipoproteins, HDL


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