WISDOM: history and early demise - was it inevitable?

In 1989, the UK Medical Research Council (MRC) agreed that, if feasible, a randomized controlled trial to assess the long-term risks and benefits of hormone replacement therapy (HRT) was a priority. Feasibility work began in 1990 and demonstrated that a large-scale multicenter trial was possible. An application for funding for a main trial was submitted to MRC in 1993 and, after extensive review, funding was released in late 1996. Set-up work for the trial - the Women's International Study of long Duration Oestrogen after Menopause (WISDOM) - began in 1997 with recruitment in 1999. In October 2002, following the early discontinuation of one arm of the US Women's Health Initiative HRT trial, the MRC decided to stop the WISDOM trial. This article, by the principal UK investigators of WISDOM, sets out the background and history of the trial

Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial.

Genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment were examined in 853 men taking part in the lower extremity arterial disease event reduction (LEADER) trial. Three polymorphisms in the peroxisome proliferator activated receptor alpha (PPARalpha) gene were investigated (L162V, G>A in intron 2 and G>C in intron 7), two in the apolipoprotein CIII (APOC3) gene (-482C>T and -455T>C) and one in the beta-fibrinogen (FIBB) gene (-455G>A). The presence of diabetes (n=158) was associated with 15% higher triglyceride levels at baseline compared to non-diabetics (n=654) (PC substitution. In the non-diabetic patients, the PPARalpha V162 allele was significantly associated with 9% higher baseline triglyceride levels (P<0.03) and a similar, but non-significant trend was seen for the intron 7 polymorphism. Overall, triglyceride levels fell by 26% with 3 months of bezafibrate treatment, and current smokers showed a poorer response compared to ex/non-smokers (23% fall compared to 28% P=0.03), but none of the genotypes examined had a significant influence on the magnitude of response. Carriers of the -455A polymorphism of the FIBB gene had, as expected, marginally higher baseline fibrinogen levels, 3.43 versus 3.36 g/l (P=0.055), but this polymorphism did not affect response to treatment. Overall, fibrinogen levels fell by 12%, with patients with the highest baseline fibrinogen levels showing the greatest decrease in response to bezafibrate. For both the intron 2 and the L162V polymorphisms of the PPARalpha gene there was a significant interaction (both P<0.01) between genotype and baseline levels of fibrinogen on the response of fibrinogen levels to bezafibrate, such that individuals carrying the rare alleles in the lowest tertile showed essentially no overall decrease compared to a 0.18 g/l fall in homozygotes for the common allele. Thus while these genotypes are a minor determinant of baseline triglyceride and fibrinogen levels, there is little evidence from this study that the magnitude of response to bezafibrate treatment in men with peripheral vascular disease is determined by variation at these loci

Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions.

BACKGROUND: Lower blood cholesterol concentrations have consistently been found to be strongly associated with lower risks of coronary disease but not with lower risks of stroke. Despite this observation, previous randomised trials had indicated that cholesterol-lowering statin therapy reduces the risk of stroke, but large-scale prospective confirmation has been needed. METHODS: 3280 adults with cerebrovascular disease, and an additional 17256 with other occlusive arterial disease or diabetes, were randomly allocated 40 mg simvastatin daily or matching placebo. Subgroup analyses were prespecified of first "major vascular event" (ie, non-fatal myocardial infarction or coronary death, stroke of any type, or any revascularisation procedure) in prior disease subcategories. Subsidiary outcomes included any stroke, and stroke sub-type. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, "intention-to-treat"), which yielded an average difference in LDL cholesterol of 1.0 mmol/L (39 mg/dL) during the 5-year treatment period. FINDINGS: Overall, there was a highly significant 25% (95% CI 15-34) proportional reduction in the first event rate for stroke (444 [4.3%] simvastatin vs 585 [5.7%] placebo; p<0.0001), reflecting a definite 28% (19-37) reduction in presumed ischaemic strokes (p<0.0001) and no apparent difference in strokes attributed to haemorrhage (51 [0.5%] vs 53 [0.5%]; rate ratio 0.95 [0.65-1.40]; p=0.8). In addition, simvastatin reduced the numbers having transient cerebral ischaemic attacks alone (2.0% vs 2.4%; p=0.02) or requiring carotid endarterectomy or angioplasty (0.4% vs 0.8%; p=0.0003). The reduction in stroke was not significant during the first year, but was already significant (p=0.0004) by the end of the second year. Among patients with pre-existing cerebrovascular disease there was no apparent reduction in the stroke rate, but there was a highly significant 20% (8-29) reduction in the rate of any major vascular event (406 [24.7%] vs 488 [29.8%]; p=0.001). The proportional reductions in stroke were about one-quarter in each of the other subcategories of participant studied, including: those with coronary disease or diabetes; those aged under or over 70 years at entry; and those presenting with different levels of blood pressure or lipids (even when the pretreatment LDL cholesterol was below 3.0 mmol/L [116 mg/dL]). INTERPRETATION: Much larger numbers of people in the present study suffered a stroke than in any previous cholesterol-lowering trial. The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events but also of ischaemic strokes, with no apparent effect on cerebral haemorrhage, even among individuals who do not have high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of ischaemic strokes by about one-quarter and so, after making allowance for non-compliance in the trial, actual use of this regimen would probably reduce the stroke rate by about a third. HPS also provides definitive evidence that statin therapy is beneficial for people with pre-existing cerebrovascular disease, even if they do not already have manifest coronary disease

Prolonged dual anti-platelet therapy in stable coronary disease: a comparative observational study of benefits and harms in unselected versus trial populations

Objective: To estimate the potential magnitude in unselected patients of the benefits and harms of prolonged dual antiplatelet therapy after acute myocardial infarction seen in selected patients with high risk characteristics in trials. Design: Observational population based cohort study. Setting: PEGASUS-TIMI-54 trial population and CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records). Participants: 7238 patients who survived a year or more after acute myocardial infarction. Interventions: Prolonged dual antiplatelet therapy after acute myocardial infarction. Main outcome measures: Recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease. Fatal, severe, or intracranial bleeding. Results: 1676/7238 (23.1%) patients met trial inclusion and exclusion criteria (“target” population). Compared with the placebo arm in the trial population, in the target population the median age was 12 years higher, there were more women (48.6% v 24.3%), and there was a substantially higher cumulative three year risk of both the primary (benefit) trial endpoint of recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease (18.8% (95% confidence interval 16.3% to 21.8%) v 9.04%) and the primary (harm) endpoint of fatal, severe, or intracranial bleeding (3.0% (2.0% to 4.4%) v 1.26% (TIMI major bleeding)). Application of intention to treat relative risks from the trial (ticagrelor 60 mg daily arm) to CALIBER’s target population showed an estimated 101 (95% confidence interval 87 to 117) ischaemic events prevented per 10 000 treated per year and an estimated 75 (50 to 110) excess fatal, severe, or intracranial bleeds caused per 10 000 patients treated per year. Generalisation from CALIBER’s target subgroup to all 7238 real world patients who were stable at least one year after acute myocardial infarction showed similar three year risks of ischaemic events (17.2%, 16.0% to 18.5%), with an estimated 92 (86 to 99) events prevented per 10 000 patients treated per year, and similar three year risks of bleeding events (2.3%, 1.8% to 2.9%), with an estimated 58 (45 to 73) events caused per 10 000 patients treated per year. Conclusions: This novel use of primary-secondary care linked electronic health records allows characterisation of “healthy trial participant” effects and confirms the potential absolute benefits and harms of dual antiplatelet therapy in representative patients a year or more after acute myocardial infarction

Cancer recording and mortality in the General Practice Research Database and linked cancer registries.

PURPOSE: Large electronic datasets are increasingly being used to evaluate healthcare delivery. The aim of this study was to compare information held by cancer registries with that of the General Practice Research Database (GPRD). METHODS: A convenience sample of 101 020 patients aged 40+ years drawn from GPRD formed the primary data source. This cohort was derived from a larger sample originally established for a cohort study of diabetes. GPRD records were linked with those from cancer registries in the National Cancer Data Repository (NCDR). Concordance between the two datasets was then evaluated. For cases recorded only on one dataset, validation was sought from other datasets (Hospital Episode Statistics and death registration) and by detailed analysis of a subset of GPRD records. RESULTS: A total of 5797 cancers (excluding non-melanomatous skin cancer) were recorded on GPRD. Of these cases, 4830 were also recorded on NCDR (concordance rate of 83.3%). Of the 976 cases recorded on GPRD but not on NCDR, 528 were present also in the hospital records or death certificates. Of the 341 cases recorded on NCDR but not on GPRD, 307 were recorded in these other two datasets. Rates of concordance varied by cancer type. Cancer registries recorded larger numbers of patients with lung, colorectal, and pancreatic cancers, whereas GPRD recorded more haematological cancers and melanomas. As expected, GPRD recorded significantly more non-melanomatous skin cancer. Concordance decreased with increasing age. CONCLUSION: Although concordance levels were reasonably high, the findings from this study can be used to direct efforts for better recording in both datasets

Bleeding Risk, Physical Functioning, and Non-use of Anticoagulation Among Patients with Stroke and Atrial Fibrillation

Background: Atrial fibrillation (AF) is common among people with stroke. Anticoagulation medications can be used to manage the deleterious impact of AF after stroke, however may not be prescribed due to concerns about post-stroke falls and decreased functioning. Thus, the purpose of this study was to identify, among people with stroke and AF, predictors of anticoagulation prescription at hospital discharge. Methods: This is a secondary analysis of a retrospective cohort study of data retrieved via medical records, including: National Institutes of Health Stroke Scale score; Functional Independence Measure (FIM) motor score (motor or physical function); ambulation on 2nd day of hospitalization; Morse Falls Scale (fall risk); and HAS-BLED score (Hypertension; Abnormal renal and liver function; Stroke; Bleeding; Labile INRs; Elderly > 65; and Drugs or alcohol). Data analyses included bivariate comparisons between people with and without anticoagulation at discharge. Logistic-regression modeling was used to assess predictors of discharge anti-coagulation. Results: There were 334 subjects included in the analyses, average age was 75 years old. Anticoagulation was prescribed at discharge for 235 (70%) of patients. In the adjusted regression analyses, only the FIM motor score (adjusted OR = 1.015, 95%CI 1.001-1.028) and the HAS-BLED score (adjusted OR = 0.36, 95%CI 0.22-0.58) were significantly associated with anticoagulation prescription at discharge. Conclusion: It appears that in this sample, post-stroke anti-coagulation decisions appear to be made based on clinical factors associated with bleed risk and motor deficits or physical functioning. However, opportunities may exist for improving clinician documentation of specific reasoning for non-anticoagulation prescription

Patient recruitment, feasibility evaluations and use of electronic health records in clinical trials - A Nordic approach

Clinical trials constitute an important cornerstone for the development of new drugs. Patient recruitment is one of the main challenges in clinical trials. Pharmaceutical companies apply feasibility evaluations to identify potential countries, investigators and study sites for their trials and to evaluate their potential for successful patient recruitment. Electronic health records (EHR) maintained by health care providers are regarded as one potential tool for improving patient identification and recruitment for clinical trials. This study investigated patient recruitment and trial feasibility evaluations in the Nordic countries and the role and usability of EHR data in those processes. The pharmaceutical industry’s view was investigated by conducting semi-structured qualitative interviews of 21 respondents from Finland, Sweden, Norway and Denmark. Additionally, the usability of one commercial EHR research platform for identifying patients from Turku University Hospital’s EHR system was tested in comparison with a manual search. The success or failure of patient recruitment was influenced by many sponsorrelated, investigator/site-related, patient-related, collaboration-related and start-uprelated factors. Most trials had recruited their patients by reviewing the hospitals’ EHR data, but its use was much less frequent already during the feasibility evaluation phase. Feasibility evaluation was found to be a complex and time-consuming process for estimating the number of potential trial patients. The sponsors did not use HER tools for such evaluations, mainly because of legislative barriers. Although the HER data search tools have limitations in accuracy, they were seen to have great potential for identifying trial participants from the hospital EHR, for example by reducing the manual work. The comprehensive data in the EHR systems in the Nordic countries offer a possibility for more accurate identification of trial participants in the feasibility evaluations and may thus contribute to the success of recruitment. The data protection legislation and its interpretation should be harmonized for the use of EHR data. Continuous improvements in the EHR systems’ technical accuracy and data quality will be needed to enhance the successful use of EHR data in future clinical trials.Potilasrekrytointi, toteutettavuuden arviointi ja elektronisten potilastietojärjestelmien hyödyntäminen kliinisissä tutkimuksissa – Pohjoismainen näkökulma Kliiniset lääketutkimukset ovat uusien lääkkeiden kehityksen kulmakivi. Tutkimuspotilaiden rekrytointi on merkittävä haaste näissä tutkimuksissa. Lääkeyritykset tekevät toteutettavuusarviointeja tunnistaakseen potentiaalisia tutkimukseen osallistuvia maita, tutkijoita ja tutkimuskeskuksia ja arvioidakseen niiden mahdollisuuksia onnistua potilaiden rekrytoinnissa. Terveydenhuolto-organisaatioiden ylläpitämät elektroniset potilastietojärjestelmät (EHR) ovat tässä eräs mahdollinen työkalu. Tässä tutkimuksessa tutkittiin potilaiden rekrytointia ja tutkimusten toteutettavuusarviointeja Pohjoismaissa ja EHR:n roolia ja käytettävyyttä näissä prosesseissa. Näitä tekijöitä tekijöitä tutkittiin lääketeollisuuden näkökulmasta laadullisilla teemahaastatteluilla (21 haastateltavaa Suomesta, Ruotsista, Norjasta ja Tanskasta). Yhden kaupallisesti saatavilla olevan EHR-hakutyökalun tarkkuutta halutun potilasjoukon löytämisessä verrattiin perinteiseen, manuaaliseen hakuun Turun yliopistollisen sairaalan potilastietojärjestelmästä. Potilaiden rekrytoinnin onnistumiseen tai epäonnistumiseen vaikutti moni toimeksiantajaan, tutkijaan/tutkimuskeskukseen, potilaaseen ja tutkimuksen aloitustoimenpiteisiin liittyvä tekijä sekä näiden tahojen yhteistyö. Valtaosassa tutkimuksista tutkittavat rekrytoitiin keskuksen omista potilaista EHR:a hyödyntäen, mutta EHR:n käyttö potilasmäärän arvioinnissa ennen tutkimuksen alkua oli vähäistä. Toteutettavuusarvioinneissa tehdyt potilasmäärien arviot nähtiin monimutkaisina ja aikaa vievinä prosesseina. Toimeksiantajat eivät käyttäneet EHRtyökaluja lainkaan, pääasiassa tietosuojalainsäädäntöön liittyvistä syistä. Vaikka EHR-hakutyökalujen tarkkuudella on rajoitteensa, niitä voidaan hyödyntää esimerkiksi vähentämään manuaalista työtä potilaiden identifioinnissa. Terveydenhuollon kattavat EHR-järjestelmät tarjoavat Pohjoismaissa hyvän mahdollisuuden tutkimuspotilaiden tarkempaan identifiointiin, joka omalta osaltaan vaikuttaa rekrytoinnin onnistumismahdollisuuksiin. Tietosuojalainsäädäntöä ja sen tulkintoja on harmonisoitava EHR:n käytön hyödyntämiseksi. EHR-hakujen teknistä tarkkuutta ja tiedon laatua on edelleen parannettava sen menestyksekkään käytön lisäämiseksi tulevaisuuden kliinisissä tutkimuksissa