Post-trial Follow-up Period Research Articles

P-761 Live-birth and neonatal outcomes from BEYOND, a randomised controlled trial comparing efficacy and safety of individualised follitropin delta dosing in GnRH agonist versus antagonist protocols

Abstract Study question What are the live birth and neonatal outcomes following an individualised follitropin delta dosing regimen in either a long GnRH agonist or GnRH antagonist protocol? Summary answer Live birth rates and neonatal outcomes were similar, supporting the efficacy and safety of follitropin delta in both GnRH agonist and antagonist protocols. What is known already Follitropin delta is used for ovarian stimulation and is administered as a fixed daily dose, individualised based on bodyweight and anti-Müllerian (AMH) levels. Registrational trials for follitropin delta used a GnRH antagonist protocol. Preliminary study data shows that individualized follitropin delta is efficacious when used with a long GnRH agonist protocol (RAINBOW trial); however, there is no comparative data for the effects on live birth rates and neonatal outcomes with individualised follitropin delta in a long GnRH agonist versus an antagonist protocol. Study design, size, duration This RCT compared the efficacy and safety of individualised follitropin delta dosing using a long GnRH agonist versus an antagonist protocol and was conducted between May 2019 and February 2022. The trial was designed to describe potential differences in the number of oocytes retrieved between the two GnRH analogue protocols (reported separately). A total of 437 participants were randomised, with a post-trial follow-up period to 4 weeks after birth to record birth and neonatal outcomes. Participants/materials, setting, methods Participants were 18–40 years old with AMH ≤35 pmol/L, undergoing their first ovarian stimulation cycle for IVF/ICSI at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway and Switzerland.Live birth rates were compared using a logistic regression model with age and AMH at screening as factors. Multiple imputation was used for randomised subjects withdrawing before start of stimulation. Subjects with transfer cancellation due to COVID-19 related reasons were excluded. Main results and the role of chance All participants had a single blastocyst transferred, except two participants ≥38 years in the agonist group who received a double transfer resulting in one dichorionic diamniotic pregnancy for one subject, complicated by maternal hypertension and preterm birth at 33 weeks. All 133 participants with ongoing pregnancies (138 fetuses) were included in this post-trial follow-up analysis. Late pregnancy losses (after confirmed ongoing pregnancy) were similar in the agonist and antagonist groups (2.7% and 1.7%). There were 130 live births (agonist group: 75 neonates [67 singletons; 4 sets of twins]; antagonist group: 60 neonates [58 singletons; 1 set of twins]). Estimated live-birth rates were 35.8% and 28.7% in the agonist and antagonist groups, respectively, per started cycle (treatment difference 7.15%; 95% CI: –2.02; 16.31; p = 0.1265). There were two neonatal deaths in the agonist group – a set of monochorionic twins born at gestational age 24 weeks + 2 days died shortly after birth due to prematurity. The two treatment groups were comparable with respect to neonatal health data for singletons and twins, and incidence of congenital malformations (2.7% and 3.3%, respectively). Neonatal admissions to intensive care units were similar for both groups (10 and six neonates, respectively). Limitations, reasons for caution Double blastocyst transfer was permitted for participants ≥38 years with no good-quality blastocysts. Neonatal health is dependent on singleton/twin status. Outcomes of transfers with cryopreserved blastocysts were not followed up – the cumulative live birth rates and neonatal outcomes after cryo-transfer are not known. Wider implications of the findings The safety profile of individualised follitropin delta dosing was similar in GnRH agonist and antagonist protocols. Live birth rates following individualised follitropin delta were also similar for both GnRH protocols. There were no safety concerns with respect to the neonatal health after ovarian stimulation with follitropin delta. Trial registration number ClinicalTrials.gov identifier: NCT03809429; EudraCT number: 2017-002783-40

Clinical and pharmacological characteristics in plasma and mononuclear blood cells in patients with coronary heart disease and low statin tolerance

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Vestre Viken Hospital Trust Background Statin-associated muscle symptoms (SAMS) cover a broader range of clinical presentations, with normal or mildly elevated creatine kinase (CK) in blood, and is a prevalent challenge in clinical practice. Our understanding of the pathophysiology of SAMS remains largely unknown. Purpose To gain new knowledge on the molecular effects of atorvastatin in plasma and blood cells in patients with coronary heart disease (CHD) and SAMS, and to identify potential diagnostic biomarkers for statin-dependent SAMS. Methods In 2019, 71 consecutively recruited CHD patients with self-perceived SAMS were randomised to 7-weeks double-blinded treatment with atorvastatin 40 mg/day and placebo in a crossover design. The primary outcome was individual mean difference in muscle symptom intensity between treatment periods, measured weekly with a Visual Analogue Scale (VAS) (0= no to 10=maximal symptoms). Twenty patients were categorised as having statin-dependent SAMS and the remaining as non-SAMS. During trial and post-trial follow-up period, a subgroup of statin-dependent SAMS, who did not tolerate statins (N=7) or only rosuvastatin 5mg/day (N=2) was identified. Atorvastatin metabolites in plasma and peripheral blood mononuclear cells (PBMC) were measured with liquid chromatography tandem mass spectrometry in blood drawn two hours after tablet intake at the last day of the atorvastatin treatment period. Statistical analyses were performed with SPSS. Results Clinical and pharmacological characteristics in patients with low statin-tolerance (N=9) and those without (N=62) are summarised in Figure 1. The reduction in LDL cholesterol (LDL-C) from the placebo period to the atorvastatin period was significantly lower in the group with low statin tolerance, despite confirmed adherence to allocated treatment. The ratio between the sum of all atorvastatin- lactones and acids (SumLactones/SumAcids) was significantly higher in the group with low statin tolerance both in plasma and PBMC analyses compared to those who tolerated statins. The atorvastatin lactone and acid ratio (AL/AA) was borderline significant in both plasma and PBMC. ROC-analyses of these four variables are displayed in Figure 2. Areas under the curves (AUCs) are 0.71 for the sumLactones/sumAcids both in plasma and PBMC, and 0.69 for the AL/AS in plasma and PBMC. There were no significant differences between the groups regarding age, gender or known pharmacogenetic variants (CYP3A and SLCO1B1) or in the differences in creatine kinase (CK) level between the atorvastatin and placebo treatment periods. Conclusions The ratio between atorvastatin lactones and acids in plasma and in mononuclear blood cells is associated with low statin tolerance in patients with CHD. Excess lactone relative to acid metabolites may be involved in the pathophysiology of SAMS. Future studies in muscle tissue may further elucidate the relationship between SAMS and atorvastatin metabolites and other biomarkers in these patients.

The Good Behaviour Game intervention to improve behavioural and other outcomes for children aged 7–8 years: a cluster RCT

BackgroundUniversal, school-based behaviour management interventions can produce meaningful improvements in children’s behaviour and other outcomes. However, the UK evidence base for these remains limited.ObjectiveThe objective of this trial was to investigate the impact, value for money and longer-term outcomes of the Good Behaviour Game. Study hypotheses centred on immediate impact (hypothesis 1); subgroup effects (at-risk boys, hypothesis 2); implementation effects (dosage, hypothesis 3); maintenance/sleeper effects (12- and 24-month post-intervention follow-ups, hypothesis 4); the temporal association between mental health and academic attainment (hypothesis 5); and the health economic impact of the Good Behaviour Game (hypothesis 6).DesignThis was a two-group, parallel, cluster-randomised controlled trial. Primary schools (n = 77) were randomly assigned to implement the Good Behaviour Game for 2 years or continue their usual practice, after which there was a 2-year follow-up period.SettingThe trial was set in primary schools across 23 local authorities in England.ParticipantsParticipants were children (n = 3084) aged 7–8 years attending participating schools.InterventionThe Good Behaviour Game is a universal behaviour management intervention. Its core components are classroom rules, team membership, monitoring behaviour and positive reinforcement. It is played alongside a normal classroom activity for a set time, during which children work in teams to win the game to access the agreed rewards. The Good Behaviour Game is a manualised intervention delivered by teachers who receive initial training and ongoing coaching.Main outcome measuresThe measures were conduct problems (primary outcome; teacher-rated Strengths and Difficulties Questionnaire scores); emotional symptoms (teacher-rated Strengths and Difficulties Questionnaire scores); psychological well-being, peer and social support, bullying (i.e. social acceptance) and school environment (self-report Kidscreen survey results); and school absence and exclusion from school (measured using National Pupil Database records). Measures of academic attainment (reading, standardised tests), disruptive behaviour, concentration problems and prosocial behaviour (Teacher Observation of Child Adaptation Checklist scores) were also collected during the 2-year follow-up period.ResultsThere was no evidence that the Good Behaviour Game improved any outcomes (hypothesis 1). The only significant subgroup moderator effect identified was contrary to expectations: at-risk boys in Good Behaviour Game schools reported higher rates of bullying (hypothesis 2). The moderating effect of the amount of time spent playing the Good Behaviour Game was unclear; in the context of both moderate (≥ 1030 minutes over 2 years) and high (≥ 1348 minutes over 2 years) intervention compliance, there were significant reductions in children’s psychological well-being, but also significant reductions in their school absence (hypothesis 3). The only medium-term intervention effect was for peer and social support at 24 months, but this was in a negative direction (hypothesis 4). After disaggregating within- and between-individual effects, we found no temporal within-individual associations between children’s mental health and their academic attainment (hypothesis 5). Last, our cost–consequences analysis indicated that the Good Behaviour Game does not provide value for money (hypothesis 6).LimitationsLimitations included the post-test-only design for several secondary outcomes; suboptimal implementation dosage (mitigated by complier-average causal effect estimation); and moderate child-level attrition (18.5% for the primary outcome analysis), particularly in the post-trial follow-up period (mitigated by the use of full information maximum likelihood procedures).Future workQuestions remain regarding programme differentiation (e.g. how distinct is the Good Behaviour Game from existing behaviour management practices, and does this makes a difference in terms of its impact?) and if the Good Behaviour Game is impactful when combined with a complementary preventative intervention (as has been the case in several earlier trials).ConclusionThe Good Behaviour Game cannot be recommended based on the findings reported here.Trial registrationThis trial is registered as ISRCTN64152096.FundingThis project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full inPublic Health Research; Vol. 10, No. 7. See the NIHR Journals Library website for further project information.

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AimsREVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period.Methods and resultsA total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3–15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10–29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7–17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0–2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants.ConclusionThe beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms.Trial registrationInternational Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Evaluation of Neuropathy, Glycemic Control, and Revascularization as Risk Factors for Future Lower Extremity Amputation among Diabetic Patients

Diabetes mellitus is a major risk factor for progression to lower extremity amputation (LEA) due to progressive neuropathy and glycemia-induced vasculopathy. In this study, we evaluated risk factors for incident LEA type 2 diabetics during a randomized controlled trial and extended post-trial follow-up. The Action to Control Cardiovascular Risk in Diabetes trial randomized 10,251 type 2 diabetics to intensive glycemic control (Hemoglobin A1c (HbA1c) target <6.0%) versus standard glycemic control (HbA1c target 7.0-7.9%). Using backward elimination logistic regression models, we examined relationships between neuropathy using the Michigan Neuropathy Screening Instrument (MNSI) and glycemic control and incident LEA during the clinical trial and subsequent follow-up. 9,746 patients were followed for a mean of 7.9 +/-3.1 (median 8.9) years after randomization. Ninety-eight (1%) participants underwent an incident LEA during the trial or post-trial follow-up period. Baseline demographics and traditional risk factors were examined by incident amputation status. Multivariable models revealed that abnormal 10 gm filament test (HR 4.50, 95% CI 2.92-6.95, P<0.0001), presence of ulceration (HR 4.22, 95% CI 1.65-10.8, P=0.0004), abnormal appearance on foot examination (HR 4.75, 95% CI 2.30-9.83, P<0.0001), and mean postrandomization HbA1c (HR 1.65, 95% CI 1.35-2.00, P<0.0001) were strongly predictive of LEA when accounting for other common risk factors for amputation. In this post hoc analysis of a large randomized controlled population of diabetic patients, we found that components of the MNSI score including presence of ulceration, abnormal appearance of the foot, and 10 gm filament monofilament scoring were strongly predictive of LEA. This adds a valuable clinical tool in the risk stratification of diabetic patients for LEA.

Follow-up results of myositis patients treated with H. P. Acthar gel

Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by proximal muscle weakness. H. P. Acthar gel [repository corticotropin injection (RCI)] is a formulation of adrenocorticotropic hormone and has been approved by Food and Drug Administration for use in IIM; however, literature is limited. In this study, we report longitudinal follow-up of myositis patients treated with RCI. Patients with refractory IIM who were enrolled in the prospective, open-label RCI trial were included in this study. The post-trial follow-up period was 6 months with assessments every 2 months, which included myositis core set measures including extra-muscular global, muscle and patient global disease activities, HAQ, and manual muscle testing. Two patients were lost to follow-up after finalization of the trial, and the remaining eight patients were enrolled in the follow-up study. One patient remained on RCI after the trial. In the follow-up period, four of eight patients had flare at on average 4.1 months after the RCI trial. Among the patients who flared, three required an increase in prednisone. One patient was restarted on RCI at 5.5 months, but had minimal improvement after 3 months. Four patients who remained stable continued to satisfy criteria for the definition of improvement through the 6-month follow-up. However, none showed any further improvement in the primary or secondary efficacy outcomes after the initial RCI trial. To our knowledge, this is the first study reporting the follow-up results of patients treated with standard dose and duration of Acthar. We believe that our study will provide the basis for the development of future randomized RCI trials in IIM.

Pet ownership and survival in the elderly hypertensive population.

To assess the association of pet ownership and all-cause and cardiovascular mortality over a long-term follow-up among elderly treated hypertensive participants. Pet-ownership data from a subcohort of the Second Australian National Blood Pressure study were used. Participants were aged 65-84 years at enrolment (1995-1997) and responded to a pet-ownership questionnaire during year 2000. Participants' survival information was determined over a median of 10.9 years that includes Second Australian National Blood Pressure in-trial period (median 4.2 years) together with posttrial follow-up period (median 6.9 years). For the current study, end points were any fatal cardiovascular event and all-cause fatal events. Of those who responded to a pet-ownership questionnaire (4039/6018 - 67%), 86% (3490/4039) owned at least one pet at any-time during their life (current or previous pet owner), with 36% (1456/4039) owning at least one pet at the time of the survey. During the follow-up period, 958 participants died including 499 deaths of cardiovascular origin. Using a Cox proportional hazard regression model adjusting for possible confounders, there was a 22 and 26% reduction in cardiovascular mortality observed among previous and current pet owners, respectively, compared with those who had never owned one. A similar nonsignificant trend was observed for all-cause mortality once adjusted for potential confounders. Pet ownership was associated with an improved cardiovascular disease survival in a treated elderly hypertensive population.

Clinical significance of 'cardiometabolic memory': a systematic review of randomized controlled trials.

'Cardiometabolic memory' has been proposed based on clinical evidence to explain how, even after the cessation of a clinical trial, the superiority of one treatment over the outcome persists. To understand the cardiometabolic memory phenomenon, we performed a systematic review of randomized controlled trials (RCTs) using PubMed in August 2016. The search terms 'randomized controlled trial', 'post-trial follow-up' and 'diabetes, hypertension or dyslipidemia' were used, and articles published after the year 2000 were searched. We judged the memory phenomenon to be positive when the cardiovascular outcome at the end of the post-trial follow-up period in the intervention group was significantly superior even though the favorable control of a risk factor (blood glucose, blood pressure or lipid level) during the trial period was lost after the cessation of the intervention. Among 907 articles retrieved in the initial screening, 21 articles were judged as describing a positive memory phenomenon. Eight, six and seven of the articles concerned diabetes, hypertension and dyslipidemia, respectively. Transient intensive glucose lowering rather easily induced memory for the suppression of diabetic microangiopathies, while memory for the suppression of macroangiopathies tended to be first evident in the post-trial follow-up period. Transient intensive blood pressure lowering was generally effective in the formation of memory for the suppression of cardiovascular events and had an especially strong impact on risk reduction of chronic heart failure. Transient intensive LDL cholesterol lowering clearly had a long-term beneficial effect on risk reduction of cardiovascular events. Our systematic review revealed the clinical relevance of cardiometabolic memory.

THE CARIES MANAGEMENT SYSTEM: UPDATING COST-EFFECTIVENESS WITH 4-YEAR POSTTRIAL DATA.

Long-term follow-up of the Caries Management System (CMS) protocol demonstrated that regular monitoring and noninvasive management of dental caries is effective in reducing the number of caries-related events over a 7-year period. This analysis complements the authors' original economic evaluation of the CMS by re-evaluating the per-protocol cost-effectiveness of the CMS approach. An individual patient-simulation Markov model was developed previously, based on 3-year randomized-controlled trial (RCT) data, to simulate the incidence and progression of dental caries, and resultant interventions, and to evaluate the lifetime cost-effectiveness of the CMS versus standard dental care from the Australian private dental practitioner perspective (in which the baseline age distribution was similar to that of the Australian population). The 4-year posttrial follow-up data are used to re-evaluate the long-term cost-effectiveness of the CMS in a more real-life setting. The reduction in caries risk was maintained among those practices within which the CMS protocols were adhered to. The per-protocol model appears to be reasonably accurate at predicting the risk of restorative events in the posttrial follow-up period. The per-protocol lifetime cost per restorative event avoided is AUD1,980 (USD1,409; 1 AUD = 0.71 USD). The current analysis confirms that the CMS approach is both effective, when the protocols are adhered to appropriately, and cost-effective compared with standard care in the Australian private practice setting.

The Caries Management System: are preventive effects sustained postclinical trial?

ObjectivesTo report, at two and 4 years post‐trial, on the potential legacy of a 3‐year randomized controlled clinical trial (RCT) of the Caries Management System (CMS) at private general dental practices. The CMS was designed to reduce caries risk and need for restorative care.MethodsNineteen dental practices located in city, urban, and rural locations in both fluoridated and nonfluoridated communities participated in the RCT. Eight practices were lost to follow‐up post‐trial; however, baseline mean DMFT balance between CMS and control practices was maintained. At the control practices, caries management following usual practice continued to be delivered. The patient outcome measure was the cumulative increment in the DMFT index score, and the practice outcome measures included the practice‐mean and practice‐median increments of patient DMFT index scores. In covariable analysis (patient‐level unit of analysis), as the patients were clustered by practices, mean DMFT increments were determined through multilevel modeling analysis. Practice‐mean DMFT increments (practice‐level unit of analysis) and practice‐median DMFT increments (also practice level) were determined through general linear modeling analysis of covariance. In addition, a multiple variable logistic regression analysis of caries risk status was conducted.ResultsThe overall 4‐year post‐trial result (years 4–7) for CMS patients was a DMFT increment of 2.44 compared with 3.39 for control patients (P < 0.01), a difference equivalent to 28%. From the clinical trial baseline to the end of the post‐trial follow‐up period, the CMS and control increments were 6.13 and 8.66, respectively, a difference of 29% (P < 0.0001). Over the post‐trial period, the CMS and control practice‐mean DMFT increments were 2.16 and 3.10 (P = 0.055) and the respective increments from baseline to year 7 were 4.38 and 6.55 (P = 0.029), difference of 33%. The practice‐median DMFT increments during the 4‐year post‐trial period for CMS and control practices were 1.25 and 2.36 (P = 0.039), and the respective increments during the period from baseline to year 7 were 2.87 and 5.36 (P < 0.01), difference of 47%. Minimally elevated odds of being high risk were associated with baseline DMFT (OR = 1.17). Patients attending the CMS practices had lower odds of being high risk than those attending control practices (OR = 0.23, 95% CI = 0.06, 0.88).ConclusionIn practices where adherence to the CMS protocols was maintained during the 4‐year post‐trial follow‐up period, patients continued to benefit from a reduced risk of caries and, therefore, experienced lower needs for restorative treatment.

Residual beneficial effects after a 3-year integrated intervention on stroke in China

To evaluate whether an intervention program designed to reduce stroke incidence would have long-term residual effects on reducing all-cause and cause-specific mortalities, including cancer 10 years after the intervention was completed. This is a posttrial analysis. We prospectively observed the mortality of a community-based trial of primary prevention of stroke in China performed between July 1987 and June 1990 by extending the follow-up to 30 June 2000. At the baseline, 26,607 adults aged 35 years or above and free from stroke were recruited from five cites of mainland China; 13,212 and 13,395 were assigned into intervention and control group, respectively. Participants in intervention group received a regularly integrated intervention including lifestyle intervention and hypertensive drug treatment. The controls did not receive intervention provided by the investigators. During the 10-year posttrial follow-up period, we observed a significant reduction on overall deaths [hazard ratio 0.91; 95% confidence interval (CI) 0.83, 0.99] and stroke mortality (hazard ratio 0.79; 95% CI 0.63, 1.00). An insignificant late trial beneficial effect was observed for hypertensive disease (hazard ratio 0.69; 95% CI 0.30, 1.58), ischemic heart disease (hazard ratio 0.87; 95% CI 0.64, 1.17), other nonmalignant diseases, and most cancer sites. This study demonstrates that a 3-year integrated intervention program successful for stroke prevention had long-term residual beneficial effects on reducing overall disease burdens among urban Chinese population, especially for the deaths from stroke. However, whether the integrated intervention also leads to reduced mortality of cardiovascular diseases and cancer would have to be confirmed by future larger studies.

Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up.

In the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, alpha-tocopherol supplementation decreased prostate cancer incidence, whereas beta-carotene increased the risk of lung cancer and total mortality. Postintervention follow-up provides information regarding duration of the intervention effects and may reveal potential late effects of these antioxidants. To analyze postintervention effects of alpha-tocopherol and beta-carotene on cancer incidence and total and cause-specific mortality. Postintervention follow-up assessment of cancer incidence and cause-specific mortality (6 years [May 1, 1993-April 30, 1999]) and total mortality (8 years [May 1, 1993-April 30, 2001]) of 25 563 men. In the ATBC Study, 29 133 male smokers aged 50 to 69 years received alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5 to 8 years. End point information was obtained from the Finnish Cancer Registry and the Register of Causes of Death. Cancer cases were confirmed through medical record review. Site-specific cancer incidence and total and cause-specific mortality and calendar time-specific risk for lung cancer incidence and total mortality. Overall posttrial relative risk (RR) for lung cancer incidence (n = 1037) was 1.06 (95% confidence interval [CI], 0.94-1.20) among recipients of beta-carotene compared with nonrecipients. For prostate cancer incidence (n = 672), the RR was 0.88 (95% CI, 0.76-1.03) for participants receiving alpha-tocopherol compared with nonrecipients. No late preventive effects on other cancers were observed for either supplement. There were 7261 individuals who died by April 30, 2001, during the posttrial follow-up period; the RR was 1.01 (95% CI, 0.96-1.05) for alpha-tocopherol recipients vs nonrecipients and 1.07 (95% CI, 1.02-1.12) for beta-carotene recipients vs nonrecipients. Regarding duration of intervention effects and potential late effects, the excess risk for beta-carotene recipients was no longer evident 4 to 6 years after ending the intervention and was primarily due to cardiovascular diseases. The beneficial and adverse effects of supplemental alpha-tocopherol and beta-carotene disappeared during postintervention follow-up. The preventive effects of alpha-tocopherol on prostate cancer require confirmation in other trials. Smokers should avoid beta-carotene supplementation.