Risk of Death in Patients With Coronary Artery Disease Taking Nitrates and Phosphodiesterase-5 Inhibitors.

BACKGROUND: Phosphodiesterase-5 inhibitor (PDE5i) treatment for erectile dysfunction is associated with lower mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). There are conflicting results regarding the impact of PDE5i treatment on mortality in conjunction with nitrate medication. OBJECTIVES: The purpose of this study was to investigate the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication. METHODS: Using the Swedish Patient Register and the Prescribed Drug Register we included men with previous MI or revascularization in 2006-2013 who had 2 dispensed nitrate prescriptions within 6 months. Exposure was defined as at least 2 filled prescriptions of any PDE5i. We performed multivariable Cox proportional hazard regression to estimate HRs with 95% CIs for all-cause, cardiovascular, and noncardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events (MACE). RESULTS: In total, 55,777 men were treated with nitrates and 5,710 men with nitrates and a PDE5i. The combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), noncardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83). CONCLUSIONS: The use of a PDE5i in combination with nitrate medication in men with stable coronary artery disease may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5is to patients with cardiovascular disease using nitrate medication is warranted.

Association between expectations and clinical outcomes in online v. face-to-face therapy - an individual participant data meta-analysis.

BACKGROUND: Online treatments are increasing in number and are currently available for a wide range of clinical problems. To date little is known about the role of treatment expectations and other placebo-like mechanisms in online settings compared to traditional face-to-face treatment. To address this knowledge gap, we analyzed individual participant data from randomized clinical trials that compared online and face-to-face psychological interventions. METHODS: MEDLINE (Ovid) and PsycINFO (Ovid) were last searched on 2 February 2021. Randomized clinical trials of therapist guided online v. face-to-face psychological interventions for psychiatric or somatic conditions using a randomized controlled design were included. Titles, abstracts, and full texts of studies were independently screened by multiple observers. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Authors of the matching trials were contacted for individual participant data. Ratings from the Credibility and Expectancy Questionnaire and the primary outcome measure from each trial were used to estimate the association between expectation ratings and treatment outcomes in online v. face-to-face interventions, using a mixed-effects model. RESULTS: Of 7045 screened studies, 62 full-text articles were retrieved whereof six studies fulfilled the criteria and provided individual participant data (n = 491). Overall, CEQ ratings predicted clinical outcomes (ß = 0.27) at end of treatment with no moderating effect of treatment modality (online v. face-to-face). CONCLUSIONS: Online treatment appears to be equally susceptible to expectancy effects as face-to-face therapy. This furthers our understanding of the importance of placebo-like factors in online treatment and may aid the improvement of healthcare in online settings.

Obesity is associated with pain and impaired mobility despite therapy in systemic lupus erythematosus.

Objective: To investigate whether abnormal BMI is associated with health-related quality of life (HRQoL) impairments, defined as patient-reported problems within the different dimensions of the three-level EQ-5D (EQ-5D-3L), before and after treatment for active systemic lupus erythematosus (SLE). Patients and methods: We conducted a post-hoc analysis of data from two phase III clinical trials of belimumab in SLE, i.e., BLISS-52 (n = 865) and BLISS-76 (n = 819). Underweight was defined as BMI <18.5 kg/m2, normal weight as BMI ≥18.5 but <25 kg/m2, pre-obesity as BMI ≥25 but <30 kg/m2, and obesity as BMI ≥30 kg/m2. We investigated associations between BMI groups and problems (level 2 or 3) within each one of the five EQ-5D dimensions before treatment initiation and at week 52, using logistic regression analysis adjusting for age, ethnicity, disease activity, and glucocorticoid dose, and for the post-treatment analysis also for belimumab treatment and baseline EQ-5D-3L responses. Results: Of 1,684 patients included, 73 (4%) were classified as underweight, 850 (50%) as normal weight, 438 (26%) as pre-obese, and 323 (19%) as obese. At baseline, obesity was associated with mild to severe problems in all EQ-5D dimensions (p < 0.05 for all), yielding the strongest association with problems in mobility (adjusted odds ratio, aOR: 2.1; 95% confidence interval, CI: 1.6-2.8; p < 0.001). Pre-obesity was also associated with problems in mobility (aOR: 1.4; 95% CI: 1.1-1.8; p = 0.005). Post-intervention, obesity was associated with problems in mobility and pain/discomfort, and pre-obesity with problems in mobility and self-care (p < 0.05 for all). Conclusion: Our study adds to the evidence that high BMI negatively affects SLE patients' HRQoL, with obesity being associated with pain and impaired mobility despite therapy.

Elite female endurance athletes are at increased risk of atrial fibrillation compared to the general population: a matched cohort study.

OBJECTIVE: Previous studies have found that endurance sport activity is associated with an increased risk of atrial fibrillation (AF) in men. However, it remains unclear whether endurance sports also influence the risk of AF in women. We aimed to examine whether participation in endurance sports may affect the risk of AF in female athletes. METHODS: We conducted a retrospective matched cohort study of top Swedish female endurance athletes (n=228) and reference individuals (n=1368) from the general population using the Swedish Total Population Register individually matched with a 6:1 ratio of female athletes. The athlete cohort was created by combining all Swedish women who ran the Stockholm Marathon faster than 3 hours 15 min in any of the races between 1979 and 1991, all women competing in the Swedish athletic national championships in the 10 000 metre race, and the top-ranked Swedish cyclists during the same period. We used the National Patient Register to determine whether the participants were diagnosed with AF. RESULTS: Mean age at the start of follow-up was 32 (SD±8.5) years. During follow-up (mean 28.8 years; SD±4.4), 33 cases of AF were diagnosed, including 10 (4.4%) among athletes and 23 (1.7%) among references. The HR for female athletes compared with the reference population was 2.56 (95% CI 1.22 to 5.37) in the univariable model and 3.67 (95% CI 1.71 to 7.87) after adjustment for hypertension. CONCLUSION: Elite female endurance athletes are at increased risk of AF than the general population.

Timing of Antithrombotic Secondary Prevention in Patients with Intracranial Hemorrhage after Stroke Thrombolysis and Thrombectomy.

In patients with acute ischemic stroke, hemorrhagic transformation (HT) of infarcted tissue frequently occurs after reperfusion treatment. We aimed to assess whether HT and its severity influences the start of secondary prevention therapy and increases the risk of stroke recurrence. In this retrospective dual-center study, we recruited ischemic stroke patients treated with thrombolysis, thrombectomy or both. Our primary outcome was the time between revascularization and the start of any secondary prevention therapy. The secondary outcome was ischemic stroke recurrence within three months. We compared patients with vs. without HT and no (n = 653), minor (n = 158) and major (n = 51) HT patients using propensity score matching. The delay in the start of antithrombotics or anticoagulants was median 24 h in no HT, 26 h in minor HT and 39 h in major HT. No and minor HT patients had similar rates of any stroke recurrence (3.4% (all ischemic) vs. 2.5% (1.6% ischemic plus 0.9% hemorrhagic)). Major HT patients had a higher stroke recurrence at 7.8% (3.9% ischemic, 3.9% hemorrhagic), but this difference did not reach significance. A total of 22% of major HT patients did not start any antithrombotic treatment during the three-month follow-up. In conclusion, the presence of HT influences the timing of secondary prevention in ischemic stroke patients undergoing reperfusion treatments. Minor HT did not delay the start of antithrombotics or anticoagulants compared to no HT, with no significant difference in safety outcomes. Major HT patients remain a clinical challenge with both a delayed or lacking start of treatment. In this group, we did not see a higher rate of ischemic recurrence; however, this may have been censored by elevated early mortality. While not reaching statistical significance, hemorrhagic recurrence was somewhat more common in this group, warranting further study using larger datasets.

Sensitivity analysis of EQ-5D-3L index scores in terms of discriminative and known-groups validity in SLE: introducing Adequate Health State.

OBJECTIVES: To investigate the ability of different EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) index scores to discriminate between verum drug and placebo (discriminant validity) as well as between responders and non-responders (known-groups validity) in the SLE patient population of two phase III clinical trials of belimumab. METHODS: Data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (N = 1684), which both showed superiority of belimumab to placebo, were utilized. Responders were defined as SLE Responder Index 4 (SRI-4) achievers at week 52. The Pearson's χ2 and Mann-Whitney U tests were used for comparisons, and logistic regression analysis was used for adjustments for confounders and assessment of independence. RESULTS: While full health state (FHS; EQ-5D index score 1) showed the best ability to discriminate between belimumab and placebo [adjusted odds ratio (OR) 1.47; 95% CI 1.11, 1.96; P = 0.008] and between SRI-4 responders and non-responders (adjusted OR 3.47; 95% CI 1.29, 10.98; P = 0.020), the discriminative ability of EQ-5D index scores 0.800 or more reached statistical significance for both discriminant validity (adjusted OR 1.29; 95% CI 1.02, 1.63; P = 0.036) and known-groups validity (adjusted OR 3.08; 95% CI 1.16, 9.69; P = 0.034). CONCLUSION: Overall, higher EQ-5D index scores were associated with increasing ability to discriminate between belimumab and placebo, and between responders and non-responders. EQ-5D index scores less stringent than FHS may be clinically relevant health-related quality of life goals of treatment in patients with SLE, introducing the concept of EQ-5D adequate health state when FHS is not achievable.

When to order genomic tests: development and external validation of a model to predict high-risk prostate cancer at the genotypic level.

PURPOSE: The aim of this study was to develop a model to predict high-genomic-risk prostate cancer (PCa) according to Decipher score, a validated 22 gene prognostic panel. By doing so, one might select the individuals who are likely to benefit from genomic testing and improve pre-op counseling about the need for adjuvant treatments. METHODS: We retrospectively reviewed IRB-approved databases at two institutions. All patients had preoperative magnetic resonance imaging (MRI) and Decipher prostate radical prostatectomy (RP), a validated 22 gene prognostic panel. We used binary logistic regression to estimate high-risk Decipher (Decipher score > 0.60) probability on RP specimen. Area under the curve (AUC) and calibration were used to assess the accuracy of the model in the development and validation cohort. Decision curve analysis (DCA) was performed to assess the clinical benefit of the model. RESULTS: The development and validation cohort included 622 and 185 patients with 283 (35%) and 80 (43%) of those with high-risk Decipher. The multivariable model included PSA density, biopsy Gleason Grade Group, percentage of positive cores and MRI extracapsular extension. AUC was 0.73 after leave-one-out cross-validation. DCA showed a clinical benefit in a range of probabilities between 15 and 60%. In the external validation cohort, AUC was 0.70 and calibration showed that the model underestimates the actual probability of the outcome. CONCLUSIONS: The proposed model to predict high-risk Decipher score at RP is helpful to improve risk stratification of patients with PCa and to assess the need for additional testing and treatments.

Analysis and modelling of mistriage in the Stockholm stroke triage system.

Introduction: The Stockholm Stroke Triage System (SSTS) is a prehospital triage system for detection of patients eligible for endovascular thrombectomy (EVT). Assessment of hemiparesis combined with ambulance-hospital teleconsultation is used to route patients directly to the thrombectomy centre. Some patients are not identified and require secondary transport for EVT (undertriage) while others taken to the thrombectomy centre do not undergo EVT (overtriage). The aims of this study were to characterize mistriaged patients, model for and evaluate alternative triage algorithms. Patients and methods: Patients with suspected stroke transported by priority 1 ground ambulance between October 2017 and October 2018 (n = 2905) were included. Three triage algorithms were modelled using prehospital data. Decision curve analysis was performed to calculate net benefit (correctly routing patients for EVT without increasing mistriage) of alternative models vs SSTS. Results: Undertriage for EVT occurred in n = 35/2582 (1.4%) and overtriage in n = 239/323 (74.0%). Compared to correct thrombectomy triages, undertriaged patients were younger and had lower median NIHSS (10 vs 18), despite 62.9% with an M1 occlusion. In overtriaged patients, 77.0% had a stroke diagnosis (29.7% haemorrhagic). Hemiparesis and FAST items face and speech were included in all models. Decision curve analysis showed highest net benefit for SSTS for EVT, but lower for large artery occlusion (LAO) stroke. Discussion: Undertriaged patients had lower NIHSS, likely due to better compensated proximal occlusions. SSTS was superior to other models for identifying EVT candidates, but lacked information allowing comparison to other prehospital scales. Conclusion: Using prehospital data, alternative models did not outperform the SSTS in finding EVT candidates.

High Risk of Early and Late Cardiovascular Events After Endovascular Aortic Aneurysm Repair.

BACKGROUND: The objective of this population-based study was to analyze short- and long-term major adverse cardiovascular events (MACE) after endovascular repair of ruptured or nonruptured thoracic (TAA) and abdominal aortic aneurysms (AAA). METHODS: Nationwide retrospective registry study including all patients who underwent endovascular repair (thoracic endovascular aortic repair, TEVAR; abdominal endovascular aneurysm repair, EVAR) for nonruptured/intact (iAAA/iTAA) or ruptured (rAAA/rTAA) abdominal or thoracic aneurysms between 2000 and 2018. The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction (MACE). RESULTS: There were 8,641 patients with TAA and AAA; 634 TEVAR procedures [iTAA 488; rTAA 146], and 8007 EVAR procedures [iAAA 7071; rAAA 936] were performed. MACE incidence at 90-day after TEVAR for iTAA was 10.2% and for rTAA 26.7% [HR 3.02, 95% CI 1.99-4.6]; MACE at 90-day after EVAR for iAAA was 3.7% and for rAAA 26.9% [HR 8.5, 95% CI: 7.16-10.11]. There was a higher cumulative incidence of MACE at 90-day after TEVAR for iTAA compared to EVAR for iAAA [HR 2.82, 95% CI 2.09-3.82] but no difference between the procedures after ruptured aneurysm repair. The median follow-up time was 3.28 years [IQR 1.31-5.94]. There was no long-term difference in MACE between EVAR and TEVAR after ruptured [90 days-5 years: HR 1.14, 95% CI 0.76-1.71; 5-10 years: HR 0.78, 95% CI 0.31-1.96] or intact [90 days-5 years: HR 1.19, 95% CI 0.97-1.46; 5-10 years: HR 0.82, 95% CI 0.56-1.21] aneurysm repair. Female gender had higher long-term incidence of MACE after intact [HR 1.14, 95% CI 1.03-1.27] and ruptured [HR 1.36, 95% CI 1.12-1.65] endovascular aortic aneurysm treatment. After intact aneurysms repair; age [HR 1.05, 95% CI 1.04-1.05], history of angina pectoris [HR 1.19, 95% CI 1.08-1.32], heart failure [HR 1.90, 95% CI 1.69-2.13], and stroke [HR 1.33, 95% CI 1.15-1.53] were associated with MACE. CONCLUSIONS: This nationwide cohort study still demonstrated a high risk of early and late cardiovascular events after endovascular aortic repair. Comprehensive strategies for postoperative cardiovascular disease prevention may be needed here.

Time Distribution of Mortality After Ruptured Abdominal Aortic Aneurysm Repair.

BACKGROUND: Ruptured abdominal aortic aneurysm (rAAA) repair is still associated with high mortality. The aim of this population-based study was to analyze the time distribution of mortality and short-term mortality trends after rAAA repair. METHODS: This was a nationwide retrospective registry study including all patients (n = 3,927) who underwent endovascular (EVAR) (n = 935) or open surgical repair (OSR) (n = 2,992) for rAAA between 2000 and 2018. The National Patient Register was used as a source to extract patient and medical data. The register was cross-linked with the national all-cause mortality registry. The postoperative time of death was divided into <48 hours, 2 to 5 days, 6 to 10 days, 11 to 20 days, 21 to 30 days, and 31 to 90 days during the year intervals 2000-2004, 2005-2009, 2010-2014, and 2015-2018, respectively. The proportion of patients who died within each postoperative time interval was calculated. RESULTS: The overall median age was 75.0 years (interquartile range [IQR] 69.0-80.0) and females were 19.6% (n = 769). The EVAR cohort was older (77 vs. 65 years; P < 0.001) and had significantly more cardiovascular risk factors and a history of malignancy. The overall postoperative 90-day mortality was 33.2%, EVAR 25.7%, and OSR 35.5%. There was an overall improvement in 90-day mortality over time (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.57-0.87; P = 0.001) but not separately for EVAR or OSR. Analyzing all postoperative mortalities within 90 days, 43.4% of deaths occurred within 48 hours followed by 16.3% in 2-5 days. The distribution of mortality proportions in each time interval after OSR was 15.4% in < 48 hours, 7.3% in 2-5 days, 4.4% in 6-10 days, 8.6% in 11-30 days, and 6.0% in 31-90 days and after EVAR 11.1% < 48 hours, 3.6% 2-5 days, 3.1% 6-10 days, 4.6% 11-30 days, and 6% 31-90 days. The overall mortality proportions for patients who died <48 hours after aortic repair had decreased over time (P = 0.024). A logistic regression analysis found the following risk factors associated with mortality <48 hours after rAAA, open repair (OR 1.48; 95% CI 1.17-1.89; P = 0.001), female gender (OR 1.41; 95% CI 1.14-1.75; P = 0.002), and history of heart failure (OR 1.63; 95% CI 1.19-2.22; P = 0.002) or angina pectoris (OR 1.37; 95% CI 1.03-1.81; P = 0.03). The recent operative year interval, 2015-2018, was associated with a lower risk for mortality <48 hours (OR 0.72; 95% 0.53-0.98; P = 0.04) and <90-days (OR 0.63; 95% CI 0.49-0.80; P < 0.001). CONCLUSIONS: Overall mortality after rAAA repair had decreased but early deaths remained a significant challenge. The mortality was highest within two days of surgery but the proportion of patients who died <48 hours after aortic repair had decreased in recent years. Open repair, female gender, and cardiovascular comorbidities were associated with mortality within 48 hours after surgery. More focused research in the early postoperative phase after rAAA is warranted.

Impact of remission and low disease activity on health-related quality of life in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate the impact of remission and lupus low disease activity state (LLDAS) on health-related quality of life (HRQoL) in systemic lupus erythematosus. METHODS: Short-Form 36 (SF-36), three-level EQ-5D (EQ-5D-3L) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials were used. Duration in remission/LLDAS required to reach a HRQoL benefit ≥ minimal clinically important differences (MCIDs) during and post-treatment was determined using quantile regression and generalized estimating equations. RESULTS: Patients (n = 1684) were assessed every fourth week (15 visits). Four cumulative (ß = 0.60) or four consecutive (ß = 0.66) visits in remission were required to achieve a benefit ≥MCID in SF-36 physical component summary (PCS) scores, and six cumulative (ß = 0.44) or five consecutive (ß = 0.49) for a benefit ≥MCID in mental component summary (MCS) scores. Eight cumulative (ß = 0.30 for both) or eight consecutive (ß = 0.32 for both) visits in LLDAS were required for a benefit in PCS/MCS ≥MCID, respectively. For EQ-5D-3L index scores ≥MCID, six cumulative (ß = 0.007) or five consecutive (ß = 0.008) visits in remission were required, and eight cumulative (ß = 0.005) or six consecutive (ß = 0.006) visits in LLDAS. For FACIT-Fatigue scores ≥MCID, 12 cumulative (ß = 0.34) or 10 consecutive (ß = 0.39) visits in remission were required, and 17 cumulative (ß = 0.24) or 16 consecutive (ß = 0.25) visits in LLDAS. CONCLUSION: Remission and LLDAS contribute to a HRQoL benefit in a time-dependent manner. Shorter time in remission than in LLDAS was required for a clinically important benefit in HRQoL, and longer time in remission for a benefit in mental compared with physical HRQoL aspects. When remission/LLDAS was sustained, the same benefit was achieved in a shorter time.

EQ-5D full health state after therapy heralds reduced hazard to accrue subsequent organ damage in systemic lupus erythematosus.

Objectives: To investigate whether self-reported EQ-5D full health state (FHS) after therapeutic intervention for active systemic lupus erythematosus (SLE) is associated with a reduced risk to accrue organ damage. In a separate analysis, we sought to investigate associations between experience of "no problems" in each one of the five dimensions of EQ-5D and the risk to accrue damage. Methods: Data from the open-label extension periods of the BLISS-52 and BLISS-76 trials of belimumab in SLE (NCT00724867; NCT00712933) were used (N = 973). FHS was defined as an experience of "no problems" in all five EQ-5D dimensions. Organ damage was assessed annually using the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI). Associations between the three-level version of the EQ-5D (EQ-5D-3L) responses at open-label baseline and the first documented increase in organ damage were investigated using Cox regression accounting for age, sex, ancestry, SDI at baseline, and background therapy, and associations with SDI items were investigated using phi (φ) correlation analyses. Results: A total of 147 patients (15.1%) accrued organ damage during follow-up, with the first increase in their SDI score occurring after a mean time of 29.1 ± 19.6 months. Lower proportions of FHS respondents accrued damage over a course of up to 7.9 years of open-label follow-up compared with no FHS respondents (p = 0.004; derived from the logrank test). FHS was associated with a reduced hazard to accrue subsequent organ damage (HR: 0.60; 95% CI: 0.38-0.96; p = 0.033) after adjustments, as was experience of "no problems" in mobility (HR: 0.61; 95% CI: 0.43-0.87; p = 0.006). "No problems" in mobility was negatively correlated with musculoskeletal damage accrual (φ = -0.08; p = 0.008) and associated with a lower hazard to accrue musculoskeletal damage in Cox regression analysis (HR: 0.38; 95% CI: 0.19-0.76; p = 0.006). Conclusion: Experience of EQ-5D-3L FHS and "no problems" in mobility after therapeutic intervention heralded reduced hazard to accrue subsequent organ damage, especially musculoskeletal damage, suggesting that optimisation of these health-related quality of life aspects constitutes a clinically relevant treatment target in patients with SLE, along with clinical and laboratory parameters.