Cost-effectiveness of rimegepant oral lyophilisate compared to best supportive care for the acute treatment of migraine in the UK.

AIMS: Migraine is the most common disabling headache disorder and is characterized by recurrent throbbing head pain and symptoms of photophobia, phonophobia, nausea, and vomiting. Rimegepant 75 mg, an oral lyophilisate calcitonin gene-related peptide antagonist, is the first treatment approved for both the acute and preventative treatment of migraine, and the first acute therapy approved in over 20-years. The objective was to assess the cost-utility of rimegepant compared with best supportive care (BSC) in the UK, for the acute treatment of migraine in the adults with inadequate symptom relief after taking at least 2 triptans, or for whom triptans are contraindicated or not tolerated. MATERIALS AND METHODS: A de novo model was developed to estimate incremental costs and quality-adjusted life years (QALYs), structured as a decision tree followed by Markov model. Patients received rimegepant or BSC for a migraine attack and were assessed for response (pain relief at 2-h). Responders and non-responders followed different pain trajectories over 48-h cycles. Non-responders discontinued treatment while responders continued treatment for subsequent attacks, with a proportion discontinuing over time. Data sources included a post-hoc pooled analysis of the phase 3 acute rimegepant trials (NCT03235479, NCT03237845, NCT03461757), and a long-term safety study (NCT03266588). The analysis was conducted from the perspective of the UK National Health Service and Personal Social Services over a 20-year time horizon. RESULTS: Rimegepant resulted in an incremental cost-utility ratio (ICUR) of £10,309 per QALY gained vs BSC, which is cost-effectiveness at a willingness to pay threshold of £30,000/QALY. Rimegepant generated +0.44 incremental QALYs and higher incremental lifetime costs (£4,492). Improved QALYs for rimegepant were a result of less time spent with severe and moderate headache pain. CONCLUSION: This study highlights the economic value of rimegepant which was found to be cost-effective for the acute treatment of migraine in adults unsuitable for triptans.

The temporal trend of placebo response in migraine prevention from 1990 to 2021: a systematic literature review and meta-analysis with regression.

BACKGROUND: Migraine affects 1.1 billion people globally and is the second leading cause of disability worldwide. In clinical trials, treatment efficacy is evaluated by comparing the differential responses in the treatment and placebo arms. Although placebo response in preventive migraine trials has been studied, there is limited research examining temporal trends. This study evaluates the trend of placebo response over thirty years in migraine prevention trials and investigates the association of potential confounders, such as patient, treatment, and study characteristics on placebo response using meta-analysis with regression. METHODS: We conducted literature searches from January 1990 to August 2021 in bibliographical databases (PubMed, Cochrane Library, and EMBASE). Studies were selected according to PICOS criteria and included randomized, double-blind, placebo-controlled trials evaluating preventive migraine treatments in adult patients diagnosed with episodic or chronic migraine, with or without aura. The protocol was registered with PROSPERO (CRD42021271732). Migraine efficacy outcomes included were either continuous (e.g., monthly migraine days) or dichotomous (e.g., ≥ 50% responder rate (yes/no)). We assessed the correlation of the change in outcome from baseline in the placebo arm, with the year of publication. The relationship between placebo response and year of publication was also assessed after accounting to confounders. RESULTS: A total of 907 studies were identified, and 83 were found eligible. For the continuous outcomes, the change from baseline in mean placebo response showed an increase over the years (rho = 0.32, p = 0.006). The multivariable regression analysis also showed an overall increase in placebo response over the years. The correlation analysis of dichotomous responses showed no significant linear trend between publication year and mean placebo response (rho = 0.08, p = 0.596). Placebo response also varied by route of administration. CONCLUSION: Placebo response increased over the past 30 years in migraine preventive trials. This phenomenon should be considered when designing clinical trials and conducting meta-analyses.

Reliability and Validity of the 6-Minute Walk Test in Hypophosphatasia.

This investigation evaluated the reliability and validity of the 6-Minute Walk Test (6MWT) in patients with pediatric hypophosphatasia (HPP). Children (aged 6 to 12 years; n = 11), adolescents (13 to 17 years; n = 4), and adults (18 to 65 years; n = 9) completed the 6MWT at screening and baseline in two clinical studies of asfotase alfa. Test-retest reliability of the 6MWT, evaluated with Pearson's correlation coefficients (r) for screening versus baseline, was high for children (r = 0.95; p < 0.0001), adolescents (r = 0.81; p = 0.125), and adults (r = 0.94; p = 0.0001). The most conservative minimal clinically important differences, estimated using distribution-based methods, were 31 m (children and adults) and 43 m (adolescents). In children, the 6MWT correlated significantly with scores on measures of skeletal disease, which included the Radiographic Global Impression of Change scale (r = 0.50; p < 0.0001) and the Rickets Severity Scale (r = -0.78; p < 0.0001), such that distance walked increased as the severity of skeletal disease decreased. Significant (p < 0.0001) correlations with the 6MWT distance walked were also observed for children with scores on parent-reported measures of disability (r = -0.67), ability to function in activities of daily living (r = 0.71 to 0.77), and parent-reported measures of pain (r = -0.39). In adolescents and adults, 6MWT distance walked correlated significantly (p < 0.05) with measures of lower extremity function (r = 0.83 and 0.60, respectively), total pain severity (r = -0.41 and -0.36, respectively), and total pain interference (r = -0.41 and -0.49, respectively). Collectively, these data indicate that the 6MWT is a reliable, valid measure of physical functioning in patients with pediatric HPP. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Quantifying risk of adverse clinical events with one set of vital signs among primary care patients with hypertension.

BACKGROUND: Hypertension is often uncontrolled. One reason might be physicians' reticence to modify therapy in response to single office measurements of vital signs. METHODS: Using electronic records from an inner-city primary care practice, we extracted information about vital signs, diagnoses, test results, and drug therapy available on the first primary care visit in 1993 for patients with hypertension. We then identified multivariable predictors of subsequent vascular complications in the ensuing 5 years. RESULTS: Of 5,825 patients (mean age 57 years) previously treated for hypertension for 5.6 years, 7% developed myocardial infarctions, 17% had strokes, 24% developed ischemic heart disease, 22% had heart failure, 12% developed renal insufficiency, and 13% died in 5 years. Controlling for other clinical data, a 10-mmHg increase in systolic blood pressure was associated with 13% increased risk (95% confidence interval [CI], 6%-21%) of renal insufficiency, 9% (95% CI, 3%-15%) increased risk of ischemic heart disease, 7% (95% CI, 3%-11%) increased risk of stroke, and 6% (95% CI, 2%-9%) increased risk of first stroke or myocardial infarction. A 10-mmHg elevation in mean blood pressure predicted a 12% (95% CI, 5%-20%) increased risk of heart failure. An increase in heart rate of 10 beats per minute predicted a 16% (95% CI, 2%-5%) increased risk of death. Diastolic blood pressure predicted only a 13% (95% CI, 4%-23%) increased risk of first stroke. CONCLUSIONS: Vital signs-especially systolic blood pressure-recorded routinely during a single primary care visit had significant prognostic value for multiple adverse clinical events among patients treated for hypertension and should not be ignored by clinicians.

Preventing coronary events by optimal control of blood pressure and lipids in patients with the metabolic syndrome.

We estimated the coronary heart disease (CHD) events that are preventable by treatment of lipids and blood pressure in patients with metabolic syndrome (MetS), a contributor to coronary heart disease (CHD). Among patients aged 30 to 74 years (without diabetes or CHD) in the United States, MetS was defined by National Cholesterol Education Program criteria. CHD events over a period of 10 years were estimated by Framingham algorithms. Events that could be prevented by statistically "controlling" blood pressure, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol to either normal or optimal levels according to national guidelines were calculated. Of 7.5 million men and 9.0 million women aged 30 to 74 years with MetS, approximately 1.5 million men and 0.45 million women, if untreated, developed CHD events in 10 years. In men and women, blood pressure control to normal levels "prevented" 28.1% and 12.5% of CHD events, respectively (p <0.01); control to optimal levels resulted in preventing 28.2% and 45.2% of events, respectively (p <0.01). Control of HDL cholesterol to normal levels resulted in preventing 25.3% of events in men and 27.3% in women; optimal control prevented 51.2% and 50.6% of events, respectively. Control of LDL cholesterol to normal levels prevented 9.3% of events in men and 9.8% of events in women; control to optimal levels prevented 46.2% and 38.1% of events (p <0.05), respectively. Control of all 3 risk factors to normal levels resulted in preventing 51.3% of events for men and 42.6% for women; control to optimal levels resulted in preventing 80.5% and 82.1% of events, respectively. Thus, many CHD events in patients with MetS may be preventable by nominal or optimal control of lipids and/or blood pressure.

Preventing heart disease by controlling hypertension: impact of hypertensive subtype, stage, age, and sex.

BACKGROUND: Hypertension is related to significant morbidity and mortality rates from coronary heart disease (CHD). This report examines the relative and absolute impact on risk for CHD by controlling hypertension to high normal and optimal levels. METHODS: Among all subjects with untreated or inadequately treated hypertension in the National Health and Nutrition Examination Survey (NHANES) III who were 30 to 74 years of age and without prior CHD, the 10-year risk of CHD was calculated. With the use of sampling weights, the number of CHD events by age group, hypertension subtype (isolated diastolic hypertension [IDH], systolic-diastolic hypertension [SDH], and isolated systolic hypertension [ISH]), and stage of hypertension was estimated. Risk was recalculated and the number of events reestimated, assuming a reduction in blood pressure (BP) to high normal and optimal levels. The number and proportion (population-attributable risk, or PAR%) of events that could be prevented were determined from the differences in events and risk between uncontrolled and controlled BP levels. Derived from this was the number of persons needing treatment per CHD event prevented. RESULTS: Control of hypertension to high normal levels could prevent approximately one fifth (PAR = 19%) of CHD events in men and one third (PAR = 31%) of CHD events in women, whereas control to optimal levels may prevent 37% and 56% of CHD events, respectively (P <.01 for differences between men and women). Of CHD events that could be prevented, the greatest proportion occurred from controlling BP among older persons, men, and those with stage 1 hypertension (vs stages 2 and 3) or with ISH (vs IDH or SDH). The number of persons with hypertension needing treatment to prevent one CHD event ranged from 20.5 in men to 38.6 in women when controlled to high normal BP and 10.7 in men and 21.3 in women when controlled to optimal BP. CONCLUSIONS: The greatest impact from control of hypertension occurs in older persons, men, and those with ISH, whereas the greatest PAR% occurred in women. Optimal control of BP could prevent more than one third of CHD events in men and more than half of events in women. Greater efforts to control hypertension in these populations may have a substantial impact in preventing CHD events.