Determinants of oral anticoagulation control in new warfarin patients: analysis using data from Clinical Practice Research Datalink.

BACKGROUND: The safety and effectiveness of warfarin therapy depends critically on the quality of anticoagulation control, often assessed using the percentage time in therapeutic International Normalised Ratio (INR) range (TTR). We aimed to identify patient characteristics related to anticoagulation control with warfarin, measured by TTR. METHOD: We carried out a population-based study using the Clinical Practice Research Datalink, including two cohorts of patients starting warfarin after a first diagnosis of atrial fibrillation (AF) or venous thromboembolism (VTE) between 2000 and 2013. We used multivariate mixed regression and logistic regression models to predict the fully-adjusted effect of each predictor variable upon TTR. RESULTS: The study population comprised 29,717 incident AF and 19,113 incident VTE patients who initiated warfarin. In real world clinical practice a minority of patients achieve good anticoagulation control with warfarin (44% AF and 36% VTE patients had TTR≥70%). Poor anticoagulation control driven by subtherapeutic INRs was observed in younger patients (<45years) and in AF patients with increased number of hospitalisations. Poor anticoagulation control driven by sub and/or supratherapeutic INRs was seen in AF and VTE patients current smokers, in patients using medications for pain and in VTE patients with active cancer. CONCLUSION: In a real world clinical practice there is a high amount of unpredictable inter-individual TTR variability and in some patients good anticoagulation control is more challenging than in others. These findings may help to identify patients who will require closer monitoring or innovative strategies to optimise the outcomes of oral anticoagulant therapy.

Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice pesearch datalink.

BACKGROUND: There is strong evidence of reductions in major vascular events from statins across all cardiovascular risk categories. However, trials of statin therapy have provided conflicting results regarding statin use and type 2 diabetes (T2DM). We aimed to assess the effect of statins on T2DM development. METHOD: We carried out a population-based cohort study using the Clinical Practice Research Datalink (CPRD), a database of computerized clinical records. Every patient aged 30-85 years old starting a statin between 1989 and 2009 was matched with up to five non-statin users. The observation period in CPRD ended in 31 December 2011. Cox proportional hazard regression was used to compare rates of T2DM between statin users and non-users, using propensity score method to adjust for systematic differences between groups. RESULTS: The study basis comprised 2,016,094 individuals, including 430,890 people who received a statin, matched to 1,585,204 people not prescribed a statin. Mean follow-up time was 5.43 years for statin users and 3.89 years for nonusers. During follow-up 130,395 individuals developed T2DM. Statin use was associated with an increased risk of T2DM (HR 1.57; 95% CI 1.54-1.59), which increases with longer duration of use. The increased risk was smaller among people with hypertension or cardiovascular disease and was only apparent after 5 or more years treatment with statins in these groups. Conversely, age-specific risk ratios decreased in older people. CONCLUSIONS: Statin use is associated with an increased risk of T2DM. Our results suggest that the relative risk is higher among people without diagnosed hypertension or cardiovascular disease. These findings should be considered in the context of the observational nature of the data which is prone to bias and unmeasured confounding.

Drug-safety alerts issued by regulatory authorities: usefulness of meta-analysis in predicting risks earlier.

PURPOSE: The purpose of this study was to evaluate how risk estimates generated from cumulative meta-analysis performs over time for drugs having their benefit/risk ratio re-evaluated due to safety issues and, additionally, assess whether results are consistent with regulatory authorities' conclusions. METHODS: Four major regulatory authorities were searched for their issued safety alerts supported by longitudinal, comparative studies (experimentals and/or observationals). The random-effects model was used to pooled odds ratios (OR) over time by including studies according to the year they first became available. RESULTS: Seventeen safety alerts were included in this study. In 2008, proton-pump inhibitors (PPIs) were associated with an increased risk for bone fractures [OR 1.25, 95 % confidence interval (CI) 1.00-1.55, P = 0.049); the US Food and Drug Association (FDA) issued a safety alert in 2010 and added warnings to the label. An increased risk for Clostridium-difficile-associated diarrhea was pooled for PPIs in 2004 (OR 1.89, 1.19-3.02, P = 0.007); US FDA issued a safety alert in 2012, adding warnings to the label. PPIs were associated with pneumonia in 2009 (OR 1.40, 1.06-1.85, P = 0.017); US FDA issued an alert in 2012 but concluded that the benefit/risk (B/R) ratio remains positive. Statins were associated with an increased risk for diabetes (OR 1.07, 1.01-1.15, P = 0.033) in 2008. The European Medicines Agency (EMA) issued an alert in 2012, including warnings to the label. The remaining cumulative meta-analyses did not estimate increased risks in advance of regulatory decisions. CONCLUSION: This study demonstrates that meta-analysis may help predict iatrogenic risks. However, between-study heterogeneity can considerably affect the estimated results, and therefore, this technique should not replace further assessments during BR ratio re-evaluations.

Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis.

BACKGROUND: Efficacy of statins has been extensively studied, with much less information reported on their unintended effects. Evidence from randomized controlled trials (RCTs) on unintended effects is often insufficient to support hypotheses generated from observational studies. We aimed to systematically assess unintended effects of statins from observational studies in general populations with comparison of the findings where possible with those derived from randomized trials. METHODS: Medline (1998 to January 2012, week 3) and Embase (1998 to 2012, week 6) were searched using the standard BMJ Cohort studies filter. The search was supplemented with reference lists of all identified studies and contact with experts in the field. We included prospective studies with a sample size larger than 1,000 participants, case control (of any size) and routine health service linkage studies of over at least one year duration. Studies in subgroups of patients or follow-up of patient case series were excluded, as well as hospital-based cohort studies. RESULTS: Ninety studies were identified, reporting on 48 different unintended effects. Statins were associated with lower risks of dementia and cognitive impairment, venous thrombo-embolism, fractures and pneumonia, but these findings were attenuated in analyses restricted to higher quality studies (respectively: OR 0.74 (95% CI 0.62 to 0.87); OR 0.92 (95% CI 0.81 to 1.03); OR 0.97 (95% CI 0.88 to 1.05); OR 0.92 (95% CI 0.83 to 1.02)); and marked heterogeneity of effects across studies remained. Statin use was not related to any increased risk of depression, common eye diseases, renal disorders or arthritis. There was evidence of an increased risk of myopathy, raised liver enzymes and diabetes (respectively: OR 2.63 (95% CI 1.50 to 4.61); OR 1.54 (95% CI 1.47 to 1.62); OR 1.31 (95% CI 0.99 to 1.73)). CONCLUSIONS: Our systematic review and meta-analyses indicate that high quality observational data can provide relevant evidence on unintended effects of statins to add to the evidence from RCTs. The absolute excess risk of the observed harmful unintended effects of statins is very small compared to the beneficial effects of statins on major cardiovascular events.

Sources of information used by regulatory agencies on the generation of drug safety alerts.

PURPOSE: The study of the grounds on which data regulatory authorities base their decisions on drug safety evaluations is an important clinical and public health issue. The aim of this study was to review the type and publication status of data sources supporting benefit/risk ratio re-evaluations conducted by the major regulatory authorities on safety issues. METHODS: A website search was carried out to identify all safety alerts published by the U.S Food and Drugs Administration, Health Canada, European Medicines Agency and the Australian Therapeutics Goods Administration. Safety alerts were included if the causal relation between a suspected drug exposure and the occurrence of an adverse event was evaluated for the first time between 2010 and 2012. Type of data sources evaluated by these regulatory authorities, publication status of the data sources and status of the drug label section with respect to updating were evaluated. RESULTS: A total of 59 safety alerts were included in this study. Of these, 33 (56%) were supported by post-marketing spontaneous reports, 24 (41%) evaluated randomized clinical trials, 16 evaluated cohort studies (27%), 13 were case-control studies (22%) and 11 evaluated case report/case series (17%). Twenty-three safety alerts (39%) were issued based. on unpublished evidence, corresponding mainly to post-marketing spontaneous reports. The "Warnings and precautions section" was the drug label section most frequently updated (n = 40; 68%). CONCLUSION: Despite the different lengths of time taken by the different regulatory authorities to come to similar decisions on the same issues-an issue which would seem to deserve further harmonization-post-marketing spontaneous reports have supported most of the benefit/risk ratio re-evaluations, thereby confirming the value of such re-evaluations in detecting unknown adverse events.

Statins for the primary prevention of cardiovascular disease.

BACKGROUND: Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of CVD is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with CVD. The case for primary prevention was uncertain when the last version of this review was published (2011) and in light of new data an update of this review is required. OBJECTIVES: To assess the effects, both harms and benefits, of statins in people with no history of CVD. SEARCH METHODS: To avoid duplication of effort, we checked reference lists of previous systematic reviews. The searches conducted in 2007 were updated in January 2012. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2022, Issue 4), MEDLINE OVID (1950 to December Week 4 2011) and EMBASE OVID (1980 to 2012 Week 1).There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials of statins versus placebo or usual care control with minimum treatment duration of one year and follow-up of six months, in adults with no restrictions on total, low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted data. Outcomes included all-cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), revascularisation, change in total and LDL cholesterol concentrations, adverse events, quality of life and costs. Odds ratios (OR) and risk ratios (RR) were calculated for dichotomous data, and for continuous data, pooled mean differences (MD) (with 95% confidence intervals (CI)) were calculated. We contacted trial authors to obtain missing data. MAIN RESULTS: The latest search found four new trials and updated follow-up data on three trials included in the original review. Eighteen randomised control trials (19 trial arms; 56,934 participants) were included. Fourteen trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (OR 0.86, 95% CI 0.79 to 0.94); as was combined fatal and non-fatal CVD RR 0.75 (95% CI 0.70 to 0.81), combined fatal and non-fatal CHD events RR 0.73 (95% CI 0.67 to 0.80) and combined fatal and non-fatal stroke (RR 0.78, 95% CI 0.68 to 0.89). Reduction of revascularisation rates (RR 0.62, 95% CI 0.54 to 0.72) was also seen. Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no evidence of any serious harm caused by statin prescription. Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life. Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta-analysis indicate that these benefits are similar in people at lower (< 1% per year) risk of a major cardiovascular event. AUTHORS' CONCLUSIONS: Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins.

Off-label drug prescribing in a Portuguese paediatric emergency unit.

BACKGROUND: Many drugs are prescribed outside the terms of the marketing authorization ("off-label"). Several studies have shown that this is a common practice in various European healthcare settings. OBJECTIVE: This study aimed to quantify and characterize off-label drug prescribing in children admitted to a Portuguese Paediatric Unit (PEU). SETTING: This study was conducted in the Paediatric Unit of the university teaching hospital of Cova da Beira Hospital Centre (CHCB), Covilhã, located in the Eastern Central Region of Portugal. METHOD: A descriptive study was conducted, including a sample of 700 children, randomly selected from those admitted between January to October 2010. Drug prescription was assessed by retrospective review of clinical files. MAIN OUTCOME MEASURE: Off-label prescribing was defined as the utilization of a drug at an indication, age, dosage, frequency or route of administration different from those recommended in the Summary of Product Characteristics (SPC). For purposes of this study only the medicines prescribed to be used after discharge from the hospital were studied. RESULTS: 364 boys and 336 girls, aged from 4 days to 18 years, were included in this study. Of the 724 medicines prescribed, 32.2 % were off-label. At least one drug was used off-label in 28.1 % of the studied population, corresponding to 46.1 % of the 427 children that received prescriptions. "Alteration in dosage" was the commonest reason for off-label prescribing (28.2 %). The off-label prescriptions comprised mainly drugs acting on the "Respiratory System" and "Anti-infectious agents for systemic use". Amoxicillin/clavulanic acid, paracetamol, amoxicillin, ibuprofen and salbutamol were the five active principles most frequently prescribed off-label. CONCLUSION: The prevalence of off-label drug prescribing in the Portuguese PEU of CHCB is high, the use in a dose or for an age group not approved in the SPC being the most common reasons for off-label prescription.

Prescribing omissions in elderly patients admitted to a stroke unit: descriptive study using START criteria.

BACKGROUND: Underuse of medication considered beneficial is particularly common in elderly patients. A new Screening Tool to Alert Doctors to the Right Treatment (START) has been published to identify potential prescribing omissions. OBJECTIVE: To quantify and characterize potential prescribing omissions of cardiovascular risk management therapy using START criteria. SETTING: This study was conducted in the Stroke Unit of the university teaching hospital of Cova da Beira Hospital Centre, Covilhã, located in the Eastern Central Region of Portugal. METHOD: During 6 months, the medical files of all elderly patients (age ≥ 65 years) admitted with acute cardiovascular disease were reviewed and the START criteria applied to the information of medication, at admission and at the time of discharge from the hospital Stroke Unit. MAIN OUTCOME MEASURE: Potential prescribing omissions of cardiovascular and endocrine pharmacological therapy were identified and the difference in the potential prescribing omissions between admission and discharge from hospital Stroke Unit was also evaluated. RESULTS: At the time of admission to the Stroke Unit, 101 potential prescribing omissions were found in 68.1 % (n = 91) of elderly (average 1.11 omissions per patient), of which 84.2 % (n = 85) were corrected at the time of discharge. In 14 patients, 16 omissions found at admission were not corrected during hospitalization, and in 5 patients 5 new omissions were detected. CONCLUSION: Prescribing omissions of beneficial drugs are highly prevalent in acutely ill admitted to a Stroke Unit. START criteria represent a simple, evidence-based and easy-to-use tool to screen underuse of cardiovascular risk management therapy in elderly patients.

Data sources on drug safety evaluation: a review of recent published meta-analyses.

PURPOSE: Meta-analysis is a quantitative approach to summarize the findings from several studies and has been applied with increasing frequency to clinical trials. Because of their sample size and duration limitations, experimental studies (ESs) could not be able to detect late or rare adverse events (AEs), which may be identified in well-designed observational studies (OSs). This study aims to identify and analyze meta-analyses from both ES and OS where safety was found to be an outcome measure. METHODS: The meta-analyses inclusion criteria was established as at least one AE as primary outcome. Safety outcomes were considered as the increase in the risk for an AE after a pharmacological intervention. A MEDLINE search for meta-analyses published in the New England Journal of Medicine, The Lancet, Journal of American Medical Association, British Medical Journal, Annals of Internal Medicine, PLoS Medicine, Annual Review of Medicine, and Archives of Internal Medicine, between October 2005 and September 2010, was carried out. RESULTS: Sixty meta-analyses met the inclusion criteria. Of these, 53 included only ES, 4 included both ES and OS, and 2 included only OS. Of the 6 meta-analyses that included OS, 4 included cohort and case-control studies, and 2 included cohort, case-control, and cross-sectional studies. One meta-analysis did not report the type of studies included. CONCLUSIONS: Experimental studies were found to be the main source of meta-analyses on drug safety. The role of meta-analyses in pharmacovigilance is a matter of ongoing debate, and efforts are being made to develop guidelines on the use of meta-analysis in drug safety assessments, to better combine evidence about harms.

Apixaban and rivaroxaban safety after hip and knee arthroplasty: a meta-analysis.

Direct experimental safety comparisons of Xa coagulation factor direct inhibitors, apixaban and rivaroxaban, on their approved therapeutic indications have not been identified. Due to recently raised safety concerns, a meta-analysis was carried out pooling data from studies identified on a Medline and Cochrane Library search in order to better evaluate the safety profile of both drugs. Abstracts from scientific meetings were also searched from 2003 to 2011. Primary and secondary outcome measures were major bleeding and total bleeding, respectively. Relative risks (RRs) were estimated using random effects models and statistical heterogeneity was estimated with I(2) statistics. Of the 160 screened publications, 12 clinical trials were included in which enoxaparin was the active control. For knee arthroplasty, apixaban was associated with significantly fewer major bleeding events (6496 patients, RR 0.56, 95% confidence interval [CI] 0.32-0.96) and fewer total bleeding events (6496 patients, RR 0.81, 95% CI 0.67-0.97). There were no significant differences in the incidence of major bleeding events (5699 patients, RR 1.40, 95% CI 0.56-3.52) or in the incidence of total bleeding events for rivaroxaban (5699 patients, RR 1.09, 95% CI 0.91-1.30). No differences were found when thromboprophylaxis after hip replacement was the case. Apixaban seems to be associated with a lower risk of the incidence of hemorrhagic events after total knee arthroplasty. For hip arthroplasty, no differences were found between the studied drugs.

Association of statin therapy with blood pressure control in hypertensive hypercholesterolemic outpatients in clinical practice.

BACKGROUND: Some clinical evidence revealed that statins, apart from lowering cholesterol levels, also have an antihypertensive effect. Our aim was to evaluate the existence of a possible association of statin therapy with blood pressure (BP) control in clinical practice. MATERIALS AND METHODS: Patients attending a hypertension/dyslipidemia clinic were prospectively evaluated. Those patients with a diagnosis of stage 1 hypertension and hypercholesterolemia who consented to participate were included in the study, either in the statin group (when taking a statin) or in the control group (when not taking a statin). Exclusion criteria included dementia, pregnancy, or breastfeeding, and history or evidence of stage 2 hypertension. Detailed clinical information was prospectively obtained from medical records. A total of 110 hypertensive patients were assigned to the study (82 in the statin group and 28 in the control group). RESULTS: Although there were no significant differences (P > 0.05) in both groups concerning gender, body mass index, antihypertensive pharmacotherapy, and serum levels of high-density lipoprotein cholesterol and triglycerides, a higher BP control was observed in the statin group (P = 0.002). Significantly lower systolic BP (-6.7 mmHg, P = 0.020) and diastolic BP (-6.4 mmHg, P = 0.002) levels were reported in the statin group. Serum levels of low-density lipoprotein were also significantly lower in the statin group (P < 0.001). CONCLUSIONS: This observational study detected an association of statin therapy with BP control in hypertensive hypercholesterolemic patients in clinical practice. These findings raise the possibility that statin therapy may be useful for BP control in the studied population.

Multiple drug exposure as a risk factor for the seriousness of adverse drug reactions.

AIM: The aim of the present study was to validate the hypothesis that multiple drug exposure is an independent risk factor for serious adverse drug reactions (ADRs). BACKGROUND: Adverse drug reactions (ADRs) are an important cause of iatrogenic disease, the majority being preventable. Multiple drug exposure, ageing and female gender have been identified as important risk factors for an increased incidence of ADRs. METHOD: ADR reports received by the central Portugal Regional Pharmacovigilance Unit, between January 2001 and December 2009, were studied. RESULTS: Nearly half (47.4%) of ADRs reports were considered serious, from which 66.7% reported multiple drug exposure (mean 3.07 ± 2.2; maximum 13). After adjusting for gender, simultaneous exposure to three or more drugs was significantly associated with an increased risk of serious ADRs [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.02-1.51]. CONCLUSIONS: The present results support that multiple drug exposure is an independent risk factor for serious ADRs. Such findings are of importance in both medicines benefit/risk ratio evaluations and patient safety monitoring. IMPLICATIONS FOR NURSING MANAGEMENT: A new level of nursing involvement is needed in both the detection of ADRs and prevention of serious outcomes, particularly in high-risk patients.

[Chronic medication in the perioperative period: usage profile and risk management]. / A medicação crónica no período perioperatório: perfil de utilização e gestão de risco.

INTRODUCTION: Currently, an increasing number of surgeries are performed in an older and higher risk population, due to the inherent comorbidity and polypharmacy associated with this population group. The characterization of drug usage profiles in the perioperative period is critically needed to understand the nature of adverse events and to achieve a more efficient iatrogenic risk management. METHODS: During 1 year, all adult patients (>18 years) consecutively admitted for elective surgery at "Cova da Beira" Hospital Center (CHCB) were included in the study. The demographic characteristics, and data on chronic medication use and their administration to the patients in study, in the perioperative period were collected. RESULTS: A total of 404 patients were evaluated. The majority of patients (69.9%) were taking chronic medication (mean 2.5 by admission), mainly "anti-hypertensive" (58.5%) and "psychotropics" (33.5%). 973 drugs were registered as chronic medication. 79.1% of these drugs were withdrawn before the surgery, 10.7% were continued and 7.7% were replaced for another drug of the same therapeutic group. CONCLUSIONS: The majority of patients, admitted for general surgery, take chronic medications, which were withdrawn before surgery, in the majority of cases. Additional assessment of perioperative complications, as result of drug withdrawal, is urgently needed for surgical therapeutic management.

Predictors of uncontrolled hypertension and antihypertensive medication nonadherence.

BACKGROUND: Although hypertension is, in most cases, a controllable major risk factor in the development of cardiovascular disease, studies have demonstrated that hypertension remains poorly controlled in Portugal. Our aim was to evaluate the covariates associated with poor blood pressure (BP) control in a Portuguese hypertensive population. PATIENTS AND RESULTS: We conducted a cross-sectional survey in a hospital hypertension outpatient clinic, located in the Eastern Central Region of Portugal. Patients attending the clinic from July to September 2009 were asked to participate in a structured interview including medication adherence and knowledge about hypertension. Eligible participants were all adults aged 18 or over with an established diagnosis of arterial hypertension and had been on antihypertensive drug treatment for at least 6 months. Exclusion criteria were dementia, pregnancy, and breastfeeding. Detailed clinical information was prospectively obtained from medical records. A total of 197 patients meeting the inclusion criteria and consenting to participate completed the interview. Of these, only 33.0% had their BP controlled according to the JNC 7 guidelines. Logistic regression analysis revealed three independent predictors of poor BP control: living alone (OR = 5.3, P = 0.004), medication nonadherence (OR = 4.8, P < 0.001), and diabetes (OR = 4.4, P = 0.011). Predictors of medication nonadherence were: unawareness of target BP values (OR = 3.7, P < 0.001), a report of drug side effects (OR = 3.7, P = 0.002), lack of BP monitoring (OR = 2.5, P = 0.015) and unawareness of medication indications (OR = 2.4, P = 0.021), and of hypertension risks (OR = 2.1, P = 0.026). CONCLUSIONS: Poor medication adherence, lack of information about hypertension, and side effects should be considered as possible underlying causes of uncontrolled BP and must be addressed in any intervention aimed to improve BP control.

Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel.

PURPOSE: To compare the results of causality assessments of reported adverse drug reactions (ADR's) obtained from decisional algorithms with those obtained from an expert panel using the WHO global introspection method (GI) and to further evaluate the influence of confounding variables on algorithms ability in assessing causality. METHOD: Two hundred sequentially reported ADR's were included in this study. An independent researcher used algorithms, while an expert panel assessed the same reports using the GI, both aimed at evaluating causality. Reports were divided into three groups according to the presence, absence or lack of information on confounding variables. RESULTS: For the total sample, observed agreements between decisional algorithms compared with GI varied from 21% to 56%, average of 47%. When confounding variables were taken into account, agreements varied between 41% and 69%, average of 58%; 8% and 65%, average of 46% and 15% and 53%, average of 42% accordingly to the absence, lack of information or presence of confounding variables, respectively. The extend of reproducibility beyond chance was low for the total sample (average Kappa = 0.26) and within the groups considered. CONCLUSION: The overall observed agreement between algorithm and GI was moderate although poorly different from chance, confounding variables being a shortcoming of algorithms ability in assessing causality.