Fluvastatin on Risk Diminishing After Acute Myocardial Infarction - FLORIDA

Description:

The goal of the Fluvastatin on Risk Diminishing After Acute Myocardial Infarction (FLORIDA) trial was to evaluate the effect of early administration of fluvastatin on ischemia in patients with acute myocardial infarction (AMI).

Hypothesis:

Investigators sought to determine whether fluvastatin, started early following AMI, reduces the incidence of residual myocardial ischemia within one year.

Study Design

Study Design:

Patients Enrolled: 540
Mean Follow Up: 1 year
Mean Patient Age: mean age 61 years
Female: 17%

Patient Populations:

AMI patients admitted to a coronary care unit; TC <6.5 mmol/l (<251 mg/dl) within 24 hours after admission; normal triglyceride levels (<4.5 mmol/l or <398 mg/dl); written informed consent; no lipid-lowering agents taken within previous three months; and no scheduled PTCA or CABG (AMI was defined as chest pain >30 minutes, or development of new Q waves and an increase in creatine kinase [CK] or CK-MB twice the upper level of normal)

Exclusions:

Age <18 years; use of lipid-lowering therapy in prior three months; triglyceride levels >4.5 mmol/l; known familial dyslipidemia; severe renal failure; known hepatic disease; severe heart failure (New York Heart Association class IV); scheduled percutaneous coronary intervention or CABG; use of medication that influences the ST segment; atrial fibrillation; Wolff-Parkinson-White syndrome; complete left bundle branch block; known pre-existent ST-segment deviations before the qualifying MI; and left ventricular hypertrophy with a pattern of strain or a permanent pacemaker

Primary Endpoints:

Residual myocardial ischemia on 48-hour ambulatory ECG at one year or a clinical endpoint event (e.g., cardiovascular death, noncardiovascular death, recurrent AMI, recurrent ischemia requiring hospitalization, percutaneous transluminal coronary angioplasty [PTCA], or coronary artery bypass graft surgery [CABG])

Secondary Endpoints:

Change in ischemic burden from baseline (at six weeks and one year); residual myocardial ischemia at six weeks; combined all-cause mortality and major endpoint events; all-cause mortality; and lipid profile (change from baseline to one year)

Drug/Procedures Used:

Patients were randomized to fluvastatin 40 mg twice a day (n=265) or placebo (n=275) initiated within eight days of admission. Forty-eight-hour ambulatory ECG monitoring was used at baseline, six weeks, and one year to evaluate patients for ST segment changes.

Concomitant Medications:

Other lipid-lowering agents were prohibited from use, no digoxin was allowed, and there were no other restrictions on concomitant medication.

Principal Findings:

Baseline total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol were similar in both arms: TC 5.3 mmol/l and LDL 3.5 mmol/l in the fluvastatin arm, and TC 5.4 mmol/l and LDL 3.6 mmol/l in the placebo arm. Beta-blockers were used in 91% of patients at baseline in both arms. Consequently, there was less residual ischemia at baseline than expected: 12% in the fluvastatin group and 13% in the placebo group. Despite relatively low baseline cholesterol levels, there was a significant 13% drop in TC and a 21% decrease in LDL (from 3.5 to 2.7 mmol/l) at one year among fluvastatin patients compared with a 9% increase in LDL in the placebo arm (from 3.6 to 3.9 mmol/l, p<0.001).

There were no significant differences in ischemia detected on 48-hour ambulatory electrocardiogram (ECG) at six weeks (9% vs. 6%, p=NS) or 12 months (7% vs. 9%, p=NS). There was no difference in the combined primary endpoint of any ischemia or major acute coronary events (32.5% fluvastatin vs. 35.8% placebo, p=0.24). The difference was most pronounced (though not statistically significant) in patients who had baseline ischemia and favored the fluvastatin group (50.0% vs. 60.7%, p=NS). There was also no difference in the composite endpoint at six weeks (18.6% vs. 16.1%, p=NS). At one year, all-cause mortality did not differ by treatment arm (2.6% in the fluvastatin arm vs. 4.0% in the placebo arm), nor did the frequency of major clinical events (23.4% vs. 24.7%, p=0.764).

Interpretation:

Among patients with AMI, early administration of fluvastatin was not associated with a reduction in the primary composite endpoint of residual myocardial ischemia or major clinical events by one year. Myocardial ischemia is common after AMI and is an important risk factor for subsequent adverse events (Gill JB, Cairns JA, Roberts RS, et al. Prognostic importance of myocardial ischemia detected by ambulatory monitoring early after acute myocardial infarction. N Engl J Med 1996;334:65-70). There has been evidence that statin therapy may improve or restore endothelial function and prevent post-AMI ischemia.

This well-treated, low-risk population saw the expected improvement in cholesterol levels with active therapy, but there were no significant beneficial effects of fluvastatin on ischemic events or ischemic burden in either the acute or the chronic phase. The presence of ischemia at baseline did show a trend toward predicting an increased risk of clinical events.

Thus, while supporting the prognostic importance of myocardial ischemia detected by ambulatory ECG early after AMI, fluvastatin did not modify this important risk factor.

This study was initiated by the Working Group on Cardiovascular Research, The Netherlands, which consists of more than 50 nonuniversity hospitals.

There was a low TC in patients in this study, which may have confounded the results, or may raise the question of whether only patients with TC at higher levels (e.g., >250 mg/dl) may benefit from early aggressive treatment. However, the MIRACL trial shows a significant reduction in late ischemic events in all patients treated.

References:

1. Liem AH, van Boven AJ, Veeger NJ, et al. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. Eur Heart J 2002;23:1931-7.

2. American Heart Association Annual Scientific Sessions, 2000, Clinical Trials, presented by Ad J. van Boven, MD, and Anho Liem, MD

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Monitoring, Ambulatory, Myocardial Infarction, Cholesterol, LDL, Coronary Care Units, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Fatty Acids, Monounsaturated, Creatine Kinase, MB Form, Risk Factors, Electrocardiography, Lipoproteins, LDL, Chest Pain, Research Personnel, Indoles, Informed Consent, Triglycerides


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