Cost-benefit effectiveness of angiotensin-II receptor blockers in patients with uncomplicated hypertension: A comparative analysis.

OBJECTIVE: The treatment of hypertensive patients (HTs) requires a long-term commitment of compliance for the patient and resources by the healthcare system. This poses an economic dilemma in countries where universal healthcare is standard. The aim of this study was to evaluate the costs/health benefit and effectiveness of treatment with angiotensin-II receptor blockers (ARBs) in uncomplicated essential hypertension. DESIGN AND METHODS: The daily and annual economic commitment for treating patients with ARBs was estimated using pharmacy dispensing records and the BP-lowering effects of candesartan, irbesartan, losartan, olmesartan, telmisartan and valsartan was evaluated retrospectively. In 114 HTs (mean age 59.4±13.5year, 57.5% men), the BP-lowering effect of ARBs as in monotherapy and in fixed-dose combination (FDC) with hydrochlorothiazide at the doses commonly used in the market to reach BP control (i.e. BP <140/90mmHg) was analyzed. The BP lowering-effect was evaluated after an average of 6-month follow-up consulting medical professionals. Analysis of variance for repeated measures was provided. RESULTS: Treatment with candesartan (14.1%) and olmesartan (32,4%) versus other ARBs resulted in a significant decrease in BP as for mono- than for FDC therapy. Our studies suggest that daily (data not shown) and annual costs of olmesartan were higher than candesartan as in mono- (4577.71±1120.55 vs. 894.25±127.75 €) than for FDC therapy (5715.90±459.90 vs. 1580.45±113.15 €). CONCLUSIONS: Treatment: of BP with candesartan appears to be the most favorable option in terms of cost-effectiveness coupled with favorable health outcomes. These data have some limitations, but open the question if candesartan should be preferred to olmesartan in BP management. Further prospective studies comparing ARBs based on their effect on BP control in uncomplicated HTs are needed for validation.

Fixed-Dose Triple Combination of Antihypertensive Drugs Improves Blood Pressure Control: From Clinical Trials to Clinical Practice.

INTRODUCTION: Blood pressure (BP) control is the main clinical goal in the management of hypertensive patients; however, BP in most of these patients remains uncontrolled, despite the widespread availability of antihypertensive drugs as free-combination therapy. This study compared the efficacy of a fixed-dose triple combination (FDTC) of antihypertensive drugs with that of a free combination of three antihypertensives in patients with uncontrolled hypertension. METHODS: Ninety-two patients (mean age 60.8 ± 12.1, 58.0% male) with uncontrolled essential hypertension (office systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg) previously treated with a renin-angiotensin-aldosterone system (RAAS) inhibitor plus hydrochlorothiazide were switched to once-daily FDTC therapy with perindopril/indapamide/amlodipine (5-10/1.25-2.5/5-10 mg). Patients were age- and sex-matched with a control group of hypertensive patients receiving free-combination therapy with three drugs including a RAAS inhibitor, a diuretic, and a calcium channel blocker. Office BP and 24-h ambulatory BP monitoring (ABPM) were evaluated at baseline and after 1 and 4 months. RESULTS: Significant reductions in ambulatory 24-h, daytime, and nighttime systolic BP, and pulse pressure (PP) were found in the FDTC group relative to reductions seen with free-combination therapy, after the first month only of follow-up. Target BP values (mean 24-h ambulatory systolic/diastolic BP < 130/80 mmHg) were reached by more recipients of FDTC than free-combination therapy (64.8% vs. 46.9%, p < 0.05) at month 4 of follow-up, despite reductions in 24-h ABPM values from baseline being similar in both groups at this time point. CONCLUSION: FDTC of perindopril/indapamide/amlodipine was effective at reducing SBP and PP in previously treated patients with uncontrolled hypertension, and well tolerated, providing support for clinicians in choosing a fixed-dose triple combination over the free-combination of a RAAS inhibitor, a diuretic, and a calcium antagonist.

Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia.

The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4-99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5-13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value.

Asymptomatic hyperuricemia is a strong risk factor for resistant hypertension in elderly subjects from general population.

OBJECTIVE: In clinical practice, patient characteristics predicting resistant hypertension (RH) include higher blood pressure levels, left ventricular hypertrophy, older age, obesity, chronic kidney disease and diabetes. On the contrary little is known about the role of serum uric acid (SUA) as a risk factor for RH in subjects from general population. MATERIAL AND METHODS: 580 elderly subjects aged ≥65 years were enrolled in the Risk Of Vascular complications Impact of Genetics in Old people (ROVIGO) study. RH was defined as the failure to maintain blood pressure values below 140mmHg (systolic) and 90mmHg (diastolic) despite therapeutic interventions that include appropriate lifestyle measures plus adherence to treatment with full doses of at least three antihypertensive drugs, including a diuretic. RH was confirmed using 24-h ambulatory blood pressure measurement. Hyperuricemic was defined as the subjects having SUA ≥6.8mg/dl or taking uricosuric drugs. Gender-specific odds ratio (OR) for RH was calculated by logistic regression analysis. RESULTS: The prevalence of RH was 5.7% in the cohort and was higher in women (8.3%) than in men (3.0%, p<0.05). Independent of chronic kidney disease (OR 3.89, 95% confidence interval 1.49-10.1), hyperuricemia predicted resistant hypertension in women (odds ratio 3.11, 95% confidence intervals 1.06-9.1, p=0.03) but not in men. CONCLUSIONS: In elderly women from the general population, an SUA value of ≥6.8mg/dl triples the risk of RH. SUA assessment should be recommended to better define the pattern of risk associated with RH.

Mood Disorders in Uncontrolled Hypertension Despite Multiple Anti-Hypertensive Medications: Searching for a Link.

INTRODUCTION: Resistant hypertension is a clinical condition in which blood pressure (BP) control is not achieved under a pharmacological therapy including a diuretic and at least two additional antihypertensive drug classes. AIM: To discuss an unusual presentation of uncontrolled hypertension despite multiple anti-hypertensive medications. METHODS AND RESULTS: A 46-year-old woman presented with resistant hypertension (HT) and with a long history of polydipsia, polyuria, weight loss and psychiatric symptoms (sudden onset of personality disorder with free anxiety, negativism and asthenia) unsuccessfully treated with antidepressant drugs. Tests for secondary HT showed a marked increase of serum renin and aldosterone both in clinostatic (342 pg/ml and 907 pmol/l, respectively) and orthostatic posture (351 pg/ml and 2845 pmol/l, respectively), hypokalemia (2.9 mmol/l) and macroalbuminuria (431 mg/day). Diagnostic examinations also revealed a focal stenosis of approximately 70 % of the proximal right renal artery with post-stenotic dilation. After percutaneous balloon angioplasty and stent implantation, BP was normalized with 5 mg/day amlodipine and psychiatric symptoms suddenly disappeared. CONCLUSIONS: Psychopathological symptoms are rare at the onset of hyperaldosteronism, and their aetiology is not well defined. A proper diagnostic and therapeutic process is mandatory in order to get the recommended therapeutic targets in short-midterm improving long-term prognosis. We also suggest not considering depressed or treat with antidepressant agents a young hypertensive subject with uncontrolled hypertension despite multiple anti-hypertensive medications without having ruled out a secondary form of hypertension.

Ultrasound in obstructive lung diseases: the effect of airway obstruction on diaphragm kinetics. A short pictorial essay.

The ultrasound study of the chest is showing a continuous development. This technique could be helpful in managing several chest diseases, but it is limited to the acoustic windows provided by intercostal spaces and by the inability to study healthy lung parenchyma and all intra-parenchymal diseases such as chronic obstructive lung disease (COPD), because the interaction between ventilated lung and ultrasound generates only artifacts. Currently, there are few applications of ultrasound that are useful in COPD, with recent studies providing some innovation potentially useful in clinical practice. The similarity of the trend between the time/volume curve of spirometry and the M-mode representation of diaphragm during forced breath allowed to identify the M-mode Index of Obstruction (MIO), an index obtained from the ratio between forced diaphragmatic excursion in the first second (FEDE1, cm) and the maximal expiratory diaphragmatic excursion (EDEMax, cm). MIO has shown a linear correlation with the ratio between forced expiratory volume in the first second (FEV1) and vital capacity (VC), used in spirometry to identify airways obstruction. The value of MIO seems to be lower in patients affected by airways obstruction as showed by a recent study. The technique is easy to learn and fast to perform and the analysis could be provided with any ultrasound machine equipped with M-mode. In conclusion, these findings, if confirmed by other studies, could suggest a new add-on screening tool for obstructive lung diseases, in particular COPD, that could be performed during a routine abdominal ultrasound exam.

Nutraceuticals for Serum Lipid and Blood Pressure Control in Hypertensive and Hypercholesterolemic Subjects at Low Cardiovascular Risk.

INTRODUCTION: Primary cardiovascular (CV) prevention may be achieved by lifestyle/nutrition changes, although a relevant role is now emerging for specific, functional foods and nutraceutical compounds (NCs). The aim of this study was to investigate the efficacy and safety of NCs in lowering blood pressure (BP) and improving lipid profile, when added to diet and lifestyle management versus diet alone in a group of patients with hypertension (HT) and hypercholesterolemia (HCh) with low CV risk. METHODS: Sixty-six patients with HT and HCh with grade 1 essential HT (mean age 56.0 ± 4.6 years) without history of CV diseases or organ damage were analyzed. These subjects were started on one tablet of an NC-containing red yeast rice, policosanol, berberine, folic acid and coenzyme Q10 once daily for 6 months and were age and gender matched with subjects following a diet program. Differences in clinic BP, 24-h ambulatory BP (24 h-ABPM), serum total cholesterol, low-density and high-density lipoprotein cholesterol (LDL-C and HDL-C) and triglyceride values were compared by analysis of variance. RESULTS: In the treatment group, a significant reduction of systolic 24 h-ABPM (141.6 ± 6.4 vs. 136.2 ± 4.8 mmHg; p < 0.05) and pulse pressure 24 h-ABPM (52.6 ± 7.2 vs. 47.3 ± 5.4 mmHg; p < 0.05) was found at the end of follow-up. A reduction of total cholesterol (-19.2%), LDL-C (-17.4%) and triglycerides (-16.3%) was observed (p < 0.001 for all); HDL-C remained unchanged. No difference was found in the control group. CONCLUSIONS: The tested NCs was found to be safe, well tolerated and effective in reducing mean 24-h systolic and 24-h pulse pressure and in improving lipid pattern.

The ROVIGO study (risk of vascular complications: impact of genetics in old people): protocol, study design, and preliminary results of the initial survey : cardiovascular epidemiology in the elderly.

BACKGROUND: The epidemiology of cardiovascular risk (CV) in the elderly is far from being defined, and the reasons why some subjects retain a healthy body while growing old while others are affected by different diseases or die prematurely are still unknown. AIMS: To compare the CV risk pattern in two elderly cohorts living in North-East Italy. MATERIALS AND METHODS: The Risk Of Vascular complications: Impact of Genetics in Old people (ROVIGO) study is a population-based study including 580 unrelated elderly subjects representative of general population living in Rovigo in the Veneto region. They were compared to a cohort of 580 age-gender-matched unrelated subjects from the CArdiovascular STudy in the Elderly (CASTEL) living in the same region in Castelfranco Veneto and Chioggia. RESULTS: Blood pressure (BP), heart rate (HR), low-density-lipoprotein cholesterol, and prevalence of coronary heart disease, heart failure and chronic pulmonary disease were lower in the ROVIGO than in the CASTEL cohort, while high-density-lipoprotein cholesterol and the prevalence of diabetes were higher in the former than in the latter. In the ROVIGO cohort, diabetes, left ventricular hypertrophy, coronary and cerebrovascular diseases were more represented in men. In the CASTEL cohort, systolic BP was higher in women. In both cohorts, the lipid pattern was less favourable and HR higher in women, chronic pulmonary disease more represented in men. CONCLUSIONS: People living in Rovigo were at lower CV risk than those in Castelfranco Veneto and Chioggia, mainly due to lower BP values, better lipid pattern and lower prevalence of CV and pulmonary disease.

Ultrasound analysis of diaphragm kinetics and the diagnosis of airway obstruction: the role of the M-mode index of obstruction.

Diaphragm motion in forced expiration can be analyzed using M-mode ultrasound in an anterior subcostal approach. Maximum expiratory diaphragmatic excursion (EDEMax) and forced expiratory diaphragmatic excursion in the first second (FEDE1) are considered the physiopathological analogues of vital capacity (VC) and forced expiratory volume in the first second (FEV1). As the FEV1/VC % ratio is used as a marker of obstruction, our aim was to determine if the ratio FEDE1/EDEMax (M-mode index of obstruction [MIO]) differs between healthy subjects and patients with airway obstruction. One hundred twenty-four outpatients were examined by diaphragm ultrasound after spirometry. The MIO, expressed as the mean ± standard deviation (range), was 87.08 ± 6.64 (72.84-100) in the healthy group (N = 61) and 67.09 ± 12.49 (33.33-91.30) in the group with obstructed airways (N = 63). The difference between the two groups was significant (p < 0.0001), and MIO was significantly correlated with FEV1/VC (p < 0.0001). A MIO <77 was identified as a possibile cutoff for suspecting an obstructive spirometric pattern with a 95.5% positive predictive value. The MIO can be interpreted as a speed index of diaphragmatic relaxation that seems to be slower in obstructed patients and could be used to screen for obstructed airway diseases.

Antihypertensive Treatment in the Elderly and Very Elderly: Always "the Lower, the Better?".

Arterial hypertension (HT) is age dependent and, with the prolongation of life expectancy, affects more and more elderly people. In the elderly, HT is a risk factor for organ damage and cardiovascular (CV) events. Both pharmacologic and nonpharmacologic reduction of blood pressure (BP) is associated with a corresponding decrease in systolic-diastolic or isolated systolic HT. Clinical trials have shown that BP lowering is associated with a decrease in stroke and other CV events. Therefore, BP reduction per se appears more important than a particular class of antihypertensive drugs. The benefit of antihypertensive treatment has been confirmed up to the age of 80 years, remaining unclear in the octogenarians. The benefit in lowering diastolic BP between 80 and 90 mmHg is well established, while that of lowering systolic BP below 140 mmHg requires further confirmations.

Renal scintigraphy predicts global cardiovascular risk in hypertensive subjects with normal serum creatinine levels.

BACKGROUND. This cross-sectional study investigates the role of renal scintigraphy on cardiovascular (CV) risk stratification in normoalbuminuric, non-diabetic hypertensive subjects (HTs) free from CV disease and renal dysfunction. METHODS. In 200 HTs aged 55-75 years, glomerular filtration rate (GFR) was measured by technetium-99m-diethylene triamine pentacetic acid clearance during renal scintigraphy. Stage III chronic kidney disease (CKD) was defined as GFR < 60 ml/min/1.73 m(2). For comparing the impact of different methods for CKD diagnosis on CV risk stratification, CKD was also considered as GFR estimated by the Modification of Diet in Renal Disease (MDRD) equation and Cockcroft-Gault's formula. Target organ damage (TOD) was assessed by echocardiography and carotid ultrasonography. Gender-specific odds ratio (OR) with 95% confidence intervals for CKD were derived from a multiple stepwise logistic regression analysis. Global CV risk was stratified according to routine examinations, TOD and CKD. RESULTS. In 38% of cases, an unknown stage III CKD was found. Independent of age, CKD was predicted by history of hypertension (OR = 1.69, p = 0.0001), albuminuria (OR = 1.25, p = 0.0001), smoking (OR = 1.85, p = 0.028) and pulse pressure (OR = 1.21, p = 0.019) in men only. Men had an increased risk of CKD (OR = 2.62, p = 0.002) in comparison with women. Prevalence of TOD was significantly higher only in HTs having CKD diagnosed by renal scintigraphy; TOD and CKD assessment added to classic risk factors modified the CV risk stratification from low-moderate to high and very high. CONCLUSIONS. Renal scintigraphy is an important aid in risk stratification and should be performed in HTs aged >55 years. Pulse pressure was the main blood pressure component that predicted the risk of stage III CKD.

Biomechanical pathogenesis of fragility fractures in vertebrae and femur.

The causes of fragility fractures in vertebrae and femur are reviewed, and the possibility of both surgical and pharmacological treatment to prevent their occurrence is indicated.

Domino Effect: mechanic factors role.

The rapid onset of the Domino Effect following the first Vertebral Compression Fracture is a direct consequence of the mechanical variations that affect the spine when physiological curves are modified. The degree of kyphosis influences the intensity of the Flexor Moment; this is greater on vertebrae D7, D8 and on vertebrae D12, L1 when the spine flexes. Fractures of D7, D8, D12 and L1 are, by far, the most frequent and also the main cause of the mechanical alterations that can trigger the Domino Effect. For these considerations vertebrae D7, D8, D12 and L1 have to be taken in consideration as "critical". In the case of critical clinical vertebral fractures it is useful to provide an indication for minimally invasive surgical reduction or intrasomatic stabilization. When occurs a fracture of a "critical vertebra", prompt restoration of the heights leads to a reduction in the Kyphosis Index and therefore in the Flexor Moment, not only of the fractured vertebra but also, in turn, of all the other metameres which, even if morphologically still intact, are structurally fragile; so, through the restoration of the mechanical vertebral proprieties, we can reduce the risk of the Domino Effect. At the same time the prompt implementation of osteoinductive therapy is indispensable in order to achieve rapid and intense reconstruction of the trabecular bone, the strength of which increases significantly in a short period of time. Clinical studies are necessary to confirm the reduction of the domino effect following a fragility fracture of "critical vertebrae" with the restoration of the mechanical properties together with anabolic therapy.

The importance of mechanics in the pathogenesis of fragility fractures of the femur and vertebrae.

This review highlights the role played by mechanical imbalances in the pathogenesis of fragility fractures of the femur and vertebrae. Particular attention is paid to vertebral fractures, and the consequences arising from mechanical imbalances are analyzed and evaluated to determine how much they contribute to worsening vertebral deformity and creating a domino effect.

Consolidation treatment with rituximab induces complete and persistent remission of mixed type Evans syndrome.

We describe a 58-year-old woman affected by immune thrombocytopenic purpura (ITP) since 1999, well controlled by low doses of steroid for 4 years, who experienced a relapse with severe mixed type Evans syndrome in March 2006. After an initial response to high doses of steroid, severe anaemia recurred 2 months later, this time resistant to second-line therapy with intravenous immunoglobulins (IVIG) and cyclophosphamide. So in May, we started the treatment with anti-CD20 monoclonal antibody rituximab with the dose of 375 mg/m2 once weekly for a total of four doses. We obtained a full normalization of haemoglobin concentration, but the disease haemolytic parameters persisted. Therefore, we decided to treat the patient with two monthly courses of rituximab, and a gradual normalization of haptoglobin and lactate dehydrogenase (LDH) plasma levels was finally achieved, with a sustained response up to date, lasting more than 12 months. We conclude that rituximab treatment is effective in refractory patients with mixed type Evans syndrome, and consolidation therapy should be considered to prolong beneficial effects achieved during the induction.

The prognostic value of 18F-FDG PET-CT in the management of Hodgkin's lymphoma: preliminary results of a prospective study.

BACKGROUND: To date, Hodgkin's lymphoma (HL) patients have achieved long-term survival of more than 80%. Unfortunately, longer follow-up has shown serious adverse effects of the treatments used. For this reason, therapeutic strategies are becoming more tailored to the individual patient s prognosis. Pre-treatment risk factors for early-stage and advanced-stage HL are well known indicators of prognosis. Recently, early interim (18)F-FDG PET has been shown as a strong and independent predictor of progression-free survival in HL. Our aim was to assess response to therapy by repeating (18)F-FDG-PET/CT after four and six chemotherapy cycles. MATERIAL AND METHODS: We evaluated 21 consecutive patients affected by (HL) and presenting for assessment over a period of three years. All patients underwent initial staging with (18)F-FDG-PET/CT along with standard staging procedures. We tailored an individual treatment plan dependent on pre-treatment risk factors and initial (18)F-FDG-PET/CT. With the aim of the best definition of response to treatment, we repeated (18)F-FDG-PET/CT after two (FDG-PET 2), four (FDG-PET 4) and six (FDG-PET 6) chemotherapy cycles. Chemotherapy was typically given for four cycles in early disease stages and was prolonged to six to eight cycles in advanced disease stages, depending on PET findings. RESULTS: Our results showed a strong negative predictive value in detecting responders in early stage HL and a positive predictive value in advanced-stage patients. Clinical stage, extra-nodal sites and the positivity of the (18)F-FDG-PET/CT performed during chemotherapy were also noted as strong determinants of response to treatment. Moreover, in our series the (18)F-FDG-PET/CT data obtained after only two chemotherapy cycles (FDG-PET 2) were the same of those obtained after FDG-PET 4 and FDG-PET 6 controls. CONCLUSION: The preliminary data of the present study confirm those of previous published studies about the negative predictive value of (18)F-FDG-PET/CT performed after four and six chemotherapy cycles, which contributed to the decision to stop treatment and to avoid radiotherapy in HL patients. Nonetheless, our preliminary data seems to suggest that only the (18)F-FDG-PET/CT performed after two cycles of chemotherapy (FDG-PET 2) is able to provide the same prognostic information of the FDG-PET 4 and FDG-PET 6 earlier.

Spontaneous evolution of essential thrombocythaemia into acute megakaryoblastic leukaemia with trisomy 8, trisomy 21 and cutaneous involvement.

Spontaneous transformation of essential thrombocythaemia (ET) into acute leukaemia is rare. We describe a case of ET that spontaneously transformed after 19 yrs uneventful follow-up into acute megakaryoblastic leukaemia. Cytogenetic analysis of bone marrow nucleated cells showed trisomy 8 and trisomy 21 at time of leukaemic transformation supporting the hypothesis that chromosomal abnormalities are part of the mechanism that drives the leukaemic progression independently of drug cytotoxicity. In addition, the very rare and intriguing finding of M7 FAB subtype evolution of ET was complicated by cutaneous involvement in the leukaemic process.