Practical Experience with the Use of Electronic Headache Diaries and Video Consultations in Migraine Care from a Longitudinal Cohort Study.

Background: Telemedicine offers a promising solution to enhance the delivery and personalization of headache care. Integrating electronic (e-)tools enables the objective monitoring of migraine. Objectives: This study aims to demonstrate the relevance of e-tools for personalized headache care, assess patient and caregiver compliance and satisfaction, and present their use in enhancing care. Methods: Firstly, a systematic review was performed to validate the diagnostic accuracy of e-diaries for diagnosing migraine. Secondly, we collected e-diary data prospectively from diagnosed adult migraine patients at the Leiden Headache Center. Finally, questionnaires were sent to evaluate satisfaction of patients and health care providers with the Leiden e-headache diary and video consultations. Results: In the systematic review, the Leiden Headache Center's e-diary was the only validated tool. Patients (n = 1,009) were followed for a median of 181 days (interquartile range [IQR] 84-240). Compliance was 96.4% (IQR 85.2 - 99.1%), with 10.8% of days missing. Factors positively associated with compliance were older age (p < 0.001), female sex (p < 0.001), higher e-diary grade (p < 0.001), and clinical use (p = 0.04). The e-diary received a median score of 8/10 and was well-liked by patients (n = 535) and providers (n = 23). Video consultations were a good alternative for physical visits according to 76.9% of patients and 84.6% of providers. Conclusion: Validated e-headache diaries and video consultations in telemedicine enhance headache care accessibility, providing convenient care at preferred times and locations.

Continuous combined oral contraceptive use versus vitamin E in the treatment of menstrual migraine: rationale and protocol of a randomized controlled trial (WHAT!).

BACKGROUND: Currently, there is no evidence-based hormonal treatment for migraine in women. Several small studies suggest a beneficial effect of combined oral contraceptives, but no large randomized controlled trial has been performed. As proof of efficacy is lacking and usage may be accompanied by potentially severe side effects, there is a great need for clarity on this topic. METHODS: Women with menstrual migraine (n = 180) are randomly assigned (1:1) to ethinylestradiol/levonorgestrel 30/150 µg or vitamin E 400 IU. Participants start with a baseline period of 4 weeks, which is followed by a 12-week treatment period. During the study period, a E-headache diary will be used, which is time-locked and includes an automated algorithm differentiating headache and migraine days. RESULTS: The primary outcome will be change in monthly migraine days (MMD) from baseline (weeks - 4 to 0) to the last 4 weeks of treatment (weeks 9 to 12). Secondary outcomes will be change in monthly headache days (MHD) and 50% responder rates of MMD and MHD. CONCLUSIONS: The WHAT! trial aims to investigate effectivity and safety of continuous combined oral contraceptive treatment for menstrual migraine. Immediate implementation of results in clinical practice is possible. TRIAL REGISTRATION: Clinical trials.gov NCT04007874 . Registered 28 June 2019.

Substance use in a Dutch migraine cohort compared with the general population.

OBJECTIVE: To evaluate self-reported substance user profiles for individuals with migraine and compare these to the general population. BACKGROUND: There is increasing attention to lifestyle influences such as substance use as presumed migraine triggers. METHODS: Data on substance use were collected by survey in a large migraine cohort and from the biannual survey in the general Dutch population for substances. A representative cohort of Dutch patients with migraine (n = 5176) and the Dutch general population (n = 8370) was included. Patients with migraine were subdivided into episodic (EM) and chronic migraine (CM). Substance consumption was compared between the general population and patients with migraine, and between migraine subgroups after standardization for sex and level of education. RESULTS: Included patients with migraine were 83.4% female (4319/5176) and had a mean (standard deviation) age of 44.8 (11.3) years. Patients with migraine reported less illicit drug use (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.42-0.55; p < 0.001), less current and lifetime smoking (OR 0.60, 95% CI 0.55-0.65; p < 0.001 and OR 0.75, 95% CI 0.71-0.79; p < 0.001), and less current alcohol consumption (OR 0.66, 95% CI 0.62-0.70; p < 0.001) compared with the general population. Prevalence of substance use was compared between CM and EM participants and showed higher illicit drug use (OR 1.73, 95% CI 1.11-2.69; p = 0.011), higher current smoking (OR 1.61, 95% CI 1.22-2.11; p < 0.001) but less alcohol use (OR 0.54, 95% CI 0.43-0.68; p < 0.001) for participants with CM compared with EM. No differences were found for a history of smoking (OR 1.18, 95% CI 0.92-1.50, p = 0.19). CONCLUSIONS: Individuals with migraine are less likely to use illicit drugs, smoke, or drink alcohol compared with the general population. Patients with CM less often consume alcohol, while they more often use illicit drugs and smoke compared to those with EM.

Migraine with and without aura in relation to the menstrual cycle and other hormonal milestones: A prospective cohort study.

BACKGROUND: Previous studies showed that the perimenstrual window is associated with an increased susceptibility to migraine attacks without aura, but had conflicting results regarding attacks with aura. METHODS: We performed a longitudinal E-diary study among 526 premenopausal women with migraine. Differences in occurrence of perimenstrual migraine attacks between women with migraine with aura and without aura were assessed using a mixed effects logistic regression model. Additionally, participants completed a questionnaire about the influence of hormonal milestones on migraine frequency. RESULTS: Prevalence of menstrual migraine did not differ between women with migraine without aura and migraine with aura (59% versus 53%, p = 0.176). The increased risk of migraine attacks without aura during the perimenstrual window was similar for women with migraine without aura (OR[95%CI]:1.53 [1.44-1.62]) and those with migraine with aura (1.53 [1.44-1.62]). The perimenstrual window was not associated with increased risk of migraine aura attacks (1.08 [0.93-1.26], p = 0.314). Women with migraine with aura more often reported increased migraine frequency during pregnancy and breastfeeding compared to women with migraine without aura, but not during hormonal contraception use. CONCLUSION: Sex hormone levels seem to differently affect the trigeminovascular system (migraine headache) and the susceptibility to cortical spreading depolarization (aura). Exclusively migraine attacks without aura should be interpreted as perimenstrual attacks.

Defining migraine days, based on longitudinal E-diary data.

BACKGROUND: There is a need for standardization of the definition of a migraine day for clinical and research purposes. METHODS: We prospectively compared different definitions of a migraine day with E-diary data of n = 1494 patients with migraine. We used a baseline definition based on migraine characteristics with a duration of ≥4 hours OR triptan intake (independently from its effect) OR (visual) aura lasting 5-60 minutes. RESULTS: Of all migraine days defined by triptan intake only, 66.2% had a duration <4 hours. Adjusting the headache duration criterion to ≥30 minutes led to a decrease in days defined by triptan intake only and resulted in a 5.4% increase in total migraine days (equals 0.45 migraine day increase in monthly migraine days). These additional migraine days had a median duration of 2.5 hours. CONCLUSION: We propose to define a migraine day as follows: 1) (a) headache duration ≥30 minutes; (b) matching ≥2 of four characteristics: unilateral, pulsating, moderate to severe pain, aggravation by or causing avoidance of routine physical activity; and (c) during headache ≥1 of the following: nausea and/or vomiting, photophobia and phonophobia or 2) (visual) aura duration 5-60 minutes or 3) a day with headache for which acute migraine-specific medication is used irrespective of its effect.

Both perimenstrual and nonperimenstrual migraine days respond to anti-calcitonin gene-related peptide (receptor) antibodies.

BACKGROUND AND PURPOSE: Anti-calcitonin gene-related peptide (CGRP) (receptor) antibodies effectively reduce overall migraine attack frequency, but whether there are differences in effect between perimenstrual and nonperimenstrual migraine days has not been investigated. METHODS: We performed a single-arm study among women with migraine. Participants were followed with electronic E-diaries during one (pretreatment) baseline month and 6 months of treatment with either erenumab or fremanezumab. Differences in treatment effect on perimenstrual and nonperimenstrual migraine days were assessed using a mixed effects logistic regression model, with migraine day as dependent variable; treatment, menstrual window, and an interaction term (treatment × menstrual window) as fixed effects; and patient as a random effect. RESULTS: There was no interaction between the menstrual window and treatment effect, indicating that the reduction in migraine days under treatment was similar during the menstrual window and the remainder of the menstrual cycle (odds ratio for treatment = 0.44, 95% confidence interval = 0.38-0.51). CONCLUSIONS: Our findings support prophylactic use of anti-CGRP (receptor) antibodies for women with menstrual migraine, as this leads to consistent reductions in number of migraine days during the entire menstrual cycle.

Sex differences in migraine attack characteristics: A longitudinal E-diary study.

OBJECTIVE: In this prospective cohort study, characteristics of perimenstrual and non-perimenstrual migraine attacks in women were compared with migraine attacks in men. BACKGROUND: Women report longer migraine attacks and more accompanying symptoms than men in cross-sectional questionnaire studies, but this has not been confirmed in longitudinal studies. Supposed differences could result from different characteristics specific to perimenstrual migraine attacks, or of attacks in women in general. METHODS: This cohort study was performed among patients with migraine who were treated at the Leiden Headache Clinic. We assessed differences in migraine attack characteristics between men and women who were prospectively followed by a previously validated electronic headache diary. The primary outcome was "attack" duration. Differences between perimenstrual (Days -2 to +3 of the menstrual cycle) and non-perimenstrual attacks in women versus attacks in men were corrected for age, chronic migraine, and medication overuse headache. RESULTS: A total of 1347 women and 284 men were included, reflecting the preponderance of women in migraine prevalence. Crude median (first and third quartile [Q1-Q3]) attack duration in men was 32.1 [17.7-53.6] h, compared to 36.7 [21.9-62.4] h for non-perimenstrual migraine attacks and 44.4 [17.9-79.0] h for perimenstrual migraine attacks in women. After correction for confounding, perimenstrual migraine attacks were 1.62 (95% confidence interval [CI] 1.47-1.79; p < 0.001) and non-perimenstrual 1.15 (95% CI 1.05-1.25; p = 0.003) times longer compared to migraine attacks in men. The mean relapse percentage in men was 9.2%, compared to 12.6% for non-perimenstrual migraine attacks, and 15.7% for perimenstrual migraine attacks. Relapse risk was greater for perimenstrual (odds ratio [OR] 2.39, 95% CI 1.93-2.95; p < 0.001), but not for non-perimenstrual (OR 1.18, 95% CI 0.97-1.45; p = 0.060) attacks. Migraine attacks in women were more often accompanied by photophobia, phonophobia, and nausea, but less often aura. CONCLUSION: Compared to attacks in men, both perimenstrual and non-perimenstrual migraine attacks are of longer duration and are more often accompanied by associated symptoms. A sex-specific approach to migraine treatment and research is needed.

Validation of diagnostic ICHD-3 criteria for menstrual migraine.

OBJECTIVE: To assess validity of ICHD-3 diagnostic criteria for menstrual migraine. METHODS: We performed a longitudinal E-diary study in premenopausal women with migraine. Menstrual migraine diagnosis was self-reported at baseline, and verified according to diary based ICHD-3 criteria and a previous proposed statistical model. Validity of self-reported menstrual migraine was compared to diary based diagnosis and statistical diagnosis. Test-retest reliability and concordance between both methods were determined. Clinical characteristics of perimenstrual and non-perimenstrual migraine attacks were compared in women with and without menstrual migraine. RESULTS: We included 607 women. Both women who did and women who did not self-report to suffer from menstrual migraine fulfilled ICHD-3 criteria in the E-diary in two thirds of cases. Pure menstrual migraine was extremely rare (<1%). Concordance between statistical and diary based diagnosis was minimal (κ = 0.28, 95% CI:0.23-0.33). Women diagnosed with menstrual migraine showed 37-50% longer attack duration and increased triptan intake (OR 1.19-1.22, p < 0.001) during perimenstrual attacks. CONCLUSION: Self-reported menstrual migraine diagnosis has extremely poor accuracy. Two thirds of women suffer from menstrual migraine, independent of self-reports. Pure menstrual migraine is rare. Women with menstrual migraine have longer attack duration and increased triptan intake during perimenstrual attacks, in contrast to women without menstrual migraine. Prospective headache (E-)diaries are required for a menstrual migraine diagnosis, also in clinical practice.

Clinical symptoms of androgen deficiency in men with migraine or cluster headache: a cross-sectional cohort study.

BACKGROUND: To compare symptoms of clinical androgen deficiency between men with migraine, men with cluster headache and non-headache male controls. METHODS: We performed a cross-sectional study using two validated questionnaires to assess symptoms of androgen deficiency in males with migraine, cluster headache, and non-headache controls. Primary outcome was the mean difference in androgen deficiency scores. Generalized linear models were used adjusting for age, BMI, smoking and lifetime depression. As secondary outcome we assessed the percentage of patients reporting to score below average on four sexual symptoms (beard growth, morning erections, libido and sexual potency) as these items were previously shown to more specifically differentiate androgen deficiency symptoms from (comorbid) anxiety and depression. RESULTS: The questionnaires were completed by n = 534/853 (63%) men with migraine, n = 437/694 (63%) men with cluster headache and n = 152/209 (73%) controls. Responders were older compared to non-responders and more likely to suffer from lifetime depression. Patients reported more severe symptoms of clinical androgen deficiency compared with controls, with higher AMS scores (Aging Males Symptoms; mean difference ± SE: migraine 5.44 ± 0.90, p <  0.001; cluster headache 5.62 ± 0.99, p <  0.001) and lower qADAM scores (quantitative Androgen Deficiency in the Aging Male; migraine: - 3.16 ± 0.50, p <  0.001; cluster headache: - 5.25 ± 0.56, p <  0.001). Additionally, both patient groups more often reported to suffer from any of the specific sexual symptoms compared to controls (18.4% migraine, 20.6% cluster headache, 7.2% controls, p = 0.001). CONCLUSION: Men with migraine and cluster headache more often suffer from symptoms consistent with clinical androgen deficiency than males without a primary headache disorder.

Comparing Perimenstrual and Nonperimenstrual Migraine Attacks Using an e-Diary.

BACKGROUND AND OBJECTIVES: Endogenous and exogenous female sex hormones are considered important contributors to migraine pathophysiology. Previous studies have cautiously suggested that perimenstrual migraine attacks have a longer duration and are associated with higher disability compared to nonperimenstrual attacks, but they showed conflicting results on acute therapy efficacy, pain intensity, and associated symptoms. We compared perimenstrual and nonperimenstrual migraine attack characteristics and assessed premenstrual syndrome (PMS) in women with migraine. METHODS: Women with migraine were invited to complete a headache e-diary. Characteristics of perimenstrual attacks and nonperimenstrual attacks were compared. The primary outcome was attack duration. Secondary outcomes were headache intensity, accompanying symptoms, acute medication intake, and pain coping. Mixed effects models were used to account for multiple attacks within patients. PMS was assessed in patients without hormonal contraceptives. Subgroup analyses were performed for women with menstrually related migraine (MRM) and nonmenstrually related migraine (non-MRM) and women with a natural menstrual cycle and women using hormonal contraceptives. RESULTS: A representative group of 500 participants completed the e-diary for at least 1 month. Perimenstrual migraine attacks (n = 998) compared with nonperimenstrual attacks (n = 4097) were associated with longer duration (20.0 vs 16.1 hours, 95% confidence interval 0.2-0.4), higher recurrence risk (odds ratio [OR] 2.4 [2.0-2.9]), increased triptan intake (OR 1.2 [1.1-1.4]), higher headache intensity (OR 1.4 [1.2-1.7]), less pain coping (mean difference -0.2 [-0.3 to -0.1]), more pronounced photophobia (OR 1.3 [1.2-1.4]) and phonophobia (OR 1.2 [1.1-1.4]), and less aura (OR 0.8 [0.6-1.0]). In total, 396/500 women completed the diary for ≥3 consecutive menstrual cycles, of whom 56% (221/396) fulfilled MRM criteria. Differences in attack characteristics became more pronounced when focusing on women with MRM and women using hormonal contraceptives. Prevalence of PMS was not different for women with MRM compared to non-MRM (11% vs 15%). DISCUSSION: The longer duration of perimenstrual migraine attacks in women (with MRM) is associated with higher recurrence risk and increased triptan use. This may increase the risk of medication overuse and emphasizes the need to develop female-specific prophylactic treatment.

Treatment with the monoclonal calcitonin gene-related peptide receptor antibody erenumab: A real-life study.

BACKGROUND AND PURPOSE: New prophylactics for migraine, targeting calcitonin gene-related peptide (CGRP), have recently emerged. Real-world data are important for a comprehensive understanding of treatment response. We assessed the consistency of response to erenumab, a monoclonal CGRP receptor antibody, in a real-world setting, in order to determine which patients may be considered responders in clinical practice. METHODS: All erenumab-treated patients (n = 100) completed a time-locked daily electronic diary, and an automated algorithm was used to monitor treatment response. Monthly migraine days (MMD), non-migrainous headache days, days of acute medication use (MAMD), well-being and coping with pain were assessed for a 6-month period. The primary outcome was reduction in MMD compared to baseline. RESULTS: The numbers of MMD and MAMD decreased in all months, in both episodic and chronic migraine patients, compared to baseline (p < 0.001), while general well-being (p < 0.001) and coping with pain (p < 0.001) also improved. Of all patients, 36% had an MMD reduction of ≥50% in ≥3/6 months, and 6% had such a reduction in all 6 months. For a ≥30% MMD reduction, the figures were 60% and 24%, respectively. Almost 90% of patients with an average MMD reduction of ≥30% over the first 3 months had a sustained response in the last 3 months. In addition, 20% of patients without an initial response (average <30%), had a delayed response (average ≥30%) in the last 3 months. CONCLUSION: Erenumab was effective in migraine patients who were highly refractory to previous prophylactics. As a practical guideline, we propose that treatment be continued for at least 6 months and that patients with a ≥30% MMD reduction in at least half of the treatment period should be considered to be responders.

Vitamin D supplementation for children with cancer: A systematic review and consensus recommendations.

BACKGROUND: Prevalent vitamin D deficiency (VDD) and low bone mineral density (BMD) have led to vitamin D supplementation for children with cancer, regardless vitamin D status. However, it remains unsettled whether this enhances bone strength. We sought to address this issue by carrying out a systematic review of the literature. METHODS: We conducted a literature search using PubMed, Embase, and Cochrane databases. Studies including children up to 5 years after cancer therapy were assessed for the association between 25-hydroxyvitamin D (25OHD) levels and BMD Z-scores or fractures, and the effect of vitamin D supplementation on BMD or fractures. Evidence quality was assessed using the GRADE methodology. RESULTS: Nineteen studies (16 observational and 3 interventional, mainly involving children with hematologic malignancies) were included. One study which analyzed 25OHD as a threshold variable (≤10 ng/ml) found a significant association between 25OHD levels and BMD Z-scores, while 25OHD as a continuous variable was not significantly associated with BMD Z-scores in 14 observational studies. We found neither a significant association between lower 25OHD levels and fractures (2 studies), nor between vitamin D (and calcium) supplementation and BMD or fracture frequency (3 studies) (very low quality evidence). CONCLUSION: There is a lack of evidence for an effect of vitamin D (and calcium) supplementation on BMD or fractures in children with cancer. Further research is needed; until then, we recommend dietary vitamin D/calcium intake in keeping with standard national guidelines, and periodic 25OHD monitoring to detect levels <20 ng/ml. Vitamin D/calcium supplementation is recommended in children with low levels, to maintain levels ≥20 ng/ml year-long.

E-diary use in clinical headache practice: A prospective observational study.

AIM: To determine whether our E-diary can be used to diagnose migraine and provide more reliable migraine-related frequency numbers compared to patients' self-reported estimates. METHODS: We introduced a self-developed E-diary including automated algorithms differentiating headache and migraine days, indicating whether a patient has migraine. Reliability of the E-diary diagnosis in combination with two previously validated E-questionnaires was compared to a physician's diagnosis as gold standard in headache patients referred to the Leiden Headache Clinic (n = 596). In a subset of patients with migraine (n = 484), self-estimated migraine-related frequencies were compared to diary-based results. RESULTS: The first migraine screening approach including an E-headache questionnaire, and the E-diary revealed a sensitivity of 98% and specificity of 17%. In the second approach, an E-migraine questionnaire was added, resulting in a sensitivity of 79% and specificity of 69%. Mean self-estimated monthly migraine days, non-migrainous headache days and days with acute medication use were different from E-diary-based results (absolute mean difference ± standard deviation respectively 4.7 ± 5.0, 6.2 ± 6.6 and 4.3 ± 4.8). CONCLUSION: The E-diary including algorithms differentiating headache and migraine days showed usefulness in diagnosing migraine. The use emphasised the need for E-diaries to obtain reliable information, as patients do not reliably recall numbers of migraine days and acute medication intake. Adding E-diaries will be helpful in future headache telemedicine.

Effect of lockdown during COVID-19 on migraine: A longitudinal cohort study.

BACKGROUND: The objective of this study was to assess whether migraine-related outcomes changed during intelligent lockdown when compared with the prior period. METHODS: This was a cohort study evaluating the first month of intelligent lockdown in the Netherlands (12 March to 8 April 2020) compared with one baseline month (13 February to 11 March 2020). We identified 870 migraine patients treated at the Leiden Headache Center with headache e-diaries during the period of interest. Adherence to the e-diary had to be ≥80%, yielding 592 enrolled patients. RESULTS: Intelligent lockdown led to a decrease in monthly migraine days (-0.48; 95% CI: -0.78 to -0.18, p = 0.002) and acute medication days (-0.48; 95% CI: -0.76 to -0.20, p < 0.001), and an increase in general well-being (0.11; 95% CI: 0.06 to 0.17, p < 0.001). No differences in non-migrainous headache days and pain coping were observed. Consistent results were found in a subset that was followed for 4 months. CONCLUSIONS: Our findings imply that intelligent lockdown measures can improve migraine disability despite of the potential negative effects of COVID-19 and lockdown. We hypothesise that this effect is a combined result of working from home, scaling down demanding social lives, and freedom to choose how to organise one's time.

Sex differences in prevalence of migraine trigger factors: A cross-sectional study.

AIM: To examine the effect of sex on migraine trigger factors. METHODS: Prevalence of 11 frequently reported trigger factors was determined in a cross-sectional study among migraine patients from a validated migraine database (n = 5725 females and n = 1061 males). Female-to-male odds ratios were calculated for each trigger, using a logistic regression model with attack frequency and migraine subtype (with or without aura) as covariates. Additionally, the effect of sex on total number of triggers per individual was determined. RESULTS: The top three most reported triggers in women were menstruation (78%), stress (77%), and bright light (69%). Men reported stress (69%), bright light (63%), and sleep deprivation (60%) most frequently as provoking factors. The following triggers were more often reported by women than men: Bright light (odds ratio 1.29 [95% CI 1.12-1.48]; p = 0.003), stress (1.47 [1.27-1.69]; p < 0.001), skipping a meal (1.24 [1.09-1.42]; p = 0.015), sleep deprivation (1.37 [1.20-1.57]; p < 0.001), high altitudes (1.70 [1.40-2.09]; p < 0.001), and weather changes (1.35 [1.18-1.55]; p < 0.001). Women reported more triggers than men, even when menstruation was disregarded (mean ± SD: 4.6 ± 2.3 and 4.3 ± 2.3; p < 0.001).Conclusion: Women report migraine trigger factors to be provocative of their attacks more frequently than men, which may be related to a lower migraine threshold due to sex hormonal changes.

Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials.

OBJECTIVE: To assess the effect of eligibility criteria on exclusion rates, generalizability, and outcome heterogeneity in amyotrophic lateral sclerosis (ALS) clinical trials and to assess the value of a risk-based inclusion criterion. METHODS: A literature search was performed to summarize the eligibility criteria of clinical trials. The extracted criteria were applied to an incidence cohort of 2,904 consecutive patients with ALS to quantify their effects on generalizability and outcome heterogeneity. We evaluated the effect of a risk-based selection approach on trial design using a personalized survival prediction model. RESULTS: We identified 38 trials. A large variability exists between trials in all patient characteristics for enrolled patients (p < 0.001), except for the proportion of men (p = 0.21). Exclusion rates varied widely (from 14% to 95%; mean 59.8%; 95% confidence interval 52.6%-66.7%). Stratification of the eligible populations into prognostic subgroups showed that eligibility criteria lead to exclusion of patients in all prognostic groups. Eligibility criteria neither reduce heterogeneity in survival time (from 22.0 to 20.5 months, p = 0.09) nor affect between-patient variability in functional decline (from 0.62 to 0.65, p = 0.25). In none of the 38 trials were the eligibility criteria found to be more efficient than the prediction model in optimizing sample size and eligibility rate. CONCLUSIONS: The majority of patients with ALS are excluded from trial participation, which questions the generalizability of trial results. Eligibility criteria only minimally improve homogeneity in trial endpoints. An individualized risk-based criterion could be used to balance the gains in trial design and loss in generalizability.