Alternative cascade-testing protocols for identifying and managing patients with familial hypercholesterolaemia: systematic reviews, qualitative study and cost-effectiveness analysis.

Background: Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective. Objectives: The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers. Design and methods: This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals. Result: Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (p < 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable. Limitations: Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants. Conclusions: Based on limited evidence, most cost-effective cascade-testing protocols, diagnosing most relatives, select index cases by genetic testing, with services directly contacting relatives, and contacting second-degree relatives even if first-degree relatives have not been tested. Combined approaches to contact relatives may be more suitable for some families. Future work: Establish a long-term familial hypercholesterolaemia cohort, measuring cholesterol levels, treatment and cardiovascular outcomes. Conduct a randomised study comparing different approaches to contact relatives. Study registration: This study is registered as PROSPERO CRD42018117445 and CRD42019125775. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 16. See the NIHR Journals Library website for further project information.

Familial hypercholesterolaemia is an inherited condition that causes raised cholesterol levels from birth and increases risk of heart disease if left untreated. After someone in a family is found to have familial hypercholesterolaemia (called an index case), their close relatives need to be contacted and checked to see if they have familial hypercholesterolaemia, using genetic or cholesterol testing. This is called 'cascade testing'. We planned to find the most cost-effective and acceptable way to do this. The relatives could be contacted for testing by the index case (indirect approach), by a health-care professional (direct approach) or by a combination of both approaches. We found, based on looking at hospital records, that more relatives were tested if health-care professionals directly contacted relatives. In previous studies, slightly more relatives were tested for familial hypercholesterolaemia with a combination approach. Interviews with patients also suggested that the direct approach was the most effective, but the most acceptable and successful approach depends on family relationships: using one approach for some families and using both for other families. Furthermore, by looking at the health-care records of large numbers of patients, we confirmed that people with a recorded diagnosis of familial hypercholesterolaemia in general practice records have a much higher risk of heart disease than the general population, and this was especially so for those with previous heart disease and/or raised cholesterols levels when diagnosed. However, one-quarter of new patients with familial hypercholesterolaemia recorded in their records were not treated within 2 years, with less than one-third reaching recommended cholesterol levels. We used what we had learned to help us estimate the most cost-effective way to do cascade testing. This showed that if the health service directly contact all relatives simultaneously for further assessment, rather than the current approach whereby close (first-degree) relatives are contacted first, this was cost-effective and good value for money.

Frequency and impact of medication reviews for people aged 65 years or above in UK primary care: an observational study using electronic health records.

BACKGROUND: Medication reviews in primary care provide an opportunity to review and discuss the safety and appropriateness of a person's medicines. However, there is limited evidence about access to and the impact of routine medication reviews for older adults in the general population, particularly in the UK. We aimed to quantify the proportion of people aged 65 years and over with a medication review recorded in 2019 and describe changes in the numbers and types of medicines prescribed following a review. METHODS: We used anonymised primary care electronic health records from the UK's Clinical Practice Research Datalink (CPRD GOLD) to define a population of people aged 65 years or over in 2019. We counted people with a medication review record in 2019 and used Cox regression to estimate associations between demographic characteristics, diagnoses, and prescribed medicines and having a medication review. We used linear regression to compare the number of medicines prescribed as repeat prescriptions in the three months before and after a medication review. Specifically, we compared the 'prescription count' - the maximum number of different medicines with overlapping prescriptions people had in each period. RESULTS: Of 591,726 people prescribed one or more medicines at baseline, 305,526 (51.6%) had a recorded medication review in 2019. Living in a care home (hazard ratio 1.51, 95% confidence interval 1.40-1.62), medication review in the previous year (1.83, 1.69-1.98), and baseline prescription count (e.g. 5-9 vs 1 medicine 1.41, 1.37-1.46) were strongly associated with having a medication review in 2019. Overall, the prescription count tended to increase after a review (mean change 0.13 medicines, 95% CI 0.12-0.14). CONCLUSIONS: Although medication reviews were commonly recorded for people aged 65 years or over, there was little change overall in the numbers and types of medicines prescribed following a review. This study did not examine whether the prescriptions were appropriate or other metrics, such as dose or medicine changes within the same class. However, by examining the impact of medication reviews before the introduction of structured medication review requirements in England in 2020, it provides a useful benchmark which these new reviews can be compared with.

Retrospective review of medication-related incidents at a major teaching hospital and the potential mitigation of these incidents with electronic prescribing and medicines administration.

OBJECTIVES: To describe the frequency of the different types of medication-related incidents that caused patient harm, or adverse consequences, in a major teaching hospital and investigate whether the likelihood of these incidents occurring would have been reduced by electronic prescribing and medicines administration (EPMA). METHODS: A retrospective review of harmful incidents (n=387) was completed for medication-related reports at the hospital between 1 September 2020 and 31 August 2021. Frequencies of different types of incidents were collated. The potential for EPMA to have prevented these incidents was assessed by reviewing DATIX reports and additional information, including results of any investigations. RESULTS: The largest proportion of harmful medication incidents were administration related (n=215, 55.6%), followed by incidents classified as 'other' and 'prescribing'. Most incidents were classified as low harm (n=321, 83.0%). EPMA could have reduced the likelihood of all incidents which caused harm by 18.6% (n=72) without configuration, and a further 7.5% (n=29) with configuration where configuration refers to adapting the software's functionality without supplier input or development. For 18.4% of the low-harm incidents (n=59) and 20.3% (n=13) of the moderate-harm incidents, EPMA could reduce the likelihood of the incident occurring without configuration. Medication errors most likely to be reduced by EPMA were due to illegibility, multiple drug charts or missing drug charts. CONCLUSION: This study found that administration incidents were the most common type of medication-related incidents. Most of the incidents (n=243, 62.8%) could not be mitigated by EPMA in any circumstance, even with connectivity between technologies. EPMA has the potential to prevent certain types of harmful medication-related incidents, and further improvements could be achieved with configuration and development.

How does cholesterol burden change the case for investing in familial hypercholesterolaemia? A cost-effectiveness analysis.

BACKGROUND AND AIMS: This study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and 'cholesterol burden', which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk. METHODS: A new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history. RESULTS: If cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history. If cholesterol burden is not considered, diagnosis resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L. CONCLUSIONS: Diagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history.

Cardiovascular outcomes and mortality after incident ischaemic stroke in patients with a recent cancer history.

BACKGROUND: Up to 10% of patients with ischaemic stroke have comorbid cancer and stroke in these patients is thought to have a poor short-term prognosis. There is little known about the long-term cardiovascular morbidity and mortality outcomes after incident ischaemic stroke in patients with recent cancer history. OBJECTIVE: To assess the risk of subsequent cardiovascular morbidity and mortality outcomes in patients with an incident ischaemic stroke and recent cancer history. METHODS: Patients aged ≥18 years with an incident ischaemic stroke between 1998 and 2017, with any diagnosis of cancer within 12 months before the stroke event, and no prior history of serious vascular event were identified from UK Clinical Practice Research Datalink (CPRD GOLD) linked to Hospital Episode Statistics (HES) data. To minimize selection bias, these patients were propensity-score matched with patients with incident ischaemic stroke and no history of cancer. Propensity-score matching was done using covariates such as demographic data, vascular risk factors, comorbid conditions, and prescribed medication. Multivariable models (Competing risks and Cox regression) were used to determine the risk of subsequent major adverse cardiovascular event (MACE) outcomes and all-cause mortality. RESULTS: Our cohort included 22,460 patients with a median age of 75 (IQR 64-83) years and a follow-up of 12.3 (IQR 7.2-16.7) years. Recent cancer was identified in 1,149 patients (5.1%) at the time of incident ischaemic stroke. The patients with recent cancer history had a lower risk of composite MACE (sub-distribution hazard ratio (SHR) 0.83 [95% CI: 0.75-0.92]) and recurrent stroke (SHR 0.85 95% CI:0.75-0.96]) and a higher risk of all-cause mortality (hazard ratio 1.67 [95% CI:1.47-1.91]). The risk of coronary heart disease, peripheral vascular disease, heart failure, and CVD-related death outcomes did not differ significantly between the groups. CONCLUSIONS: After incident ischaemic stroke, patients with recent cancer history have a lower risk of composite MACE and recurrent stroke outcomes but a higher risk of all-cause mortality when compared with patients without a prior history of cancer.

Comparison of Risk of Serious Cardiovascular Events after Hemorrhagic versus Ischemic Stroke: A Population-Based Study.

BACKGROUND: Patients with ischemic stroke are considered a very high risk population for subsequent cardiovascular events and guidelines recommend intensive preventive strategies. However, there is no clear recommendation that patients with hemorrhagic stroke should also be regarded as a very high cardiovascular risk population. OBJECTIVE: To compare the risk of subsequent cardiovascular morbidity/mortality between patients with incident hemorrhagic and ischemic stroke. METHODS: Patients aged ≥18 years with incident hemorrhagic or ischemic stroke between 1998 and 2017 and no prior history of serious vascular event were identified from UK Clinical Practice Research Datalink (CPRD GOLD) linked to Hospital Episode Statistics data. RESULTS: The cohort included 32,091 patients with an overall follow-up of 381,237 person-years (median: 11.8 years). After adjusting for potential confounders, patients with incident hemorrhagic stroke had no significantly different risk of subsequent cardiovascular morbidity compared with patients with incident ischemic stroke-coronary heart disease (CHD; hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.32), recurrent stroke (HR: 0.92, 95% CI: 0.83-1.02), peripheral vascular disease (PVD; HR: 1.15, 95% CI:0.56-2.38), or heart failure (HR: 1.03, 95% CI: 0.61-1.74). Patients with incident hemorrhagic stroke had significantly higher risk of subsequent cardiovascular disease (CVD)-related mortality (HR: 2.35, 95% CI: 2.04-2.72) and all-cause mortality (HR: 2.16, 95% CI: 1.94-2.41). Propensity-score matched analysis of 1,039 patients with hemorrhagic stroke and 1,039 with ischemic stroke showed similar risk in subsequent cardiovascular morbidity-CHD (stratified HR [sHR]: 0.92, 95% CI: 0.55-1.54), recurrent stroke (sHR: 0.93, 95% CI: 0.82-1.02), PVD (sHR: 1.04 95% CI: 0.45-2.41), or heart failure (sHR: 0.71, 95% CI: 0.39-1.27). CONCLUSION: The risk of subsequent cardiovascular events is similar between patients with incident hemorrhagic and ischemic stroke. Patients with previous hemorrhagic stroke should be regarded as a population at very high risk for subsequent CVD.

Determining propensity for sub-optimal low-density lipoprotein cholesterol response to statins and future risk of cardiovascular disease.

BACKGROUND: Variability in low-density lipoprotein cholesterol (LDL-C) response to statins is underappreciated. We characterised patients by their statin response (SR), baseline risk of cardiovascular disease (CVD) and 10-year CVD outcomes. METHODS AND RESULTS: A multivariable model was developed using 183,213 United Kingdom (UK) patients without CVD to predict probability of sub-optimal SR, defined by guidelines as <40% reduction in LDL-C. We externally validated the model in a Hong Kong (HK) cohort (n = 170,904). Patients were stratified into four groups by predicted SR and 10-year CVD risk score: [SR1] optimal SR & low risk; [SR2] sub-optimal SR & low risk; [SR3] optimal SR & high risk; [SR4] sub-optimal SR & high risk; and 10-year hazard ratios (HR) determined for first major adverse cardiovascular event (MACE). Our SR model included 12 characteristics, with an area under the curve of 0.70 (95% confidence interval [CI] 0.70-0.71; UK) and 0.68 (95% CI 0.67-0.68; HK). HRs for MACE in predicted sub-optimal SR with low CVD risk groups (SR2 to SR1) were 1.39 (95% CI 1.35-1.43, p<0.001; UK) and 1.14 (95% CI 1.11-1.17, p<0.001; HK). In both cohorts, patients with predicted sub-optimal SR with high CVD risk (SR4 to SR3) had elevated risk of MACE (UK HR 1.36, 95% CI 1.32-1.40, p<0.001: HK HR 1.25, 95% CI 1.21-1.28, p<0.001). CONCLUSIONS: Patients with sub-optimal response to statins experienced significantly more MACE, regardless of baseline CVD risk. To enhance cholesterol management for primary prevention, statin response should be considered alongside risk assessment.

Statin treatment and LDL-cholesterol treatment goal attainment among individuals with familial hypercholesterolaemia in primary care.

OBJECTIVES: Guidance recommends statin treatment in familial hypercholesterolaemia (FH) to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). We assessed statin prescribing rates and LDL-C treatment goal attainment among individuals with FH in primary care. METHODS: Using primary care electronic health records from the UK Clinical Practice Research Datalink, we identified adults with recorded diagnosis of FH, statin treatment and measures of LDL-C prior to (baseline) and 12 months after initiating statin treatment. The percentage change in LDL-C was determined, and then baseline and treatment characteristics were assessed by LDL-C treatment goal attainment. RESULTS: Of 3064 adults (mean age 50.8 years) with recorded diagnosis of FH and repeat LDL-C measures, 50% reduction in LDL-C from baseline was attained in 895 individuals (29.2%) in 12 months. Compared with those who did not attain this goal, these people were predominantly women; they were older at time of FH diagnosis (53.4 years vs 49.7 years) and first statin treatment (53.2 years vs 49.2 years) and had higher pretreatment total cholesterol (8.20 (SD 1.38) mmol/L vs 7.57 (SD 1.39) mmol/L) and pretreatment LDL-C (5.83 (SD 1.36) mmol/L vs 5.25 (SD 1.40) mmol/L). A higher proportion of individuals who attained the treatment goal was prescribed high-potency and medium-potency statins (24.3% and 71.7% vs 20.2% and 69.3%, respectively). CONCLUSIONS: Less than a third of individuals on statin treatment for FH in the community achieve recommended reductions in LDL-C. Greater awareness and optimisation of treatment for FH using higher-potency statins are needed.

Obesity and long-term outcomes after incident stroke: a prospective population-based cohort study.

BACKGROUND: The association between obesity, major adverse cardiovascular events (MACE), and mortality in patients with incident stroke is not well established. We assessed the relationship between body mass index (BMI) and MACE in patients with incident stroke. METHODS: The population-based cohort study identified 30 702 individuals from the Clinical Practice Research Datalink (CPRD GOLD) and Hospital Episode Statistics (HES) databases from the United Kingdom. Individuals were aged ≥18 years with incident stroke between 1-1-1998 and 31-12-2017, a BMI recorded within 24 months before incident stroke, and no prior history of MACE. BMI was categorized as underweight (<18.5 kg/m2 ), normal (18.5-24.9 kg/m2 ), overweight (25.0-29.9 kg/m2 ), obesity class I (30.0-34.9 kg/m2 ), class II (35.0-39.9 kg/m2 ) and class III (≥40 kg/m2). MACE was defined as a composite of incident coronary heart disease, recurrent stroke, peripheral vascular disease (PVD), heart failure, and cardiovascular-related mortality. Multivariable Cox regression was used to assess differences in MACE risk between BMI categories. RESULTS: At baseline, 1217 (4.0%) were underweight, 10 783 (35.1%) had a normal BMI, 10 979 (35.8%) had overweight, 5206 (17.0%) had obesity Class I, 1749 (5.7%) Class II, and 768 (2.5%) Class III. In multivariable analysis, higher BMI were associated with lower risk of subsequent MACE [overweight: HR 0.96, 95% CI 0.93-0.99)]; PVD [overweight: 0.65 (0.49-0.85); obesity Class III: 0.19 (0.50-0.77)]; cardiovascular-related death [overweight: 0.80 (0.74-0.86); obesity Class I: 0.79 (0.71-0.88); Class II: 0.80 (0.67-0.96)]; and all-cause mortality [overweight: 0.75 (0.71-0.79); obesity Class I: 0.75 (0.70-0.81); Class II: 0.77 (0.68-0.86)] when compared to those with normal BMI. The results were similar irrespective of sex, diabetes mellitus, smoking or cancer at time of incident stroke. CONCLUSIONS: In patients with incident stroke, overweight or obesity were associated with a more favourable prognosis for subsequent MACE, PVD, and mortality, irrespective of sex, diabetes mellitus, smoking, or cancer at baseline. As with other cohort studies, our study demonstrates an association. Randomized control trials should be considered to robustly evaluate the impact of weight management recommendations on subsequent cardiovascular outcomes in stroke survivors.

Long-term body mass index changes in overweight and obese adults and the risk of heart failure, cardiovascular disease and mortality: a cohort study of over 260,000 adults in the UK.

BACKGROUND: Although obesity is a well-recognised risk factor for cardiovascular disease (CVD), the impact of long-term body mass index (BMI) changes in overweight or obese adults, on the risk of heart failure, CVD and mortality has not been quantified. METHODS: This population-based cohort study used routine UK primary care electronic health data linked to secondary care and death-registry records. We identified adults who were overweight or obese, free from CVD and who had repeated BMI measures. Using group-based trajectory modelling, we examined the BMI trajectories of these individuals and then determined incidence rates of CVD, heart failure and mortality associated with the different trajectories. Cox-proportional hazards regression determined hazards ratios for incident outcomes. RESULTS: 264,230 individuals (mean age 49.5 years (SD 12.7) and mean BMI 33.8 kg/m2 (SD 6.1)) were followed-up for a median duration of 10.9 years. Four BMI trajectories were identified, corresponding at baseline, with World Health Organisation BMI classifications for overweight, class-1, class-2 and class-3 obesity respectively. In all four groups, there was a small, stable upwards trajectory in BMI (mean BMI increase of 1.06 kg/m2 (± 3.8)). Compared with overweight individuals, class-3 obese individuals had hazards ratios (HR) of 3.26 (95% CI 2.98-3.57) for heart failure, HR of 2.72 (2.58-2.87) for all-cause mortality and HR of 3.31 (2.84-3.86) for CVD-related mortality, after adjusting for baseline demographic and cardiovascular risk factors. CONCLUSION: The majority of adults who are overweight or obese retain their degree of overweight or obesity over the long term. Individuals with stable severe obesity experience the worst heart failure, CVD and mortality outcomes. These findings highlight the high cardiovascular toll exacted by continuing failure to tackle obesity.

Sex differences in cardiovascular morbidity associated with familial hypercholesterolaemia: A retrospective cohort study of the UK Simon Broome register linked to national hospital records.

BACKGROUND AND AIMS: The UK Simon Broome (SB) familial hypercholesterolaemia (FH) register previously reported 3-fold higher standardised mortality ratio for cardiovascular disease (CVD) in women compared to men from 2009 to 2015. Here we examined sex differences in CVD morbidity in FH by national linkage of the SB register with Hospital Episode Statistics (HES). METHODS: Of 3553 FH individuals in the SB register (aged 20-79 years at registration), 2988 (52.5% women) had linked HES records. Standardised Morbidity Ratios (SMbR) compared to an age and sex-matched UK general practice population were calculated [95% confidence intervals] for first CVD hospitalisation in HES (a composite of coronary heart disease (CHD), myocardial infarction (MI), stable or unstable angina, stroke, TIA, peripheral vascular disease (PVD), heart failure, coronary revascularisation interventions). RESULTS: At registration, men had significantly (p < 0.001) higher prevalence of previous CHD (24.8% vs 17.6%), previous MI (13.2% vs 6.3%), and were commenced on lipid-lowering treatment at a younger age than women (37.5 years vs 42.3 years). The SMbR for composite CVD was 6.83 (6.33-7.37) in men and 7.55 (6.99-8.15) in women. In individuals aged 30-50 years, SMbR in women was 50% higher than in men (15.04 [12.98-17.42] vs 10.03 [9.01-11.17]). In individuals >50 years, SMbR was 33% higher in women than men (6.11 [5.57-6.70] vs 4.59 [4.08-5.15]). CONCLUSIONS: Excess CVD morbidity due to FH remains markedly elevated in women at all ages, but especially those aged 30-50 years. This highlights the need for earlier diagnosis and optimisation of lipid-lowering risk factor management for all FH patients, with particular attention to young women with FH.

Is the apparently protective effect of maternal nicotine replacement therapy (NRT) used in pregnancy on infant development explained by smoking cessation?: secondary analyses of a randomised controlled trial.

OBJECTIVE: To investigate relationships between maternal smoking status in pregnancy and infant development. The largest randomised controlled trial of nicotine replacement therapy (NRT) for smoking cessation in pregnancy, the smoking, nicotine and pregnancy (SNAP) trial, found that at 1 month after randomisation, smoking cessation rates were doubled in the NRT group compared with the placebo group. At delivery, there was no significant difference in cessation rates between groups. Surprisingly, infants born to women randomised to NRT were more likely to have unimpaired development at 2 years. We hypothesised that this apparently protective effect was due to smoking cessation caused by NRT and so, investigate this relationship using the same cohort. DESIGN: Secondary analysis of a randomised controlled trial. SETTING: Seven antenatal hospitals in the Midlands and North-West England. PARTICIPANTS: Eight hundred and eighty-four pregnant smokers randomised to receive either NRT patches or visually-identical placebo in the SNAP trial. Participants' smoking behaviour were recorded at randomisation, 1 month after their target quit date and at delivery. METHODS: Using logistic regression models, we investigated associations between participants' smoking measures and infant development (assessed using the Ages and Stages questionnaire) at 2 years. MAIN OUTCOME MEASURES: 2 year infant development. RESULTS: Developmental impairment was reported for 12.7% of study 2 year olds. Maternal heaviness of smoking at randomisation (OR: 1.26, 95% CI: 0.82 to 1.96, p=0.091), validated smoking abstinence recorded at 1 month after a quit date (OR: 1.02, 95% CI: 0.60 to 1.74, p=0.914) and validated smoking abstinence recorded at both 1 month after a quit date and at the end of pregnancy (OR: 1.52, 95% CI: 0.81 to 2.85, p=0.795) were not independently associated with infant developmental impairment at 2 years. CONCLUSION: We found no evidence that NRT treatment improved infants' developmental outcomes through smoking cessation. TRIAL REGISTRATION NUMBER: CTA03057/0002/001-0001; Post-results.

Risk of cardiovascular disease outcomes in primary care subjects with familial hypercholesterolaemia: A cohort study.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is a known major cause of premature heart disease. However, the risks of atherosclerotic disease in other vascular regions are less known. We determined the risk of major cardiovascular disease (CVD) outcomes associated with clinical FH. METHODS: In a retrospective cohort study (1 January, 1999 to 22 July, 2016), we randomly-matched 14,097 UK subjects with clinical FH diagnoses or characteristics (Simon-Broome definite or Dutch Lipid Clinic Score >8) to 42,506 subjects without FH by age, sex, general practice. We excluded those with CVD at baseline. Incident rates for coronary heart disease (CHD), stroke or transient ischaemic attack (TIA) and peripheral vascular disease (PVD) were estimated. Cox proportional hazards regression, stratified on matched-pairs, determined adjusted hazards ratios (HR) for incident CVD. RESULTS: During follow-up (median 13.8 years), incidence rates (95% CI) of CVD (per 1000 person-years) were 25.6 (24.8-26.3) in FH and 2.9 (2.8-3.1) in non-FH subjects. The risk of CHD, stroke/TIA and PVD was higher in FH compared to non-FH subjects: CHD (HR 10.63, 95% CI 9.82-11.49), stroke/TIA (HR 6.74, 95% CI 5.84-7.77), PVD (HR 7.17, 95% CI 6.08-8.46). The risk of CVD was greater in those with FH characteristics (HR 13.52, 95% CI 12.48-14.65) than those with clinical diagnoses (HR 1.66, 95% CI 1.42-1.93). CONCLUSIONS: In addition to the recognised increased risk of CHD, subjects with FH have greatly elevated risk of stroke/TIA and PVD. This emphasises need for early diagnosis and preventive interventions beyond CHD, to reduce CVD risk in these individuals.

Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease.

OBJECTIVE: To assess low-density lipoprotein cholesterol (LDL-C) response in patients after initiation of statins, and future risk of cardiovascular disease (CVD). METHODS: Prospective cohort study of 165 411 primary care patients, from the UK Clinical Practice Research Datalink, who were free of CVD before statin initiation, and had at least one pre-treatment LDL-C within 12 months before, and one post-treatment LDL-C within 24 months after, statin initiation. Based on current national guidelines, <40% reduction in baseline LDL-C within 24 months was classified as a sub-optimal statin response. Cox proportional regression and competing-risks survival regression models were used to determine adjusted hazard ratios (HRs) and sub-HRs for incident CVD outcomes for LDL-C response to statins. RESULTS: 84 609 (51.2%) patients had a sub-optimal LDL-C response to initiated statin therapy within 24 months. During 1 077 299 person-years of follow-up (median follow-up 6.2 years), there were 22 798 CVD events (12 142 in sub-optimal responders and 10 656 in optimal responders). In sub-optimal responders, compared with optimal responders, the HR for incident CVD was 1.17 (95% CI 1.13 to 1.20) and 1.22 (95% CI 1.19 to 1.25) after adjusting for age and baseline untreated LDL-C. Considering competing risks resulted in lower but similar sub-HRs for both unadjusted (1.13, 95% CI 1.10 to 1.16) and adjusted (1.19, 95% CI 1.16 to 1.23) cumulative incidence function of CVD. CONCLUSIONS: Optimal lowering of LDL-C is not achieved within 2 years in over half of patients in the general population initiated on statin therapy, and these patients will experience significantly increased risk of future CVD.