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Biomedical subjects

John C LaRosa

Publications and source records attributed to John C LaRosa.

At least 19 recordsLinked to original sources
PubMed2006

Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study.

OBJECTIVE: We sought to assess the effects on cerebrovascular events of treating patients with stable coronary disease with low-density lipoprotein cholesterol (LDL-C) levels substantially below 100 mg/dl. BACKGROUND: Lowering LDL-C with statins has been shown to reduce the risk of stroke in patients with stable coronary disease. In observational studies, naturally low cholesterol levels have been associated with an increased risk of hemorrhagic stroke. The cerebrovascular benefits of treating patients with stable coronary disease to LDL-C levels substantially below 100 mg/dl have not been previously investigated. METHODS: We describe an analysis of cerebrovascular events in the Treating to New Targets study, a trial where 10,001 patients with documented coronary disease were randomized to treatment with atorvastatin at 10 mg/day or 80 mg/day and followed for a median of 4.9 years. RESULTS: Mean LDL-C levels were 101 mg/dl on 10 mg atorvastatin and 77 mg/dl on 80 mg. In addition to the reduction in major cardiovascular events (hazard ratio 0.78, 95% confidence interval [CI] 0.69 to 0.89; p = 0.0002), the primary end point of the trial, patients in the 80-mg arm experienced a reduction in cerebrovascular events (hazard ratio 0.77, 95% CI 0.64 to 0.93; p = 0.007) and stroke (hazard ratio 0.75, 95% CI 0.59 to 0.96; p = 0.02). Each 1-mg/dl reduction in LDL-C with treatment was associated with a 0.6% relative risk reduction in cerebrovascular events (p = 0.002) and a 0.5% relative risk reduction in stroke (p = 0.041). The incidence of hemorrhagic stroke was similar in the 80-mg and 10-mg groups, 16 and 18 respectively, and the hemorrhagic strokes were distributed evenly across quintiles of achieved LDL-C during treatment. CONCLUSIONS: Among patients with established coronary disease, treating to an LDL-cholesterol substantially below 100 mg/dl with 80 mg/day atorvastatin reduces both stroke and cerebrovascular events by an additional 20% to 25% compared with the 10 mg/day dose. An increase in hemorrhagic stroke was not seen at low LDL-C levels. (Treating to New Targets; http://www.clinicaltrials.gov; NCT00327691).

Aged↗
PubMed2006

Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study.

BACKGROUND: Despite the prognostic value of metabolic syndrome for predicting cardiovascular events, few trials have investigated the effects of statin therapy on cardiovascular morbidity and mortality in patients with the metabolic syndrome. Our post hoc analysis of the Treating to New Targets (TNT) study assessed whether intensive lowering of low-density lipoprotein cholesterol with high-dose atorvastatin therapy results in cardiovascular benefits for patients with both coronary heart disease and the metabolic syndrome. METHODS: The TNT study was a prospective, double blind, parallel-group trial done at 256 sites in 14 countries between April, 1998, and August, 2004, with a median follow-up of 4.9 years. 10,001 patients were enrolled aged 35-75 years with clinically evident coronary heart disease. Our analysis includes 5584 patients with metabolic syndrome based on the 2005 NCEP ATP III criteria. Patients were randomly assigned to receive either atorvastatin 10 mg per day (n=2820) or 80 mg per day (n=2764). The primary outcome measure was time to first major cardiovascular event, defined as death from coronary heart disease, non-fatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or non-fatal stroke. FINDINGS: In patients with coronary heart disease and metabolic syndrome, mean on-treatment low-density lipoprotein cholesterol concentrations at 3 months were 2.6 mmol/L (99.3 mg/dL) with atorvastatin 10 mg, and 1.9 mmol/L (72.6 mg/dL) with atorvastatin 80 mg. At a median follow-up of 4.9 years, major cardiovascular events occurred in 367 (13%) patients receiving atorvastatin 10 mg, compared with 262 (9.5%) receiving atorvastatin 80 mg (hazard ratio 0.71; 95% CI 0.61-0.84; p<0.0001). Irrespective of treatment assignment, significantly more patients with metabolic syndrome (11.3%) had a major cardiovascular event at a median of 4.9 years than those without metabolic syndrome (8.0%; hazard ratio 1.44; 95% CI 1.26-1.64; p<0.0001). This increased risk was significantly reduced by intensive therapy with atorvastatin 80 mg beyond that achieved with atorvastatin 10 mg. INTERPRETATION: These data indicate that patients with coronary heart disease and metabolic syndrome derive incremental benefit from high-dose atorvastatin therapy, irrespective of the presence of diabetes.

Adult↗
PubMed2005

Intensive lipid lowering with atorvastatin in patients with stable coronary disease.

BACKGROUND: Previous trials have demonstrated that lowering low-density lipoprotein (LDL) cholesterol levels below currently recommended levels is beneficial in patients with acute coronary syndromes. We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary heart disease (CHD). METHODS: A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. RESULTS: The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin. The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P<0.001). A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P<0.001). There was no difference between the two treatment groups in overall mortality. CONCLUSIONS: Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day. This occurred with a greater incidence of elevated aminotransferase levels.

Adult↗
PubMed2005

Is aggressive lipid-lowering effective and safe in the older adult?

With improvements in diet and health care over the last several decades, the elderly have become the fastest-growing segment of the U.S. population. Along with this progress, however, has come increasing morbidity, much of which is attributable to cardiovascular disease, and which is burdensome both to patients and to the health-care system. New medications, including HMG-CoA reductase inhibitors (statins) have the potential to prevent or delay the progression of disease and vascular events. Large, randomized, placebo-controlled trials continue to show that elderly patients benefit from statin therapy and that aggressive therapy is generally very safe in this population; however, statins remain under-used in older individuals. This paper reviews the benefits of statin therapy in the elderly and discusses the reality versus the perception of risk, selection of appropriate patients, and ways in which any risks that may exist can be minimized further.

Aged↗
PubMed2005

The benefits of statin therapy--what questions remain?

Early hydroxymethylglutaryl-CoA reductase inhibitor (statin) trials provided the first evidence of the benefits of statin therapy in secondary prevention of coronary heart disease (CHD). Outcomes data from more recent trials involving atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, have since expanded the patient population shown to benefit from statin therapy. Current studies are evaluating the benefits of lowering lipid levels with statins to below current goals, as well as examining benefits in special patient populations and evaluating the value of surrogate markers of CHD. Early trials provided a solid foundation of knowledge on the efficacy and safety of statins. Recent and ongoing trials generate new data to resolve remaining questions in the fields of CHD prevention and lipidology.

Cerebrovascular Disorders↗
PubMed2005

Cardiovascular risk factors in minorities.

Recent clinical trials have confirmed the value of intervention on major risk factors, particularly hypertension and hyperlipidemia, in preventing the progression and clinical sequelae of atherosclerosis. Less is known about the prevalence and impact of atherosclerosis risk factors in minorities. A review of recent literature reporting the prevalence of established and new predictors of atherosclerotic events in minority populations and the inclusion of minorities in clinical trials is presented. The prevalence of risk factors differs considerably in minority populations. The role of "premature" coronary death and the level of some risk factors, particularly obesity and blood pressure in African descendants and high triglycerides, low high-density lipoproteins, and diabetes in some Hispanics, is higher than in whites. With few exceptions, however, minorities have not been included in clinical trials in sufficient numbers to determine whether significant differences in the benefit of risk factor intervention exists. Prevalence of key risk factors differs among minority groups. Risk factor intervention should be pursued in minority groups but with the understanding that clinical trials have not ruled out the possibility of qualitative or quantitative differences in response rates among different groups.

Cardiovascular Diseases↗
PubMed2004

Past, present, and future standards for management of dyslipidemia.

Evolution of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines for lipid lowering reflects a movement toward global risk assessment, including improved identification of risk in individuals without established coronary heart disease (CHD), and toward more aggressive lipid-lowering targets to reduce CHD risk. The current guidelines, for example, identify a segment of the population without established CHD as being at high risk on the basis of criteria that indicate CHD risk equivalency, recommend a low-density lipoprotein cholesterol (LDL-C) plasma level <100 mg/dL as optimal in all individuals, and establish the metabolic syndrome as a secondary target for therapeutic intervention. Many questions remain for future guidelines to address: To what extent should plasma levels of LDL-C be lowered by therapy to afford optimal risk reduction? Can risk assessment be improved, e.g., by using novel risk measures (such as high-sensitivity C-reactive protein) to indicate patients at higher risk who may benefit from more aggressive interventions? Should the metabolic syndrome be considered a high-risk state warranting aggressive intervention irrespective of risk categorization using current scoring methods? Guidelines for lipid management represent a synthesis of constantly emerging and evolving data: ongoing efforts to improve understanding of the relation between dyslipidemia and cardiovascular disease, to increase knowledge of and ability to measure other CHD risk factors, and to improve therapeutic practices and options will be reflected in future guidelines.

Cholesterol, LDL↗
PubMed2004

New and emerging data from clinical trials of statins.

Recent clinical trials of statins have clearly demonstrated the benefit of statin therapy in preventing both coronary and cerebral vascular events. These benefits have been demonstrated to be present without reference to older age, sex, or comorbid conditions, including hypertension and diabetes. Future trials will test the value of more aggressive low-density lipoprotein cholesterol lowering, the value of immediate statin intervention during acute coronary syndromes, the role of cholesterol lowering with or without angioplasty, and the role of cholesterol lowering in stroke prevention.

Cholesterol, LDL↗
PubMed2003

Understanding risk in hypercholesterolemia.

Atherosclerosis was relatively uncommon 100 years ago, when researchers first established its link to elevated cholesterol. As the twentieth century progressed, however, factors such as high-fat diets, sedentary lifestyles, cigarette smoking, and urbanization combined to increase the prevalence of both hypercholesterolemia and coronary heart disease (CHD) throughout the developed world. Atherogenesis begins at an early age and progresses throughout life, and cholesterol levels during young adulthood strongly predict the risk of CHD and related mortality during the ensuing decades. The total cholesterol level in youth also determines the actual age at which a critical level of atherosclerosis will be reached. Early studies on the primary and secondary prevention of CHD failed to identify a linear relationship between lipid lowering and risk reduction, primarily because older lipid-lowering agents lacked the potency to reduce cholesterol levels significantly enough to achieve lower cardiovascular event and mortality rates. The introduction of the statins, with their powerful lipid-lowering activity, overcame this limitation. Several large-scale trials of statins firmly established the efficacy of these agents in both primary and secondary CHD prevention. With the availability of statin therapy, we are now able to reduce the risk of major adverse CHD events by an average of 30%, regardless of patient age or gender.

Aged↗
PubMed2003

Reduction of serum LDL-C levels: a relationship to clinical benefits.

The association between elevated serum cholesterol levels and cardiovascular risk was established several decades ago by studies such as the Framingham study and the Multiple Risk Factor Intervention Trial (MRFIT). Both primary and secondary prevention trials of cholesterol lowering, using HMG-CoA reductase inhibitors, have demonstrated clear benefits for lipid lowering in preventing both cardiovascular morbidity and mortality over a wide spectrum of coronary heart disease (CHD) risk. Even so, risk of events has been reduced by about 30% in these trials, leaving 70% of events occurring even in the presence of substantial cholesterol lowering. It is unknown whether further reduction of serum cholesterol levels will lower risk factors. The relationship between cholesterol lowering and cardiovascular risk, moreover, is not completely defined; it is unclear, at lower cholesterol levels, whether that relationship follows a threshold, a linear, or a curvilinear model. Early studies of low-density lipoprotein-cholesterol (LDL-C) lowering with HMG-CoA reductase inhibitors suggested that non-cardiovascular mortality might be increased at low serum LDL-C levels, however, these concerns have not been supported by subsequent clinical trials. Recent studies have shed further light on the potential benefits of lowering serum cholesterol levels beyond current guideline targets with HMG-CoA reductase inhibitors. More potent agents in development are likely to make such levels more readily achievable, as well as making guideline targets attainable for many of the large number of patients who currently fail to reach them.

Cholesterol, LDL↗
PubMed2002

Chemoprevention of coronary atherosclerosis: the role of lipid interventions. A position paper of the American Council on Science and Health.

Atherosclerosis is not an inexorable part of aging. Addressing unhealthy lifestyle behaviors will go a long way toward reducing the current burden of atherosclerosis without widespread drug therapy. The question is whether this is possible, given the demand of our modern culture. It is not yet clearly established precisely where pharmaceutical lipid lowering or chemoprevention fits in the broader spectrum of prevention and treatment of atherosclerosis and its complications. Anatomic interventions, such as angioplasty or bypass surgery, targeted to obstructing but stable lesions, are likely to be only of limited effectiveness. On the other hand, cholesterol interventions, not only as a long-term means of dealing with atherosclerotic sequelae but as a short-term means of reducing plaque activity and events, are demonstrably effective. Aggressive cholesterol lowering will, moreover, substantially reduce the requirement for angioplasty and bypass procedures. Although more difficult to prove, earlier intervention can almost surely lower the risk of later, potentially lethal, coronary events.

Cholesterol, LDL↗
PubMed2002

What do the statins tell us?

Until the recent introduction of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), the potential effect of cholesterol lowering on the prevention of clinical manifestations of coronary disease was a matter of debate. In trials conducted before the introduction of statins, cholesterol levels were lowered, on average, by only approximately 10%, resulting in prevention of coronary events but with no effect on total mortality rates. However, statins have been able to reduce low-density lipoprotein cholesterol levels by a mean of roughly 28%, significantly decreasing both relative and absolute risk levels of coronary events and total mortality. These benefits have been demonstrated not only in middle-aged men but also in women and patients aged >65 years. Aggressive cholesterol lowering has also been shown to yield larger decreases in the incidence of subsequent coronary events than angioplasty, and to reduce the occurrence of such events in patients who have undergone coronary artery bypass graft surgery, which raises the question of whether these procedures should be relegated to symptom relief, with cholesterol lowering as the primary means of coronary heart disease event prevention. Statins, therefore, have unequivocally shown the importance of cholesterol lowering in the prevention of morbidity and mortality due to coronary disease. Ongoing research will elucidate the role of statin therapy in the prevention of strokes and in the treatment of patients aged >75 years, and future trials will be needed to evaluate the potential role of statins in primary prevention for younger populations who cannot control cholesterol with lifestyle changes.

Age Distribution↗
PubMed2002

Outcomes of lipid-lowering treatment in postmenopausal women.

Elevated triglycerides and low high-density lipoprotein (HDL) levels are more important coronary risk factors in women, and elevated low-density lipoprotein (LDL) levels less important in women, than men. There is clear-cut evidence in clinical trials that the benefit of cholesterol lowering in women and men is virtually identical. Modifiers of lipids and lipoproteins in women include diabetes mellitus, bodyweight and its distribution, and menopausal status. Diabetes is a more powerful predictor of risk in women than men. This may relate to the importance of elevated triglycerides as a risk factor in women, and to the effects of lipoprotein glycosylation, which lead to increased susceptibility to arterial deposition of LDL and decreased reverse cholesterol transport with HDL. Therapy for lipoprotein disorders in women and men is identical. For the overwhelming majority of patients, treatment with statin therapy is both highly efficacious and well tolerated.

Body Weight↗