CODAP: A multidisciplinary consensus among Portuguese experts on the definition, detection and management of atherogenic dyslipidemia. / CODAP: um consenso multidisciplinar sobre a definição, diagnóstico e tratamento da dislipidemia aterogénica em Portugal.

INTRODUCTION AND AIMS: Atherogenic dyslipidemia is an important contributor to residual cardiovascular (CV) risk, but it is underdiagnosed and undertreated. This study aimed to assess the opinion of Portuguese experts to generate a consensus concerning the diagnosis and treatment of atherogenic dyslipidemia, as well as to contribute toward standardization of clinical practice in this disorder. METHODS: The study consisted in the application of a questionnaire to an expert panel, following a modified Delphi methodology. RESULTS: The majority (88.4%) of the proposed items were found to be consensual. The expert panel recognized the importance of the atherogenic dyslipidemia phenotype, the role played by low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol as risk markers and therapeutic targets, the choice of statins as first-line lipid-lowering drugs, and the value of associating statins with fenofibrate as a means to reduce residual CV risk. However, the role played by triglycerides in CV risk and the therapeutic value of fibrates lacked consensus. Taking into consideration the state of the art and the opinions expressed in this study, the scientific committee developed a treatment algorithm aimed to improve the perception and treatment of atherogenic dyslipidemia. CONCLUSIONS: The experts involved in this study were shown to be familiar with the concept and the importance of atherogenic dyslipidemia. The few situations in which a consensus could not be found were mainly related to the interpretation and/or relevance of the available evidence.

Prevalence of cardiovascular risk factors and other comorbidities in patients with hypertension in Portuguese primary health care populations: The PRECISE study. / Prevalência de fatores de risco cardiovascular e outras comorbilidades em doentes com hipertensão arterial assistidos nos Cuidados de Saúde Primários: estudo Precise.

INTRODUCTION: Cardiovascular (CV) disease is the leading cause of death in Portugal. The prevalence of hypertension, the second most important risk factor accounting for overall disability-adjusted life years (DALYs), is significant. Hypertension rarely occurs in isolation, but is usually associated with other determining risk factors that contribute to greater overall CV risk. The main objective of the PRECISE study, a cross-sectional epidemiological study, was to determine the prevalence of other concomitant modulating CV risk factors in hypertensive patients. METHODS: The prevalence of other CV risk factors and target organ damage was assessed in 2848 hypertensive patients of both sexes followed in primary health care centers. Demographic, anthropometric and clinical data and antihypertensive and lipid-lowering therapies prescribed were collected. RESULTS: Of the study population (mean age 65.8±11.0 years, 60.8% women), 98.0% were treated for hypertension, but only 56.7% had controlled blood pressure. Hypercholesterolemia was the most frequent concomitant CV risk factor (82.1%), followed by sedentary behavior (71.4%). Prevalences of concomitant modulating risk factors were significantly different between the sexes and age groups. Overall, 81.7% of hypertensive patients had three or more concomitant CV risk factors. CONCLUSIONS: The study showed that, in Portugal, hypertensive patients have a high prevalence of other CV risk factors, confirming the need to identify these factors, calculate overall CV risk and continuously monitor the care provided and the results obtained.

Hemodynamic patterns in obesity associated hypertension.

BACKGROUND: Obesity is a well-known condition of resistant hypertension (HT). Insights to the hemodynamic patterns that characterize obesity related hypertension may help guide therapeutic adjustments and shorten time to HT control. METHODS: We performed a retrospective analysis of 202 patients followed at our Hypertension Clinic with the diagnosis of primary HT and who performed an impedance cardiography (ICG) test. Obtained data was analyzed to identify differences between obese and non-obese patients and to identify predictors of uncontrolled HT (≥ 140 and/or ≥ 90 mmHg) in obese patients. RESULTS: One hundred patients were male (49.5%) and average age 54.6 ± 13.9 years. Average systolic and diastolic pressures were 136.5 ± 22.4 mmHg and 82.9 ± 5.1 mmHg, respectively. The average BMI was 28.9 ± 5.1 Kg/m2. Seventy one patients (35.1%) had systolic arterial pressure (AP) ≥140 mmHg and 45 patients (22.3%) diastolic AP ≥90 mmHg. BMI correlated with systolic and diastolic AP (Pearson's coefficient 0.235; p < 0.001 and 0.163; p < 0.001, respectively). Obese patients presented increased cardiac index (CI) (p < 0.001), left cardiac work index (LCWI) (p < 0.001) and systemic vascular resistance index (SVRI) (p < 0.001) but reduced systemic arterial compliance index (SACI) (p < 0.001). Obese patients with uncontrolled HT had greater BMI (p < 0.001), CI (p < 0.001) and SVRI (p < 0.001) but lower SACI (p < 0.001) and LCWI (p < 0.001). In multivariate analysis, however, only CI remained predictive, conferring a risk 1.47 higher of uncontrolled HT. CONCLUSIONS: Obese patients, including those with uncontrolled HT, had increased CI and SVRI. The only predictor of uncontrolled HT, however, was CI, suggesting that the obese present a state of hyperinotropy and may benefit of "add-on" or increase treatment with beta-blockers.

Sacubitril/valsartan: An important piece in the therapeutic puzzle of heart failure. / Sacubitril/valsartan: um importante avanço no puzzle terapêutico da insuficiência cardíaca.

Sacubitril/valsartan (LCZ696), a supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, was recently approved in the EU and the USA for the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF) (NYHA class II-IV). Inhibition of chronically activated neurohormonal pathways (the renin-angiotensin-aldosterone system [RAAS] and sympathetic nervous system [SNS]) is central to the treatment of chronic HFrEF. Furthermore, enhancement of the natriuretic peptide (NP) system, with favorable cardiovascular (CV) and renal effects in HF, is a desirable therapeutic goal to complement RAAS and SNS blockade. Sacubitril/valsartan represents a novel pharmacological approach that acts by enhancing the NP system via inhibition of neprilysin (an enzyme that degrades NPs) and by suppressing the RAAS via AT1 receptor blockade, thereby producing more effective neurohormonal modulation than can be achieved with RAAS inhibition alone. In the large, randomized, double-blind PARADIGM-HF trial, replacement of an angiotensin-converting enzyme inhibitor (ACEI) (enalapril) with sacubitril/valsartan resulted in a significant improvement in morbidity and mortality in patients with HFrEF. Sacubitril/valsartan was superior to enalapril in reducing the risk of CV death or HF hospitalization (composite primary endpoint) and all-cause death, and in limiting progression of HF. Sacubitril/valsartan was generally well tolerated, with a comparable safety profile to enalapril; symptomatic hypotension was more common with sacubitril/valsartan, whereas renal dysfunction, hyperkalemia and cough were less common compared with enalapril. In summary, sacubitril/valsartan is a superior alternative to ACEIs/ARBs in the treatment of HFrEF, a recommendation that is reflected in many HF guidelines.

Pasteurella infections in a tertiary centre - from cellulitis to multiple-organ failure: Retrospective case series.

The purpose of this article is to review the clinical features of pasteurellosis in a tertiary centre over a period of 4½ years. We have identified eight cases of Pasteurella multocida and one case of Pasteurella canis infection, with a large diversity of clinical pictures and outcomes. All patients were elderly and/or immunocompromised and 55.6% reported animal exposure. Soft tissue infections were the most prevalent (55.6%), followed by pneumonia (22.2%) and sepsis (22.2 %). All isolates were susceptible to beta-lactam antibiotics using in vitro sensitivity testing. The overall mortality was 33.3%, which occurred in patients with no evidence of animal contact.

Defining the Place of Ezetimibe/Atorvastatin in the Management of Hyperlipidemia.

Statin-ezetimibe combinations are a potentially advantageous therapeutic option for high-risk patients who need additional lowering of low-density lipoprotein cholesterol (LDL-C). These combinations may overcome some of the limitations of statin monotherapy by blocking both sources of cholesterol. Recently, a fixed-dose combination with atorvastatin, one of the most extensively studied statins, was approved and launched in several countries, including the USA. Depending on atorvastatin dose, this combination provides LDL-C reductions of 50-60%, triglyceride reductions of 30-40%, and high-density lipoprotein cholesterol (HDL-C) increases of 5-9%. Studies comparing the lipid-lowering efficacy of the atorvastatin-ezetimibe combination with the alternatives of statin dose titration or switching to a more potent statin consistently showed that combination therapy provided greater LDL-C reduction, translating into a greater proportion of patients achieving lipid goals. Simvastatin-ezetimibe combinations have been shown to reduce the incidence of major atherosclerotic events in several clinical settings to a magnitude that seems similar to that observed with statins for the same degree of absolute LDL-C lowering. The atorvastatin-ezetimibe combination has also been shown to induce the regression of coronary atherosclerosis measured by intravascular ultrasound in a significantly greater proportion of patients than atorvastatin alone. Atorvastatin-ezetimibe combinations are generally well tolerated. Previous concerns of a possible increase in the incidence of cancer with ezetimibe were dismissed in large trials with long follow-up periods. In this paper, we examine the rationale for an atorvastatin-ezetimibe combination, review the evidence supporting it, and discuss its potential role in the management of dyslipidemia.

Use of CPAP to reduce arterial stiffness in moderate-to-severe obstructive sleep apnoea, without excessive daytime sleepiness (STIFFSLEEP): an observational cohort study protocol.

INTRODUCTION: Sleepiness is a cardinal symptom in obstructive sleep apnoea (OSA) but most patients have unspecific symptoms. Arterial stiffness, evaluated by pulse wave velocity (PWV), is related to atherosclerosis and cardiovascular (CV) risk. Arterial stiffness was reported to be higher in patients with OSA, improving after treatment with continuous positive airway pressure (CPAP). This study aims to assess whether the same effect occurs in patients with OSA and without sleepiness. METHODS AND ANALYSIS: This observational study assesses the CV effect of CPAP therapy on a cohort of patients with moderate-to-severe OSA; the effect on the subcohorts of sleepy and non-sleepy patients will be compared. A systematic and consecutive sample of patients advised CPAP therapy will be recruited from a single outpatient sleep clinic (Centro Hospitalar de Lisboa Central-CHLC, Portugal). Eligible patients are male, younger than 65 years, with confirmed moderate-to-severe OSA and apnoea-hypopnea index (AHI) above 15/hour. Other sleep disorders, diabetes or any CV disease other than hypertension are exclusion criteria. Clinical evaluation at baseline includes Epworth Sleepiness Scale (ESS), and sleepiness is defined as ESS above 10. OSA will be confirmed by polygraphic study (cardiorespiratory, level 3). Participants are advised to undertake an assessment of carotid-femoral PWV (cf-PWV) and 24 hours evaluation of ambulatory blood pressure monitoring (ABPM), at baseline and after 4 months of CPAP therapy. Compliance and effectiveness of CPAP will be assessed. The main outcome is the variation of cf-PWV over time. ETHICS AND DISSEMINATION: This protocol was approved by the Ethics Committees of CHLC (reference number 84/2012) and NOVA Medical School (number36/2014/CEFCM), Lisbon. Informed, written consent will be obtained. Its results will be presented at conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02273089; Pre-results.

Health-related quality of life impact of a triple combination of olmesartan medoxomil, amlodipine besylate and hydrochlorotiazide in subjects with hypertension.

BACKGROUND: A post-hoc analysis was performed on the data from a 54 weeks phase III study (ClinicalTrials.gov identifier: NCT00923091) to measure changes in the health-related quality of life (HRQoL) of 2,690 patients aged ≥18 with moderate-to-severe hypertension who received one of six doses of olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ), using the MINICHAL and EQ-5D instruments. METHODS: Descriptive statistics were used to assess blood pressure and HRQoL scores over the study period. Analysis of covariance (ANCOVA) was used to identify those factors that could possibly have influenced HRQoL. Linear regression was used to assess the relationship between changes in blood pressure and HRQoL scores. RESULTS: Patients' baseline MINICHAL mood and somatic domains scores were 5.5 and 2.6. Over the study period HRQoL improved as both MINICHAL scores decreased by 31-33%. Patients' baseline EQ-5D index and VAS scores were 0.9 and 73.4 respectively, increasing by 6% and 12% over the study period. Patients' QALY gain over the 54 weeks study period was estimated to be 0.029 QALYs. The ANCOVA showed that changes in patients' HRQoL was likely to have been influenced by patients' achievement of blood pressure control, the amount of concomitant medication and patients' last used dosage strength of antihypertensive. Linear regression showed that blood pressure improvement may have been associated with improved HRQoL. CONCLUSIONS: This study showed that OLM/AML/HCTZ reduced blood pressure and significantly increased blood pressure control whilst improving patients' HRQoL. Achieving blood pressure control, amount of concomitant medication and dosage strength of antihypertensive impacted on patients' HRQoL.

Prevalence of microalbuminuria in hypertensive patients with or without type 2 diabetes in a Portuguese primary care setting: The RACE (micRoAlbumin sCreening survEy) study.

INTRODUCTION AND OBJECTIVES: To determine the prevalence of microalbuminuria (MAU) in outpatients with hypertension and/or type 2 diabetes mellitus (DM) and in normotensive, non-diabetic outpatients (control group); and, as secondary objectives, to examine the differences in the distribution of MAU in the four subgroups and the association of different clinical and epidemiological variables with MAU. METHODS: RACE (micRoAlbumin sCreening survEy) was a multicenter, descriptive observational cross-sectional study, which enrolled outpatients followed in primary care in Portugal. Patients with potential reasons for a false-positive MAU test were excluded. The main outcome measures were the prevalence of MAU as assessed by Micral(®) test strips and blood pressure. Demographic variables, presence of comorbidities, use of cardiovascular and antidiabetic drugs and biochemical variables were also analyzed. RESULTS: A total of 9198 patients (3769 with hypertension, 3100 with both DM and hypertension, 423 with DM and without hypertension, and 1906 controls), 54.7% women, were included in the primary analysis. Overall prevalence of MAU was 58% in patients with DM and hypertension, 51% in patients with DM, 43% in patients with hypertension, and 12% in controls (chi-square: p<0.001 for all subgroups). In multivariate analysis, predictors for MAU were the presence of DM or hypertension, HbA1C, male gender, age, systolic blood pressure and total cholesterol. CONCLUSIONS: MAU is extremely common in outpatients with DM and/or hypertension followed in primary care, especially in those with both hypertension and DM and high cardiovascular risk. MAU screening would help identify individuals at risk and increase awareness of kidney disease and target organ damage.

Persistent lipid abnormalities in statin-treated patients: Portuguese diabetic subpopulation of the Dyslipidaemia International Study (DYSIS).

AIMS: To assess the treatment patterns and prevalence of persistent lipid abnormalities in Portuguese statin-treated patients with diabetes. METHODS: DYSIS was an epidemiological, cross-sectional and multicentre international study. Outpatients ≥ 45 years old seen at primary and secondary care centres and treated with statins for at least three months were enrolled. This study presents the results for the Portuguese subpopulation, focusing on lipid control of the diabetic patients. RESULTS: Of the 916 patients recruited, 348 (38%) had diabetes mellitus (DM). The majority of the diabetic patients (58%) failed to attain an LDL-C < 2.5 mmol/L, and 77% did not reach the optional goal of LDL-C < 2.0 mmol/L set by the 2007 recommendations of the European Society of Cardiology. The most frequently used statin was simvastatin, both in patients with and without diabetes (55.7% vs. 57.1%, p = 0.68). The mean (SD) statin dose in simvastatin-equivalent units was 26.1 (9.2) mg in diabetics and 25.3 (8.8 mg) in non-diabetics (p = 0.19). CONCLUSIONS: The majority of Portuguese diabetic patients treated with statins failed to attain the recommended LDL cholesterol goals. Relatively low doses of medium potency statins were the prevailing therapy. There seems to be considerable room for improvement through the use of more potent statins, dose up-titration and/or the addition of other lipid-modifying therapies.

[Old and new oral anticoagulants. Pharmacological perspective]. / Velhos e novos anticoagulantes orais. Perspetiva farmacológica.

Oral anticoagulant therapy is changing. In several clinical settings, warfarin and acenocumarol remain the standard oral anticoagulants. However, in view of the limitations of vitamin K antagonists, resulting from its slow onset of pharmacological action, its narrow therapeutic window, its variable metabolism, dependent of citochrome P450, its multiple pharmacological and food interactions and its potential risk for hemorrhagic complications, the last years have witnessed the emergence of new pharmacological groups in oral anticoagulant therapy, that can overcome these problems. At present, pharmacological investigation is focused in the development of new non-peptide molecules, which can inhibit essential moments of the coagulation system (thrombin and factor Xa), with a predictable and consistent pharmacodynamic and pharmacokinetic pattern, administered orally. Of these compounds, three of them (dabigatran, rivaroxaban and apixaban) already have defined (or to be defined) therapeutic indications, built on large interventional phase III studies, while many others are in less advanced development phases. This review summarizes and discusses the pharmacology of warfarin/acenocumarol and of the new direct thrombin and factor Xa inhibitors, exemplifying similarities and stressing differences that help us justify out therapeutic options.

Atorvastatin versus Bezafibrate in Mixed Hyperlipidaemia : Randomised Clinical Trial of Efficacy and Safety (the ATOMIX Study).

OBJECTIVE: Combined hyperlipidaemia is a common and highly atherogenic lipid phenotype with multiple lipoprotein abnormalities that are difficult to normalise with single-drug therapy. The ATOMIX multicentre, controlled clinical trial compared the efficacy and safety of atorvastatin and bezafibrate in patients with diet-resistant combined hyperlipidaemia. PATIENTS AND STUDY DESIGN: Following a 6-week placebo run-in period, 138 patients received atorvastatin 10mg or bezafibrate 400mg once daily in a randomised, double-blind, placebo-controlled trial. To meet predefined low-density lipoprotein-cholesterol (LDL-C) target levels, atorvastatin dosages were increased to 20mg or 40mg once daily after 8 and 16 weeks, respectively. RESULTS: After 52 weeks, atorvastatin achieved greater reductions in LDL-C than bezafibrate (percentage decrease 35 vs 5; p < 0.0001), while bezafibrate achieved greater reductions in triglyceride than atorvastatin (percentage decrease 33 vs 21; p < 0.05) and greater increases in high-density lipoprotein-cholesterol (HDL-C) [percentage increase 28 vs 17; p < 0.01 ]. Target LDL-C levels (according to global risk) were attained in 62% of atorvastatin recipients and 6% of bezafibrate recipients, and triglyceride levels <200 mg/dL were achieved in 52% and 60% of patients, respectively. In patients with normal baseline HDL-C, bezafibrate was superior to atorvastatin for raising HDL-C, while in those with baseline HDL-C <35 mg/dL, the two drugs raised HDL-C to a similar extent after adjustment for baseline values. Both drugs were well tolerated. CONCLUSION: The results show that atorvastatin has an overall better efficacy than bezafibrate in concomitantly reaching LDL-C and triglyceride target levels in combined hyperlipidaemia, thus supporting its use as monotherapy in patients with this lipid phenotype.