The role of Real-World Data and evidence in oncology medicines approved in EU in 2018-2019.

Use of Real-World Data (RWD) has gained the interest of different stakeholders in cancer care. The aim of this study was to identify and describe the use of RWD/RWE during the pre-authorization phase of products authorized by the EMA in 2018 and 2019 (n = 111), with the focus on oncology medicines (n = 24). Information was extracted from the European Public Assessment Report (EPAR) summaries and recorded for 5 stages (11 categories) of the drug development lifecycle (discovery, early development, clinical development, registration/market launch, lifecycle management). Specific chapters of full EPAR were reviewed to substantiate the findings on RWD/RWE use in clinical trial design, efficacy, safety, and effectiveness evaluation. RWD/RWE is present in all stages of the oncology drug development; 100.0 % in discovery, 37.5 % early development, 58.3 % in clinical development, 62.5 % in registration decision and 100.0 % in post-authorization lifecycle management. Examples showed that trial design supported by RWD/RWE included use of open label/single arm studies; efficacy was about using either comparison of results to historical controls, supplying survey data obtained outside the clinical trial or utilizing expert panel advice; safety about including literature findings in evidence; and effectiveness on comparison of trial results of the given product to historical data or existing standard of care. The findings of this study provide specific insights into how RWD/RWE is used in development of cancer therapeutics, how it contributes to regulatory decision making and can guide further policy developments in this field.

Recommendations on TNFα inhibitor biosimilar use in clinical practice: a comparison of European gastroenterology IBD guidance.

BACKGROUND: Professional associations publish guidance advising gastroenterologists on prescribing biosimilars; however, guidelines differ between countries and change over time. This study aimed to map the presence and content of guidance from European gastroenterology associations on TNFα inhibitor biosimilar use and its development over time. RESEARCH DESIGN AND METHODS: Guidelines on biosimilar prescribing from national gastroenterology associations in the European Economic Area (EEA) partnered with the European Crohn's and Colitis Organization (ECCO) were collected. Treatment guidelines and biosimilar position papers from 2010 to 2022 were included. Data were extracted using a template. RESULTS: 26 of 30 EEA countries have an ECCO-partnered gastroenterology association, of which 14 (53.8%) had national guidelines addressing biosimilars, four (15.4%) followed ECCO's position, and three (11.6%) had treatment guidelines without mentioning biosimilars. From five countries (19.2%) no guidelines were retrieved. Among 18 countries with guidance, 14 (77.8%) associations endorsed initiating biological treatment with biosimilars, and 13 (72.2%) endorsed transitioning from originator to biosimilar. Nine associations published multiple guidelines over time addressing biosimilars; overall, their positions became more encouraging. CONCLUSIONS: The majority of gastroenterology associations endorsed biosimilar use. The lack of (up-to-date) guidelines for some associations indicates an area of improvement to support biosimilar use in clinical practice.

The association between patient satisfaction with information and adherence to oral anticancer agents.

INTRODUCTION: Adherence to anticancer agents is a critical factor in achieving adequate clinical response, and became a major challenge for patients and caregivers since the increased substitution of parenteral cytostatic by oral drugs. One of the factors that influences adherence is how well informed patients are about their therapy. This study assesses the association between patient satisfaction with information about oral anticancer agents and adherence. MATERIALS AND METHODS: This study was conducted among patients (≥18 years) who began oral anticancer therapy. Patients satisfaction with information and adherence were assessed using validated questionnaires. Adherence was also assessed using refill data. Logistic regression was applied to assess the association between overall patient satisfaction with information and both self-reported adherence and adherence based on an MPR value of above 80%. RESULTS: In total, 124 patients were included in the study. The median (IQR) satisfaction with information was 15.0(4) on a scale of 0-17. Eighty-two percent of participants reported adherence, while the refill data demonstrated that 64.5% of patients had an adherence rate of 80% or higher. Overall satisfaction with information was not significantly associated with self-reported adherence (OR adj 0.98 [95% CI 0.85-1.15]) or refill-based adherence (OR adj 1.11 [95% CI 0.99-1.24]). CONCLUSION: The findings indicate no significant relationship between patient satisfaction with information and adherence. The population was highly satisfied with information about the oral anticancer agents, which indicates a high level of satisfaction with usual care. However, the refill data reveals that 35.5% of patients were not adherent.

Nature and timing of post-approval manufacturing changes of tumour necrosis factor α inhibitor products: A 20-year follow-up study of originators and biosimilars.

The manufacturing of biopharmaceuticals is complex, and minor changes in the process may affect quality attributes (QAs) that may, in turn, impact clinical outcomes. Regulatory documents from the European Medicines Agency were used to characterize two aspects, nature and timing, of post-approval MCs for originators and biosimilars TNF-α inhibitors that were on the European market up to May 2021. The nature of MCs was evaluated in two ways: (1) the type of MCs related to the drug substance (DS) or drug product (DP), classified as manufacturing, quality control, composition, packaging, or stability with various subtypes; and (2) the risk level according to the potential impact of the MCs on QAs, classified as low, medium, or high. Timing was defined as the date of the regulatory decision on the MC in relation to the approval date. We identified 801 post-approval MCs implemented to originators (mean: 137, range: 112-175) and biosimilars (mean: 30, range: 0-133). Most of implemented MCs for originators and biosimilars were classified as low and medium risk (88.1%), and a small fraction were considered high-risk (11.9%). The average incidence rates were comparable for both originators and biosimilars (7.0/year for MCs, 0.8/year for high-risk MCs). In 20% of MCs introduced to biosimilars, the DP manufacturing site was involved (9% for originators). In contrast, 16% of MCs introduced to originators were related to the DS manufacturing processes (only 7% for biosimilars). In conclusion, while the overall MC incidence rate and the risk level of MCs was not substantially different between TNF-α inhibitor products, we observed some differences in a few types of MCs related to DS manufacturing process and DP manufacturing site between originators and biosimilars. As far as our data shows there is no reasons to assume that post-approval MCs will lead to differences between TNF-α-i originators and biosimilars in clinical practice.

Patients Retransitioning from Biosimilar TNFα Inhibitor to the Corresponding Originator After Initial Transitioning to the Biosimilar: A Systematic Review.

BACKGROUND: Transitioning patients from an originator to a corresponding biosimilar has been extensively studied in both randomized controlled trials and observational studies. Although transitioning is considered well-tolerated, with no negative impacts on efficacy and/or safety, 2.6-25.8% of patients restart treatment with the originator (retransitioning). Retransitioning to the originator can be considered an indication of biosimilar treatment failure or dissatisfaction with biosimilar treatment. Increasing our knowledge of patients who retransition might help to reduce the number of patients retransitioning. OBJECTIVE: Our objective was to estimate the cumulative incidence of patients who retransitioned from a tumor necrosis factor (TNF)-α inhibitor biosimilar to originator and to explore potential patient, disease, and treatment and implementation strategy factors associated with retransitioning. METHOD: We conducted a systematic literature search in the PubMed, EMBASE, and Cochrane Central Register of controlled trials databases until March 2021. Studies on TNFα inhibitors, biosimilar transitioning, and retransitioning were included. Transitioning was defined as switching from an originator to a biosimilar, and retransitioning was defined as switching from an originator to a biosimilar and back to the originator. Characteristics of the studies were descriptively analyzed. Studies were weighted by the number of patients transitioning, and the primary outcome was the median cumulative incidence of retransitioning. For each of the factors related to patient, disease, and treatment and implementation strategy, studies were stratified according to the categories of that factor. The weighted medians and interquartile ranges (IQRs) of the cumulative incidence of retransitioning in these studies were calculated and compared to explore whether a potential association existed between these factors and the cumulative incidence of retransitioning. RESULTS: Of 994 screened publications, 37 were included. The weighted median cumulative incidence of retransitioning was 7.6% (IQR 6.8-17.2). Studies that included only patients with inflammatory bowel disease (6.6 vs. 15.1-17.7% for other indications), included only patients with stable disease (7.0 vs. 13.7% for including all patients), and did not offer retransitioning at the introduction of the biosimilar (7.0 vs. 11.1% for studies that offered retransitioning) reported less retransitioning. In addition, the incidence of retransitioning was lower when extra laboratory monitoring was part of the implementation strategy (1.6 vs. 6.1%) and when gainsharing (patients' healthcare directly benefits from financial savings from transitioning) (1.4 vs. 7.2% for studies without gainsharing) was applied. CONCLUSIONS: In studies on transitioning patients from TNFα originator to biosimilar, 8% of patients retransitioned. Retransitioning appeared to be lower in studies that included only patients with stable disease and in studies that did not offer patients the option of retransitioning at the introduction of the biosimilar. In addition, retransitioning appeared to be lower in studies that implemented extra laboratory monitoring as part of the biosimilar implementation strategy. Clinicians should consider implementing these suggestions as they might reduce retransitioning rates and improve the introduction of biosimilars in clinical practice. PROSPERO registration ID: CRD42021226381.

Use of Real-World Data and Evidence in Drug Development of Medicinal Products Centrally Authorized in Europe in 2018-2019.

Real-world data/real-world evidence (RWD/RWE) are considered to have a great potential to complement, in some cases, replace the evidence generated through randomized controlled trials. By tradition, use of RWD/RWE in the postauthorization phase is well-known, whereas published evidence of use in the pre-authorization phase of medicines development is lacking. The primary aim of this study was to identify and quantify the role of potential use of RWD/RWE (RWE signatures) during the pre-authorization phase, as presented in the initial marketing authorization applications of new medicines centrally evaluated with a positive opinion in 2018-2019 (n = 111) by the European Medicines Agency (EMA). Data for the study was retrieved from the evaluation overviews of the European Public Assessment Reports (EPARs), which reflect the scientific conclusions of the assessment process and are accessible through the EMA website. RWE signatures were extracted into an RWE Data Matrix, including 11 categories divided over 5 stages of the drug development lifecycle. Nearly all EPARs included RWE signatures for the discovery (98.2%) and life-cycle management (100.0%). Half of them included RWE signatures for the full development phase (48.6%) and for supporting regulatory decisions at the registration (46.8%), whereas over a third (35.1%) included RWE signatures for the early development. RWE signatures were more often seen for orphan and conditionally approved medicines. Oncology, hematology, and anti-infectives stood out as therapeutic areas with most RWE signatures in their full development phase. The findings bring unprecedented insights about the vast use of RWD/RWE in drug development supporting the regulatory decision making.

Switching TNFα inhibitors: Patterns and determinants.

The aim of this study was to assess switching patterns and determinants for switching in patients initiating TNFα inhibitor (TNFα-i) treatment. Patients were included who started TNFα-i treatment between July 1, 2012 and December 31, 2017, from three Dutch hospitals, and were diagnosed with rheumatic diseases (RD), inflammatory bowel disease (IBD), or psoriasis. Outcomes were switching, defined as initiating another biological; switching patterns including multiple switches until the end of follow-up; determinants for first switch, assessed using multivariate logistic regression. A total of 2228 patients were included (median age 43.3 years, 57% female), of which 52% (n = 1155) received TNFα-i for RD, 43% (n = 967) for IBD, and 5% (n = 106) for psoriasis. About 16.6% of RD patients, 14.5% of IBD patients, and 16.0% of psoriasis patients switched at least once, mainly to another TNFα-i. TNFα-i dose escalation (OR 13.78, 95% CI 1.40-135.0) and high-dose corticosteroids initiation (OR 3.62, 95% CI 1.10-12.15) were determinants for switching in RD patients. TNFα-i dose escalation (OR 8.22, 95% CI 3.76-17.93), immunomodulator initiation/dose escalation (OR 2.13, 95% CI 1.04-4.34), high-dose corticosteroids initiation (OR 6.91, 95% CI 2.81-17.01) and serum concentration measurement (OR 5.44, 95% CI 2.74-10.79) were determinants for switching in IBD patients. Switching biological treatment occurred in about one in six patients. RD patients with TNFα-i dose escalation and/or high-dose corticosteroids initiation were more likely to switch. IBD patients with TNFα-i or immunomodulator initiation/dose escalation, high-dose corticosteroids initiation or serum concentration measurement were more likely to switch. These findings might help clinicians anticipating switching in TNFα-i treatment.

Prescribers' compliance with summary of product characteristics of dabigatran, rivaroxaban and apixaban-A European comparative drug utilization study.

Despite a tremendous increase of direct oral anticoagulants (DOACs) prescriptions in recent years, only few data is available analysing prescribers' adherence to Summary of Product Characteristics (SmPC). We aimed to assess adherence to registered indications, contraindications, special warnings/precautions, and potential drug-drug interactions for three DOAC compounds (dabigatran, rivaroxaban, and apixaban) in six databases of five European countries (The Netherlands, United Kingdom, Spain, Denmark, and Germany). We included adult patients (≥18 years) initiating DOACs between 2008 and 2015. For several SmPC items, broad definitions were used due to ambiguous SmPC terms or lacking data in some databases. Within the study period, a DOAC was initiated in 407 576 patients (rivaroxaban: 240 985 (59.1%), dabigatran: 95 303 (23.4%), and apixaban: 71 288 (17.5%)). In 2015, non-valvular atrial fibrillation was the most common indication (>60% in most databases). For the whole study period, a substantial variation between the databases was found regarding the proportion of patients with at least one contraindication (inter-database range [IDR]: 8.2%-55.7%), with at least one special warning/precaution (IDR: 35.8%-75.2%) and with at least one potential drug-drug interaction (IDR: 22.4%-54.1%). In 2015, the most frequent contraindication was "malignant neoplasm" (IDR: 0.7%-21.3%) whereas the most frequent special warning/precaution was "prescribing to the elderly" (≥75 years; IDR: 25.0%-66.4%). The most common single compound class interaction was "concomitant use of non-steroidal anti-inflammatory drugs" (IDR: 3.0%-25.3%). Contraindications, special warnings/precautions, and potential drug-drug interactions were present in a relevant number of new DOAC users. Due to broad definitions used for some SmPC terms, overall proportions for contraindications are prone to overestimation. However, for unambiguous SmPC terms documented in the databases sufficiently, the respective estimates can be considered valid. Differences between databases might be related to "true" differences in prescription behaviour, but could also be partially due to differences in database characteristics.

Regulatory Safety Learning Driven by the Mechanism of Action: The Case of TNF-α Inhibitors.

The summary of product characteristics (SmPCs) is an important information source that includes the adverse drug reactions (ADRs) associated with the drug. Drugs with the same mechanism of action are expected to have a similar ADR profile and thus a substantial overlap of the described ADRs in the SmPC. The objective of this study is to assess this overlap. We extracted all ADRs (excluding hypersensitivity and administration site reactions) that were described in the first and all subsequent versions of the SmPCs of all approved TNF-α inhibitors in the European Union. The Medical Dictionary for Regulatory Activities was used to characterize the ADRs. At the end of follow-up, 293 unique ADRs (at high level term level) were described in the SmPCs of the 5 TNF-α inhibitors. There was substantial variation in the number of ADRs described in the SmPC among the TNF-α inhibitors. Of the 293 ADRs, 133 (45%) were described in the SmPC of one TNF-α inhibitor and 39 (13%) in the SmPCs of all 5 TNF-α inhibitors. Serious ADRs and ADRs classified as important risks were described approximately four times more often in a second SmPC than ADRs not classified as such. In conclusion, the ADRs described in the SmPCs of the TNF-α inhibitors differ considerably in number and type. In order to adequately inform prescribers and patients, acquired knowledge of the safety profile of drugs with the same mechanism of action should increasingly be taken into account in the assessment of all drugs within the class.

Reoperation for bleeding following coronary artery bypass surgery with special focus on long-term outcomes.

Objectives: We studied the incidence and risk factors of reoperation for bleeding following CABG in a nationwide cohort with focus on long-term complications and survival. Design: A retrospective study on 2060 consecutive, isolated CABG patients operated 2001-2016. Outcome of reoperated patients (n = 130) were compared to non-reoperated ones (n = 1930), including major adverse cardiac and cerebrovascular events (MACCE) and overall survival. Risk factors for reoperation were determined using multivariate logistic regression and a Cox proportional hazards model to assess prognostic factors of long-term survival. Median follow-up was 7.6 years. Results: One hundred thirty patients (6.3%) were reoperated with an annual decrease of 4.1% per year over the study period (p=.04). Major complications (18.5 vs. 9.6%) and 30-day mortality (8.5 vs. 1.9%,) were higher in the reoperation group (p<.001). The use of clopidogrel preoperatively (OR 3.62, 95% CI: 1.90-6.57) and reduced left ventricular ejection fraction (OR 2.23, 95% CI: 1.25-3.77) were the strongest predictors of reoperation, whereas off-pump surgery was associated with a lower reoperation risk (OR 0.44, 95% CI: 0.22-0.85). After exluding patients that died within 30 days postoperatively, no difference in long-term survival or freedom from MACCE was found between groups, and reoperation was not an independent risk factor for long-term mortality in multivariate analysis. Conclusions: The reoperation rate in this study was relatively high but decreased significantly over time. Reoperation was associated with twofold increased risk for major complications and fourfold 30-day mortality, but comparable long-term MACCE and survival rates. This implies that if patients survive the first 30 days following reoperation, their long-term outcome is comparable to non-reoperated patients.

[No significant association between obesity and long-term outcome of coronary artery bypass grafting].

OBJECTIVES:  Our objective was to investigate long-term outcomes of obese patients undergoing coronary artery bypass grafting (CABG) in Iceland. MATERIALS AND METHODS:  A retrospective analysis on 1698 patients that underwent isolated CABG in Iceland between 2001-2013. Patients were divided into four groups according to body mass index (BMI); Normal=18.5-24.9kg/m2 (n=393), ii) overweight=25-29.9 kg/m2 (n=811), iii) obese=30-34.9 kg/m2 (n=388) and iv) severely obese ≥35kg/m2 (n=113). Thirty-day mortality and short-term complications were documented as well as long-term complications that were pooled into major adverse cardiac and cerebrovascular events (MACCE) and included myocardial infarction, stroke, repeated CABG, percutaneous coronary intervention with or without stenting, and death. After pooling the study groups, survival and freedom from MACCE plots (Kaplan- Meier) were generated and Cox regression analysis used to identify predictive factors of survival. Average follow-up time was 5.6 years. RESULTS:  Severely obese and obese patients were significantly younger than those with a normal BMI, more often males with identifiable risk factors of coronary artery disease (CAD) and a lower EuroSCORE II (1.6 vs. 2.7, p=0.002). The incidence of major early complications, 30-day mortality (2%), long-term survival (90% at 5 years, log-rank test p=0.088) and MACCE-free survival (81% at 5 years, log-rank test p=0.7) was similar for obese and non-obese patients. BMI was neither an independent predictor for long-term (OR: 0.98 95%-CI: 0.95-1.01) nor MACCE-free survival (OR: 1.0 95%-CI: 0.98-1.02).  Conclusions: Obese patients that undergo CABG in Iceland are younger and have an increased number of risk factors for coronary disease when compared to non-obese patients. However, BMI neither predicted long-term survival or long-term complications. The outcomes following CABG in obese patients are good in Iceland.

Exploring the Association between Monoclonal Antibodies and Depression and Suicidal Ideation and Behavior: A VigiBase Study.

INTRODUCTION: Several monoclonal antibodies (mAbs) have been linked to neuropsychiatric adverse effects in patients, including depression and suicidal ideation and behavior. OBJECTIVE: The aim of this study was to quantify and characterize spontaneously reported adverse drug reactions (ADRs) of depression and suicidal ideation and behavior related to mAb users, and to explore a possible association with their mechanism of action. METHODS: We included mAb ADRs that were reported in VigiBase, and identified those related to depression and suicidal ideation and behavior. Reporting odds ratios (RORs) were estimated for each mAb (bevacizumab as the reference) and according to their influence on the immune system (not directly targeting [reference], stimulating, or suppressing). Those suppressing the immune system were further divided into their intended indication (auto-immune diseases, cancer). RESULTS: Overall, 2,924,319 ADRs for 44 mAbs were included; 9455 ADRs were related to depression and 1770 were related to suicidal ideation and behavior. The association was strongest for natalizumab and belimumab, both for depression (ROR 5.7, 95% confidence interval [CI] 5.0-6.4; and ROR 5.1, 95% CI 4.2-6.2) and suicidal ideation and behavior (ROR 12.0, 95% CI 7.9-18.3; and ROR 20.2, 95% CI 12.4-33.0). Those suppressing the immune system showed higher ROR, i.e. 1.9 (95% CI 1.8-2.0) for depression and 3.6 (95% CI 3.0-4.4) for suicidal ideation and behavior. This finding was only seen for mAbs used for treating autoimmune diseases. CONCLUSION: Depression and suicidal ideation and behavior are seen in patients using mAbs, particularly mAbs used for treating autoimmune diseases that suppress the immune system. For interpretation of these data, the indications for use and other characteristics require further consideration.

Psychotropic drugs use and psychotropic polypharmacy among persons with Alzheimer's disease.

Psychotropic drugs are frequently used for the treatment of behavioural and psychological symptoms of dementia in persons with Alzheimer's disease (AD). Evidence for benefits are limited and concerns have been raised about the safety, especially for the concomitant use of multiple psychotropic drugs. The objective of this study was to investigate prevalence of psychotropic drug and psychotropic polypharmacy (PPP) use and associations with PPP among persons with and without AD, from five years before until four years after AD diagnosis at time points every six months. Data is a part of the nationwide MEDALZ cohort, including all community-dwelling persons who received a clinically verified diagnosis of AD between 2005 and 2011 in Finland (n = 70,719). Register-based data included purchased prescription drugs, comorbidities, and hospital discharge diagnoses. Prevalence and factors associated with PPP were studied with logistic regression. The prevalence of psychotropic drug use, especially use of antipsychotics and antidepressants, increased during the course of AD. The use of ≥ 2 psychotropic drugs increased from 5.9% five years before to 18.3% four years after AD diagnosis. The most frequently used combination was antipsychotics and antidepressants. Predictors for PPP were younger age (< 75 years), female sex and history of psychiatric disease. The use of acetylcholinesterase inhibitors was inversely associated with PPP. The high prevalence of PPP is concerning because of possible higher risks for adverse effects and events.

Antipsychotic Use and the Risk of Initiating Medication for Benign Prostate Hyperplasia in Persons With Alzheimer Disease: A Matched Cohort Study.

BACKGROUND: Antipsychotics (APs) are known to exacerbate symptoms of benign prostate hyperplasia (BPH) and may even cause urinary retention. The anticholinergic effects of APs and their dopamine D2- and α-receptor blockade may lead to voiding dysfunction of BPH patients. The objective of our study was to investigate whether the use of APs is associated with an increased risk of initiating medication for BPH in men with Alzheimer disease (AD). METHODS: Data from the nationwide MEDALZ (MEDication use and ALZheimer's disease) cohort, including all community-dwelling persons diagnosed with AD in Finland, were utilized. Register-based data included medication dispensing, comorbidities, and hospital discharge diagnoses. Men who initiated APs (n = 4579) were 1:1 matched with men who did not initiate APs (n = 4579), according to time since AD diagnoses and age. The risk of starting BPH medication was investigated with Cox regression. RESULTS: Among AP users, BPH medication was initiated to 345 persons (7.5%). Antipsychotic use was not associated with risk of initiating BPH medication (comorbidity-adjusted hazard ratio, 0.92; 95% confidence interval, 0.74-1.15) compared with no use of APs. In addition, no risk was found when AP drug substances were analyzed separately. CONCLUSIONS: Use of APs did not increase the risk of initiating medication for BPH in men with AD.

[Outcome of coronary artery bypass grafting in women in Iceland].

Introduction The aim of this study was to evaluate the outcome of coronary artery bypass grafting (CABG) in women compared to men, with focus on short-term and long-term complications, 30 day mortality and survival. Materials and methods This was a retrospective study on all CABG patients operated in Iceland between 2001 and 2013. Clinical information was gathered from hospital charts and survival data was obtained from the National Statistics in Iceland. Overall survival was estimated with the Kaplan- Meier method. Logistic and Cox regression analysis were used to identify predictors of operative mortality and long-term survival. Mean follow-up was 6.8 years. Results Of 1755 patients 318 were women (18%). Women were on average four years older than men at the time of operation (69 vs. 65 yrs, p<0.001). Female patients had a higher incidence of hypertension (72 vs. 64%, p=0.009) and their EuroSCOREst was higher (6.1 vs. 4.3, p<0.001). The prevalence of diabetes, dyslipidemia and the extent of coronary artery disease was comparable between groups. The rate of short-term complications, both minor (53% vs. 48%, p=0.07) and major (27% vs. 32%, p=0.2), was similar and operative mortality for women was not statistically different from males (4% vs. 2%, p=0.08). Female gender was neither found to be a predictor of 30-day mortality (OR 0.99; 95%-CI: 0.98-1.01) nor survival (HR 1,08; 95%-ÖB: 0,82-1,42). Conclusions The number of women that undergo CABG is low and they are four years older than men when operated on. As is the case with men, outcome following CABG in Iceland is very good for women, their overall five-year survival being 87%.

Favourable long-term outcome after coronary artery bypass grafting in a nationwide cohort.

OBJECTIVES: In a nationwide cohort, we analyzed long-term outcome following coronary artery bypass grafting, using the combined strategy of left internal mammary artery to the left anterior descending artery and saphenous vein as secondary graft to other coronary targets. METHODS: 1,507 consecutive patients that underwent myocardial revascularization during 2001-2012 in Iceland. Mean follow-up was 6.8 years. Major adverse cardiac and cerebrovascular events were depicted using the Kaplan-Meier method. Cox-regression was used to define risk factors. Relative survival was estimated by comparing overall survival to the survival of Icelanders of the same age and gender. RESULTS: Mean age was 66 years, 83% were males, mean EuroSCOREst was 4.5, and 23% of the procedures were performed off-pump. At 5 years, 19.7% had suffered a major adverse cardiac or cerebrovascular event, 4.5% a stroke, 2.2% myocardial infarction, and 6.2% needed repeat revascularization. Overall 5-year survival was 89.9%, with a relative survival of 0.990. Independent predictors of major adverse cardiac and cerebrovascular events were left ventricular ejection fraction ≤30%, a previous history of percutaneous coronary intervention, chronic obstructive lung disease, chronic kidney disease, diabetes, and old age. The same variables and an earlier year of operation were predictors of long-term mortality. CONCLUSIONS: The long-term outcome following myocardial revascularization, using the left internal mammary artery and the great saphenous vein as conduits, is favourable and improving. This is reflected by the 5-year survival of 89.9%, deviating minimally from the survival rate of the general Icelandic population, together with a freedom from major adverse cardiac and cerebrovascular events of 80.3%.