Resumption of migraine preventive treatment with CGRP(-receptor) antibodies after a 3-month drug holiday: a real-world experience

Background: Migraine frequency increases after the cessation of successful preventive treatment with CGRP(-receptor) monoclonal antibodies (mAbs). In this study, we aimed to evaluate the course of migraine after treatment resumption. Methods: Patients with migraine, who started treatment with the same CGRP(-R) mAb after a three-month drug holiday were included in this analysis. We collected headache data at four prospective visits: 1) during the four weeks before the initial mAb treatment (baseline); 2) during the four weeks before the last mAb injection; 3) in weeks 13-16 of the drug holiday; 4) in weeks 9-12 after treatment restart. Outcomes were the changes in monthly migraine days (MMD), monthly headache days (MHD), monthly days with acute medication use (AMD) and Headache Impact Test-6 (HIT-6) scores across the observation period. Results: This study included 39 patients (erenumab n = 16; galcanezumab/ fremanezumab n = 23). MMD decreased from 12.3 +/- 6.3 at the end of the drug holiday to 7.8 +/- 5.5 three months after treatment restart (p = 0.001). The improvement after treatment resumption was similar to the response in the initial treatment period (baseline: 12.3 +/- 6.3 MMD vs. 7.5 +/- 5.2 MMD before treatment interruption). MHD and AMD showed a significant improvement after treatment restart. HIT-6 scores decreased, indicating a diminished impact of headache on everyday life. Conclusions: Reinitiation of treatment with CGRP(-R) mAbs after a drug holiday leads to a significant reduction of migraine frequency and medication use as well as improvement in quality of life

Deterioration of headache impact and health-related quality of life in migraine patients after cessation of preventive treatment with CGRP(−receptor) antibodies

Background Migraine preventive treatment with CGRP(-receptor) monoclonal antibodies (mAbs) has a positive effect on patients' health-related quality of life (HRQoL). The German treatment guidelines recommend discontinuing successful treatment with CGRP(-receptor) mAbs after 6-12 months. We aimed to evaluate headache-specific and generic HRQoL for three months after discontinuation of CGRP(-receptor) mAb treatment. Methods We conducted a prospective, longitudinal cohort study, including patients with migraine after 8-12 months of therapy with a CGRP(-R) mAb and before a planned discontinuation attempt. HRQoL was assessed at the time of the last mAbs injection (V1), eight weeks later (V2), and sixteen weeks later (V3). For headache-specific HRQoL, we used the Headache Impact Test-6 (HIT-6). Generic HRQoL was determined with the EuroQol-5-Dimension-5-Level (ED-5D-5L) form, and the Short-Form 12 (SF-12), which comprises a Physical Component Summary (PCS-12) and a Mental Component Summary (MCS-12). Questionnaires' total scores were compared across the three observation points using nonparametric procedures. Results The study cohort consisted of n = 61 patients (n = 29 treated with the CGRP-receptor mAb erenumab and n = 32 with the CGRP mAbs galcanezumab or fremanezumab). The HIT-6 sum score was 59.69 +/- 6.90 at V1 and increased by 3.69 +/- 6.21 at V3 (p < 0.001), indicating a greater headache impact on patients' lives. The mean total EQ-D5-L5 score declined from 0.85 +/- 0.17 at V1 by - 0.07 +/- 0.18 at V3 (p = 0.013). Both Mental and Physical Component Scores of the SF-12 worsened significantly during treatment discontinuation: The PCS-12 total score decreased by - 4.04 +/- 7.90 from V1 to V3 (p = 0.013) and the MCS-12 score by - 2.73 +/- 9.04 (p = 0.003). Changes in all questionnaires' scores but the MCS-12 were already significant in the first month of the drug holiday (V2). Conclusions Our results show a significant decline in headache impact and generic HRQoL of migraine patients after treatment discontinuation of a CGRP(-R) mAb. The observed deterioration is above the established minimally clinically important differences for each of the questionnaires and can therefore be considered clinically meaningful. Monitoring HRQoL during a discontinuation attempt could facilitate the decision whether or not to resume preventive treatment with CGRP(-R) mAbs

Cardiac Troponin and Recurrent Major Vascular Events after Minor Stroke or Transient Ischemic Attack

Objective: This study was undertaken to investigate whether high-sensitivity cardiac troponin T (hs-cTnT) is associated with major adverse cardiovascular events (MACE) in patients with minor stroke or transient ischemic attack (TIA), and whether this association differs after risk stratification based on the Age, Blood Pressure, Clinical Features, Duration of Symptoms, Diabetes (ABCD2 ) score. Methods: INSPiRE-TMS was a randomized controlled trial allocating patients with minor stroke or TIA to an intensified support program or conventional care. In this post hoc analysis, participants were categorized using hs-cTnT levels (5th generation; Roche Diagnostics, Manheim, Germany; 99th percentile upper reference limit [URL] = 14ng/l). Vascular risk was stratified using the ABCD2 score (lower risk = 0-5 vs higher risk = 6-7). Cox proportional hazard regression was performed using covariate adjustment and propensity score matching (PSM) for the association between hs-cTnT and MACE (stroke/nonfatal coronary event/vascular death). Results: Among 889 patients (mean age = 70 years, 37% female), MACE occurred in 153 patients (17.2%) during a mean follow-up of 3.2 years. hs-cTnT was associated with MACE (9.3%/yr, >URL vs 4.4%/yr, ≤URL, adjusted hazard ratio [HR] = 1.63 [95% confidence interval (CI) = 1.13-2.35], adjusted HR [Q4 vs Q1 ] = 2.57 [95% CI = 1.35-4.97], adjusted HR [log-transformed] = 2.31 [95% CI = 1.37-3.89]). This association remained after PSM (adjusted HR = 1.76 [95% CI = 1.14-2.72]). There was a significant interaction between hs-cTnT and ABCD2 category for MACE occurrence (pinteraction = 0.04). In the lower risk category, MACE rate was 9.5%/yr in patients with hs-cTnT > URL, which was higher than in those ≤URL (3.8%/yr) and similar to the overall rate in the higher risk category. Interpretation: hs-cTnT levels are associated with incident MACE within 3 years after minor stroke or TIA and may help to identify high-risk individuals otherwise deemed at lower risk based on the ABCD2 score. If confirmed in independent validation studies, this might warrant intensified secondary prevention measures and cardiac diagnostics in stroke patients with elevated hs-cTnT

Retinal microvascular signs and recurrent vascular events in patients with TIA or minor stroke

Background and purposeRetinal pathologies are an independent risk factor for ischaemic stroke, but research on the predictive value of retinal abnormalities for recurrent vascular events in patients with prior stroke is inconclusive. We investigated the association of retinal pathologies with subsequent vascular events.MethodsIn a substudy of the Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS) trial, we enrolled patients with recent transient ischaemic attack (TIA) or minor stroke with at least one modifiable risk factor. Primary outcome was the composite of subsequent vascular events. Retinal photographs were taken at baseline and categorised into three different fundus groups by a telemedically linked ophthalmologist.Results722 patients participated in the current study and 109 major vascular events occurred. After multivariable adjustments, we did not find a significant association between fundus categories and risk for subsequent vascular events (HRs for moderate vascular retinopathy and vascular retinopathy with vessel rarefaction in comparison to no vascular retinopathy 1.03 (95% CI 0.64 to 1.67), p=0.905 and 1.17 (95% CI 0.62 to 2.20), p=0.626). In a selective post hoc analysis in patients with diabetes mellitus and hypertension, patients with vascular retinopathy with vessel rarefaction had a higher risk for recurrent stroke (HR 24.14 (95% CI 2.74 to 212.50), p=0.004).ConclusionsRetinal changes did not predict major subsequent vascular events in patients with recent TIA or minor stroke. Further studies are needed to examine the utility of fundus photography in assessing the risk of stroke recurrence in patients with diabetes mellitus and hypertension

Effect of switching to erenumab in non-responders to a CGRP ligand antibody treatment in migraine: A real-world cohort study

Background: Therapeutic options for migraine prevention in non-responders to monoclonal antibodies (mAbs) targeting Calcitonin Gene-Related Peptide (CGRP) and its receptor are often limited. Real-world data have shown that non-responders to the CGRP-receptor mAb erenumab may benefit from switching to a CGRP ligand mAb. However, it remains unclear whether, vice versa, erenumab is effective in non-responders to CGRP ligand mAbs. In this study, we aim to assess the efficacy of erenumab in patients who have previously failed a CGRP ligand mAb. Methods: This monocentric retrospective cohort study included patients with episodic or chronic migraine in whom a non-response (= 30% responder rates and the absolute reduction of monthly headache days at 3 and 6 months of treatment with erenumab in this cohort. Results: From May 2019 to July 2022, we identified 20 patients who completed 3 months of treatment with erenumab after non-response to a CGRP ligand mAb. Fourteen patients continued treatment for >= 6 months. The >= 30% responder rate was 35% at 3 months, and 45% at 6 months of treatment with erenumab, respectively. Monthly headache days were reduced from 18.6 +/- 5.9 during baseline by 4.1 +/- 3.1 days during month 3, and by 7.0 +/- 4.8 days during month 6 compared to the month before treatment with erenumab (p < 0.001, respectively). Responders and non-responders to erenumab did not differ with respect to demographic or headache characteristics. Conclusion: Switching to erenumab in non-responders to a CGRP ligand mAb might be beneficial in a subgroup of resistant patients, with increasing responder rates after 6 months of treatment. Larger prospective studies should aim to predict which subgroup of patients benefit from a switch

A support programme for secondary prevention in patients with transient ischaemic attack and minor stroke (INSPiRE-TMS): an open-label, randomised controlled trial

Background: Patients with recent stroke or transient ischaemic attack are at high risk for a further vascular event, possibly leading to permanent disability or death. Although evidence-based treatments for secondary prevention are available, many patients do not achieve recommended behavioural modifications and pharmaceutical prevention targets in the long-term. We aimed to investigate whether a support programme for enhanced secondary prevention can reduce the frequency of recurrent vascular events. Methods: INSPiRE-TMS was an open-label, multicentre, international randomised controlled trial done at seven German hospitals with acute stroke units and a Danish stroke centre. Patients with non-disabling stroke or transient ischaemic attack within 2 weeks from study enrolment and at least one modifiable risk factor (ie, arterial hypertension, diabetes, atrial fibrillation, or smoking) were included. Computerised randomisation was used to allocate patients (1:1) either to the support programme in addition to conventional care or to conventional care alone. The support programme used feedback and motivational interviewing strategies with eight outpatient visits over 2 years aiming to improve adherence to secondary prevention targets. The primary outcome was the composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death, assessed in the intention-to-treat population (all patients who underwent randomisation, did not withdraw study participation, and had at least one follow-up). Outcomes were assessed at annual follow-ups using time-to-first-event analysis. All-cause death was monitored as a safety outcome. This trial is registered with ClinicalTrials.gov, NCT01586702. Findings: From Aug 22, 2011, to Oct 30, 2017, we enrolled 2098 patients. Of those, 1048 (50·0%) were randomly assigned to the support programme group and 1050 (50·0%) patients were assigned to the conventional care group. 1030 (98·3%) patients in the support group and 1042 (99·2%) patients in the conventional care group were included in the intention-to-treat analysis. The mean age of analysed participants was 67·4 years and 700 (34%) were women. After a mean follow-up of 3·6 years, the primary outcome of major vascular events had occurred in 163 (15·8%) of 1030 patients of the support programme group and in 175 (16·8%) of 1042 patients of the conventional care group (hazard ratio [HR] 0·92, 95% CI 0·75–1·14). Total major vascular event numbers were 209 for the support programme group and 225 for the conventional care group (incidence rate ratio 0·93, 95% CI 0·77–1·12; p=0·46) and all-cause death occurred in 73 (7·1%) patients in the support programme group and 85 (8·2%) patients in the conventional care group (HR 0·85, 0·62–1·17). More patients in the support programme group achieved secondary prevention targets (eg, in 1-year-follow-up 52% vs 42% [p<0·0001] for blood pressure, 62% vs 54% [p=0·0010] for LDL, 33% vs 19% [p<0·0001] for physical activity, and 51% vs 34% [p=0·0010] for smoking cessation). Interpretation: Provision of an intensified secondary prevention programme in patients with non-disabling stroke or transient ischaemic attack was associated with improved achievement of secondary prevention targets but did not lead to a significantly lower rate of major vascular events. Further research is needed to investigate the effects of support programmes in selected patients who do not achieve secondary prevention targets soon after discharge. Funding: German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation