Effect of felodipine on arterial blood flow and venous function at rest in patients with mild essential hypertension

OBJECTIVES: Lipid-lowering drugs as 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors and cholestyramine are effective in reducing cardiovascular morbidity both in primary and secondary prevention. Patient compliance is an important determinant of the outcome of therapy. This study was designed to compare compliance with tolerance and lipid-lowering effectiveness of pravastatin and/or cholestyramine in primary care. DESIGN: Nine hundred and eighty nine women and 1047 men were randomized to treatment at 100 primary-care centres in Sweden. After dietary intervention, an eligible patient was randomly assigned to one of four programs of daily treatment: group Q, 16 g cholestyramine, group QP, 8 g cholestyramine and 20 mg pravastatin, group P20, 20 mg pravastatin or group P40, 40 mg pravastatin. RESULTS: In group Q, group QP, group P20 and group P40 the reductions in low density lipoprotein (LDL)-cholesterol were 26%, 36%, 27% and 32%. The dose actually taken was 91-95% of the prescribed for the pravastatin treatment groups and 77-88% for the cholestyramine groups. In the pravastatin and cholestyramine groups 76-78% and 44-53%, respectively, completed the trial. Only 8-27% of the patients reached a serum cholesterol target level of 5.2 mmol L-1. There was no difference in lipid-lowering effect between women and men. CONCLUSION: Pravastatin alone is efficacious and compliance is high, independent of dose. Combined treatment with cholestyramine and pravastatin had a better cholesterol lowering effect (although not statistically significant) than 40 mg pravastatin. Despite this, only 8-27% of the patients actually reached a serum cholesterol level of 5.2 mmol L-1. No unexpected serious adverse events were detected in any of the treatment groups. As predicted, the gastrointestinal disturbances were more common on cholestyramine treatment. These two factors suggest that an increase in the dosage of the HMG-CoA reductase inhibitor may be appropriate. Results from other studies indicate that there also might be other positive effects of statin treatment beyond cholesterol lowering.     

What happens with patients after participation in a clinical trial?

107 patients with primary hypercholesterolaemia participated for five years in a clinical trial with dietary and drug treatment (a statin) at the Lipid Clinic. At the end of the study the patients were referred back to their own physicians, with written advice on diet and drug therapy. At a recall two years later we studied to what extent recommended therapy and follow-up had been implemented. 15% had no follow-up after participating in the study and 18% had not measured their cholesterol for one year or more. The majority of the patients did not follow the recommended diet and level of physical activity satisfactorily, and 20% had stopped their lipid-lowering medication. In general they had been prescribed too low doses of the lipid-lowering agent, and 70% of the patients had not reached the target of the LDL-cholesterol. In conclusion, adequate treatment and a five-year follow-up is not sufficient to keep the patient compliant when the follow-up becomes less intensive. When a clinical trial is terminated, greater efforts should be made to secure better compliance to therapy.     

Management of atherogenic hyperlipidemia

After defining the type of hyperlipoproteinaemia (the three main are IIa, IIb and IV), confirming its primary nature (i.e. after eliminating the various causes of secondary hyperlipoproteinaemia) and after defining the therapeutic objective (different according to the context of primary or secondary cardiovascular prevention), treatment must be prescribed. It always consists of diet, and very often a lipid-lowering drug. The remarkable results obtained with statins in studies of primary prevention, secondary prevention and regression of atherosclerosis does not mean that they can be prescribed blindly. Therapeutic indications depend on the type of hyperlipidaemia. By limiting the discussion to the three main types of atherogenic hyperlipoproteinaemia, treatment consists of: in pure type IIa hypercholesterolaemia: a first-line statin (or fibrate or resin in the case of adverse effects); in pure type IV hypertriglyceridaemia: a fibrate and possibly omega-3 fatty acids; in combined or mixed type IIb hyperlipidaemia: a statin in the case of type IIb with predominant hypercholesterolaemia, a fibrate in the case of type IIb with predominant hypertriglyce-ridaemia, failure to comply with these rules can lead to poor laboratory results.     

Cardiovascular prevention, primary or secondary, in high risk patients

Two groups of patients admitted to hospital consecutively for coronary artery disease in 36 university hospital departments were interrogated about the advice received and followed concerning cardiovascular prevention both before the clinical onset of the disease (Group I), those with disease of less than one month duration (primary prevention), or after this period (Group II), those with disease for over six months (secondary prevention). The follow-up of risk factors or medical advice concerning prevention (dietary and/or treatment) was more common, and compliance to the advice was better, in secondary prevention. However, in both groups, with the exception of hypertension, the diagnosis and follow-up of the risk factors were incomplete with 19% vs 41% (p < or = 0.001) of serum cholesterol levels unmeasured before the onset of clinical disease; during the last 5 years, 41% vs 12% (cholesterol, p < or = 0.001) and 27% vs 9% (serum glucose, p < or = 0.001) were not checked. At least one measure of prevention had been advised to 66% vs 80% (p < or = 0.001) of patients and the measures taken concern 53 vs 75% (p < or = 0.001) of patients: serum cholesterol 27% vs 51% (p < or = 0.001), hypertension 32% vs 36% (NS) and serum glucose 14% vs 21% (p < or = 0.05). Compliance with advice was mediocre with regards to diet and cholesterol lowering drugs. A large proportion of patients in both groups had higher than recommended levels, including those on diet or treatment. These observations, confirmed in France and abroad, suggest that cardiovascular prevention should be better organised.     

Treatment of hypercholesterolemia with statins

The etiology of arteriosclerosis is a complicated interaction of many factors, among which aberrations in the cholesterol metabolism appear to play an important role. Several studies have shown that lipid-lowering therapy with statins improves survival and reduces complications in patients with coronary artery disease. Until recently, the role of cholesterol-lowering in patients with elevated cholesterol, but without diagnosed coronary disease, was not clear. New studies suggest that men in this group may benefit from treatment with statins. This article focuses on some of the problems connected with the widespread use of statins, namely: proper selection of patients, the safety of long-term statin therapy, economics, and the need for additional therapy and for the continuation of population-based general measures.     

Rationale, design, and baseline characteristics of a trial comparing aggressive lipid lowering with Atorvastatin Versus Revascularization Treatments (AVERT)

This study describes the design, methodologic features, and baseline characteristics of an open-label randomized trial to determine whether aggressive lipid-lowering therapy with atorvastatin is an alternative to angioplasty or other catheter-based revascularization procedures in patients with significant coronary artery disease. Three-hundred forty-one patients with low-density lipoprotein (LDL) cholesterol > or = 115 mg/dl and > or = 1 defined narrowing of a major coronary artery were randomized to atorvastatin or the indicated catheter-based revascularization and conventional care (including lipid-lowering therapy if prescribed). Ischemic events are tracked for 18 months. The primary efficacy parameter is the incidence of an ischemic event, defined as 1 of the following: cardiovascular death, cardiac arrest, nonfatal myocardial infarction, the need for coronary bypass grafting or angioplasty, cerebrovascular accident, and worsening angina verified by objective evidence requiring hospitalization (including unstable angina).     

Hypercholesterolemia: to treat or not to treat? That is the question

Numerous epidemiological studies have confirmed the positive correlation of elevated serum cholesterol levels to increased coronary risk. Clinical and angiographical trials have shown that modification of hypercholesterolaemia by diet or drugs can lower cardiovascular morbidity and mortality. No good evidence exists that lowering serum cholesterol is harmful. In some meta-analyses enhancing statistical power, total mortality appears to be decreased in primary prevention trials if hypercholesterolaemia is sufficiently reduced. Current guidelines for cholesterol modification should include the primary prevention with identification of individuals at high risk, combined with population information, and the secondary prevention for the patients with symptomatic coronary heart disease.     

Risk factors for cerebral hemorrhage in the era of well-controlled hypertension. Melbourne Risk Factor Study (MERFS) Group

BACKGROUND AND PURPOSE: Given that hypertension is now relatively well controlled and use of antiplatelet agents has increased, our primary aims were to investigate the risk of intracerebral hemorrhage (ICH) associated with hypertension and use of antiplatelet agents. METHODS: In this city-wide case-control study, 370 consecutive cases of primary ICH, verified by CT or autopsy, were identified from one of 13 Melbourne hospitals. Ten subjects (or their next of kin) could not be located and 29 refused to participate, resulting in 331 eventual cases. Patients were aged between 18 and 80 years and had no prior stroke. Population-based control subjects were individually age- (+/- 5 years), sex-, and geographically matched to subject cases. A questionnaire administered to participants (or next of kin) elicited information about prior exposure to various potential risk factors. RESULTS: Hypertension approximately doubled the risk of ICH (odds ratio, 2.55; 95% confidence interval, 1.72 to 3.79). The use of aspirinlike drugs, in doses used for secondary prevention of ischemic stroke or cardiac disease, was not associated with an increased risk of ICH (odds ratio, 0.66; 95% confidence interval, 0.20 to 2.21). Factors associated with a reduced risk of ICH were a history of cardiovascular disease, arthritis, or high cholesterol level; being moderately overweight or using hormone replacement therapy; and drinking coffee. CONCLUSIONS: Hypertension was the most important risk factor for ICH but not as high as previously reported, nor was it higher than that reported for ischemic stroke. There was no evidence for any association between the use of aspirinlike drugs and ICH.     

The Veterans Affairs Implantable Insulin Pump Study: effect on cardiovascular risk factors

OBJECTIVE: To determine whether implantable insulin pump (IIP) and multiple-dose insulin (MDI) therapy have different effects on cardiovascular risk factors in insulin-requiring patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized clinical trial was conducted at seven Veterans Affairs medical centers in 121 male patients with type 2 diabetes between the ages of 40 and 69 years receiving at least one injection of insulin per day and with HbA1c, levels of > or =8% at baseline. Weights, blood pressures, insulin use, and glucose monitoring data were obtained at each visit. Lipid levels were obtained at 0, 4, 8, and 12 months, and free and total insulin levels were obtained at 0, 6, and 12 months. All medications being taken were recorded at each visit. RESULTS: No difference in absolute blood pressure, neither systolic nor diastolic, was seen between patients receiving MDI or IIP therapy, but significantly more MDI patients required anti-hypertensive medications. When blood pressure was modeled against weight and time, IIP therapy was significantly better than MDI therapy for systolic blood pressure in patients with BMI <33 and for diastolic blood pressure in patients with BMI >34 kg/m2. Total cholesterol levels decreased in the overall sample, but IIP patients exhibited significantly higher levels than MDI patients. Triglyceride levels increased over time for both groups, with IIP patients having significantly higher levels than patients in the MDI group. BMI was a significant predictor of, and inversely proportional to, HDL cholesterol level. No difference in lipid-lowering drug therapy was seen between the two groups. Free insulin and insulin antibodies tended to decrease in the IIP group as compared with the MDI group. C-peptide levels decreased in both groups. CONCLUSIONS: IIP therapy in insulin-requiring patients with type 2 diabetes has advantages over MDI therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Both therapies reduce total cholesterol and C-peptide levels.     

Specialty differences in cardiovascular disease prevention practices

OBJECTIVES: The aim of this study was to examine physician specialty differences in cardiovascular disease prevention practices. BACKGROUND: Despite the importance of cardiovascular disease prevention, little is known about current national practices, particularly physician specialty differences. METHODS: Using a national survey of office visits, we evaluated differences in the propensity of physicians of different specialties to provide prevention services. We analyzed 30,929 adult visits to 1,521 physicians selected by stratified random sampling in the 1995 National Ambulatory Medical Care Survey. Standard and ordinal multiple logistic regression models were employed to estimate the independent effects of physician and patient characteristics. RESULTS: A variety of cardiovascular disease prevention services were provided during an estimated 547 million adult office visits to US physicians in 1995, including blood pressure measurement (50% of visits), cholesterol testing (5%) and counseling for exercise (12%), weight (6%), cholesterol (4%) and smoking (3%). In addition, medication management was reflected by the report of antihypertensives in 12% of visits and lipid-lowering medications in 2%. Across these eight services, propensity to provide services varied consistently with specialty. Controlling for patient and visit characteristics and compared to general internists, the likelihood of providing services was higher for cardiologists (adjusted odds ratio 1.65, 95% confidence interval 1.44 to 1.89) but lower for obstetrician/gynecologists (0.75, 0.68 to 0.82), family physicians (0.69, 0.64 to 0.74), general practitioners (0.58, 0.53 to 0.63), other medical specialists (0.65, 0.59 to 0.72) and surgeons (0.06, 0.05 to 0.06). CONCLUSIONS: Cardiologists have the greatest propensity to provide cardiovascular disease prevention services, while primary care physicians vary substantially in their practices. These findings suggest a need to address variations in cardiovascular disease prevention.     

Management of hyperlipidemia in children with refractory nephrotic syndrome: the effect of statin therapy

The efficacy and safety of hydroxymethylglutaric coenzyme A reductase inhibitor (statins) in the treatment of hyperlipidemia were evaluated in 12 infants and children with steroid-resistant nephrotic syndrome followed prospectively for 1 to 5 years. All patients experienced a hypolipidemic response with a marked reduction in their total cholesterol (40%), low-density lipoprotein cholesterol (44%), and triglyceride levels (33%), but no appreciable change in high-density lipoprotein cholesterol. Statin therapy was well tolerated without clinical or laboratory adverse effects. In spite of a significant hypolipidemic response to statin therapy there were no changes observed in the degree of proteinuria, hypoalbuminemia, or in the rate of progression to chronic renal failure. Long-term controlled studies with statin therapy are needed to further document or negate their renoprotective role in refractory nephrotic syndrome.     

Are physicians less likely to recommend preventive services to low-SES patients?

BACKGROUND: Do low-SES adult patients visiting private primary care clinics differ from higher SES adult patients in their need for eight preventive services or in receiving either a recommendation for or the needed services? METHODS: Randomly identified adult patients were surveyed within 2 weeks of a visit to 22 clinics in the Minneapolis-St. Paul area. Questions assessed patient recollection of the latest receipt of eight services and whether needed services had been recommended during the visit or received then soon after. RESULTS: Of those surveyed, 4,245 patients (1,650 low SES) responded (84.3%), showing that low SES patients were less likely to be up to date for cholesterol measurement, Pap smear, mammography, breast exam, and flu or pneumonia shots (P < 0.004), but not for blood pressure measurement. Low-SES patients needing services received recommendations to have them and actually received them at the same rate as higher SES patients. CONCLUSIONS: The 22 primary care clinics studied appear to be recommending and providing needed preventive services to visiting patients at the same rate regardless of income or insurance status. The reasons for differences in prevention status by SES are complex but the low proportion of all patients receiving recommendations for needed services suggests the need to take advantage of all visits for updating prevention needs.     

Brain serotonin (5-HT) neuroendocrine function in patients taking cholesterol-lowering drugs

Brain serotonin (5-HT) neuroendocrine function, plasma tryptophan, and platelet 5-HT content were examined in 20 patients treated in a lipid clinic for hypercholesterolaemia with combined drug and diet therapy and in 20 healthy matched controls. Treatment had produced a substantial decrease in total cholesterol concentrations in the patients, but they still had higher cholesterol and triglyceride levels than control subjects. The patients were somewhat more depressed than controls but did not differ from them in degree of hostility, free or total plasma tryptophan, or prolactin response to 30 mg of d-fenfluramine. This study does not reveal evidence of abnormal brain 5-HT neuroendocrine function in hypercholesterolaemic patients receiving cholesterol-lowering medications and diet.     

Primary prevention of coronary heart disease: role of cholesterol control in the United States

The benefit of cholesterol-lowering drug therapy in patients with existing coronary heart disease (CHD) is well established through clinical trials. Prevention of recurrent coronary morbidity and mortality in CHD patients is called secondary prevention. In contrast, primary prevention is delaying or preventing altogether new-onset-CHD. There are three categories of primary prevention: high-risk, moderate-risk, and long-term (life-time). A recent clinical trial has documented benefit of cholesterol-lowering drugs for prevention of coronary morbidity and mortality and total mortality in hyper-cholesterolemic, middle-aged men. This trial lends support for including aggressive cholesterol reduction in high-risk primary prevention. However, for such therapy to be cost effective at present-day prices of cholesterol-lowering drugs, only those patients in the higher ranges of risk can be selected for treatment. This leaves a large number of people at moderately high risk for premature CHD because of high cholesterol levels. These persons deserve increased professional attention to risk reduction. In general the nondrug approach is indicated. The latter approach includes eliminating other risk factors, e.g. cigarette smoking and hypertension, and reducing serum cholesterol levels by decreased intakes of saturated fatty acids, cholesterol, and excess total calories. Some moderate-risk patients may require low doses of cholesterol-lowering drugs to achieve the goals for cholesterol reduction. Finally, public health strategies need to be developed for applying the same nondrug approach for the general population for reducing the overall incidence of CHD.     

Cholesterol management in high-risk patients without heart disease. When is lipid-lowering medication warranted for primary prevention?

A particularly important question for primary prevention of CHD is when to initiate cholesterol-lowering drugs in patients at risk. The two most important factors to consider are the serum LDL cholesterol level and the absolute risk, based on the presence or absence of other risk factors. The intensity of therapy can be modified according to the other risks at play. For example, diabetes mellitus is a particularly powerful risk factor for morbidity and mortality from CHD. Therefore, middle-aged or elderly diabetic patients can reasonably be treated as if they already have established CHD. Other risk factors are less dangerous, but when a patient has several such factors, intensive cholesterol-lowering therapy often is indicated. Except for patients at highest risk, a 3- to 6-month trial of nondrug therapy is warranted in an effort to achieve the target of therapy without drugs or with low doses of drugs. If patients are appropriately selected for therapy, cholesterol management for primary prevention of CHD should rival secondary prevention in reducing the burden this disorder imposes on society.     

Genetics of lipoprotein disorders

The study of lipoprotein metabolism has led to major breakthroughs in the fields of cellular physiology, molecular genetics, and protein chemistry. These advances in basic science are reflected in medicine in the form of improved diagnostic methods and better therapeutic tools. Perhaps the greatest benefit is the improved ability to identify at an early stage patients who are at high risk for atherosclerosis, providing clinicians the opportunity to proceed swiftly with intensive lipid-lowering therapy for the prevention of cardiovascular complications. Recent clinical trials have shown that such an approach is not only cost-effective but saves lives while improving the quality of life. They also emphasize the important role physicians can have in prevention. More than half of patients with premature CAD have a familial form of dyslipoproteinemia. This review of the genetics of atherogenic lipoprotein disorders underscores the importance of identifying major genetic defects. It also stresses the need to take into account multifactorial etiologies and clustering of risk factors, as well as gene-gene and gene-environment interactions in assessing the atherogenic potential of a lipid transport disorder. Table 2 summarizes the key points in the diagnosis, clinical implications, and treatment of the major inherited atherogenic dyslipidemias.     

Treatment of essential arterial hypertension with hypercholesterolemia. Effects of an alpha-adrenergic blocker and an inhibitor of the angiotensin converting enzyme

BACKGROUND: Hypertension and hypercholesterolemia are frequently associated with this leading to considerable cardiovascular risk. METHODS: An open parallel randomized study was performed in which the effects of doxazosin, an alpha-adrenergic blocker and enalapril, an inhibitor of the angiotensin converting enzyme were compared in 70 patients with essential high blood pressure and plasma cholesterol levels greater than 240 mg/dl. Following 2-4 weeks of placebo administration the patients were randomly treated with one of the two drugs. When required doses were increased and hydrochlorothiazide added until blood pressure lower than 160/95 mmHg was achieved. After this period the patients were observed for a minimum of 8 weeks. The mean length of the study was of 22 weeks. RESULTS: Both drugs significantly reduced blood pressure without modifying cardiac frequency. Doxazosin tended to favorably modify the lipid profile of the plasma while enalapril significantly reduced the levels of cholesterol, lipids and high density lipoproteins (HDL). Upon termination of the study the total HDL/cholesterol index increased 8.6% in those treated with doxazosin and decreased 5.5% in those receiving enalapril (p < 0.05). CONCLUSIONS: Although doxazosin and enalapril are potent antihypertensive drugs, the effects on plasma lipid obtained with doxazosin indicate that a reduction in cardiovascular risk was achieved with this drug in the patients included in this study.     

Management of dyslipidemia in adults

The importance of treating dyslipidemias based on cardiovascular risk factors is highlighted by the National Cholesterol Education Program guidelines. The first step in evaluation is to exclude secondary causes of hyperlipidemia. Assessment of the patient's risk for coronary heart disease helps determine which treatment should be initiated and how often lipid analysis should be performed. For primary prevention of coronary heart disease, the treatment goal is to achieve a low-density lipoprotein (LDL) cholesterol level of less than 160 mg per dL (4.15 mmol per L) in patients with only one risk factor. The target LDL level in patients with two or more risk factors is 130 mg per dL (3.35 mmol per L) or less. For patients with documented coronary heart disease, the LDL cholesterol level should be reduced to less than 100 mg per dL (2.60 mmol per L). A step II diet, in which the total fat content is less than 30 percent of total calories and saturated fat is 8 to 10 percent of total calories, may help reduce LDL cholesterol levels to the target range in some patients. A high-fiber diet is also therapeutic. The most commonly used options for pharmacologic treatment of dyslipidemia include bile acid-binding resins, HMG-CoA reductase inhibitors, nicotinic acid and fibric acid derivatives. Other possibilities in selected cases are estrogen replacement therapy, plasmapheresis and even surgery in severe, refractory cases.     

Treatment for all: the computer as a patient assistant

Hypertension and hyperlipidemia are common and powerful risk factors for cardiovascular disease. Although they may coexist in the same individual by chance, the syndrome of insulin resistance is the common mechanism in many individuals, in whom there is a specific lipoprotein profile of small, dense, low-density lipoprotein particles, reduced plasma high-density lipoprotein cholesterol levels, and increased plasma triglycerides. This lipoprotein profile may be exacerbated by diuretics or beta-blockers. Initial management of the insulin resistance syndrome is by weight loss and dietary measures. Optimum antihypertensive and lipid-lowering drug strategy remains to be established.     

Treatment strategies for management of serum lipids: lessons learned from lipid metabolism, recent clinical trials, and experience with the HMG CoA reductase inhibitors

The Adult Treatment Panel (ATP) guidelines, published initially in 1988 and revised in 1993, are based on sentinel observations and early clinical trials in support of treating and preventing coronary artery disease by cholesterol lowering. With the conclusion of several large long-term trials using HMG CoA reductase inhibitors for primary and secondary coronary prevention, the ATP II recommendations, which remain remarkably accurate, can be supplemented with more evidence-based strategies. Increasing evidence suggests that thoughtful lipid management for coronary prevention should include a more complete assessment of lipoproteins with an emphasis on apolipoproteins, triglycerides, and very low-density (VLDL) remnant particles, LDL particle size, and lipoprotein(a). This review summarizes clinically relevant lipid metabolism with an emphasis on the concept of atherogenic plasma lipids, discusses the clinical benefits and specific uses of each of the lipid-lowering drug classes, and provides an analysis of recent cholesterol-lowering primary and secondary coronary prevention trials from which a new treatment strategy can be derived.