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Aims To describe the characteristics of patients receiving evolocumab in clinical practice across 12 European countries and simulate the association between low-density lipoprotein cholesterol (LDL-C) reduction and cardiovascular (CV) risk reduction. Methods and results The characteristics of hyperlipidaemic patients at initiation of evolocumab and treatment patterns study—HEYMANS (n = 1952) is a prospective registry of patients ≥18 years old who initiated evolocumab from 1 August 2015 onwards. Mean (standard deviation) age was 60 (10.8), 85% had a prior CV event, 45% were diagnosed with familial hypercholesterolaemia (FH), and 60% had statin intolerance. At evolocumab initiation, 43% were receiving any statin, 16% were receiving ezetimibe without statin, and 41% received no background lipid-lowering therapy (LLT), with LDL-C levels reflecting local proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) reimbursement criteria. Median LDL-C decreased from 3.98 to 1.63 mmol/L within 3 months of evolocumab initiation and was maintained over 24 months. Overall, 58% achieved risk-based 2019 European Society of Cardiology/European Atherosclerosis Society LDL-C goals but that proportion was higher (68%) in patients receiving background LLT compared with those not receiving background LLT (44%). In patients with atherosclerotic cardiovascular disease without FH, the simulated relative CV risk reduction associated with evolocumab treatment was 34% (25–44%). Conclusion Across Europe, LDL-C levels at evolocumab initiation were three times higher than recommended thresholds for PCSK9i initiation, reflecting disparities between implementation and guidelines. More patients attained risk-based LDL-C goals when receiving evolocumab in combination with LLT vs. those not receiving combination therapy. Population health could be improved and LDL-C goals better attained if LDL-C thresholds for PCSK9i reimbursement were lowered, enabling more patients to receive combination therapy when needed.

Contains fulltext : 291332.pdf (Publisher’s version ) (Open Access) INTRODUCTION: The 2019 European Society of Cardiology and European Atherosclerosis Society (2019 ESC/EAS) guidelines stress the importance of managing low-density lipoprotein cholesterol (LDL-C) after myocardial infarction (MI) to reduce the risk of cardiovascular events. Information on guideline implementation is limited. The aim of this survey was to describe current clinical practice regarding LDL-C management in the first year post-MI across Europe, improving understanding of the role of ESC/EAS guidelines on clinical practice. METHODS: A qualitative web-based cross-sectional physician survey about the patient pathway and LDL-C management post-MI was conducted in 360 physicians from France, Italy, Germany, The Netherlands, Spain, and the UK (n = 60/country) between December 2019 and June 2020. Secondary and primary care physicians (SCPs/PCPs) described their experiences treating patients post-MI over the preceding 2 months. RESULTS: Physicians reported that on average 90.7% of patients not prescribed lipid-lowering therapy (LLT) before an MI initiated LLT as inpatients; for patients already taking LLT, treatment was intensified for 64.7% of inpatients post-MI. SCPs reported prescribing higher-intensity statins and/or ezetimibe for between 72.3% (Italy) and 88.6% (UK) of patients post-MI. More than 80.0% of SCPs and 51.2% of PCPs stated that they would initiate a change in LLT immediately if patients did not achieve their LDL-C treatment goal by 12 weeks post-MI; 82.0% of SCPs and 55.1% of PCPs reported referring to 2019 ESC/EAS guidelines for management of patients post-MI. Barriers to initiating PCSK9 inhibitors (PCSK9is) included prior prescription of a maximally tolerated dose of statin (49.4%) and/or ezetimibe (38.9%), requirement to reach threshold LDL-C levels (44.9%), and pre-authorization requirements (30.4%). CONCLUSION: Differences in clinical practice post-MI were reported across the countries surveyed, including divergence between 2019 ESC/EAS and local guidelines. Increased use of innovative medicines to achieve LDL-C goals should reduce risk of subsequent cardiovascular events in very high-risk patients post-MI. 01 januari 2023

Author(s): Fonarow, Gregg C; Kosiborod, Mikhail N; Rane, Pallavi B; Nunna, Sasikiran; Villa, Guillermo; Habib, Mohdhar; Arellano, Jorge; Mues, Katherine E; Sun, Kainan; Wade, Rolin L | Abstract: BackgroundThe risk for subsequent major cardiovascular (CV) events among patients with very high-risk (VHR) atherosclerotic CV disease (ASCVD) remains to be fully elucidated.HypothesisWe assessed the characteristics and major CV event rates of patients with VHR versus non-VHR ASCVD in a real-world setting in the United States (US), hypothesizing that patients with VHR ASCVD would have higher CV event rates.MethodsThis was a retrospective cohort study conducted from January 01, 2011, to June 30, 2018, in the US using the Prognos LDL-C database linked to the IQVIA PharMetrics Plus® database supplemented with the IQVIA prescription claims (Dx/LRx) databases. Patients were ≥18 years old and had ≥2 non-ancillary medical claims in the linked databases at least 30 days apart. The study was conducted in 2 stages: (1) identification of patients with ASCVD who met the definition of VHR ASCVD and a matched cohort of non-VHR ASCVD patients using the incidence density sampling (IDS) approach; (2) estimation of the occurrence of major CV events.ResultsAmong patients with ≥1 major ASCVD event (N=147,679), most qualified as VHR ASCVD (79.5%). There were 115,460 patients each in IDS-matched VHR and non-VHR ASCVD cohorts. The composite myocardial infarction/ischemic stroke event rates in the VHR and non-VHR ASCVD cohorts were 8.04 (95% confidence interval [95% CI]: 7.87-8.22) and 0.82 (95% CI: 0.77-0.88) events per 100 patient-years, respectively, during the 1-year post-index period.ConclusionsMost patients with ≥1 previous major ASCVD event treated in real-world US clinical practice qualified as VHR ASCVD. Patients with VHR ASCVD had much higher rates of major CV events versus non-VHR ASCVD patients.

Background In patients at risk of cardiovascular (CV) events, the effectiveness of lipid-lowering therapies (LLT) is affected by both intensity and adherence. Our study evaluated the association between LLT intensity (statin and/or ezetimibe) and adherence, and CV events in patients with a history of myocardial infarction (MI) in France. Methods Using the French national healthcare database (SNDS), we included patients with a history of MI, an initial LLT prescription in 2011–2013, and a second prescription within one year. LLT intensity was defined using the expected percent reduction in low-density lipoprotein cholesterol; adherence was measured as the proportion of days covered. Cox proportional hazards models were used to assess associations between intensity and/or adherence, and the risk of major adverse CV event (MACE). Results 164,565 patients were included; mean (SD) age, 66·3 (13·8) years; 73·6% men. Following an MI, only half of patients were treated with high-intensity LLT and approximately 40% of those on LLT remained non-adherent during follow-up (mean (SD) follow-up, 2·6 (1·4) years). Each 10% increase in treatment intensity, adherence, or adherence-adjusted intensity was respectively associated with a 16% (HR 0.84, 95%CI 0.84–0.85), 7% (HR 0.93, 95%CI 0.93–0.94), and 15% (HR 0.85, 95%CI 0.84–0.86) decrease in the risk of MACE. Conclusions Among patients with a history of MI, prescriptions of high-intensity LLT were limited and adherence to LLT was low. Higher intensity and/or adherence to statins was associated with a significantly lower risk of MACE, highlighting the importance of compliance with clinical guidelines to improve patient outcomes.

ObjectivesTo compare treatment patterns, risk factors and cardiovascular disease (CVD) event rates in the UK from 2008 to 2017.DesignRetrospective cohort study using the Clinical Practice Research Datalink.SettingUK primary care.ParticipantsWe selected 10 annual cohorts of patients with documented CVD receiving lipid-lowering therapy and the subsets with myocardial infarction (MI). Each cohort included patients ≥18 years old, with ≥1 year of medical history and ≥2 lipid-lowering therapy prescriptions in the prior year.Primary and secondary outcome measuresFor each annual cohort, we identified cardiovascular risk factors and lipid-lowering therapy and estimated the 1-year composite rate of fatal and non-fatal MI, ischaemic stroke (IS) or revascularisation.ResultsThe documented CVD cohort mean age was 71.6 years in 2008 (N=173 424) and 72.5 (N=94 418) in 2017; in the MI subset, mean age was 70.1 years in 2008 (N=38 999) and 70.4 in 2017 (N=25 900). Both populations had larger proportions of men. In the documented CVD cohort, the proportion receiving high-intensity lipid-lowering therapy from 2008 to 2017 doubled from 16% to 32%; in the MI subset, the increase was 20% to 48%. In the documented CVD cohort, the proportion of patients with low-density lipoprotein cholesterol (LDL-C) ConclusionsDespite an increase in high-intensity therapy use and a decline in revascularisation, more than half of patients did not receive high-intensity lipid-lowering therapy by 2017 and incidence rates of MI and IS remained virtually unchanged.

There is little evidence on the relationship between achieved low-density lipoprotein cholesterol (LDL-C) levels and costs in patients on lipid-lowering therapy (LLT). We described healthcare resource use and costs (direct and indirect) by achieved LDL-C in patients receiving LLT after a recent myocardial infarction (MI) in Spain.This was a retrospective observational study of anonymized electronic medical records from seven regions in Spain (BIG-PACOf 6025 patients (mean age, 69.7 years; 77% male), only 11% achieved LDL-C goals as defined in the 2016 ESC/EAS guidelines ( 70 mg/dL), and just 1% reached the lower target ( 55 mg/dL) in the current 2019 guidelines. Achieving lower LDL-C levels translated to lower healthcare resource use and costs. Mean total (direct and indirect) costs ranged from €5044 for patients with LDL-C 55 mg/dL to €7567 for patients with LDL-C ≥ 130 mg/dL.Very few patients achieved recommended LDL-C goals despite using LLT. Achieving lower LDL-C levels after an MI might be associated with lower healthcare resource use and costs. Use of more intensive LLT, leading to greater reductions in LDL-C, could therefore be beneficial both from a clinical and an economic perspective.

Aims To assess the cost-effectiveness of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab added to standard-of-care lipid-lowering treatment [maximum tolerated dose (MTD) of statin and ezetimibe] in Swedish patients with a history of myocardial infarction (MI). Methods and results Cost-effectiveness was evaluated using a Markov model based on Swedish observational data on cardiovascular event rates and efficacy from the FOURIER trial. Three risk profiles were considered: recent MI in the previous year; history of MI with a risk factor; and history of MI with a second event within 2 years. For each population, three minimum baseline low-density lipoprotein cholesterol (LDL-C) levels were considered: 2.5 mmol/L (≈100 mg/dL), based on the current reimbursement recommendation in Sweden; 1.8 mmol/L (≈70 mg/dL), based on 2016 ESC/EAS guidelines; and 1.4 mmol/L (≈55 mg/dL), or 1.0 mmol/L (≈40 mg/dL) for MI with a second event, based on 2019 ESC/EAS guidelines. Proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab was associated with increased quality-adjusted life-years and costs vs. standard-of-care therapy. Incremental cost-effectiveness ratios (ICERs) were below SEK700 000 (∼€66 500), the generally accepted willingness-to-pay threshold in Sweden, for minimum LDL-C levels of 2.3 (recent MI), 1.7 (MI with a risk factor), and 1.7 mmol/L (MI with a second event). Sensitivity analyses demonstrated that base-case results were robust to changes in model parameters. Conclusion Proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab added to MTD of statin and ezetimibe may be considered cost-effective at its list price for minimum LDL-C levels of 1.7–2.3 mmol/L, depending on risk profile, with ICERs below the accepted willingness-to-pay threshold in Sweden.

Background: Oral lipid-lowering treatment (LLT) is the standard of care for patients with cardiovascular disease (CVD). However, insufficient treatment intensity and poor adherence can lead to suboptimal treatment benefit, rendering patients at increased risk of CVD. Aims: The objective of this study was to evaluate trends in LLT intensity and adherence in Sweden over time, and their association with major adverse cardiovascular events (MACE) after recent myocardial infarction (MI), and also to assess the impact of transition from secondary to primary care on intensity and adherence. Methods and results: This retrospective observational cohort study used data from Swedish nationwide patient registers and included patients on LLT after an MI in the years 2010–2016 (n = 50,298; mean age, 68 years; 69% men). LLT intensity was evaluated over time (overall, for 2010–2013 and for 2014–2016) as the proportion of patients prescribed low-, moderate-, and high-intensity LLT. Adherence was assessed as the proportion of days covered. A combined measure of intensity and adherence was also considered. Differences in treatment patterns and MACE were assessed. Initiation of high-intensity LLT increased over the two time periods studied (2010–2013, 32%; 2014–2016, 91%). Adherence varied by LLT intensity and was highest in patients receiving high-intensity LLT (>80%), especially during the first time period. Little change in treatment intensity or the combined measure of intensity and adherence was observed after transition to primary care. There was a significant association between the combined measure of intensity and adherence and MACE reduction (hazard ratio [95% confidence interval] per 10% increase in the combined measure: 0.84 [0.82–0.86]; P < 0.01). Conclusion: The proportion of post-MI patients with high LLT intensity and adherence has increased in recent years, with little change after transfer from specialist to primary care. The combination of LLT intensity and adherence is important for preventing future cardiovascular events.

Background/Introduction FOURIER included 22,351 patients with a history of myocardial infarction (MI) and a median low-density lipoprotein cholesterol (LDL-C) of 2.4 mmol/L. Reducing LDL-C with evolocumab reduced the risk of major cardiovascular (CV) events by 1.3%, in absolute terms, over 2.2 years. Whether similar benefits might be observed in real-world evidence from evolocumab use is unknown. Purpose Simulate CV risk and assess the potential CV risk reduction among a large European cohort of evolocumab users with a history of MI. Methods We used interim data from HEYMANS, a register of patients initiating evolocumab in routine clinical practice across 12 European countries, from August 2015 with follow-up through July 2020. Demographic and clinical characteristics, lipid-lowering therapy (LLT), and lipid values were collected from routine medical records (6 months prior to evolocumab initiation through 30 months post initiation). Patients with a history of MI were considered and two sub-cohorts were created: recent MI (MI ≤1 year before evolocumab initiation) and remote MI (MI >1 year before evolocumab initiation). For each patient, we 1) simulated their CV risk using three different sources, correcting for age and LDL-C: i) the REACH equation, ii) FOURIER, iii) an observational study including FOURIER-like patients; 2) calculated their absolute LDL-C reduction on evolocumab; 3) simulated their relative risk reduction (RRR) by randomly sampling from the inverse probability distribution of the rate ratio per 1 mmol/L from the key secondary endpoint in the FOURIER landmark analysis; 4) calculated their absolute risk reduction (ARR) and number needed to treat (NNT) over 2 years (recent MI) or 10 years (remote MI). Results Our analysis included 90 recent MI and 489 remote MI patients initiating evolocumab in clinical practice per local reimbursement criteria, with up to 24 months follow-up. Median (inter-quartile range) age was 59 (53–67) and 61 (53–68) years in recent MI and remote MI patients, respectively. LDL-C before evolocumab was 3.8 (3.2–4.6) and 3.6 (3.0–4.5) mmol/L. Absolute LDL-C reduction on evolocumab was 2.2 (1.4–2.8) and 2.2 (1.6–2.8) mmol/L, meaning relative LDL-C reduction of 60% (44%-73%) and 62% (47%-72%), respectively. Predicted ARR with evolocumab was substantial, whether over 2 years (recent MI) or over 10 years (remote MI). See Table 1. Conclusions This cohort of evolocumab users in clinical practice had a higher baseline LDL-C and CV risk than patients enrolled in FOURIER. LDL-C reduction and RRR were very similar in recent MI and remote MI patients. However, patients with a recent MI had a higher short-term CV risk and therefore showed a larger ARR on evolocumab. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen

Background Cost-effectiveness analyses in patients with migraine require estimates of patients’ utility values and how these relate to monthly migraine days (MMDs). This analysis examined four different modelling approaches to assess utility values as a function of MMDs. Methods Disease-specific patient-reported outcomes from three erenumab clinical studies (two in episodic migraine [NCT02456740 and NCT02483585] and one in chronic migraine [NCT02066415]) were mapped to the 5-dimension EuroQol questionnaire (EQ-5D) as a function of the Migraine-Specific Quality of Life Questionnaire (MSQ) and the Headache Impact Test (HIT-6™) using published algorithms. The mapped utility values were used to estimate generic, preference-based utility values suitable for use in economic models. Four models were assessed to explain utility values as a function of MMDs: a linear mixed effects model with restricted maximum likelihood (REML), a fractional response model with logit link, a fractional response model with probit link and a beta regression model. Results All models tested showed very similar fittings. Root mean squared errors were similar in the four models assessed (0.115, 0.114, 0.114 and 0.114, for the linear mixed effect model with REML, fractional response model with logit link, fractional response model with probit link and beta regression model respectively), when mapped from MSQ. Mean absolute errors for the four models tested were also similar when mapped from MSQ (0.085, 0.086, 0.085 and 0.085) and HIT-6 and (0.087, 0.088, 0.088 and 0.089) for the linear mixed effect model with REML, fractional response model with logit link, fractional response model with probit link and beta regression model, respectively. Conclusions This analysis describes the assessment of longitudinal approaches in modelling utility values and the four models proposed fitted the observed data well. Mapped utility values for patients treated with erenumab were generally higher than those for individuals treated with placebo with equivalent number of MMDs. Linking patient utility values to MMDs allows utility estimates for different levels of MMD to be predicted, for use in economic evaluations of preventive therapies. Trial registration ClinicalTrials.gov numbers of the trials used in this study: STRIVE, NCT02456740 (registered May 14, 2015), ARISE, NCT02483585 (registered June 12, 2015) and NCT02066415 (registered Feb 17, 2014).

Objectives To identify risk equations for cardiovascular diseases (CVDs) in primary and secondary prevention settings that are used or recommended by health technology assessment (HTA) organizations and in clinical guidelines (CGs). Methods A targeted literature review was conducted using a two-stage search strategy. First, HTA reviews of manufacturers’ drug submissions, reports from established HTA organizations (Europe, Canada, and Australia), and CGs from countries with and without HTA organizations, including the United States, were identified. Documents published between September 30, 2006 and September 30, 2016, were examined for cardiovascular risk equations, recommendations, and commentaries. Next, publications associated with risk equations and cited by HTA and CG documents were retrieved. This literature was examined to extract commentaries and risk equation study characteristics. Results The review identified 47 risk equations, 25 in the primary CVD prevention setting (i.e., patients with no CVD history), including 5 for CVD prevention in diabetes and 22 solely in secondary prevention settings; 11 were identified for heart failure, 3 for stroke or transient ischemic attack, 2 for stable angina, and 11 for acute coronary syndrome or related conditions. A small set of primary prevention equations was found to be commonly used by HTAs, whereas secondary prevention equations were less common in HTA documents. CGs provided more risk equations as options than HTA documents. Conclusions Although there is an abundance of risk equations developed for primary and secondary prevention, there remains a need for additional research to provide sufficient clinical and HTA guidance for risk estimation, particularly in high-risk or secondary prevention settings.

Background Health economic models are critical tools to inform reimbursement agencies on health care interventions. Many clinical trials report outcomes using the frequency of an event over a set period of time, for example, the primary efficacy outcome in most clinical trials of migraine prevention is mean change in the frequency of migraine days (MDs) per 28 days (monthly MDs [MMD]) relative to baseline for active treatment versus placebo. Using these cohort-level endpoints in economic models, accounting for variation among patients is challenging. In this analysis, parametric models of change in MMD for migraine preventives were assessed using data from erenumab clinical studies. Methods MMD observations from the double-blind phases of two studies of erenumab were used: one in episodic migraine (EM) (NCT02456740) and one in chronic migraine (CM) (NCT02066415). For each trial, two longitudinal regression models were fitted: negative binomial and beta binomial. For a thorough comparison we also present the fitting from the standard multilevel Poisson and the zero inflated negative binomial. Results Using the erenumab study data, both the negative binomial and beta-binomial models provided unbiased estimates relative to observed trial data with well-fitting distribution at various time points. Conclusions This proposed methodology, which has not been previously applied in migraine, has shown that these models may be suitable for estimating MMD frequency. Modelling MMD using negative binomial and beta-binomial distributions can be advantageous because these models can capture intra- and inter-patient variability so that trial observations can be modelled parametrically for the purposes of economic evaluation of migraine prevention. Such models have implications for use in a wide range of disease areas when assessing repeated measured utility values. Electronic supplementary material The online version of this article (10.1186/s12874-019-0664-5) contains supplementary material, which is available to authorized users.

Introduction The impact of additional risk factors on major cardiovascular event (MACE) rates in patients with a history of myocardial infarction (MI) or ischaemic stroke (IS) treated with statins is not well defined. Methods In this retrospective population-based cohort study, patients with a history of MI or IS treated with moderate- or high-intensity statins were identified using Swedish national register data. Patients were incident (index event between July 2006 and December 2014 and followed from diagnosis) or prevalent (MI or IS before July 2006 and followed thereafter). Four subgroups were defined on the basis of additional risk factors associated with increased cardiovascular risk: diabetes mellitus with target organ damage; chronic kidney disease stages 3–4; index event within 2 years after prior MI or IS; and polyvascular disease. First and total MACE rates (i.e. MI, IS, or cardiovascular death) were calculated, and first MACE 10-year risks (prevalent cohort only) were predicted. Results Numerically, MACE rates in subgroups were 1.5–3 times higher than in overall populations, and were highest in the 2 years after the index event. First MACE rates in the additional risk factor subgroups were 17.2–33.5 per 100 person-years for the incident cohorts and 9.9–13.2 per 100 person-years for the prevalent cohorts. Total MACE rates per 100 person-years were 20.1–39.8 per 100 person-years and 12.4–17.6 per 100 person-years, respectively. Conclusion Despite previous use of moderate- or high-intensity statins, patients with a history of MI or IS, and additional risk factors remain at very high cardiovascular risk. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01852-1.

Background and aims Untreated Familial Hypercholesterolemia (FH) leads to premature morbidity and mortality. In France, its epidemiology and management are understudied in ambulatory care. We described the clinical profile, pharmacological management, and clinical outcomes in a French sample of FH patients. Methods This was a retrospective longitudinal study on patients from The Health Improvement Network (THIN®) database in France, between October 2016-June 2019. Patients ≥18 years, with probable/definite FH based on the Dutch Lipid Clinic Network (DLCN) criteria were included. Baseline characteristics, lipid profile, lipid-lowering therapy (LLT), low-density lipoprotein-cholesterol (LDL-C) goal achievement; and disease management at 6-month of follow-up were analyzed. Results 116 patients with probable (n = 70)/definite (n = 46) FH were included (mean age:57.8±14.0 years; 56.0% women; 9.5% with personal history of cardiovascular events); 90 patients had data available at follow-up. At baseline, 77.6% of patients had LDL-C>190 mg/dL, 27.6% were not receiving LLTs, 37.9% received statins alone, 20.7% statins with other LLTs, and 7.7% other LLTs. High-intensity statins were prescribed to 11.2% of patients, 30.2% received moderate-intensity statins, and 8.6% low-intensity statins. Only 6.0% of patients achieved LDL-C goal. At 6-month of follow-up, statins discontinuation and switching were 22.7% and 2.3%, respectively. None of the patients received proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors at baseline nor follow-up. Conclusions Despite the existence of effective LLTs, FH patients are suboptimally-treated, do not achieve LDL-C goal, and exhibit worsened pharmacological management over time. Future studies with longer follow-up periods and assessment of factors affecting LDL-C management, including lifestyle and diet, are needed.

espanolResumen A lo largo del siglo XVI, la institucion juridica de la esclavitud se extendio en Nueva Espana mediante la importacion de personas desde Africa. Si bien la historiografia tradicional ha priorizado el aspecto sociopolitico y narrativo de la rebelion de esclavos liderada por Yanga en Veracruz, el objetivo del presente trabajo es esclarecer las implicaciones juridicas de este conflicto y las politicas de defensa y diplomacia que adoptaron las autoridades virreinales para enfrentarse al mismo. La actitud conciliadora y diplomatica del virrey Luis de Velasco, en aras de evitar erogaciones innecesarias, se vio sustituida gradualmente por una politica agresiva de defensa interior que culmino con el pacto que daria origen al primer pueblo libre del continente, de naturaleza foral. EnglishAbstract Throughout the XVI century, the legal institution of slavery spread across Nueva Espana, as people were imported from Africa. Whereas traditional historiography has emphasized the sociopolitical aspect of the slave rebellion in Veracruz led by Yanga, this paper aims to clarify the juridical implications of the conflict, as well as the defensive and diplomatic policies implemented by the vice-royal authorities. The pragmatically prudent and diplomatic initial attitude of Viceroy Luis de Velasco towards the rebellious slaves, to avoid unnecessary public spending, switched gradually to an aggressive policy of interior defense that culminated with the pact that gave origin to the first free town in the American continent, which had an ex gratia legal nature.

Background Previous reviews have evaluated economic analyses of lipid-lowering therapies using lipid levels as surrogate markers for cardiovascular disease. However, drug approval and health technology assessment agencies have stressed that surrogates should only be used in the absence of clinical endpoints. Objective The aim of this systematic review was to identify and summarise the methodologies, weaknesses and strengths of economic models based on atherosclerotic cardiovascular disease event rates. Methods Cost-effectiveness evaluations of lipid-lowering therapies using cardiovascular event rates in adults with hyperlipidaemia were sought in Medline, Embase, Medline In-Process, PubMed and NHS EED and conference proceedings. Search results were independently screened, extracted and quality checked by two reviewers. Results Searches until February 2016 retrieved 3443 records, from which 26 studies (29 publications) were selected. Twenty-two studies evaluated secondary prevention (four also assessed primary prevention), two considered only primary prevention and two included mixed primary and secondary prevention populations. Most studies (18) based treatment-effect estimates on single trials, although more recent evaluations deployed meta-analyses (5/10 over the last 10 years). Markov models (14 studies) were most commonly used and only one study employed discrete event simulation. Models varied particularly in terms of health states and treatment-effect duration. No studies used a systematic review to obtain utilities. Most studies took a healthcare perspective (21/26) and sourced resource use from key trials instead of local data. Overall, reporting quality was suboptimal. Conclusions This review reveals methodological changes over time, but reporting weaknesses remain, particularly with respect to transparency of model reporting.

Introduction: We reviewed the evolution of the methods used in cost-effectiveness analyses of granulocyte colony-stimulating factors (G-CSFs) in the primary and secondary prevention of febrile neutropenia (FN) in patients receiving myelosuppressive cancer chemotherapy.Areas covered: FN is a side effect of myelosuppressive chemotherapy associated with significant morbidity, mortality, and costs. The risk of FN may depend on the drugs used within a chemotherapy regimen, and an FN event may cause chemotherapy dose reductions or delays in subsequent cycles.Expert commentary: More recent pharmacoeconomic models have reflected these clinical observations by modeling sequential chemotherapy regimens to account for FN risk on a per-cycle basis, and by accounting for chemotherapy dose reductions and consequent survival losses.

Objective The objective of this study was to evaluate the cost effectiveness of no prophylaxis, primary prophylaxis (PP), or secondary prophylaxis (SP) with granulocyte colony-stimulating factors (G-CSFs), i.e., pegfilgrastim, lipegfilgrastim, filgrastim (6- and 11-day), or lenograstim (6- and 11-day), to reduce the incidence of febrile neutropenia (FN) in patients with stage II breast cancer receiving TC (docetaxel, cyclophosphamide) and in patients with non-Hodgkin lymphoma (NHL) receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) over a lifetime horizon from a Belgian payer perspective. Methods A Markov cycle tree tracked FN events during chemotherapy (3-week cycles) and long-term survival (1-year cycles). Model inputs, including the efficacy of each strategy, risk of reduced relative dose intensity (RDI), and the impact of RDI on mortality, utilities, and costs (in €; 2014 values) were estimated from public sources and the published literature. Incremental cost-effectiveness ratios (ICERs) were assessed for each strategy for costs per FN event avoided, life-year (LY) saved, and quality-adjusted LY (QALY) saved. LYs and QALYs saved were discounted at 1.5% annually. Deterministic and probabilistic sensitivity analyses (DSAs and PSAs) were conducted. Results Base-case ICERs for PP with pegfilgrastim relative to SP with pegfilgrastim were €15,500 per QALY and €14,800 per LY saved for stage II breast cancer and €7800 per QALY and €6900 per LY saved for NHL; other comparators were either more expensive and less effective than PP or SP with pegfilgrastim or had lower costs but higher ICERs (relative to SP with pegfilgrastim) than PP with pegfilgrastim. Results of the DSA for breast cancer and NHL comparing PP and SP with pegfilgrastim indicate that the model results were most sensitive to the cycle 1 risk of FN, the proportion of FN events requiring hospitalization, the relative risk of FN in cycles ≥2 versus cycle 1, no history of FN, and the mortality hazard ratio for RDI (

Objective Our study aimed to estimate the impact of addressing modifiable risk factors on the future burden of cardiovascular diseases (CVD) in the general population and in two high-risk populations (heterozygous familial hypercholesterolemia and secondary prevention) for Turkey. Methods One model investigated the impact of reaching the World Health Organization (WHO) voluntary targets for tobacco use, hypertension, type 2 diabetes, obesity and physical inactivity in the general population. Another model estimated the impact of reducing LDL-cholesterol in two high-risk populations through increased access to effective treatment. Inputs for the models include disease and risk factor prevalence rates, a population forecast, baseline CVD event rates, and treatment effectiveness, primarily derived from the published literature. Direct costs to the public health care system and indirect costs from lost production are included, although the cost of programs and pharmacological interventions to reduce risk factors were not considered. Results The value of reaching WHO risk factor reduction targets is estimated at US$9.3 billion over the next 20 years, while the value of reducing LDL-cholesterol is estimated at up to US$8.1 billion for high-risk secondary prevention patients and US$691 million for heterozygous familial hypercholesterolemia patients. Conclusion Efforts to achieve WHO risk factor targets and further lower LDL-cholesterol through increased access to treatment for high-risk patients are projected to greatly reduce the growing clinical and economic burden of CVD in Turkey.

Aims The aims of this study were to re-estimate the international REduction of Atherothrombosis for Continued Health (REACH) risk equation using United Kingdom data and to distinguish different relative hazards for specific atherosclerotic cardiovascular disease event histories. Methods and results Patients in the UK Clinical Research Practice Datalink (CPRD) were included as of 1 January 2005 if they were 40 years or older, had 2 or more years of prior data, received one or more moderate or high-intensity statin in the previous year, and had a history of myocardial infarction, ischemic stroke, or other atherosclerotic cardiovascular disease. Patients were followed until a composite endpoint of myocardial infarction, ischemic stroke or cardiovascular death, loss to follow-up, or end of observation. We re-estimated the REACH risk equation hazard ratios (HRs) using CPRD data (re-estimated REACH model). Our event history model replaced the REACH vascular bed variables with more specific event histories. There were 60,838 patients with 5.25 years of mean follow-up. In the validation model, HRs were in the same direction, and generally greater than REACH. In the event history model, HRs compared to other atherosclerotic cardiovascular disease alone included: recurrent myocardial infarction (HR 1.19, 95% confidence interval (CI) 1.05–1.34), recurrent ischemic stroke (HR 1.36, 95% CI 1.03–1.80), myocardial infarction and other atherosclerotic cardiovascular disease (HR 1.31, 95% CI 1.23–1.38), ischemic stroke and other atherosclerotic cardiovascular disease (HR 1.40, 95% CI 1.23–1.60), myocardial infarction and ischemic stroke (HR 1.94, 95% CI 1.23–3.04), and myocardial infarction, ischemic stroke and other atherosclerotic cardiovascular disease (HR 1.93, 95% CI 1.47–2.54). Conclusion A detailed cardiovascular event history may be useful for estimating the relative risk of future cardiovascular events.

Aims This study aimed to estimate the rate of cardiovascular (CV) events in the real world in patients at high risk of recurrent CV events similar to the FOURIER trial population. Methods and results A retrospective population-based cohort study was conducted using Swedish national registers from 1 July 2001 to 31 December 2015. Patients in the atherosclerotic cardiovascular disease (ASCVD) prevalent cohort met the FOURIER-like inclusion criteria, including treatment with high/moderate-intensity statins, on 1 July 2006. Additionally, two cohorts defined by diagnosis of incident ischaemic stroke (IS) and incident myocardial infarction (MI), meeting the FOURIER-like inclusion criteria were followed from date of diagnosis. Event rates were calculated for the hard major adverse cardiovascular events (MACE) composite: MI, IS, and CV death; and the ASCVD composite: MI, IS, unstable angina, coronary revascularization, and CV death. Approximately half of patients experienced a CV event (ASCVD composite) during follow-up. The MACE composite rates/100 person-years were 6.3, 11.9, and 12.3 in the ASCVD prevalent (n = 54 992), MI incident (n = 45 895), and IS incident (n = 36 134) cohorts, respectively. The ASCVD composite rates/100 person-years were 7.0, 21.7, and 12.9 in the ASCVD prevalent, MI incident, and IS incident cohorts, respectively. The multiple-event MACE composite rates/100 person-years were 8.5 (ASCVD prevalent cohort), 15.4 (MI incident cohort), and 14.4 (IS incident cohort). Conclusion In this real-world setting, CV event rates were high in all studied cohorts. In particular, the MACE composite rates were two to three times higher than in the FOURIER clinical trial, indicating a substantial disease burden despite treatment with moderate or high-intensity statins.

Background European and American guidelines recommend different LDL-C goals for ASCVD patients. We simulated the residual CV risk for 2019 ESC/EAS versus 2018 ACC/AHA LDL-C goals (

Randomized trials have shown marked reductions in low‐density lipoprotein cholesterol (LDL‐C), a risk factor for cardiovascular disease (CVD), when evolocumab is administered. We hypothesized that evolocumab added to standard of care (SOC) vs SOC alone is cost‐effective in the treatment of patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic CVD (ASCVD) with or without statin intolerance and LDL‐C >100 mg/dL. Using a Markov cohort state transition model, primary and recurrent CVD event rates were predicted considering population‐specific trial‐based mean risk factors and calibrated against observed rates in the real world. The LDL‐C–lowering effect from population‐specific phase 3 randomized studies for evolocumab was used together with estimated LDL‐C–lowering effect on CVD event rates per 38.67‐mg/dL LDL‐C lowering from a statin‐trial meta‐analysis. Costs and utilities were included from published sources. Evolocumab treatment was associated with both increased cost and improved quality‐adjusted life‐years (QALY): HeFH (incremental cost: US$153 289, incremental QALY: 2.02, incremental cost‐effectiveness ratio: US$75 863/QALY); ASCVD (US$158 307, 1.12, US$141 699/QALY); and ASCVD with statin intolerance (US$136 903, 1.36, US$100 309/QALY). Evolocumab met both the American College of Cardiology/American Heart Association (ACC/AHA) and World Health Organization (WHO) thresholds in each population evaluated. Sensitivity and scenario analyses confirmed that model results were robust to changes in model parameters. Among patients with HeFH and ASCVD with or without statin intolerance, evolocumab added to SOC may provide a cost‐effective treatment option for lowering LDL‐C using ACC/AHA intermediate/high value and WHO cost‐effectiveness thresholds. More definitive information on the clinical and economic value of evolocumab will be available from the forthcoming CVD outcomes study.

Background Migraine is associated with a substantial physical and emotional burden for patients. There is also a large economic burden associated with migraine, in terms of lost productivity and healthcare resource use. By reducing the number of monthly migraine days (MMD) experienced by patients, effective preventive treatments can reduce acute medication use and costs of lost productivity. Methods Patient level data from three erenumab clinical trials (NCT02456740, NCT02483585 and NCT02066415) were combined and migraine day frequencies were examined. The number of days per month on which patients used acute medication was estimated as a function of MMD. Productivity losses were estimated based on patient responses to the Migraine Disability Assessment questionnaire. Zero-inflated Poisson regression models were used to predict acute medication use and productivity losses per MMD. Results The results demonstrated that as MMD increased, use of acute medication also increased. Similarly, as MMD increased, loss of productivity (due to absenteeism and presenteeism) also increased. The relationship of MMD to both acute headache medication use and lost productivity was non-linear, with marginal outcomes increasing with frequency. Conclusions As MMD increased, acute medication use and productivity loss also increased, but the relationship was non-linear. Therefore, it is important that the distribution of MMD patients is accounted for when estimating the outcomes of migraine patients. By reducing the MMD experienced by patients, effective preventive agents may reduce the requirement for acute medication and also reduce productivity loss, which may translate into potential economic savings. Electronic supplementary material The online version of this article (10.1007/s41669-018-0105-0) contains supplementary material, which is available to authorized users.