Clinical trials. A pending subject. / Ensayos clínicos. Una asignatura pendiente.

Clinical trials are essential tools for the progress of clinical medicine in its diagnostic and therapeutic aspects. Since the first trial in 1948, which related tobacco use with lung cancer, there have been more than 150,000 clinical trials to date in various areas (paediatrics, cardiology, oncology, endocrinology, etc.). This article highlights the importance for all physicians to participate, over the course of their professional career, in a clinical trial, due to the inherent benefits for patients, the progress of medicine and for curricular prestige. The authors have created a synthesis of their experience with clinical trials on hypertension, diabetes, dyslipidaemia and ischaemic heart disease over the course of almost 3 decades. Furthermore, a brief reference has been made to the characteristics of a phase I unit, as well as to a number of research studies currently underway.

Blood pressure-lowering effects of nifedipine/candesartan combinations in high-risk individuals: subgroup analysis of the DISTINCT randomised trial.

The DISTINCT study (reDefining Intervention with Studies Testing Innovative Nifedipine GITS-Candesartan Therapy) investigated the efficacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including those with renal impairment (estimated glomerular filtration rate<90 ml min-1, n=422), type 2 diabetes mellitus (n=202), hypercholesterolaemia (n=206) and cardiovascular (CV) risk factors (n=971), as well as the impact of gender, age and body mass index (BMI). Participants with grade I/II hypertension were randomised to treatment with nifedipine GITS (N) 20, 30, 60 mg and/or candesartan cilexetil (C) 4, 8, 16, 32 mg or placebo for 8 weeks. Mean systolic BP and diastolic BP reductions after treatment in high-risk participants were greater, overall, with N/C combinations vs respective monotherapies or placebo, with indicators of a dose-response effect. Highest rates of BP control (ESH/ESC 2013 guideline criteria) were also achieved with highest doses of N/C combinations in each high-risk subgroup. The benefits of combination therapy vs monotherapy were additionally observed in patient subgroups categorised by gender, age or BMI. All high-risk participants reported fewer vasodilatory adverse events in the pooled N/C combination therapy than the N monotherapy group. In conclusion, consistent with the DISTINCT main study outcomes, high-risk participants showed greater reductions in BP and higher control rates with N/C combinations compared with respective monotherapies and lesser vasodilatory side-effects compared with N monotherapy.

Utility of transcranial sonography in the diagnosis of drug-induced parkinsonism: a prospective study.

BACKGROUND AND PURPOSE: Drug-induced parkinsonism usually resolves after discontinuation of the causative agent. However, it persists in some patients, who actually have subclinical neurodegenerative parkinsonism. Identification of this condition is important because these patients could benefit from therapeutic measures. The objective of this study was to prove whether transcranial sonography, a technique used in the diagnosis of neurodegenerative parkinsonism, can be used for the said identification. METHODS: In this prospective study, patients with drug-induced parkinsonism were followed for at least 6 months after discontinuation of the causative drug and performance of blinded transcranial sonography. Patients were categorized as having iatrogenic parkinsonism if the clinical presentation had resolved or subclinical drug-exacerbated parkinsonism if it persisted. Once the patient was classified into one of the two groups, an expert assessed the transcranial sonography findings and their agreement with the clinical diagnosis. RESULTS: Twenty patients composed the group for analysis of results. Assessing hyperechogenicity in the substantia nigra >20 mm2 and/or hyperechogenic lentiform nucleus, differences were detected between the iatrogenic parkinsonism and the subclinical drug-exacerbated parkinsonism groups, although they did not reach statistical significance (Fisher's exact test 0.09). Joint assessment of sonographic alterations in both structures had a negative predictive value of 85.7% for diagnosis of drug-induced parkinsonism, with a negative likelihood ratio of 0.3. CONCLUSIONS: Although in our study statistically significant differences were not found between the transcranial sonography characteristics of subclinical drug-exacerbated parkinsonism and iatrogenic parkinsonism patients, we believe that transcranial sonography is a valid technique for diagnosis of drug-induced parkinsonism.

Immediate and late benefits of treating very elderly people with hypertension: results from active treatment extension to Hypertension in the Very Elderly randomised controlled trial.

OBJECTIVE: To assess if very elderly people with hypertension obtain early benefit from antihypertensive treatment. DESIGN: One year open label active treatment extension of randomised controlled trial (Hypertension in the Very Elderly Trial (HYVET)). SETTING: Hospital and general practice based centres mainly in eastern and western Europe, China, and Tunisia. PARTICIPANTS: People on double blind treatment at the end of HYVET were eligible to enter the extension. INTERVENTIONS: Participants on active blood pressure lowering treatment continued taking active drug; those on placebo were given active blood pressure lowering treatment. The treatment regimen was as used in the main trial-indapamide SR 1.5 mg (plus perindopril 2-4 mg if required)-with the same target blood pressure of less than 150/80 mm Hg. MAIN OUTCOME MEASURES: The primary outcome was all stroke; other outcomes included total mortality, cardiovascular mortality, and cardiovascular events. RESULTS: Of 1882 people eligible for entry to the extension, 1712 (91%) agreed to participate. During the extension period, 1682 patient years were accrued. By six months, the difference in blood pressure between the two groups was 1.2/0.7 mm Hg. Comparing people previously treated with active drug and those previously on placebo, no significant differences were seen for stroke (n = 13; hazard ratio 1.92, 95% confidence interval 0.59 to 6.22) or cardiovascular events (n = 25; 0.78, 0.36 to 1.72). Differences were seen for total mortality (47 deaths; hazard ratio 0.48, 0.26 to 0.87; P = 0.02) and cardiovascular mortality (11 deaths; 0.19, 0.04 to 0.87; P = 0.03). CONCLUSION: Very elderly patients with hypertension may gain immediate benefit from treatment. Sustained differences in reductions of total mortality and cardiovascular mortality reinforce the benefits and support the need for early and long term treatment. Trial registration Clinical trials NCT00122811.

Efficacy and safety of extended-release niacin/laropiprant plus statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia.

BACKGROUND: Co-administration of niacin with statin offers the potential for additional lipid management and cardiovascular risk reduction. However, niacin is underutilised because of the side effects of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). A combination tablet containing extended-release niacin and laropiprant (ERN/LRPT), a PGD(2) receptor (DP1) antagonist, offers improved tolerability. This study assessed the efficacy and safety of ERN/LRPT added to statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia who were not at their National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal based on their coronary heart disease risk category (high, moderate or low). METHODS: After a 2- to 6-week run-in statin (simvastatin 10 or 20 mg or atorvastatin 10 mg) period, 1216 patients were randomised equally to one of two treatment groups in a double-blind fashion: group 1 received ERN/LRPT (1 g) plus the run-in statin dose and advanced to ERN/LRPT (2 g) after 4 weeks for an additional 8 weeks, with no adjustments to the run-in statin dose; group 2 received simvastatin or atorvastatin at twice their run-in statin dose and remained on this stable dose for 12 weeks. RESULTS: ERN/LRPT added to statin (pooled across statin and statin dose) significantly improved key lipid parameters vs. the doubled statin dose (pooled): the between-treatment group difference in least squares mean per cent change [95% confidence interval (CI)] from baseline to week 12 in LDL-C (primary end-point) was -4.5% (-7.7, -1.3) and in high-density lipoprotein cholesterol (HDL-C) was 15.6% (13.4, 17.9) and in median per cent change for triglyceride (TG) was -15.4% (-19.2, -11.7). Treatment-related adverse experiences (AEs) related to flushing, pruritis, rash, gastrointestinal upset and elevations in liver transaminases and fasting serum glucose occurred more frequently with ERN/LRPT added to statin vs. statin dose doubled. CONCLUSIONS: The addition of ERN/LRPT to ongoing statin treatment produced significantly improved lipid-modifying benefits on LDL-C, HDL-C and TG and all other lipid parameters compared with doubling the statin dose in patients with primary hypercholesterolaemia or mixed dyslipidaemia. The types of AEs that occurred at a greater frequency in the ERN/LRPT group were those typically associated with niacin.

[Some reflections and findings of a Hypertension [corrected] Unit in Spain]. / Algunas reflexiones y hallazgos de una Unidad de Hipertensión en España.

The Hypertension Unit, University Hospital San Cecilio of Granada, on fulfilling 15 years and after the experience acquired in this extended period, wants to stress various "facts": 1) the importance of correctly measuring blood pressure, avoiding rounding off "numbers" and making three consecutive measurements, taking the mean value of the last two; 2) carefully using the concept of "white coat" hypertension; the continuous follow-up of these cases and the use of ambulatory blood pressure monitoring reveal that they are really hypertensive; 3) using those values less than 130/85 mmHg as normality values; 4) the high rate of risk factors (obesity, diabetes, hyperuricemia, smoking, etc.) accompanying recently diagnosed hypertension; and 5) the need to give an intensive treatment in many cases (high doses, greater number of drugs, etc.). The experience of more than fifteen years and thousands of patients seen support the ideas included herein.

Comparison of the antihypertensive effects of the fixed dose combination enalapril 10 mg/nitrendipine 20 mg vs losartan 50 mg/hydrochlorothiazide 12.5 mg, assessed by 24-h ambulatory blood pressure monitoring, in essential hypertensive patients.

Fixed combinations of calcium channel blockers and angiotensin converting enzyme inhibitors represent an alternative to diuretic-based combination therapy. The aim of the present study was to compare the antihypertensive efficacy of the combination enalapril 10 mg/nitrendipine 20 mg (E/N) vs losartan 50 mg/hydrochlorothiazide 12.5 mg (L/H), assessed by 24-h ambulatory blood pressure monitoring. This multicentre, double-blind, parallel study included 97 hypertensive patients (office diastolic blood pressure (DBP) 90-109 mmHg and daytime DBP > 85 mmHg). After a 2- to 3-week period of single-blind placebo, they were randomized to receive double-blind treatment with E/N (n = 48) or L/H (n = 49) for a 4-week period. The primary outcome measure was the difference in 24-h DBP reduction between treatments from randomization to the end of the double-blind period. Secondary efficacy variables included differences in 24-h systolic (S) BP reduction, daytime, night-time and office SBP and DBP reduction, proportion of responders and controlled patients, trough-to-peak ratio and smoothness indexes. Safety was assessed by the proportion of patients with adverse events and the detection of laboratory abnormalities. No significant differences were observed in the primary outcome measure. The group receiving E/N tended to show greater reductions in most measures (24 h, daytime and office SBP and DBP) and higher BP control rates, but only the difference in the rate of office SBP control (< 140 mmHg) reached statistical significance (42.2 vs 22.4%; P = 0.048). The trough-to-peak ratios and smoothness indexes were similar in both groups. The incidence of adverse events related to the treatment was 27.1% (95% CI 14.5-39.6%) in E/N-treated patients and 14.3% (95% CI 4.5-45.8%) in the L/H group, but differences were not significant. The kind of event more frequently observed were flushing and headache in E/N, and dizziness and asthenia in L/H; all observed adverse events were mild. We conclude that E/N and L/H have a similar antihypertensive efficacy, assessed by office or ambulatory blood pressure monitoring. E/N achieved a significantly higher office SBP control rate, but this was accompanied by an apparently higher proportion of mild adverse events.

Efficacy and tolerability of fixed-dose combinations of telmisartan plus HCTZ compared with losartan plus HCTZ in patients with essential hypertension.

Telmisartan, an angiotensin II receptor blocker, is an effective once-daily antihypertensive agent available either alone or in fixed-dose combination with hydrochlorothiazide (HCTZ). This multicentre, prospective, randomised, open-label, blinded-endpoint (PROBE) study assessed the efficacy and safety of six weeks' treatment with telmisartan 40 mg/HCTZ 12.5 mg (n = 199) and telmisartan 80 mg/HCTZ 12.5 mg (n = 200) versus losartan 50 mg/HCTZ 12.5 mg (n = 198) in patients with mild to moderate essential hypertension. During the last six hours of the dosing interval, telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg reduced mean ambulatory diastolic blood pressure (DBP) to a greater extent than losartan 50 mg/HCTZ 12.5 mg (treatment differences 1.8 mmHg [p < 0.05] and 2.5 mmHg [p < 0.001], respectively). Telmisartan 80 mg/HCTZ 12.5 mg also lowered mean 24-hour DBP by 2.3 mmHg more than losartan 50 mg/HCTZ 12.5 mg (p < 0.001). Telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg produced greater reductions in ambulatory systolic blood pressure versus losartan 50 mg/HCTZ 12.5 mg of 2.5 mmHg and 3.4 mmHg, respectively, during the last six hours of the dosing interval (p < 0.05), and of 2.1 mmHg and 3.4 mmHg, respectively, over the entire 24-hour dosing interval (p < 0.05). All treatments were well tolerated.

The adjunctive effect of telmisartan in patients with hypertension uncontrolled on current antihypertensive therapy.

This prospective, double-blind, randomised, parallel-group, multicentre study assessed the adjunctive effect of telmisartan monotherapy versus placebo in controlling blood pressure during the last six hours of the 24-hour dosing period. After a two-week run-in phase, 375 patients with essential hypertension uncontrolled on existing therapy were randomised to either placebo or telmisartan (40 mg uptitrated to 80 mg after four weeks, if needed) for eight weeks. Ambulatory blood pressure monitoring (ABPM) was conducted at randomisation (baseline) and treatment end. The change from baseline in diastolic blood pressure (DBP) over the last six hours (primary endpoint) was significantly greater with telmisartan than placebo (adjusted mean treatment difference in favour of telmisartan: -3.7 mmHg, 95% confidence interval (CI) -5.5, -1.9 mmHg, p < or = 0.001, n = 350), as was the reduction in 24-hour DBP (adjusted mean treatment difference: -5.0 mmHg, 95% CI -6.5, -3.5 mmHg, p < or = 0.001). Telmisartan also reduced mean systolic blood pressure significantly more than placebo over the last six hours and the entire 24-hour dosing interval. Responder rates (ABPM DBP, seated DBP, and overall [seated SBP/DBP]) at 8 weeks were significantly higher with telmisartan than with placebo (p < or = 0.01). All treatments were well tolerated. When added to existing antihypertensive regimens, telmisartan offers additional effectiveness while maintaining placebo-like tolerability.

[Study of 1,595 brucellosis cases in the Almeria province (1972-1998) based on epidemiological data from disease reporting]. / Estudio de 1.595 casos de brucelosis en la provincia de Almería (1972-1998) según datos epidemiológicos de declaración de la enfermedad.

OBJECTIVE: To know clinical, diagnostic, and treatment issues of brucellosis in the Almeria province. METHODS: Descriptive, epidemiological study from 1,595 disease report cards in the Almeria province during the 1972-1998 period. Issues concerning complications and treatment were reported in 890 cards (57.8%), symptoms, signs and hemograms in 565 (35.4%), and other diagnostic findings in all cards. The chi2 test was used to compare independent qualitative parameters for a 95% CI. RESULTS: In the early phase the most common symptom was asthenia (95.2%); sweating in the chronic stage (95.8%). The most commonly recorded sign was spleen enlargement (37.5%) and the most commonly reported complication was bone and joint involvement (22.8%). No changes in symptoms occurred over years. The hemogram revealed anemia in 30.3% of cases. Blood culture was positive for 91.2%. Regarding serological diagnosis, rose Bengal was positive for 99.2% of cases; the most common agglutination titer to Brucella or B. mellitensis was 1/640 (13.5%). The most commonly used therapy consisted of the association tetracycline plus streptomycin (42.4%). For 42.6% of cards, patients were transferred to hospital, particularly since 1984. CONCLUSIONS: Generally speaking, clinical data recorded in the reporting card regarding brucellosis disease reveal the clinical features of the disease, after a long surveillance period. Rose Bengal should be used as screening test for the diagnosis of this disease.

Nebivolol vs amlodipine as first-line treatment of essential arterial hypertension in the elderly.

The antihypertensive efficacy of nebivolol and amlodipine and their tolerability were compared in a multicentre, randomized, active-controlled, double-blind parallel-group trial in elderly patients with mild to moderate essential arterial hypertension. One hundred and eighty-four subjects aged > or = 65 years were screened. After a run-in phase of 4 weeks, only 168 of these were randomized with either nebivolol 2.5-5 mg daily (n = 81) or amlodipine 5-10 mg daily (n = 87) over a period of 12 weeks. The response rate to treatment and the changes of sitting diastolic blood pressure (BP) at week 12 were similar between the two groups. A lower sitting systolic BP (SBP) was detected with amlodipine at week 4 (p < 0.05) and at week 8 (p < 0.05). Standing BP showed no changes between the two groups; only SBP was lower with amlodipine at week 8 (p < 0.05). Heart rate was lower at all treatment visits with nebivolol (p < 0.001). The incidence of adverse events was no different between the two groups; however the incidence of headache and ankle oedema was significantly higher with amlodipine (p < 0.05). In elderly subjects with essential hypertension, the antihypertensive efficacy of nebivolol and amlodipine was similar. Both drugs were well tolerated, although amlodipine was accompanied by higher incidence of drug-related adverse events.

Blood pressure and urinary excretion of electrolytes in Spanish schoolchildren.

Despite the importance of hypertension in adults, its effects on child health are poorly understood. This cross-sectional epidemiological study was designed to look for a relationship between elevated blood pressure (BP) in children and 24-h urinary excretion of sodium (Na) and potassium (K), and between BP and dietary salt intake. The study population was all 59 856 schoolchildren aged 6 to 14 years in the province of Almería in southern Spain, among whom 613 participants were chosen randomly for study. We measured 24-h urinary Na and K concentrations, systolic and diastolic BP, body weight and height. There was a weak correlation between Na excretion and systolic BP (r = 0.18, 95% confidence interval 0.10-0.26), and between K excretion and systolic BP (r = 0.49, 95% CI = 0.04-0.20). Body weight was the variable that best correlated with systolic (r = 0.49, 95% CI = 0.43-0.55) and diastolic BP, and with Na excretion (r = 0.48, 95% CI = 0.42-0.55). Multiple regression analysis also showed that body weight was the variable that best correlated with systolic BP (b = 0.58), although the variables in the equation explained little of the total variability in BP (26%). These correlations were significant at P < 0.05. In conclusion urinary electrolytes correlated poorly with BP in a sample of Spanish schoolchildren. Body weight was the only variable that showed a weak relationship with BP and Na excretion.