Assessment of Long-term Follow-up of Randomized Trial Participants by Linkage to Routinely Collected Data

Key Points Question Does follow-up of clinical trial participants by linkage to routinely collected data sources provide important insights into the long-term benefits and harms of treatment? Findings This scoping review of the published literature found only 113 trials that had been extended by record linkage. Analysis showed that some benefits of treatment extend beyond the trial, and some harms of treatment only become apparent after the trial is complete. Meaning The fate of patients after participation in clinical trials is a neglected topic, and the authors recommend that researchers routinely request permission from trial participants to study long-term treatment effects using linkage to routinely collected data.


eTable 2. Summary of Data Abstraction Guide
• Was a clear reason given to perform extension? o If so, specify; e.g. to determine the long-term benefits of treatment? • Additional follow-up (e.g. years, months) offered through trial extension. • Average total follow-up (in months) -or maximum follow-up time when multiple trials were included or where mean/ median are not explicitly stated • Did the follow-up involve subgroups of the original trial population? If so, briefly describe. • Sample size used for follow-up study • Were outcomes reported according to randomization? • List the outcomes reported by the follow-up study. State primary and secondary outcomes. • Do the outcomes reported in the follow-up study differ from those reported in the original trial report? Describe.
• Did the authors also report outcomes in an additional population? If yes, specify (e.g. individuals in a registry).
• Main results of follow-up study (i.e., those reported in the abstract) • What additional information did the trial extension provide? E.g. original intervention effects were sustained/lost. Were there new findings involving other outcomes? • Were any of the authors of the original study involved in the follow-up study?
Follow-Study Data and Funding Sources • State the types of routinely collected data used in the follow-up study, e.g. vital statistics, administrative claims data, registry data, etc. • Did the authors use data other than vital statistics or population registries? • Was the method of linkage used reported or referenced? If so, specify (e.g. probabilistic, deterministic) • Do the authors report the % (or number) of study participants successfully linked? If so, record.
• Did the authors report if Research Ethics Board (REB) approval was sought?
o Please record any mention to ethics and page number. o Was REB approval specific to the long-term follow-up study? • Did the authors have access to details of interventions after the original trial was closed?
o If yes, specify. • If they had access to trial intervention data, how did they use it? • How did the authors state how they treated the analysis? i.e., per-protocol, intention to treat, or as-treated. • If they had access to post trial treatment or potential confounding variables, please describe whether they included them in any time-varying analyses.
o Did the authors adjust for any covariates (time-varying or other)? • Did the authors comment on any challenges they experienced with completing the follow-up study? (e.g. time or cost requirements). If so, please record with page number.    Table 3 (Summary of results of trial extension studies), which categorizes all reported analyses (n=155). In this table studies were placed in categories according to a hierarchy in which superiority in the trial extension phase> harms in the trial extension phase> null effects in the trial extension phase> benefits lost in the trial extension phase > analyzed as an observational study. Thus, each study only appears once in the table (n=113). Men and women 45 to 74 years of age, history of MI 6 months but ,5 years before enrollment into the study and/or stable angina pectoris confirmed by coronary angiography, and/or radionuclear studies or standard exercise tests. In addition, a lipid profile of serum total cholesterol between 180 to 250 mg/dL, LDL-C #180 mg/dL (#160 mg/dL for patients >50 years), HDL-C #45 mg/dL, and triglycerides #300 mg/dL was required. Men and women were recruited using a 2-stage sampling design. The study drew an age-stratified (60-74, 75 years), random sample of patients with an upcoming appointment. Physicians notified sampled patients by mail allowing patients to decline contact. Research associates telephoned the remaining sample to confirm study eligibility: age 60 years or older, ability to give informed consent, Mini-Mental State Examination (MMSE) score44 of 18 or higher, and ability to communicate in English. With oral consent, eligible patients were screened for depression using the Centers for Epidemiologic Studies Depression scale (CES-D). The study invited all patients with a CES-D score higher than 2046 as well as a 5% random sample of patients with lower scores to enroll in the research protocol. Premenopausal high-risk patients with breast cancer. High-risk status was defined as consisting of one or more of the following: involvement of axillary lymph nodes, a tumor size of more than 5 cm, and invasion of the cancer to skin or pectoral fascia (pathological stage II or III). A woman was considered premenopausal if she had had amenorrhea for less than five years or had had a hysterectomy before the age of 55. Male inmates were eligible to participate if they: (1) were assessed as suitable for MMT by a detailed interview with medical staff which confirmed they had a heroin problem; (2) were serving prison sentences longer than 4 months at time of interview; and (3)  younger than 40 years of age, cerebrovascular event occurred before 3 months, previously experienced disabling major stroke, attacks were definitely due to something other than arterial thromboembolism, likely to experience adverse events from aspirin (allergy, intolerance, previous abnormal bleeding, alcoholism etc.) and confound analyses by taking aspirin 90 days prior to randomization or having myocardial infarction within 3 months prior to randomization, might have difficulty with follow-up, comply poorly and had severe intercurrent non vascular disease. BMDAS: All male doctors resident in the United Kingdom in 1978 who were born this century, who had replied to a questionnaire about their smoking habits that was sent to them in 1951 (as part of another study), and who were still listed in the 1977 Medical Directory. Ineligible: already taking aspirin for various reasons, could not take it, and history of peptic ulcer, stroke, or definite myocardial infarction.

eTable 4. Details of participants interventions and outcomes measured in the original and extended trials included in the review
(patients received two 150 mg aspirin tablets in the morning and two placebo tablets in the evening); C: Placebo (patients received two placebo tablets twice daily). BMDAS: I: daily aspirin (500mg) unless some contraindication was thought to have developed C: avoid aspirin and products containing aspirin unless some specific indication for aspirin was thought to have developed (no placebo).
Secondary: time to "major stroke, myocardial infarction or vascular death". Men and women who were 21 to 74 years of age, had LDL cholesterol levels of no more than 200 mg per deciliter, and had had at least two saphenous-vein coronary bypass grafts placed 1 to 11 years before the start of the study. Of these patients, we deemed eligible those who had LDL cholesterol levels of 130 to 175 mg per deciliter (4.5 mmol per liter) and triglyceride levels below 300 mg per deciliter (3.4 mmol per liter), as measured at any visit to a study physician after the initiation of a Step 1 diet23; two patent saphenous-vein grafts (with stenosis of less than 75 percent) in men (one in women); and an ejection fraction of no less than 30 percent. Men and women aged 18 to 70. Serum creatine level of 1.2 to 7.0 mg/dL for women and 1.4 to 7.0 mg/dL for men or a creatinine clearance less than 70 mL/min; and mean arterial pressure of 125 mm Hg or less. Patients were excluded if they had diabetes requiring insulin, proteinuria of 10 g/d or more, or body weight less than 80% or more than 160% of standard body weight. Men and women based on the criteria of the American Rheumatism Association for rheumatoid arthritis; age between 18 and 65 years; duration of symptoms of less than 2 years; active disease with three or more swollen joints and at least three of the following: erythrocyte sedimentation rate (ESR), at least 28 mm/h or C-reactive protein (CRP) concentration above 19 mg/L; morning stiffness of 29 min or more; more than five swollen joints and more than ten tender joints Men and women with congestive heart failure, ejection fraction < 0.35 already taking drugs other than an angiotensin converting enzyme inhibitor as part of treatment for congestive heart failure.

BMDAS:
i: enalapril at an initial dose of 2.5 mg twice daily, gradually increase to 10 mg twice daily unless side effects developed c: placebo Total mortality. Secondary: incidence of heart failure, rate of heart failure Primary: total mortality. Secondary: causespecific mortality Men whose risk for coronary heart disease was assessed using measurements of serum cholesterol, diastolic BP, and selfreported cigarette smoking. Men who were in the upper 15% (changed to 10% after one third of the screening was completed) of risk, a serum creatinine 2.0 mg/dl and without evidence of cardiovascular or other lifethreatening diseases were included. I: special intervention (SI) received group and individual counseling on a fat-modified diet; a stepped-care drug treatment program for hypertension (after an initial attempt to control BP by weight reduction, if indicated); and for cigarette smokers, counseling aimed to achieve cessation. C: usual care Primary: mortality from coronary heart disease Secondary: blood pressure Primary: CVD Mortality. Secondary: non-fatal CVD outcomes (CHD, MI, CHF, coronary surgery) Stewart JC, 2014. Unützer J, 2002 Men and women were selected based on the following 2 strategies. The first strategy relied on referrals of depressed older adults from primary care practitioners, other clinic staff, or patients themselves in response to clinic promotions of the program. The second method consisted of systematic depression screening of English-speaking, I: IMPACT intervention (access to a depression care manager who was supervised by a psychiatrist and a primary care expert and who offered education, care management, and support of antidepressant management by the Men and women: 1) age 18 years or older; 2) discharged to home with a diagnosis of CHF as confirmed by a cardiologist; 3) persistent moderate-to-severe symptoms (New York Heart Association [NYHA] functional class II to IV); and 4) a recent history of 1 admissions for acute heart failure. I: specialized CHF clinicbased intervention (CBI); C: home-based intervention (HBI) Primary: all-cause, unplanned hospitalization or death during 12-to 18-month follow-up. Secondary: type and duration of hospitalization and healthcare costs. Men and women with symptoms of ischaemia that were increasing or occurring at rest, or that warranted the suspicion of acute myocardial infarction, with the last episode within 48 h before the start of dalteparin or standard heparin treatment. Exclusion criteria were raised risk of bleeding episodes, anaemia, or indication for or treatment in the past 24 h with thrombolysis, angioplasty in the past 6 months, being on a waiting list for coronary revascularisation, All residents of Groningen, Netherlands aged 28-75 were sent a questionnaire and asked to send in a morning urine sample. The key entry criteria of the PREVEND IT were persistent microalbuminuria (a urinary albumin concentration 10 mg/L in 1 early morning spot urine sample and a concentration of 15 to 300 mg/24 hours in 2 24-hour urine samples at least once), a blood pressure 160/100 mm Hg and no use of antihypertensive medication, and a total cholesterol level 8.0 mmol/L, or 5.0 mmol/L in case of previous yocardial infarction, and no use of lipid-lowering medication. Men and women with primary dysplasia, or stage Tis, stage T1, grade 3 and multiple recurrent stage TaPT1, grade 1 or 2 disease with normal liver and kidney function tests, and no chemotherapy during the prior 6 months. Exclusion criteria were previous or ongoing intravesical treatment with mitomycin C, BCG or radiotherapy, any secondary malignancy except treated carcinoma in situ of the uterine cervix or basal cell carcinoma of the skin, ongoing corticosteroid therapy, leukocytes less than 3,000/ mm., thrombocytes less than 100,000/mm., untreated urinary tract infection, urethral stricture preventing cystoscopy, active tuberculosis, pregnancy and expected difficulties during followup (for example Karnofsky performance index less than 50, senility, psychotic disease or any other reason that might prevent follow-up. I: Mitomycin C (40 mg); C: Pasteur strain BCG (120 mg) Recurrence and progression of superficial bladder carcinoma.
Progression, later treatments and survival in this group of patients with highrisk urinary bladder cancer that was not muscle-invasive. Any Danish man or woman aged 30-50 years (as of Jan 1, 1991) registered with a general practitioner was included in the study.
i1: health check which included being screened for cardiovascular risk factors, lung and liver function, fitness, sight and hearing and an optional test for the human immunodeficiency virus (HIV); this group received written feedback from the general practitioner. i2: also given a health check and written feedback; in addition, they were given the opportunity to attend their general practitioner to discuss preventive health. c: not invited to participate Primary: describe the baseline health status of participants including: presence of CVD risk factors, lung and liver function, fitness, sight, hearing and (optionally) their HIV status. Secondary: report on the extent of health advice given as a result of a health check (and on how many healthy people did not require health advice following a health check) and on health goals that participants set following discussion of their health with their general practitioner. The number of referrals to specialists following the health talks was also examined to determine whether the screening would result Men and women receiving their first or second cadaveric renal transplant, were at least 18 years old, and were able to receive oral medication. Patients with a history of malignancy (except successfully treated nonmetastatic basal or squamous cell carcinoma of the skin), serologic evidence of human immunodeficiency virus or hepatitis B, systemic infections requiring continued antibiotic therapy at the time of entry, severe diarrhea, gastrointestinal disorders, or active peptic ulcer disease were excluded from entry, as were pregnant women, nursing mothers, and patients who did not agree to use adequate contraception.