Jorge Polónia

Physicians' attitudes and adverse drug reaction reporting : a case-control study in Portugal.

AbstractObjectives: Voluntary adverse drug reaction (ADR) reporting is fundamental to medical drug safety surveillance; however, substantial under-reporting exists and is the main limitation of the system. This study sought to identify the knowledge-and attitude-related factors associated with ADR reporting by physicians in Northern Portugal. Methods: Case-control study covering a population of National Health Service medical practitioners. The 88 cases comprised physicians who had reported at least one ADR to the drug surveillance unit from the year 2000 to the date of enrolment in the study. The 771 controls were randomly selected from among the remaining physicians. All interviews were conducted using a self-administered questionnaire. Knowledge and attitudes regarding spontaneous ADR reporting were based on Inman’s ‘seven deadly sins’. Agreement with the questions included in the questionnaire was measured using a horizontal, continuous visual analogue scale, which was unnumbered. Recorded answers were read in a range from zero (total disagreement) to ten (total agreement). We used logistic regression to determine the ADR reporting adjusted odds ratio (ORadj) for a change in exposure corresponding to the interquartile range for each attitude. Results: A total of 397 questionnaires were received from 731 eligible practitioners (54.3%). Physicians who worked in primary versus hospital care (ORadj 7.74 [95% CI 1.85, 32.30]) and in general medicine (ORadj 1.05 [95% CI 0.30, 3.69]) versus medical specialities were more likely to report ADRs. In contrast, physicians working in the medical-surgical/surgical fields were significantly less likely to report ADRs compared with medical specialists (ORadj 0.10 [95% CI 0.02, 0.46]). Attitudes to ADRs were strongly associated with reporting probability. Hence, an interquartile decrease in any of the following attitudes increased the probability of reporting by: (i) 87% (p < 0.05) for complacency (the belief that really serious ADRs are well documented by the time a drug is marketed); (ii) 109% (p < 0.01) for insecurity (the belief that it is nearly impossible to determine whether a drug is responsible for a particular adverse reaction); (iii) 143% (p < 0.001) for diffidence (the belief that one would only report an ADR if one were sure that it was related to the use of a particular drug); (iv) 220% (p < 0.001) for indifference (the belief that the one case an individual doctor might see could not contribute to medical knowledge); and (v) 71% (p < 0.05) for ignorance (the belief that it is only necessary to report serious or unexpected ADRs). Conclusion: This study shows that there are attitudes strongly associated with under-reporting. The implementation of purpose-designed educational interventions based on the attitudes identified in this study may serve to improve reporting substantially.

Influence of Pharmacists' attitudes on adverse drug reaction reporting : A case-control study in portugal

AbstractIntroduction: Pharmacists can play a fundamental role in adverse drug reaction (ADR) reporting, although the factors that affect underreporting among these professionals are unknown. The objectives of this study were to identify (i) professional or demographic characteristics; and (ii) attitudes associated with pharmacists’ ADR reporting in northern Portugal. Methods: We conducted a case-control study on a population of pharmacists employed in hospital and community pharmacies across Portugal’s Northern Regional Health Authority catchment area in 2003. Cases (n = 34) comprised pharmacists who had reported at least one ADR to the northern region’s drug surveillance unit, and controls (n = 280) were randomly sampled from pharmacists who had never reported an ADR. All were interviewed using a mail questionnaire. Most attitudes were based on Inman’s ‘seven deadly sins’ and were measured using a continuous visual analogue scale. Answers were recorded in a range from 0 (total disagreement) to 10 (total agreement). Logistic regression was used to determine the ADR reporting adjusted odds ratio (OR) for a change in exposure corresponding to the interquartile range for each attitude. Results: The response rate was 86.8%. Reporting probability proved higher among hospital versus community pharmacists (adjusted OR 20.0; 95 CI 3.3, 125.0; p < 0.001). Attitudes to ADRs were strongly associated with reporting probability. Hence, an interquartile decrease in any of the following attitudes increased the probability of reporting by (i) 223% (95% CI 51, 595; p < 0.05) for “Really serious ADRs are well documented by the time a drug is marketed”; (ii) 240% (95% CI 89, 508; p = 0.002) for “I would only report an ADR if I were sure that it was related to the use of a particular drug”; (iii) 316% (95% CI 44, 1104; p = 0.010) for It is only necessary to report serious or unexpected ADRs; and (iv) 171% (95% CI 13, 549; p = 0.020) for “I do not have time to think about the involvement of the drug or other causes in ADRs”. Conclusions: ADR under-reporting is strongly associated with certain attitudes, possibly indicating that under-reporting could be minimised through educational interventions targeted at changing such attitudes. Pharmacists’ ADR education must be improved and educational programmes should be focused on altering attitudes identified by the study as being associated with under-reporting. Our data also indicate that community pharmacists must be a priority target for this intervention.

Correlates of plasma atrial natriuretic factor in health and hypertension.

Plasma concentrations of atrial natriuretic factor (ANF) were compared in normotensive subjects and subjects with untreated, uncomplicated essential hypertension (n = 21 pairs) matched for age, sex, and race. Plasma peptide values were slightly greater (45 +/- 3 vs 36 +/- 3 pg/ml; p less than 0.05) in the hypertensive group. On univariate analysis, age (r = 0.52, n = 47, p less than 0.001) and creatinine clearance (r = -0.30, n = 47, p less than 0.05) were significantly related to plasma ANF concentrations, but arterial pressure was not (r = 0.14, n = 47), in an extended group of normal subjects. In contrast, plasma ANF values were related to arterial pressure in both an extended group of subjects with untreated essential hypertension (r = 0.54, n = 38, p less than 0.001) and in our total heterogeneous pool of hypertensive patients (r = 0.46, n = 79, p less than 0.001), but weak positive associations with age and inverse relationships with creatinine clearance were not statistically significant in either hypertensive group. Similar weak inverse relationships between plasma ANF values and renin-angiotensin-aldosterone system activity were found in both normal and hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic Effect of the Nocturnal Blood Pressure Fall in Hypertensive Patients: The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) Meta-Analysis.

The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment ( P <0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels. # Novelty and Significance {#article-title-42}The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment (P<0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels.

Prevalence, awareness, treatment and control of hypertension and salt intake in Portugal: changes over a decade. The PHYSA study.

Objective: To determine prevalence, awareness, treatment and control of hypertension and the 24-h sodium excretion (24h-UNa) in the Portuguese adult population and to examine their changes from a similar study done in 2003. Design and setting: A population-based cross-sectional survey conducted in 2011–2012. Methods: A multistage-stratified (by age and sex) sampling method was used to select a representative sample of the 18–90-year-old population yielding 3720 participants (52.6% women, 97.1% Caucasians). Hypertension was defined as a SBP of at least 140 mmHg or DBP of at least 90 mmHg [average of 2–3 blood pressure (BP) measurements by trained observers with OMRON M6] or reported knowledge or treatment with antihypertensive drugs at the first visit (V1). A complete clinical information was obtained with a standard questionnaire. This procedure was repeated 10–15 days after visit 2 (V2) and 24-h urinary sample was collected for 24h-UNa, 24-h potassium excretion and creatinine excretion. Results: The overall prevalence of hypertension at V1 was 42.2% (44.4% in men, 40.2% in women) (42.1% in 2003). The age-specific prevalence of hypertension was 6.8, 46.9 and 74.9% in people below 35 years, 35–64 years and above 64 years. Comorbidities were 2.2–6.3 times more common in hypertensive patients vs. normotensive individuals. Overall, among the hypertensive patients, 76.6% were aware of the hypertension condition, 74.9% were treated and 42.5% were controlled (BP <140/90 mmHg), that is, respectively, 1.7, 1.9 and 3.8 times higher vs. data in 2003, with lower values in men vs. women and younger vs. older people. Global mean BP was 127.4/74.6 ± 17.7/10.5 vs. 134.7/80.4 ± 21.2/14.1 mmHg in 2003. From V1 to V2, control of hypertension increased on average by 14.8%. Multivariate analysis showed that age and BMI were independently associated with prevalence of hypertension. 24h-UNa (84% valid urinary samples) was 182.5 ± 64.7 mmol/day (10.7 g salt/day) and 24-h potassium excretion 75.2 ± 26.1 mmol/day. 24h-UNa was higher in patients with hypertension than in normotensive individuals (185.4 ± 64.8 vs. 177.8 ± 64.5 mmol/day; P < 0.02) and correlated with SBP (r = 0.05), age (r = 0.08) and BMI (r = 0.10) (P < 0.01). Conclusion: Hypertension prevalence among Portuguese adults remained stable in the past decade, but proportions of awareness, treatment and control of hypertension improved significantly. Salt intake is still high being almost double the WHO recommendations.

Prognostic impact from clinic, daytime, and night-time systolic blood pressure in nine cohorts of 13,844 patients with hypertension.

Background and method: To determine which SBP measure best predicts cardiovascular events (CVEs) independently, a systematic review was conducted for cohorts with all patients diagnosed with hypertension, 1+ years follow-up, and coronary artery disease and stroke outcomes. Lead investigators provided ad hoc analyses for each cohort. Meta-analyses gave hazard ratios from clinic SBP (CSBP), daytime SBP (DSBP), and night-time SBP (NSBP). Coefficients of variation of SBP measured dispersion. Nine cohorts (n = 13 844) were from Europe, Brazil, and Japan. For sleep–wake SBP classification, seven cohorts used patient-specific information. Results: Overall, NSBPs dispersion exceeded DSBPs dispersion by 22.6% with nonoverlapping confidence limits. Within all nine cohorts, dispersion for NSBP exceeded that for CSBP and DSBP. For each comparison, P = 0.004 that this occurred by chance. Considered individually, increases in NSBP, DSBP, and CSBP each predicted CVEs: hazard ratios (95% confidence intervals) = 1.25 (1.22–1.29), 1.20 (1.15–1.26), and 1.11 (1.06–1.16), respectively. However, after simultaneous adjustment for all three SBPs, hazard ratios were 1.26 (1.20–1.31), 1.01 (0.94–1.08), and 1.00 (0.95–1.05), respectively. Cohorts with baseline antihypertensive treatment and cohorts with patient-specific information for night–day BP classification gave similar results. Within most cohorts, simultaneously adjusted hazard ratios were greater for NSBP than for DSBP and CSBP: P = 0.023 and 0.012, respectively, that this occurred by chance. Conclusion: In hypertensive patients, NSBP had greater dispersion than DSBP and CSBP in all cohorts. On simultaneous adjustment, compared with DSBP and CSBP, increased NSBP independently predicted higher CVEs in most cohorts, and, overall, NSBP independently predicted CVEs, whereas CSBP and DSBP lost their predictive ability entirely.

Nail changes secondary to docetaxel (Taxotere).

Docetaxel is a new taxoid antineoplastic drug widely used for advanced breast cancer. Skin and nail toxicity are one of the more frequent nonhematologic adverse reactions. Besides dark pigmentations and Beau’s lines, subungual hemorrhage, orange discoloration, acute painful paronychia, onycholysis, subungual hyperkeratosis and transverse loss of the nail plate are described. The type of nail alteration is related with the number of cycles administered and there are no efficacious preventive measures to avoid its development. Clinicians should recognize the clinical picture of these adverse nail reactions because docetaxel is used for several neoplastic disorders.

Arterial stiffness predicts cardiovascular outcome in a low-to-moderate cardiovascular risk population: the EDIVA (Estudo de DIstensibilidade VAscular) project.

Background Pulse wave velocity (PWV) is a recognized marker of arterial stiffness, although little knowledge exists of their relationship to long-term cardiovascular risk in general populations. Methods and results A prospective, multicenter, observational study included 2200 Portuguese nationals (1290 men), aged between 18 and 91 years (mean 46.33 ± 13.76 years). They underwent clinical assessment and annual PWV measurement using a Complior device, and major adverse cardiovascular events (MACEs) – death, stroke, myocardial infarction, unstable angina, peripheral arterial disease, revascularization, or renal failure – were recorded. During a mean follow-up of 21.42 ± 10.76 months, there were 47 nonfatal MACEs (2.1% of the sample). PWV was significantly higher in individuals with events than in those without events (11.76 ± 2.13 vs. 10.01 ± 2.01 m/s, respectively, P < 0.001). The study population was divided into two groups by PWV, classified as normal (PWV < 95th percentile) or high (PWV >95th percentile), according to predefined criteria for normality. Cumulative event-free survival at 2 years was 99.3% in the normal PWV group and 95% in the high PWV group. The hazard ratio for MACE in the high PWV group was 9.901 [95% confidence interval (CI) 5.00–19.59, P < 0.001], and 4.832 (95% CI 2.35–9.94, P < 0.001) when adjusted for other risk factors. For absolute PWV, the adjusted hazard ratio (per 1 m/s change) was 1.316 (95% CI 1.13–1.53, P < 0.001). Conclusion The results of the initial analysis of this study highlight the clinical relevance of PWV as a cardiovascular risk marker and demonstrate that PWV measurement can make an important contribution to assessment of cardiovascular prognosis.

Influence of non-steroidal anti-inflammatory drugs on renal function and 24h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients.

Objective: To evaluate the influence of non-steroidal anti-inflammatory drugs (NSAIDs; aspirin and indomethacin) on the renal and antihypertensive effects of enalapril and nifedipine gastrointestinal therapeutic system (GITS) in patients with essential hypertension. Design and methods: In a crossover study, 18 patients on an unrestricted-salt diet were randomly assigned to receive either enalapril (20-40 mg/day) or nifedipine-GITS (30-60mg/day) for 4-8 weeks, followed by aspirin (100 mg/day for 2 weeks) and then indomethacin (75 mg/day for 1 week). Blood pressure was measured by 24 h ambulatory monitoring. Results: Enalapril and nifedipine-GITS significantly reduced blood pressure compared with placebo. Aspirin did not alter the antihypertensive effect of either drug. Indomethacin attenuated (by 45%) the antihypertensive effect of enalapril throughout the 24 h period of evaluation, but did not interfere with the effect of nifedipine. Furthermore, indomethacin significantly reduced the fractional excretion of sodium and plasma levels of prostaglandins in a similar way when added to either the enalapril or the nifedipine regimen. Conclusions: Vasodilatory prostaglandins are probably involved in the antihypertensive effects of enalapril but not of nifedipine, and this interaction seems to be independent of any indomethacin-induced decrease in renal sodium excretion. Nifedipine may be an appropriate drug to treat hypertensive patients requiring concomitant therapy with NSAID.

Low-dose oral contraceptives and 24-hour ambulatory blood pressure

Objective: To evaluate in normotensive women the influence of low‐dose oral contraceptives (OC, monophasic formulations containing 30 μg of estrogen) on 24‐h blood pressure. Methods: We evaluated prospectively in 15 normotensive healthy women (three smokers) the influence of OC on 24‐h ambulatory blood pressure monitoring (ABPM). ABPM was performed (SpaceLabs 90207) before and after 6–9 months of use of OC. We also evaluated ABPM in eight women (two smokers) before and after 6–8 months on an intrauterine device (IUD) as contraceptive method — these were used as control subjects. Results: OC produced a significant increase in 24‐h ABPM values (from 120±3/75±2 to 128±4/81±2 mmHg, P<0.04) which was particularly evident for night‐time values (from 108±2/64±2 to 120±4/73±2 mmHg, P<0.02). After OC, two normotensive women developed ‘hypertensive values’. In OC users there was a slight but significant increase in body weight which did not correlate with the increase of blood pressure. In contrast, in the control group (IUD) neither ABPM values nor weight were modified by the contraceptive maneuver. Conclusions: In normotensive women, low‐dose OC may increase blood pressure to an extent that, at least in some women, may affect blood pressure control towards ‘hypertensive values’. This stresses the importance of monitoring blood pressure values during OC treatment.