Familial Atherosclerosis Treatment Study Research Articles

P.572 Safety with or without treatment: a post-hoc analysis comparing stable patients discontinuing cariprazine treatment versus patients taking cariprazine long-term

Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia.The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study—Observational Study.Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40–80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model.UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26–0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15–0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27–1.14, P = .11).Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study—Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.

Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study—Observational Study

Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. The clinical benefit of intensive lipid therapy over 25years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study. Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191mg/dL and mean age of 50years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40mg/d), niacin (2.5g/d), and colestipol (20g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10mg and simvastatin 40 to 80mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR]=0.45, 95% confidence interval [CI]: 0.26-0.77, P=.003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR=0.34, 95% CI: 0.15-0.80, P=.009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR=0.55, 95% CI: 0.27-1.14, P=.11). Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.

Prolonged combination lipid therapy is associated with reduced carotid intima-media thickness: a case-control study of the 20-year Familial Atherosclerosis Treatment - Observational Study (FATS-OS).

Studies have documented the short-term vascular benefits of combination lipid therapy. Our objective was to evaluate the long-term effects of combination lipid therapy on carotid intima-media thickness (CIMT) in patients with coronary artery disease. We performed a case-control study in patients who had finished the Familial Atherosclerosis Treatment Study (FATS) and returned to usual care with statin therapy alone or had elected to participate in the 20-year FATS-Observational Study (FATS-OS) and received combination therapy with lovastatin (40mg/day), niacin (2-3 g/day), and colestipol (20 gm/day) for 11years, then continued with simvastatin (10-80mg/day) or lovastatin (40-80mg/day) plus niacin (2-4 g/day). After 17.8±0.8years with combination therapy and 19.0±0.8years with usual care, cholesterol levels and CIMT were collected in 43 FATS-OS patients and 26 usual care patients. Combination therapy group had a greater decrease in total cholesterol (-42±14% vs -31±17%, P=.008) and low-density lipoprotein cholesterol (LDL-C) (-57±13% vs -38±25%, P<.001) and greater increase in high-density lipoprotein cholesterol (HDL-C) (38±43% vs 15±23%, P=.02) as compared with usual care. CIMT (0.902±0.164 vs 1.056±0.169mm, P<.001) on intensive therapy was significantly less compared with usual care. Multivariate regression analysis (coefficient, 95% CI) showed that combination therapy (-0.13; -0.21 to -0.04, P=.003) and on-therapy LDL-C (0.15; 0.02 to 0.28, P=.03) were significant independent predictors of CIMT. Prolonged combination lipid therapy is associated with greater improvements in LDL-C and HDL-C levels and less atherosclerotic burden as compared with statin therapy alone.

Effects of Niacin on Glucose Levels, Coronary Stenosis Progression, and Clinical Events in Subjects With Normal Baseline Glucose Levels (

Although the effect of niacin on the glucose levels in subjects with diabetes mellitus has been investigated, niacin's effects on the glucose levels and atherosclerosis in subjects with normal glucose levels have not been well established. We examined the effect of niacin on the glucose levels, coronary stenosis progression using quantitative coronary angiography, and clinical events in 407 subjects who had a baseline glucose level <100 mg/dl and were enrolled in the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), or Carotid Plaque Composition by MRI during lipid-lowering (CPC) study testing active niacin therapy. Although the fasting glucose levels increased significantly within 3 years in both subjects treated with niacin (from 85.6 ± 9.5 to 95.5 ± 19.7 mg/dl, p <0.001) and without niacin (from 85.2 ± 9.6 to 90 ± 17.9 mg/dl, p = 0.009), those treated with niacin had a significantly larger increase in glucose levels than those not taking niacin (9.88 vs 4.05 mg/dl, p = 0.002). Overall, 29% of subjects developed impaired fasting glucose within 3 years. Incident impaired fasting glucose was significantly more likely to be observed in subjects treated with niacin than in those who were not. However, the frequency of new-onset diabetes mellitus did not differ significantly between the 2 groups (5.6% vs 4.8%, p = 0.5). Niacin-treated subjects compared to untreated subjects had significantly less change in mean coronary stenosis (0.1 ± 0.3% vs 2 ± 12%, p <0.0001) and less major cardiovascular events (8% vs 21%, p = 0.001). In conclusion, the use of niacin for 3 years in subjects with normal baseline glucose levels was associated with an increase in blood glucose levels and the risk of developing impaired fasting glucose, but not diabetes mellitus, and was associated with a significantly reduced incidence of coronary stenosis progression and major cardiovascular events.

Effects of Combination Lipid Therapy on Coronary Stenosis Progression and Clinical Cardiovascular Events in Coronary Disease Patients With Metabolic Syndrome: A Combined Analysis of the Familial Atherosclerosis Treatment Study (FATS), the HDL-Atherosclerosis Treatment Study (HATS), and the Armed Forces Regression Study (AFREGS)

We examined the impact of metabolic syndrome (MS) on coronary stenosis progression and major cardiovascular (CV) events and investigated the mitigating effects of low-density lipoprotein (LDL) cholesterol lowering and LDL cholesterol lowering plus high-density lipoprotein (HDL) cholesterol increasing. This analysis combined individual patient data from 445 subjects who participated in 3 double-blinded, randomized, placebo-controlled trials (FATS, HATS, and AFREGS) comparing intensive lipid therapy to placebos on coronary stenosis progression by quantitative coronary angiography and on major CV events. The primary end points were change in mean proximal coronary diameter stenosis (Delta%S(prox)) over 3 years and the frequency of the predefined composite of coronary artery disease death, nonfatal myocardial infarction, stroke, and revascularization due to worsening ischemia. Patients with MS had 50% more rapid coronary stenosis progression and 64% increased CV event frequency compared to those without. More rapid coronary stenosis progression was significantly and independently associated with a 3.5-fold increased event risk (p <0.001). Combination lipid therapy significantly decreased stenosis progression by 83% (Delta%S(prox) 0.5 vs 2.9, p <0.001) in patients with MS and induced a small net regression in those without (Delta%S(prox) -0.3 vs 2.0, p <0.001). Combination therapy decreased the event rate by 54% (13% vs 28%, p = 0.03) in those with MS and by 82% (3% vs 17%, p = 0.002) without. On average, each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was significantly associated with a 0.3 Delta%S(prox) decrease. Each 10% decrease in LDL cholesterol or 10% increase in HDL cholesterol was associated with 11% (p = 0.02) or 22% (p <0.001) event risk decrease. In conclusion, patients with MS have significantly more rapid coronary stenosis progression and a higher frequency of CV events. Greater stenosis progression rate is associated with a higher event rate. LDL cholesterol-lowering and HDL cholesterol-increasing therapies independently and significantly decrease coronary stenosis progression and decrease CV events.

Maximizing coronary disease risk reduction using nicotinic acid combined with LDL-lowering therapy

Treatment with statins markedly reduces levels of LDL-cholesterol, and large, welldesigned evaluations of these agents have demonstrated reductions in cardiovascular event rates of 20–40%. Additional therapeutic strategies will be required to make further inroads into the substantial residual burden of cardiovascular disease in statin-treated patients. Epidemiological studies over several decades and outcome studies with agents that raise levels of this lipoprotein (nicotinic acid or fibrates) have established low HDL-cholesterol as an important therapeutic target. Combining agents which decrease LDL-cholesterol and increase HDL-cholesterol within a single regimen might provide a means of improving cardiovascular prognosis beyond that possible with statins alone. Six randomized clinical trials involving treatment with nicotinic acid in combination with a statins or bile acid sequestrant have demonstrated regression, or markedly slowed progression, of atherosclerosis in patients at high risk of a cardiovascular event. Three of these trials, the HDL-Atherosclerosis Treatment Study, the Familial Atherosclerosis Treatment Study, and the Armed Forces Regression Study, have associated these benefits with significant improvements in clinical outcomes. Correcting low HDL-cholesterol in statin-treated patients may provide a means to achieve the next leap forward in the management of cardiovascular disease.

Niacin: a powerful adjunct to other lipid-lowering drugs in reducing plaque progression and acute coronary events.

Recent clinical trial data have demonstrated the benefits of utilizing niacin therapy in the management of dyslipidemia. In the Familial Atherosclerosis Treatment Study and the HDL Atherosclerosis Treatment Study (HATS), niacin combination therapy with a statin or resin resulted in significant reduction in cardiovascular events. The angiographic benefits in the HATS trial appear to be related to the change in large, high-density lipoprotein particle concentration, which is a prominent effect of niacin treatment. Recent evaluation in diabetic populations also has demonstrated a reduction in clinical events. Changes in hemoglobin Alc levels with niacin appear to be clinically insignificant and, therefore, the relative underutilization of niacin in diabetic patients is probably not warranted based on the most recent data.

Introduction

The concept that aggressive lipid-lowering therapy with HMG-CoA reductase inhibitors (“statins”) could yield measurable regression of coronary heart disease (CHD) was first demonstrated in the Familial Atherosclerosis Treatment Study (FATS) and Specialized Centers of Research (SCOR) trials. Since then, extensive epidemiologic and clinical data have demonstrated the benefits of cholesterol reduction with statins in modifying atherogenic risk.1–5 The extent of these benefits was first seen in the Scandinavian Simvastatin Survival Study (4S), which showed that statin therapy produces a significant decrease in mortality in patients with CHD.1 In this landmark study, simvastatin was found to reduce coronary mortality by 42% in hypercholesterolemic patients with angina or previous myocardial infarction. Additional clinical trials have confirmed that statin therapy is beneficial in both primary and secondary prevention settings. In the West of Scotland Coronary Prevention Study (WOSCOPS)2 and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),4 for example, statins were shown to reduce the risk of CHD events in high- and moderate-risk patients without clinical CHD. It is therefore well established that patients with varying degrees of CHD risk can benefit from statin therapy. However, there are still many unanswered questions about identification of, risk assessment in, and optimal treatment of specific populations, such as patients with type 1 or type 2 diabetes mellitus or other high-risk groups. With these issues in mind, we present 5 articles on atherosclerotic disease and lipid management based on presentations at a symposium held at the 50th Scientific Session of the American College of Cardiology in March 2001.

LDL particle size: an important drug target?

Low density lipoprotein (LDL) is the main carrier of plasma cholesterol and a major component of atherosclerotic plaque [1]. Lowering LDL cholesterol reduces coronary events and mortality from coronary artery disease (CAD) [2–4], however, the relation between LDL cholesterol concentration and (CAD) is complex. Many patients with CAD have plasma LDL cholesterol concentrations in the normal rangefor the general population [5]. Thus, it could be that coronary risk goes beyond LDL cholesterol concentration to the characteristics of the LDL particles themselves. The purpose of this communication is to address the issue of whether LDL particle size and density influences its atherogenecity and how this might be modified by drug therapy.

Evidence for a New Pathophysiological Mechanism for Coronary Artery Disease Regression

Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy. Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels >/=125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional therapy with placebo alone or with colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%; P<0.01) and niacin-colestipol therapy (10.3%; P<0.01), whereas HL decreased in both groups (-14% [P<0.01] and -17% [P<0.01] with lovastatin-colestipol and niacin-colestipol, respectively). Changes in LDL buoyancy and HL activity were associated with changes in disease severity (P<0.001). In a multivariate analysis, an increase in LDL buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (P<0.01), followed by reduction in apolipoprotein Bl (5% of variance; P<0.05). These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.

Importance of endothelial function in mediating the benefits of lipid-lowering therapy

Trials of lipid lowering by various methods have clearly demonstrated the benefits, clinically and angiographically. Evidence of slowed arterial disease progression and even regression has been convincing but modest, at best. For example, among those treated intensively in the Familial Atherosclerosis Treatment Study (FATS), the mean improvement in proximal stenosis severity was <1% per patient, and only 12% of all lesions showed convincing regression. Despite these modest arterial benefits, the associated reductions in major cardiovascular events have been surprisingly great (24–35% in 3 recent large trials and ≥50% in angiographic trials using combination therapies). The process of plaque disruption helps explain this discrepancy. Disruption can be predicted by a large accumulation of core lipid in the plaque and a high density of lipid-laden macrophages in its thinned fibrous cap. Lesions with these characteristics comprise only 10–20% of the overall lesion population but account for 60–90% of the acute clinical events. Lipid-lowering therapy has beneficial effects on these “high-risk” features of plaque morphology. The composite of data presented here supports the hypothesis that lipid-lowering therapy selectively depletes lipids from this relatively small but dangerous subgroup of fatty lesions, effectively stabilizing them.

Use of Niacin, Statins, and Resins in Patients With Combined Hyperlipidemia

Patients in the original Familial Atherosclerosis Treatment Study (FATS) cohort were subgrouped into those with triglyceride levels ≤120 mg/dL (n = 26) and those with triglyceride levels ≥190 mg/dL (n = 40). Their therapeutic responses to niacin plus colestipol, lovastatin plus colestipol, colestipol alone, or placebo were determined. Therapeutic response was also determined in the same 2 triglyceride subgroups (n = 12 and n = 27, respectively) of patients selected for low levels of high-density lipoprotein (HDL) cholesterol and coronary artery disease. These triglyceride criteria were chosen to identify patient subgroups with high likelihood of “pattern A” (normal-size low-density lipoprotein [LDL] particles and triglyceride ≤120 mg/dL) or “pattern B” (small dense LDL and triglyceride ≥190 mg/dL). Our findings in these small patient subgroups are consistent with the emerging understanding that coronary artery disease patients presenting with high triglyceride levels have lower HDL-C, smaller less buoyant LDL-C, and greater very low-density lipoprotein (VLDL) cholesterol and VLDL apolipoprotein B, and are more responsive to therapy as assessed by an increase in HDL-C and reduction in triglycerides, VLDL-C, and VLDL apolipoprotein B. In the FATS high-triglyceride subgroup with these characteristics, a tendency toward greater therapeutic improvement in coronary stenosis severity was observed among those treated with either of the 2 forms of intensive cholesterol-lowering therapy. This improvement is associated with therapeutic reduction of LDL-C and elevation of HDL-C, but also appears to be associated with drug-induced improvement in LDL buoyancy.

Effects of Lipid Lowering on Coronary Plaques and Coronary Events

C linical trials evaluating the efficacy of interventions to lower serum total and LDL-cholesterol levels often use angiographic induction of regression and slowing of progression of coronary narrowing as endpoints.1,2 In the Program on the Surgical Control of the Hyperlipidemias (POSCH), Buchwald et al3 used partial ileal bypass and dietary management to lower total and LDL-cholesterol levels in men and women with healed myocardial infarction. At 5 years, there was a 35% reduction in combined CAD-related death and confirmed nonfatal myocardial infarction in the surgery group compared to the control group (dietary counseling alone; 125 vs 82, p 5 0.001). Mean serum total cholesterol levels were decreased by 23% (p ,0.0001) and LDL-cholesterol levels decreased by 38% (p ,0.0001). Follow-up of coronary arteriograms at 3, 5, 7, and 10 years demonstrated significantly less progression (p ,0.001) in the surgery group. The POSCH trial also reported a decrease in new coronary narrowing and some reversal of previously existing narrowing.3 Several angiographic trials have evaluated the ability of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and other lipid-lowering drugs to promote regression and slow progression of coronary atherosclerotic plaques in CAD patients. Overall, these trials have demonstrated a reduction in coronary events. Some major trials included the Multicentre Anti-Atheroma Study (MAAS), the Stanford Coronary Risk Intervention Project (SCRIP), and the Familial Atherosclerosis Treatment Study (FATS).4–6 In MAAS, patients treated with simvastatin 20 mg/day over 4 years had significantly less progression and more regression of their atherosclerotic disease combined when compared to placebo (p 5 0.02). Reductions in total and LDL-cholesterol levels were 23% and 31%, respectively, when compared to placebo. Although the study was not designed to look at clinical outcomes, fewer patients in the simvastatintreated group had coronary angioplasty or bypass procedures.4 In SCRIP, intensive risk reduction including diet, exercise, weight loss, smoking cessation, and lipid-lowering therapy was evaluated in patients with atherosclerosis. The study disclosed a reduced rate of progression of narrowing in coronary arteries (p ,0.02), fewer new narrowings per patient (p 5 0.06), and fewer segments with new narrowings (p 5 0.05).5 Mortality rates were similar, and hospitalization for cardiac causes were reduced. In the FATS trial, the efficacy of cholesterol-lowering drug therapy was evaluated in men with existing CAD.6 At 2.5 years, patients treated with lovastatin plus colestipol had a 33% reduction in serum total cholesterol, with reductions of 23% and 3% found in the colestipol plus niacin and placebo groups, respectively. Plaque regression, as measured by angiography, was more common in the treatment groups. The frequency of combined fatal and nonfatal myocardial infarction was lower in the drug treatment groups compared to placebo (lovastatin/colestipol 5 4%, niacin/colestipol 5 6%, placebo 5 19%). Clinical trial data indicate that the slowing of progression or regression of coronary atherosclerosis results in a decrease in coronary events. Although many of these trials were not designed to show the effect on clinical outcome, the results provide information consistent with cholesterol lowering trials such as the Scandinavian Simvastatin Survival Study (4S) and the Coronary and Recurrent Events (CARE) trials that evaluated clinical events as a primary outcome.7,8

Monotherapy with hMG‐CoA reductase inhibitors and secondary prevention in coronary artery disease

Although thrombolytic drugs, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting have provided major advances in the treatment of coronary artery disease, the use of lipid-lowering drugs for secondary prevention has significantly reduced cardiovascular events in the population with coronary artery disease. Secondary prevention trials using HMG-CoA reductase inhibitors include the Familial Atherosclerosis Treatment Study (FATS), the Monitored Atherosclerosis Regression Study (MARS), the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the Asymptomatic Carotid Artery Progression Study (ACAPS), the Multi Anti-Atheroma Study (MAAS), the Scandinavian Simvastatin Survival Study (4S), the Pravastatin Limitation of Atherosclerosis in Coronary Arteries (PLAC I), the Regression Growth Evaluation Statin Study (REGRESS), the Pravastatin Multinational Study, and the Pravastatin, Lipids, and Atherosclerosis in Carotids (PLAC II). Mean changes from baseline of lipid fractions in these trials included: total cholesterol 18 to 35% reduction; low-density lipoprotein (LDL) cholesterol 26 to 46% reduction; high-density lipoprotein (HDL) cholesterol 5 to 15% increase; and triglyceride 7 to 22% reduction. Angiographic regression or lack of progression was statistically demonstrated in the FATS, MARS, CCAIT, MAAS, PLAC I, and REGRESS trials. Cardiovascular events decreased 25 to 92% in all trials, and there was a significant reduction in both cardiovascular and total mortality in the 4S. The greater reduction in cardiovascular events than in anatomic changes suggests that the HMG-CoA reductase inhibitors stabilized the surface of plaques. Monotherapy with HMG-CoA reductase inhibitors provides the clinical opportunity to modify the natural history of coronary artery disease.

Reversal of Atherosclerosis with Therapy: Update of Coronary Angiographic Trials

Publisher Summary There is now serial angiographic evidence for atherosclerotic lesion improvement induced by diverse modes of intervention. The weight of evidence indicates that atherosclerotic lesions as well as clinical coronary events are reduced by intervention. The Cholesterol-Lowering Atherosclerosis Study (CLAS) gave the first clear indication of the importance of triglyceride-rich lipoproteins in lesion progression-an effect manifested after LDL-C was removed as a risk factor. Although clinical events were not significantly different between drug and placebo groups during the 2 years of intervention, 10 year follow-up indicates a significantly lower clinical coronary event rate in the drug group. This chapter concentrates on familial atherosclerosis treatment study (FATS), NHLBl type II coronary intervention study, cholesterol-lowering atherosclerosis study (CLAS), research intervention trials, monitored atherosclerosis regression study (MARS), multicentre anti-atheroma study (MAAS), Heidelberg exercise-diet study, and the program on the surgical control of the hyperlipidemias (POSCH). Many interesting and important findings have resulted from coronary angiographic trials that need further attention if it is to increase our success with secondary preventive measures. The majority of the coronary angiographic trials, NHLBI Type II, CLAS, FATS, STARS, MARS, CCAIT, MAAS, Leiden Intervention Trial, and Lifestyle Heart Trial indicate that LDL-C reduction preferentially regresses lesions 250%S and typically retards coronary artery lesion progression in only 50 to 80% of subjects. Improved therapeutic regimens to alter progression of coronary atherosclerosis may require adjunctive therapy in concert with LDL-C reduction to prevent new lesion formation or to induce early lesion regression, such as for lesions

Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a)

<h3>Objective.</h3> —To determine if lowering elevated low-density lipoprotein cholesterol (LDL-C) levels offsets the adverse effect of raised lipoprotein(a) (Lp[a]) levels on coronary artery disease (CAD) in men. <h3>Design.</h3> —Randomized, double-blind, placebo-controlled trial of lipid lowering for CAD. <h3>Setting.</h3> —Post hoc analysis of the Familial Atherosclerosis Treatment Study. <h3>Participants.</h3> —A total of 146 men aged 62 years or younger with CAD and apolipoprotein B levels of at least 125 mg/dL. <h3>Intervention.</h3> —Patients received a Step II Diet and lovastatin (40 mg daily) plus colestipol (30 g daily), niacin (4 g daily) plus colestipol, or placebo (plus colestipol if LDL-C &gt;90th percentile) for 2.5 years. They were grouped by their LDL-C responses: "minimal" if LDL-C decreased by 10% or less from baseline (mean [SD] change, +6% [13%]) and "substantial" if LDL-C decreased more than 10% (mean [SD] change, —40% [16%]). <h3>Main Outcome Measure.</h3> —Impact of lowering elevated LDL-C on the cardiac event rate (death, myocardial infarction, and revascularization for refractory ischemia) and CAD change associated with elevated Lp(a). <h3>Results.</h3> —In multivariate analyses, the best correlate of baseline CAD severity was Lp(a) (<i>r</i>=0.30;<i>P</i>&lt;.001). For 36 patients with minimal LDL-C reduction, CAD progression correlated only with in-treatment Lp(a) levels (<i>r</i>=0.45;<i>P</i>&lt;.01), but for 84 patients with substantial LDL-C reduction, disease regressed and its change correlated with in-treatment LDL-C (<i>r</i>=0.24;<i>P</i>&lt;.05) but not with Lp(a) (<i>r</i>=—0.05). Lipoprotein(a) levels were not significantly altered in either group. For 40 patients with Lp(a) at the 90th percentile or higher, events were frequent (39%) if reduction of LDL-C was minimal, but were few (9%) if reduction was substantial (relative risk, 0.23; 95% confidence interval, 0.06 to 0.99). <h3>Conclusions.</h3> —In men with CAD and elevated LDL-C, Lp(a) levels were dominant correlates of baseline disease severity, its progression, and event rate over 2.5 years. However, with substantial LDL-C reductions, persistent elevations of Lp(a) were no longer atherogenic or clinically threatening. This provides a possible direction for treatment in such patients with elevated Lp(a) and LDL-C. (<i>JAMA</i>. 1995;274:1771-1774)

What benefit can be derived from treating normocholesterolemic patients with coronary artery disease?

Controversy still remains regarding the possible clinical or arteriographic benefit of intensive lipid-altering therapy in patients who have coronary artery disease and apparently normal lipid levels. Resolution of this controversy appears to depend on an improved understanding of the role of variables other than total or low density lipoprotein cholesterol levels. A comparison of the "normolipidemic" subgroup of The Familial Atherosclerosis Treatment Study patients and The Harvard Atherosclerosis Reversibility Project patients indicates that low levels of high density lipoprotein cholesterol and elevated levels of apolipoprotein B appear to increase considerably the likelihood of benefit from intensive lipid-altering therapy. Other risk-related variables such as systolic blood pressure and lipoprotein(a) further contribute to the prediction of risk and possibly to the potential for treatment benefit.

Benefits of lipid-lowering therapy in men with elevated apolipoprotein B are not confined to those with very high low density lipoprotein cholesterol

Objectives. Do the benefits of intensive lipid-lowering therapy extend to patients with only borderline or moderately elevated levels of low density lipoprotein (LDL) cholesterol?Background. The merits of the present LDL cholesterol treatment goal of ≤100 mg/dl need to be clarified for patients without high levels of LDL cholesterol, particularly for those patients previously classified as having only borderline high (130 to 159 mg/dl) or desirable (101 to 130 mg/dl) levels.Methods. Disease change and clinical events were examined in LDL cholesterol subgroups in the Familial Atherosclerosis Treatment Study (FATS) trial, a randomized, blinded, quantitative arteriographie comparison of one conventional and two intensive lipid-lowering strategies in men with coronary artery disease, a positive family history and apolipoprotein B ≥125 mg/dl. The primary end point, disease change per patient, was measured as the mean change in severity of stenosis (Δ%SProx) among nine standard proximal segments.Results. Of the 120 patients completing the 30-month protocol, 60 had a baseline LDL cholesterol <90th percentile (mean LDL cholesterol 152 mg/dl) and 60 >90th percentile (mean LDL cholesterol 221 mg/dl). Thirty-one patients had levels <160 mg/dl (mean LDL cholesterol 134 mg/dl) and 89 >160 mg/dl (mean LDL cholesterol 205 mg/dl). Patients with LDL cholesterol <90th percentile benefited angiographically from therapy (Δ%SProx= −1.5% diameter stenosis [regression] during intensive therapy vs. 4-2.3% diameter stenosis [progression] during conventional therapy, p < 0.01), as did patients with LDL cholesterol <160 mg/dl (Δ%SProx= −4.2% vs. +3.3% diameter stenosis, p = 0.0001). By comparison, angiographie benefit was less pronounced among those entdring with very high LDL cholesterol (Δ%SProx= −0.2% vs. +1.9% diameter stenosis, p = 0.07) or with LDL cholesterol ≥160 mg/dl (Δ%SProx= +0.2% vs. +1.6% diameter stenosis, p = 0.13). Intensive therapy resulted in a statistically significant reduction in clinical events only in the subgroup with baseline LDL cholesterol < 90th percentile (2 of 42 vs. 8 of 29 patients initially enrolled, p = 0.01) and a trend toward fewer events in patients with LDL cholesterol < 160 mg/dl (2 of 20 vs. 6 of 15 patients, p = 0.05). No such difference was seen in the higher LDL cholesterol subgroups.Conclusions. Treatment benefit in the FATS trial was not confined to patients with very high levels of LDL cholesterol and was in fact particularly evident in those patients with levels < 160 mg/dl. Such patients should be considered more likely, not less, to benefit from intensive lipid-lowering therapy.

Impact of intensive lipid modulation on angiographically defined coronary disease: clinical implications.

We reviewed all randomized, controlled angiographic trials to assess the impact of intensive lipid modulation on the progression or regression of angiographically defined coronary disease. Five of seven trials satisfied selection criteria: Cholesterol-Lowering Atherosclerosis Study, Program on the Surgical Control of the Hyperlipidemias, Familial Atherosclerosis Treatment Study, Regression of Coronary Atherosclerosis During Treatment of Familial Hypercholesterolemia, and St. Thomas' Atherosclerosis Regression Study. We compared patient selection, baseline and on-trial lipid values, changes in angiographic disease scores, and clinical outcomes. In all five trials, treatment reduced levels of low-density lipoprotein (LDL) cholesterol substantially (range -32% to -46%). Treatment reduced risk of angiographic progression by almost 50% compared to controls. Furthermore, nearly one third of drug-treated patients showed angiographic regression of disease. Regression correlated well with reduction in LDL cholesterol. Although overall improvement in stenosis was modest, reduction in clinical events was impressive. Intensive lipid modulation may "stabilize" existing lesions, making them less "active" (ie, less prone to rupture or thrombosis), thereby reducing risk of acute coronary syndromes. These studies clearly support intensive lipid modulation in patients with established coronary disease.

Atherosclerosis regression, plaque disruption, and cardiovascular events: a rationale for lipid lowering in coronary artery disease.

In the Familial Atherosclerosis Treatment Study (FATS), the reduction in clinical events (75%) far outweighed the modest frequency and magnitude of lesion regression observed among those receiving intensive lipid-lowering therapy. To understand this result, the disruptive changes in plaque that trigger clinical events (cardiac death, myocardial infarction, unstable angina) are described. Data are presented in support of the idea that the clinical benefits of lipid-lowering therapy are best explained by stabilization, by depletion of lipid, of the "dangerous" subpopulation of lipid-rich plaques that are often associated with only mild or moderate coronary narrowing.