Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Polypill Strategy in Secondary Cardiovascular Prevention.

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

Available Bleeding Scoring Systems Poorly Predict Major Bleeding in the Acute Phase of Pulmonary Embolism.

We aimed to compare six available bleeding scores, in a real-life cohort, for prediction of major bleeding in the early phase of pulmonary embolism (PE). We recorded in-hospital characteristics of 2754 PE patients in a prospective observational multicenter cohort contributing 18,028 person-days follow-up. The VTE-BLEED (Venous Thrombo-Embolism Bleed), RIETE (Registro informatizado de la enfermedad tromboembólica en España; Computerized Registry of Patients with Venous Thromboembolism), ORBIT (Outcomes Registry for Better Informed Treatment), HEMORR2HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol) scores were assessed at baseline. International Society on Thrombosis and Haemostasis (ISTH)-defined bleeding events were independently adjudicated. Accuracy of the overall original 3-level and newly defined optimal 2-level outcome of the scores were evaluated and compared. We observed 82 first early major bleedings (3.0% (95% CI, 2.4-3.7)). The predictive power of bleeding scores was poor (Harrel's C-index from 0.57 to 0.69). The RIETE score had numerically higher model fit and discrimination capacity but without reaching statistical significance versus the ORBIT, HEMORR2HAGES, and ATRIA scores. The VTE-BLEED and HAS-BLED scores had significantly lower C-index, integrated discrimination improvement, and net reclassification improvement compared to the others. The rate of observed early major bleeding in score-defined low-risk patients was high, between 15% and 34%. Current available scoring systems have insufficient accuracy to predict early major bleeding in patients with acute PE. The development of acute-PE-specific risk scores is needed to optimally target bleeding prevention strategies.

An Original Risk Score to Predict Early Major Bleeding in Acute Pulmonary Embolism: The Syncope, Anemia, Renal Dysfunction (PE-SARD) Bleeding Score.

BACKGROUND: Improved prediction of the risk of early major bleeding in pulmonary embolism (PE) is needed to optimize acute management. RESEARCH QUESTION: Does a simple scoring system predict early major bleeding in acute PE patients, identifying patients with either high or low probability of early major bleeding? STUDY DESIGN AND METHODS: From a multicenter prospective registry including 2,754 patients, we performed post hoc multivariable logistic regression analysis to build a risk score to predict early (up to hospital discharge) major bleeding events. We validated the endpoint model internally, using bootstrapping in the derivation dataset by sampling with replacement for 500 iterations. Performances of this novel score were compared with that of the VTE-BLEED (Venous Thrombo-Embolism Bleed), RIETE (Registro informatizado de la enfermedad tromboembólica en España; Computerized Registry of Patients with Venous Thromboembolism), and BACS (Bleeding, Age, Cancer, and Syncope) models. RESULTS: Multivariable regression identified three predictors for the occurrence of 82 major bleeds (3.0%; 95% CI, 2.39%-3.72%): Syncope (+1.5); Anemia, defined as hemoglobin <12 g/dL (+2.5); and Renal Dysfunction, defined as glomerular filtration rate <60 mL/min (+1 point) (SARD). The PE-SARD bleeding score was calculated by summing all the components. Overall, 52.2% (95% CI, 50.29%-54.11%) of patients were classified as low bleeding-risk (score, 0 point), 35.2% (95% CI, 33.39%-37.04%) intermediate-risk (score, 1-2.5 points), and 12.6% (95% CI, 9.30%-16.56%) high-risk (score >2.5 points). Observed bleeding rates increased with increasing risk group, from 0.97% (95% CI, 0.53%-1.62%) in the low-risk to 8.93% (95% CI, 6.15%-12.44%) in the high-risk group. C-index was 0.74 (95% CI, 0.73-0.76) and Brier score 0.028 in the derivation cohort. Similar values were calculated from internal bootstrapping. Performance of the PE-SARD score was better than that observed with the VTE-BLEED, RIETE, and BACS scores, leading to a high proportion of bleeding-risk reclassification in patients who bled and those who did not. INTERPRETATION: The PE-SARD bleeding risk score is an original, user-friendly score to estimate risk of early major bleeding in patients with acute PE.

Impact of Midregional N-Terminal Pro-Atrial Natriuretic Peptide and Soluble Suppression of Tumorigenicity 2 Levels on Heart Rhythm in Patients Treated With Catheter Ablation for Atrial Fibrillation: The Biorhythm Study.

Background We assessed the impact of preprocedural plasma levels of MRproANP (midregional N-terminal pro-atrial natriuretic peptide) and sST2 (soluble suppression of tumorigenicity 2) on recurrence of atrial fibrillation (AF) at 1 year after catheter ablation of AF. Methods and Results This was a prospective, multicenter, observational study including patients undergoing catheter ablation of AF. MRproANP and sST2 were measured in a peripheral venous blood preprocedure, and MRproANP was assessed in the right and left atrial blood during ablation. The primary end point was recurrent AF between 3 and 12 months postablation, defined as a documented (>30 seconds) episode of AF, flutter, or atrial tachycardia. We included 106 patients from December 2017 to March 2019; 105 had complete follow-up, and the mean age was 63 years with 74.2% males. Overall, 34 patients (32.1%) had recurrent AF. In peripheral venous blood, MRproANP was significantly higher in patients with recurrent AF (median, 192.2; [quartile 1-quartile 3, 155.9-263.9] versus 97.1 [60.9-150.7] pmol/L; P<0.0001), as was sST2 (median, 30.3 [quartile 1-quartile 3, 23.3-39.3] versus 23.4 [95% CI, 17.4-33.0] ng/mL; P=0.0033). In the atria, MRproANP was significantly higher than in peripheral blood and was higher during AF than during sinus rhythm. Receiver operating characteristic curve analysis identified a threshold of MRproANP>107.9 pmol/L to predict AF recurrence at 1 year and a threshold of >26.7 ng/mL for sST2. By multivariate analysis, MRproANP>107.9 pmol/L was the only independent predictor of recurrent AF (OR, 24.27; 95% CI, 4.23-139.18). MRproANP<107.9 pmol/L identified subjects at very low risk of recurrence (negative predictive value >95%). Conclusions Elevated MRproANP level independently predicts recurrent AF, whereas sST2 levels do not appear to have any prognostic value in assessing the risk of recurrence of AF up to 1 year after catheter ablation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03351816.

Renal dysfunction improves risk stratification and may call for a change in the management of intermediate- and high-risk acute pulmonary embolism: results from a multicenter cohort study with external validation.

BACKGROUND: Renal dysfunction influences outcomes after pulmonary embolism (PE). We aimed to determine the incremental value of adding renal dysfunction, defined by estimated glomerular filtration rate (eGFR), on top of the European Society of Cardiology (ESC) prognostic model, for the prediction of 30-day mortality in acute PE patients, which in turn could lead to the optimization of acute PE management. METHODS: We performed a multicenter, non-interventional retrospective post hoc analysis based on a prospectively collected cohort including consecutive confirmed acute PE stratified per ESC guidelines. We first identified which of three eGFR formulae most accurately predicted death. Changes in global model fit, discrimination, calibration and reclassification parameters were evaluated with the addition of eGFR to the prognostic model. RESULTS: Among 1943 patients (mean age 67.3 (17.1), 50.4% women), 107 (5.5%) had died at 30 days. The 4-variable Modification of Diet in Renal Disease (eGFRMDRD4) formula predicted death most accurately. In total, 477 patients (24.5%) had eGFRMDRD4 < 60 ml/min. Observed mortality was higher for intermediate-low-risk and high-risk PE in patients with versus without renal dysfunction. The addition of eGFRMDRD4 information improved model fit, discriminatory capacity, and calibration of the ESC model. Reclassification parameters were significantly increased, yielding 18% reclassification of predicted mortality (p < 0.001). Predicted mortality reclassifications across risk categories were as follows: 63.1% from intermediate-low risk to eGFR-defined intermediate-high risk, 15.8% from intermediate-high risk to eGFR-defined intermediate-low risk, and 21.0% from intermediate-high risk to eGFR-defined high risk. External validation in a cohort of 14,234 eligible patients from the RIETE registry confirmed our findings with a significant improvement of Harrell's C index and reclassification parameters. CONCLUSION: The addition of eGFRMDRD4-derived renal dysfunction on top of the prognostic algorithm led to risk reclassification within the intermediate- and high-risk PE categories. The impact of risk stratification integrating renal dysfunction on therapeutic management for acute PE requires further studies.

Long-term outcomes after acute myocardial infarction in patients with familial hypercholesterolemia: The French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction program.

BACKGROUND: Patients with familial hypercholesterolemia (FH) are prone to develop acute myocardial infarction (AMI) at a younger age. OBJECTIVES: The aim of the present study was to assess 5-year outcomes after AMI according to the presence of FH in a large multicenter cohort of patients. METHODS: The French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction consists of nationwide surveys recruiting patients over a 1- to 2-month period every 5 years. Patients recruited in 2005 and 2010 were followed up to 5 years. RESULTS: Of 5147 patients discharged alive and in whom FH status could be assessed, 2.8% had probable/definite FH, using an adapted Dutch Lipid Clinic score. They were 12 years younger, on average, than non-FH patients. Before adjustment, their 5-year survival and event-free survival did not differ from non-FH patients. After adjustment, however, both mortality (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.15-2.89; P = .011) and the combined endpoint of death, AMI, or stroke (HR 2.22, 95% CI: 1.51-3.26; P < .001) were higher in FH patients. The higher risk in FH patients was also present in patients receiving high-intensity lipid-lowering therapy at discharge: adjusted HR for mortality 2.29, 95% CI: 1.18 to 4.47, P = .015; HR for cardiovascular events 2.57, 95% CI: 1.48 to 4.48, P = .001. Concordant results were observed in propensity score-marched cohorts. CONCLUSIONS: The risk of long-term mortality and cardiovascular events is twice as high in FH than in non-FH patients, when adjusted on baseline characteristics, even for those receiving high-intensity lipid-lowering therapy. Additional therapeutic measures are needed in these patients.

An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial.

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%. Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease. Interventions: Patients were randomized 1:1 to evolocumab or placebo. Design, Setting, and Participants: Exploratory analysis of the FOURIER trial, which enrolled 27 564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020. Main Outcomes and Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model. Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P = .002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P = .001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P = .14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. Conclusions and Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

Association between rs4149056 variant in SLCO1B1 and early discontinuation of statin after acute myocardial infarction.

Data from two French surveys were used to analyze the association between in-hospital statin discontinuation and SLCO1B1 polymorphism (rs4149056) in patients with acute myocardial infarction. Using TaqMan allelic discrimination assay, 1674 and 1708 patients were genotyped for SLCO1B1 in 2005 and 2010, respectively. The association with in-hospital statin discontinuation was assessed after adjusting for confounding factors. In 2005, homozygosity for the reduced-function allele was associated with an increased risk of in-hospital statin discontinuation (OR: 3.68; p = 0.004) compared with the wild-type allele but this association disappeared in 2010. However, statin type and intensity-dose differed significantly between the surveys. SLCO1B1 polymorphism (rs4149056) does not seem to be a major determinant of early 'in-hospital' statin discontinuation after acute myocardial infarction.

Clinical patterns and significance of non-compliance with guideline-recommended treatment of acute pulmonary embolism.

BACKGROUND: Evidence-based clinical practice guidelines define initial management of acute pulmonary embolism (PE) according to risk stratification for early death. AIMS: The aims of the present study were to investigate patterns of non-compliance with guidelines for the acute PE treatment, and the associated risk of adverse events. METHODS: We performed an observational, multicentre, cohort study of acute PE. Inclusion criteria were all patients with pulmonary embolism admitted to the participating centres between January 2011 and April 2017. The measure of 100% compliance was used to allocate patients in the compliant or non-compliant groups. The primary outcome was all-cause death at 6 months. Secondary outcomes included recurrent venous thromboembolism and major bleeding. RESULTS: In total, 1285 patients were included. Treatment was not in compliance with the guidelines in 172 patients (13.4%). Four factors were identified to be related to non-compliance with the guidelines: shock or hypotension (relative risk [RR] 5.23, 95% confidence interval [CI] 2.64-10.30; P<0.001), renal insufficiency (RR 1.80, 95% CI 1.41-2.28; P<0.001), active cancer (RR 1.35, 95% CI 1.24-1.48; P<0.001) and right ventricular dysfunction at admission (RR 1.06, 95% CI 1.01-1.11; P=0.01). The primary endpoint of all-cause death at 6 months occurred in 62 of 172 patients (36.0%) in the non-compliant group and in 131 of 1113 patients (11.8%) in the compliant group (hazard ratio 2.02, 95% CI 1.45-2.81; P<0.001). The rates of recurrent venous thromboembolism (8.7% vs 1.1%; P<0.001) and major bleeding (13.4% vs 4.9%, P=0.04) from admission to 6-month follow-up were higher in the non-compliant group. CONCLUSION: Non-compliance with guidelines was independently associated with worse outcomes, including death, recurrent venous thromboembolism and bleeding.

In-hospital outcomes and 5-year mortality following an acute myocardial infarction in patients with a history of cancer: Results from the French registry on Acute ST-elevation or non-ST-elevation myocardial infarction (FAST-MI) 2005 cohort.

BACKGROUND: Cancer and acute myocardial infarction (AMI) have important prognostic consequences. Treatment of some cancers may affect coronary artery disease, myocardial function and/or AMI management. Whether the early and long-term mortality of patients with AMI differ according to their history of cancer remains questionable. AIMS: To determine in-hospital outcomes and 5-year mortality following AMI according to patient history of cancer. METHODS: The FAST-MI registry is a nationwide French survey collecting data on characteristics, management and outcomes of 3670 consecutive patients admitted for AMI during October 2005. RESULTS: Overall, 246/3664 patients (6.7%) admitted for an AMI (47.6% with ST-segment elevation myocardial infarction [STEMI]; 52.4% with non-STEMI [NSTEMI]) had a history of cancer. In-hospital mortality was not significantly different for patients with versus without a history of cancer, overall (adjusted odds ratio [OR]: 1.15, 95% confidence interval [CI]: 0.68-1.94; P=0.61) and in patients with STEMI (adjusted OR: 1.37, 95% CI: 0.69-2.71; P=0.37) or NSTEMI (adjusted OR: 0.97, 95% CI: 0.41-2.28; P=0.95). All-cause mortality at 5 years was higher among patients with a history of cancer (adjusted hazard ratio [HR]: 1.36, 95% CI: 1.08-1.69; P=0.008), whereas 5-year cardiovascular mortality did not differ (adjusted HR: 1.17, 95% CI: 0.89-1.53; P=0.25), regardless of whether the patients had STEMI or NSTEMI. Similar results were found in populations matched on a propensity score including baseline characteristics and early management. CONCLUSION: A history of cancer, per se, does not appear to be a risk factor for increased in-hospital mortality or long-term cardiovascular mortality in patients admitted for AMI.

Impact of post-procedural glycemic variability on cardiovascular morbidity and mortality after transcatheter aortic valve implantation: a post hoc cohort analysis.

BACKGROUND: Glycemic variability is associated with worse outcomes after cardiac surgery, but the prognosis value of early glycemic variability after transcatheter aortic valve implantation is not known. This study was therefore designed to analyze the prognosis significance of post-procedural glycemic variability within 30 days after transcatheter aortic valve implantation. METHODS: A post hoc analysis of patients from our center included in the FRANCE and FRANCE-2 registries was conducted. Post-procedural glycemic variability was assessed by calculating the mean daily δ blood glucose during the first 2 days after transcatheter aortic valve implantation. Major complications within 30 days were death, stroke, myocardial infarction, acute heart failure, and life-threatening cardiac arrhythmias. RESULTS: We analyzed 160 patients (age (median [interquartile] = 84 [80-88] years; diabetes mellitus (n) = 41 (26%) patients; logistic Euroscore = 20 [12-32]). The median value of mean daily δ blood glucose was 4.3 mmol l-1. The rate of major complications within 30 days after procedure among patients with the lowest quartile of glycemic variability was 12%, increasing from 12 to 26%, and 39% in the second, third, and fourth quartiles, respectively. In multivariate analysis, glycemic variability was independently associated with an increased risk of major complications within 30 days after the procedure (odds ratio [95% CI] = 1.83 [1.19-2.83]; p = 0.006). CONCLUSIONS: This study showed that post-procedural glycemic variability was associated with an increased risk of major complications within 30 days after transcatheter aortic valve implantation. Trial registration Clinical trial registration number https://www.clinicaltrials.gov/ ; identifier: NCT02726958; date: April 4th, 2016.

Prescription patterns of direct oral anticoagulants in pulmonary embolism: A prospective multicenter French registry.

BACKGROUND: Data regarding the use of direct oral anticoagulants (DOACs) for the treatment of acute pulmonary embolism (PE) are sparse. We conducted a prospective multicentre registry study to describe patterns of DOAC prescription for the treatment of acute PE, and the associated risk of 6-month adverse events in daily practice. METHODS: We included all PE patients discharged since the availability of DOACs for the dedicated indication of acute PE treatment. Clinical data and 6-month outcomes, including death, recurrent venous thromboembolism (VTE), bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH) were recorded prospectively. Temporal trends in DOAC prescription were tested. RESULTS: Between 09/2012 and 04/2017, 1082 patients were included: 60.6% (n = 656) were treated with DOACs and 39.4% (n = 426) with another anticoagulant. The prescription rate of DOACs increased sharply just after their release on the market to reach a plateau over time, between 56% and 72% of the total prescription per year in PE patients (p for trend = 0.33). Active malignancy and renal function impairment were factors independently associated with non-prescription of DOACs. Overall, prescription of DOACs was appropriate in 95.3% of patients. The rate of use of non-recommended DOAC doses was 4.2% (n = 28). The rate of death, recurrent VTE, bleeding and CTEPH were 2.4%, 1.2%, 7.2%, and 1.9%, respectively in the DOAC group. CONCLUSION: The choice to prescribe DOACs or not is related to patient characteristics. The overall appropriateness of prescription is high, while the rate of adverse events observed in patients treated with DOAC is low in our registry.

End-of-life situations in cardiology: a qualitative study of physicians' and nurses' experience in a large university hospital.

BACKGROUND: Professional societies call for integration of end-of-life discussions early in the trajectory of heart failure, yet it remains unclear where current practices stand in relation to these recommendations. We sought to describe the perceptions and attitudes of caregivers in cardiology regarding end-of-life situations. METHODS: We performed a qualitative study using semi-directive interviews in the cardiology department of a university teaching hospital in France. Physicians, nurses and nurses' aides working full-time in the department at the time of the study were eligible. Participants were asked to describe how they experienced end-of-life situations. Interviews were recorded, transcribed and coded using thematic analysis to identify major and secondary themes. RESULTS: All physicians (N = 16)(average age 43.5 ± 13 years), 16 nurses (average age 38.5 ± 7.6 years) and 5 nurses' aides (average age 49 ± 7.8 years) participated. Interviews were held between 30 March and 17 July 2017. The main themes to emerge from the physicians' discourse were the concept of cardiology being a very active discipline, and a very curative frame of mind was prevalent. Communication (with paramedical staff, patients and families) was deemed to be important. Advance directives were thought to be rare, and not especially useful. Nurses also reported communication as a major issue, but their form of communication is bounded by several factors (physicians' prior discourse, legislation). They commonly engage in reconciling: between the approach (curative or palliative) and the reality of the treatment prescribed; performing curative interventions in patients they deem to be dying cases causes them distress. The emergency context prevents nurses from taking the time necessary to engage in end-of-life discussions. They engage in comfort-giving behaviors to maximize patient comfort. CONCLUSION: Current perceptions and practices vis-à-vis end-of-life situations in our department are individual, heterogeneous and not yet aligned with recommendations of professional societies.

Non-recommended dosing of direct oral anticoagulants in the treatment of acute pulmonary embolism is related to an increased rate of adverse events.

Dose adjustment of direct oral anticoagulants (DOACs) is not required in the setting of acute PE treatment according to the manufacturer's labelling, beyond the contraindication in severe renal insufficiency. We designed a prospective, multicenter cohort study to investigate the impact of prescription of non-recommended DOAC doses on 6-month adverse events. The primary endpoint was a composite of all-cause death, recurrent VTE, major bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH). In total, among 656 patients discharged with DOACs between 09/2012 and 10/2016, 28 (4.3%) were not treated with a recommended DOAC dose. All the non-recommended DOAC dose prescriptions were under-dosed according to the drug labelling. After multivariate adjustment, age > 70 years, a history of coronary artery disease, creatinine clearance < 50 mL/min and concomitant aspirin therapy were independently associated with non-recommended DOAC dose prescription (C-statistic: 0.82; Hosmer Lemeshow test: 0.50). The primary composite endpoint occurred in 7/28 patients (25.0%) in the non-recommended dose group and in 38/628 patients (6.1%) in the recommended dose group, yielding a relative risk of 3.19 in the non-recommended dose group (95% CI 1.16-8.70; p < 0.001). The higher primary endpoint rate observed in the non-recommended dose group was driven by a significantly higher rate of major bleeding (7.1 vs. 1.4%; p = 0.008), with a non-significant trend toward a higher rate of death (7.1 vs. 2.2%; p = 0.23), recurrent VTE (3.6 vs. 1.4%; p = 0.31), and CTEPH (7.1 vs. 1.6%; p = 0.32). In conclusion, empiric dose reduction of DOACs was associated with 6-month adverse events in our real-life registry.

Long-Term Clinical Outcomes According to Previous Manifestations of Atherosclerotic Disease (from the FAST-MI 2010 Registry).

The prognosis of patients with acute myocardial infarction (AMI) has notably improved in the past 20 years. Using the French Registry of ST-Elevation and Non-ST-elevation Myocardial Infarction (FAST-MI) 2010 registry, we investigated whether previous manifestations of atherosclerotic disease (i.e., previous MI, or a history of any form of atherosclerotic disease) are at truly increased risk compared with those in whom AMI is the first manifestation of the disease. FAST-MI 2010 is a nationwide French registry including 3,079 patients with AMI, among whom 1,062 patients had a history of cardiovascular atherosclerotic disease and 498 patients had a history of MI. Overall, patients with a history of atherosclerotic disease (or MI) were older compared with patients without known cardiovascular disease (71 ± 13 vs 63 ± 14 years) and had higher cardiovascular risk profiles and co-morbidities. Using fully adjusted Cox multivariate analysis, previous manifestations of atherosclerotic disease were associated with higher 3-year mortality (hazard ratio 1.80, 95% confidence interval 1.40 to 2.31; p <0.001) as history of previous MI alone (hazard ratio 1.32, 95% confidence interval 1.00 to 1.73; p = 0.048). Similar results were found in patients discharged alive. In conclusion, previous cardiovascular atherosclerotic disease represents 1/3 of patients with AMI and are strongly associated with worse long-term clinical outcomes. Intensive follow-up and therapy should be encouraged in this high-risk population.

Effect of coronary thrombus aspiration during primary percutaneous coronary intervention on one-year survival (from the FAST-MI 2010 registry).

Results from randomized trials evaluating thrombus aspiration (TA) in patients with ST-elevation myocardial infarction (STEMI) are conflicting. We assessed 1-year survival in STEMI patients participating in the French Registry of Acute ST-Elevation and non-ST-Elevation Myocardial Infarction (FAST-MI) 2010 according to the use of TA during primary percutaneous coronary intervention (PCI). FAST-MI 2010 is a nationwide French registry that included 4,169 patients with acute myocardial infarction at the end of 2010 in 213 centers. Of those, 2,087 patients had STEMI, of whom 1,538 had primary PCI, with TA used in 671 (44%). Patients with TA were younger (61 ± 13.5 vs 63 ± 14 years), with a similar risk score of the Global Registry of Acute Coronary Events (140 ± 31 vs 143 ± 34) and a shorter median time from symptom onset (245 vs 285 minutes); location of acute myocardial infarction, history of myocardial infarction, PCI, or coronary artery bypass surgery did not differ significantly. Thirty-day mortality was 2.1% versus 2.1% (adjusted p = 0.18), and the rate of 1-year survival was 95.5% versus 94.8%. Using fully adjusted Cox multivariate analysis, hazard ratio for 1-year death was 1.13 (95% confidence interval 0.66 to 1.94). After propensity score matching (480 patients per group), 1-year survival was also similar with both strategies. In a real-world setting of patients admitted with STEMI, the use of TA during primary PCI was not associated with improved 1-year survival.

[Is coronary artery disease different in women?]. / Les syndromes coronaires sont-ils différents chez la femme ?

Coronary artery disease (CAD) is the primary cause of death in women. Although acute coronary syndrome (ACS) is relatively infrequent in young women, failure to recognize ACS in this population can incur a major risk and registry data show that there is still plenty of room for improvement in this area. Women may suffer from "classical" CAD with development of atherosclerosis with a delay of about 10 years as compared to men, reflecting hormonal protection in women. Besides this classical presentation, angina in women often corresponds to impaired microcirculation, a syndrome known to associate typical angina, demonstrable myocardial ischemia, but no lesions on the coronary angiography. Finally, spasm, spontaneous dissection or coronary thrombosis through endothelial rupture are more frequent in women. The influence of risk factors on the development of CAD is comparable in both women and men. Recent registry studies show that in France, in particular, diabetes, obesity, and smoking are all risk factors that are on the rise in women. In addition, certain other risk factors are more specific to women, namely psycho-social stress. The methods to evaluate risk and detect CAD were mainly developed in male study populations, and these tools thus perform less well in female patients. In case of ACS, women benefit just as much from invasive management, but are at greater risk of iatrogenic complications, particularly with anti-thrombotic therapy or during revascularization procedures.