Long-term achievement of the therapeutic objectives of lipid-lowering agents in primary prevention patients and cardiovascular outcomes: an observational study.

AIMS: Lowering elevated cholesterol levels reduces cardiovascular (CV) morbidity and mortality. Nonetheless, most patients treated with lipid-lowering agents (LLA) do not reach recommended therapeutic objectives. In a setting of primary care in France, we investigated the association between LDL-cholesterol goal attainment and the occurrence of CV events in primary prevention patients with multiple CV risk factors (> or = 3). According to national guidelines, the therapeutic objective (TO) for such patients is an LDL-cholesterol value below 130 mg/dL. METHODS: 579 patients treated with LLA and with LDL-cholesterol values documented at least once a year over a period of at least 3 years (2000-2002) were allocated to three groups based on the number of years the TO was attained during the follow-up period: in all 3 years (TO+++: n=145), only part of the time (TO intermediate: n=256), and never (TO---: n=178). CV events (angina pectoris, myocardial infarction, heart failure, stroke, peripheral artery disease) occurring during the last year of observation (2002) were retrospectively collected. The occurrence risk (OR) of CV events was assessed based on TO status, with a logistic regression model to adjust for baseline differences in CV risk factors. RESULTS: Only a quarter of patients attained TO during all 3 study years. CV events during the third year of observation occurred in 5.5%, 10.5% and 12.9% of patients in the TO+++, TO intermediate and TO--- groups, respectively. Compared with TO+++ patients, the risk of CV events increased significantly in TO intermediate (OR=2.34, 95% CI=[1.01-5.39]) and TO--- patients (OR=2.99, 95% CI=[1.26-7.08]). CONCLUSION: In real practice, a prolonged attainment of TO is rarely observed in high CV risk patients treated with LLA as primary prevention. Therapeutic failure is related to an increased incidence of cardiovascular morbidity. Our data strongly support the need to improve adherence to treatment guidelines to achieve effective cardiovascular prevention.

Inhibition of (-) [125I]-iodocyanopindolol binding to rat lung beta adrenoceptors by uremic plasma ultrafiltrates.

Numerous data have suggested that beta-adrenoceptor-mediated responses were decreased in uremia and that parathormone could be implicated in this phenomenon. In a previous paper we have shown that the beta2 receptor density of mononuclear cells of uremic patients is significantly increased despite a significant increase in plasma epinephrine, suggesting that an endogenous substance could interfere and disregulate the beta 2 receptor density. In order to further evaluate this phenomenon we have firstly studied the influence of one non uremic and five uremic plasma ultrafiltrates on the binding of (-)-[125I]iodocyanopindolol using rat lung beta adrenoceptors. The results show that uremic plasma ultrafiltrates induce a decrease in the Bmax value without any variation on the Kd value. In a second step we have assessed the ability of human synthetic 1-34 and 53-84 parathormone to interact directly with beta-adrenoceptors. No variation in the (-)-[125I]iodocyanopindolol binding parameters was observed. These results suggest that an uremic endogenous substance might interfere on the beta adrenergic receptors and that the alteration in the beta-adrenergic response in uremia is probably not due to a direct action of parathormone on the beta-adrenoceptors.

Impaired regulation of beta 2-adrenergic receptor density in mononuclear cells during chronic renal failure.

Previous investigations have suggested that beta-adrenoceptor-mediated responses were decreased in uremia. To evaluate this phenomenon further, beta 2-receptor density in mononuclear cells, plasma catecholamines and plasma parathyroid hormone were studied in two groups of normotensive patients: group U, twenty-five chronic uremic patients with end-stage renal failure; group C, twenty-eight control subjects. Each group was divided into three age and sex-matched subgroups. Beta 2-receptor density was determined using (-)125 iodocyanopindolol. Despite a significant increase in plasma epinephrine in the group of uremic patients, there was a significant increase in beta 2-adrenoceptor density. On the other hand the uremic state did not influence (-)125 iodocyanopindolol binding affinity and plasma norepinephrine. Parathyroid hormone, as expected, was significantly elevated in all the uremic subgroups. It can be concluded that the uremic state is associated with an unexpected upregulation of beta 2-receptor density in mononuclear cells. The role of an endogenous beta-blocking substance is suggested.

An economic evaluation of Losartan therapy in type 2 diabetic patients with nephropathy: an analysis of the RENAAL study adapted to France.

BACKGROUND: The RENAAL study enrolled 1,513 patients with type 2 diabetes mellitus and nephropathy defined by the presence of proteinuria (urinary albumin: creatinine ratio 300 mg/g or proteinuria > 500 mg per day). Compared to placebo, losartan therapy reduced by 16% (p=0.02) the risk of a composite endpoint (doubling of baseline serum creatinine level, end stage renal disease, or death) and by 28% (p=0.002) the risk of progression to end stage renal disease (ESRD). METHODS: The objective of this study was to compare, using French economic data, the additional cost of losartan therapy with the savings in cost generated by a decrease in the number of end stage renal disease days. Prospectively collected health care resource utilization were used (N(losartan)=751, N(placebo)=762). The follow-up period was 4 years. RESULTS: The mean cumulative cost of losartan over 4 years was 1,603 euros per patient. The reduction in the number of ESRD days over 4 years in patients treated with losartan significantly decreased costs associated with ESRD by 7,438 euros per patient (CI 95%: 3,029 euros - 11,847 euros, p=0.001). Compared to the placebo group, the average cost per patient over 4 years in the losartan group was lower by 5,834 euros (CI 95%: 1,407 euros - 10,301 euros, p=0.01). CONCLUSION: In addition to the medical benefit, this analysis demonstrated the economic relevance of treatment with losartan in type 2 diabetic patients with nephropathy.

Management of hypertension and screening of renal complications by GPs in diabetic type 2 patients (France--2001).

BACKGROUND: Our aim was to assess the quality of the medical management by GPs of hypertension and renal insufficiency in type 2 diabetic patients. METHODS: A retrospective cohort study was run on a national random representative sample of 5,518 patients presenting with type 2 diabetes mellitus treated pharmacologically by a general practitioner from April 2000 to April 2001. RESULTS: Sixty percent of patients underwent a HbA(1c) measurement during the last 6 months and among them 27% exceeded the threshold of 8%. Glomerular Filtration Rate, calculated with the Cockcroft formula, was below 60 ml/min (confirmed renal failure) in 21.9% of patients and was in the 61-80 ml/min range (probable early renal insufficiency) in 27%. Proteinuria was documented in 30.1% of patients, 13.7% of whom were positive. Microalbuminuria was documented in 36%, 15% of whom were positive. Hypertension was treated pharmacologically in 59.6% of the sample (39.3% on monotherapy, 34.2% on double combination therapy and 26.5% on triple combination therapy or more). Blood pressure was >140 and/or 80 mmHg in 81.6% of treated patients and in 27% among untreated. CONCLUSION: These findings suggest that significant progress still needs to be made in the care and treatment of type 2 diabetic patients, especially those with hypertension, in order to reduce or delay the incidence of renal and cardiovascular complications.

[Left ventricular hypertrophy in hypertensive patients. Epidemiology and prognosis]. / Hypertrophie ventriculaire gauche chez l'hypertendu. Epidémiologie et pronostic.

The aim of this review is to analyze the epidemiology and prognosis of left ventricular hypertrophy (LVH) in hypertensive patients through literature data and to identify clinical factors contributing to its development. After an exhaustive review of literature through Medline database, eighteen studies (including 8 European ones) have been selected. The prevalence of LVH diagnosed by EKG (7 studies) is steadily over 15%. It can reach 50% in some subgroups of the Framingham study. Among 11 studies using echocardiography as diagnostic tool, the prevalence varies from 14 to 44% (Bordeaux cohort). In the Framingham study, 32% of men and 45% of women over 60 years presented an echography-defined LVH. The variations observed in different studies may be explained by differences on the modes of enrollment and diagnosis. The clinical factors associated with the occurrence of LVH are age, which can be confounded with the duration of presence of hypertension, the severity and lack of therapeutic management of hypertension. Thirteen studies permitted to quantify the cardiovascular risk related to hypertension. In hypertensive patients, the presence of EKG-LVH or the one observed by echocardiography would correspond to a two-fold increase of cardiovascular mortality and morbidity. Moreover, a cardiovascular risk gradient is observed according to the LVH geometry (concentric remodeling, followed by eccentric LVH and concentric LVH). Three studies including the Framingham study demonstrated that LVH is a major risk factor of stroke. This exhaustive literature review stresses on the high prevalence and the severity of LVH during hypertension. Its diagnosis allows to identify high cardiovascular risk patients suffering from hypertension. It emphasizes on the importance of an early and careful therapeutic management of hypertension.

[Double blind randomized comparative study of two antihypertensive combinations. Enalapril-hydrochlorothiazide versus enalapril-nifedipine in 240 hypertensive patients resistant to monotherapy]. / Etude comparative randomisée en double aveugle de deux associations anti-hypertensives. Enalapril-hydrochlorothiazide versus enalapril nifédipine chez 240 hypertendus résistants à une monothérapie.

The combination of two antihypertensive drugs is recommended when mild to moderate hypertension is not controlled by sequential monotherapy. The aim of our study was to compare the efficacy and the safety of the combination enalapril 20 mg-hydrochlorothiazide 12.5 mg to that of enalapril 20 mg-nifedipine SL 20 mg x 2. Two hundred and forty four hypertensive patients not controlled (DPB > 95 mmHg) by a single dose of enalapril 20 mg/24 h, received for 4 weeks, one of these two combined therapies in a randomized double-blind trial. The efficacy was of same amplitude in the two groups (DBP: -10.8 mmHg enalapril-hydrochlorothiazide vs-10.3 mmHg enalapril-nifedipine). The side effects were less frequent in the enalapril-hydrochlorothiazide group (14 per cent vs 24 per cent, p = 0.04).

[Comparative study of enalapril, hydrochlorothiazide and their combination in the treatment of essential hypertension]. / Etude comparative de l'énalapril, de l'hydrochlorothiazide et de leur association dans le traitement de l'HTA essentielle.

This was a randomized double-blind, multiclinic, parallel, three treatments group study to compare the safety and efficacy of a fixed-ratio combination of enalapril/hydrochlorothiazide (E/HCTZ: 20/12.5-40/25 N = 46) to enalapril (E = 20-40 mg, N = 49) and hydrochlorothiazide (HCTZ: 12.5-25 mg, N = 51) once daily, in the treatment of patients with moderate to severe essential hypertension (100 less than or equal to supine diastolic blood pressure less than or equal to 120 mmHg). A significant decrease of systolic and diastolic blood pressure was shown in the 3 subgroups of patients. The decrease of blood pressure was significantly greater in the E/HCTZ subgroup. After 8 weeks of treatment, the E/HCTZ group had the greatest proportion of normotensive patients (65.9 p. cent, DBP less than or equal to 90 mmHg) and of responders (81.8 p. cent, diastolic blood pressure decrease greater than 10 mmHg). The treatment groups did not differ significantly with respect to clinical adverse events. The study results document the well-known hyperuricemic effect of diuretics and also indicate that the combination of enalapril and HCTZ ameliorates this effects. In this study plasma potassium was slightly but not significantly decreased by HCTZ. The combination of enalapril and hydrochlorothiazide did not alter this parameter. The results support the conclusion that in the treatment of moderate to severe hypertension, the combination enalapril/HCTZ 20/12.5 to 40/25 mg, taken once daily, is more effective than either its components used alone. This combination is well tolerated, probably due to an adequate enalapril/HCTZ dosage ratio.

[Vectorcardiography in the diagnosis of the association of inferior necrosis--left intraventricular conduction disorders]. / Apport du vectocardiogramme au diagnostic de l'association nécrose inférieure--troubles de conduction intraventriculaire gauche.

The authors study 53 vectorcardiograms (VCG) which demonstrate the association of inferior myocardial necrosis with left intraventricular conduction disturbances (LIVCD) consisting of 44 left anterior hemi-blocks (LAHB), 2 left posterior hemi-blocks (LPHB) and 7 complete left branch blocks (CLBB). In the presence of LAHB, the ECG and VCG diagnosis concur in 37 cases, with a more obvious appearance on the VCG in 16 cases. In 7 cases, only the VCG provided the diagnosis of this association. In the presence of LPHB, the ECG, in one case, only showed signs of necrosis and only the VCG revealed the hemi-block; in the other case, the ECG showed signs of LPHB, but the Q waves did not present the criteria of necrosis. Once again, only the VCG provided the diagnosis of the association. Finally, in the presence of CLBB, the diagnosis were in agreement in only 3 cases. In two cases, only the VCG revealed the necrosis, in one case, the ECG was superior and in the remaining case, the ECG and the VCG were equally ineffective in confirming the inferior necrosis which was nevertheless definitely present. On the basis of these findings, the authors discuss the ECG criteria of the association of inferior necrosis and LIVCD.

Ineffectiveness of lipid-lowering therapy in primary care.

BACKGROUND: Evidence confirms the positive effects of lipid-lowering agents on the risk of cardiovascular disease. Local guidelines in France (AFSSAPS) have defined therapeutic objectives for LDL-cholesterol. These objectives vary with the number of cardiovascular risk factors in addition to dyslipidaemia. We determined the proportions of patients at therapeutic objective in different classes of cardiovascular risk to test the hypothesis that compliance with guidelines varies across the levels of risk. Comparison with international guidelines (ANDEM) was also performed. METHODS: A group of 3173 dyslipidaemic patients treated with lipid-lowering agents and managed by general practitioners was randomly selected from BKL-Thales panel, a French computerized database. For each patient, history of coronary heart disease and the number of cardiovascular risk factors were documented. Compliance with guidelines was assessed from achievement of therapeutic objective. RESULTS: The study population included 79% primary prevention patients (1.6, 25.5, 31.7 and 20.1%, with 1, 2, 3, and >3 risk factors, respectively) and 21.0% secondary prevention patients. Applying AFSSAPS guidelines, the proportions of primary prevention patients not at LDL-cholesterol objectives varied across risk categories (P < 0.0001), from 3.9% for patients with one risk factor to 46.5% for patients with >3 risk factors, and therapeutic failure reached 39.9% in secondary prevention. Only 26% of patients who were at high cardiovascular risk (>3 risk factors or prior coronary heart disease) and not at therapeutic objective received high doses (>standard recommended doses) of lipid-lowering agents in monotherapy. Applying ANDEM guidelines, 74% of secondary prevention patients were not at treatment goal. CONCLUSION: Compliance with guidelines varied inversely with the level of cardiovascular risk. Besides, most patients not at therapeutic objective were not up-titrated. The use of lipid-lowering agents is inadequate, depriving many patients of an effective protection against cardiovascular diseases.