Using joint models for longitudinal and time-to-event data to investigate the causal effect of salvage therapy after prostatectomy.

Prostate cancer patients who undergo prostatectomy are closely monitored for recurrence and metastasis using routine prostate-specific antigen measurements. When prostate-specific antigen levels rise, salvage therapies are recommended in order to decrease the risk of metastasis. However, due to the side effects of these therapies and to avoid over-treatment, it is important to understand which patients and when to initiate these salvage therapies. In this work, we use the University of Michigan Prostatectomy Registry Data to tackle this question. Due to the observational nature of this data, we face the challenge that prostate-specific antigen is simultaneously a time-varying confounder and an intermediate variable for salvage therapy. We define different causal salvage therapy effects defined conditionally on different specifications of the longitudinal prostate-specific antigen history. We then illustrate how these effects can be estimated using the framework of joint models for longitudinal and time-to-event data. All proposed methodology is implemented in the freely-available R package JMbayes2.

Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study.

BACKGROUND: Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with low-risk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants. METHODS: For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database. FINDINGS: Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1-17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04-3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55-2·36; p=0·72). INTERPRETATION: The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants. FUNDING: None.

Increasing Systemic Immune-inflammation Index During Treatment in Patients With Advanced Pancreatic Cancer is Associated With Poor Survival: A Retrospective, Multicenter, Cohort Study.

BACKGROUND AND OBJECTIVES: A high systemic immune-inflammation index (SIII) at diagnosis of various cancers, including pancreatic cancer, is associated with poor prognosis. The impact of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) chemotherapy or stereotactic body radiotherapy on this index is unknown. In addition, the prognostic value of changes in the SIII during treatment is unclear. In this retrospective analysis, we aimed to find answers regarding patients with advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer treated with FOLFIRINOX chemotherapy alone or with FOLFIRINOX chemotherapy followed by stereotactic body radiotherapy between 2015 and 2021 in 2 tertiary referral centers were included. Baseline characteristics, laboratory values at 3 time points during treatment, and survival outcomes were collected. The patient-specific evolutions of SIII and their association with mortality were assessed with joint models for longitudinal and time-to-event data. RESULTS: Data of 141 patients were analyzed. At a median follow-up time of 23.0 months (95% CI: 14.6-31.3), 97 (69%) patients had died. Median overall survival was 13.2 months (95% CI: 11.0-15.5). During treatment with FOLFIRINOX, the log (SIII) was reduced by -0.588 (95% CI: -0.0978, -0.197; P = 0.003). One unit increase in log (SIII) increased the hazard ratio of dying by 1.604 (95% CI: 1.068-2.409; P = 0.023). CONCLUSIONS: In addition to carbohydrate antigen 19-9, the SIII is a reliable biomarker in patients with advanced pancreatic cancer.

Prenatal alcohol exposure results in brain region- and sex-specific changes in circHomer1 expression in adult mouse brain.

Circular RNAs (circRNAs) are a novel category of covalently-closed non-coding RNAs mainly derived from the back-splicing of exons or introns of protein-coding genes. In addition to their inherent high overall stability, circRNAs, have been shown to have strong functional effects on gene expression via a multitude of transcriptional and post-transcriptional mechanisms. Furthermore, circRNAs, appear to be particularly enriched in the brain and able to influence both prenatal development and postnatal brain function. However, little is known about the potential involvement of circRNAs in the long term influence of prenatal alcohol exposure (PAE) in the brain and their relevance for Fetal Alcohol Spectrum Disorders (FASD). Using circRNA-specific quantification, we have found that circHomer1, an activity-dependent circRNA derived from Homer protein homolog 1 (Homer1) and enriched in postnatal brain, is significantly down-regulated in the male frontal cortex and hippocampus of mice subjected to modest PAE. Our data further suggest that the expression of H19, an imprinted embryonic brain-enriched long non-coding RNA (lncRNA), is significantly up-regulated in the frontal cortex of male PAE mice. Furthermore, we show opposing changes in the developmental- and brain region specific- expression of circHomer1 and H19. Lastly, we show that knockdown of H19 results in robust increases in circHomer1 but not linear HOMER1 mRNA expression in human glioblastoma cell lines. Taken together, our work uncovers notable sex- and brain region-specific alterations in circRNA and lncRNA expression following PAE and introduces novel mechanistic insights with potential relevance to FASD.

The clinical impact of tricuspid regurgitation in patients with a biatrial orthotopic heart transplant.

In this study, we aim to elucidate the clinical impact and long-term course of tricuspid regurgitation (TR), taking into account its dynamic nature, after biatrial orthotopic heart transplant (OHT). All consecutive adult patients undergoing biatrial OHT (1984-2017) with an available follow-up echocardiogram were included. Mixed-models were used to model the evolution of TR. The mixed-model was inserted into a Cox model in order to address the association of the dynamic TR with mortality. In total, 572 patients were included (median age: 50 years, males: 74.9%). Approximately 32% of patients had moderate-to-severe TR immediately after surgery. However, this declined to 11% on 5 years and 9% on 10 years after surgery, adjusted for survival bias. Pre-implant mechanical support was associated with less TR during follow-up, whereas concurrent LV dysfunction was significantly associated with more TR during follow-up. Survival at 1, 5, 10, 20 years was 97% ± 1%, 88% ± 1%, 66% ± 2% and 23% ± 2%, respectively. The presence of moderate-to-severe TR during follow-up was associated with higher mortality (HR: 1.07, 95% CI (1.02-1.12), p = 0.006). The course of TR was positively correlated with the course of creatinine (R = 0.45). TR during follow-up is significantly associated with higher mortality and worse renal function. Nevertheless, probability of TR is the highest immediately after OHT and decreases thereafter. Therefore, it may be reasonable to refrain from surgical intervention for TR during earlier phase after OHT.

Male-Female Differences in Ascending Aortic Aneurysm Surgery: 25-Year Single Center Results.

The aim of this study was to improve insight into male-female differences in patients undergoing ascending aortic aneurysm surgery. Consecutive patients that underwent ascending aortic aneurysm surgery between January 1991-December 2016 were retrospectively analyzed. Patient and procedural characteristics, 30-day mortality, and survival were compared between male and female patients. Multivariable Cox-regression analysis was performed to explore differences in factors associated with long-term mortality. Of 631 included patients, 36% were female patients. They were older (66 (55.9-72.9) vs 56 (44.1-67.3) years, p < 0.001), had a higher logistic EuroSCORE (12 (8-17) vs 8 (5-12), p < 0.001), and underwent concomitant arch surgery more often (74% vs 54%, p < 0.001). Aortic diameter (5.5 (5.0.6.5) vs 5.5 (5.0-6.0) cm, p = 0.025) and Aortic Size Index (3.15 (2.80-3.65) vs 2.70 (2.42-3.00) cm/m2, p < 0.001) were larger in female patients. Early mortality was 0.9% in female patients and 2.0% in male patients (p = 0.51). Adjusted 15-year survival was comparable between male and female patients. Multivariable Cox-regression did not identify an independent association between female sex and mortality. In males a larger aortic diameter (HR1.38 per centimeter increase, 95%-CI 1.03-1.85, p = 0.003) was an independent factor associated with mortality, and in female patients a larger BSA (HR0.08 per 1kg/m2 increase, 95%-CI 0.01-0.49, p = 0.007) was an independent risk-reducing factor. Female patients presented at older age and with more advanced disease. Increased awareness for ascending aortic pathology and timely referral may result in better preoperative profiles in female patients. This may improve outcomes after ascending aortic aneurysm surgery.

Clinical Characteristics and Outcomes of Immunocompromised Patients With Coronavirus Disease 2019 Caused by the Omicron Variant: A Prospective, Observational Study.

BACKGROUND: Illness after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is less severe compared with previous variants. Data on the disease burden in immunocompromised patients are lacking. We investigated the clinical characteristics and outcomes of immunocompromised patients with coronavirus disease 2019 (COVID-19) caused by Omicron. METHODS: Organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients infected with the Omicron variant were included. Characteristics of consenting patients were collected and patients were contacted regularly until symptom resolution. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed. RESULTS: 114 consecutive immunocompromised patients were enrolled. Eighty-nine percent had previously received 3 mRNA vaccinations. While only 1 patient died, 23 (20%) were hospitalized for a median of 11 days. A low SARS-CoV-2 immunoglobulin G (IgG) antibody response (<300 BAU [binding antibody units]/mL) at diagnosis, being older, being a lung transplant recipient, having more comorbidities, and having a higher frailty score were associated with hospital admission (all P < .01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% had a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of these patients, and 1 died. CONCLUSIONS: While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. In addition to vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients.

Outcomes of different aortic arch replacement techniques.

BACKGROUND: Consensus on the best treatment for aortic arch pathology is unresolved due to an emerging variety of procedures. We aimed to compare the outcomes of two major techniques for open aortic arch replacement involving the supra-aortic branches and to identify the risk factors for specific adverse events. METHODS: Between 1974 and 2017, 172 patients were treated with either the en bloc (island, n = 59; 34.3%) or branched graft technique (n = 113, 65.7%). Most of the patients were treated in an emergent/urgent setting (52.4%). RESULTS: Patients who underwent the en bloc procedure had significantly shorter cardiopulmonary bypass (median: 241 vs 271 minutes, P = .041) and aortic cross clamp times (median: 124 vs 168 minutes, P = .005) than patients who underwent the separate graft technique. Overall, the hospital mortality was lower in the en bloc group, 8.5% vs 19.5%, although the difference was not significant (P = .077). No difference was found in the survival between the separate graft and en bloc groups at 1 (77.0 vs 86.3%), 5 (67.7 vs 66.3%) and 10 years (42.4 vs 51.3%), (P = .63). The postoperative stroke rate was comparable between the en bloc and separate graft cohorts (14.3 vs 19.6%, P = .52). Diabetics and those who underwent an elephant trunk procedure were at a higher risk for reintervention. CONCLUSIONS: The separate graft technique, which is more common today, showed no difference from the en bloc technique with regard to hospital mortality and morbidity. Furthermore, the late survival and reintervention rates were similar after both procedures.

Influence of pregnancy on long-term durability of allografts in right ventricular outflow tract.

BACKGROUND: There is very limited published evidence about the influence of pregnancy on allograft durability in right ventricular outflow tract position. We present the first study using mixed and joint modeling. METHODS: This retrospective study compared clinical and valve related outcomes of all consecutive female hospital survivors in their fertile life phase (18-50 years) based on pregnancy. Serial echocardiographic measurements of pulmonary gradient and regurgitation were analyzed for their association with valve replacement using joint models for longitudinal and time-to-event data. Occurrence of first pregnancy was included as a time-dependent intermediate event in both the longitudinal and survival analyses of the joint model to assess its impact on the hemodynamic and clinical outcome. RESULTS: In total, 196 consecutive women in their fertile life-phase with an allograft were included. Complete information of 176 (90%) allografts in 165 women was available, including 1395 echocardiograms. Of these women, 51 (30.9%) women had 84 completed pregnancies at an average age of 29.1 ± 3.9 (SD) years; 8.1 ± 6.1 years since allograft implantation. Tetralogy of Fallot was the most common diagnosis in both groups. After a mean follow-up of 15.2 years (range 0.1-30), 7 (13.7%) parous women underwent valve replacement versus 20 (17.5%) nulliparous women. During this follow-up, the mean allograft gradient in parous (24.2 mm Hg) and nulliparous (21.0 mm Hg) women was comparable (P = .225). A 1-mm Hg increase in pulmonary gradient increased the instantaneous risk of pulmonary valve replacement (PVR) by a ratio of 1.051 (P < .001), regardless of pregnancy. Similarly, development of moderate or severe regurgitation increased the risk of PVR (P = .038), regardless of pregnancy. Pregnancy was not associated with a change in the allograft gradient (P = .258), regurgitation grade (P = .774), or hazard of PVR (P = .796) during follow-up. CONCLUSIONS: Pregnancy is not associated with impaired allograft durability in women with good cardiac health.

Individualized dynamic prediction of survival with the presence of intermediate events.

Often, in follow-up studies, patients experience intermediate events, such as reinterventions or adverse events, which directly affect the shapes of their longitudinal profiles. Our work is motivated by two studies in which such intermediate events have been recorded during follow-up. In both studies, we are interested in the change of the longitudinal evolutions after the occurrence of the intermediate event and in utilizing this information to improve the accuracy of dynamic prediction of their risk. To achieve so, we propose a flexible joint modeling framework for longitudinal and time-to-event data, which includes features of the intermediate event as time-varying covariates in both the longitudinal and survival submodels. We consider a set of joint models that postulate different effects of the intermediate event in the longitudinal profile and the risk of the clinical endpoint, with different formulations for the association structure while allowing its functional form to change after the occurrence of the intermediate event. Based on these models, we derive dynamic predictions of conditional survival probabilities which are adaptive to different scenarios with respect to the occurrence of the intermediate event. We evaluate the predictive accuracy of these predictions with a simulation study using the time-dependent area under the receiver operating characteristic curve and the expected prediction error adjusted to our setting. The results suggest that accounting for the changes in the longitudinal profiles and the instantaneous risk for the clinical endpoint is important, and improves the accuracy of the dynamic predictions.

Bioprosthetic Aortic Valve Replacement in Nonelderly Adults: A Systematic Review, Meta-Analysis, Microsimulation

Background To support decision-making in aortic valve replacement in nonelderly adults, we aim to provide a comprehensive overview of reported outcome after bioprosthetic aortic valve replacement and to translate this to age-specific patient outcome estimates. Methods and Results A systematic review was conducted for papers reporting clinical outcome after aortic valve replacement with currently available bioprostheses in patients with a mean age <55 years, published between January 1, 2000, and January 9, 2016. Pooled reported event rates and time-to-event data were pooled and entered into a microsimulation model to calculate life expectancy and lifetime event risk for the ages of 25, 35, 45, and 55 years at surgery. Nineteen publications were included, encompassing a total of 2686 patients with 21 117 patient-years of follow-up (pooled mean follow-up: 7.9±4.2 years). Pooled mean age at surgery was 50.7±11.0 years. Pooled early mortality risk was 3.30% (95% CI, 2.39-4.55), late mortality rate was 2.39%/y (95% CI, 1.13-2.94), reintervention 1.82%/y (95% CI, 1.31-2.52), structural valve deterioration 1.59%/y (95% CI, 1.21-2.10), thromboembolism 0.53%/y (95% CI, 0.42-0.67), bleeding 0.22%/y (95% CI, 0.16-0.32), endocarditis 0.48%/y (95% CI, 0.37-0.62), and 20-year pooled actuarial survival was 58.7% and freedom from reintervention was 29.0%. Median time to structural valve deterioration was 17.3 years and median time to all-cause first reintervention was 16.9 years. For a 45-year-old adult, for example, this translated to a microsimulation-based estimated life expectancy of 21 years (general population: 32 years) and lifetime risk of reintervention of 78%, structural valve deterioration 71%, thromboembolism 12%, bleeding 5%, and endocarditis 9%. Conclusions Aortic valve replacement with bioprostheses in young adults is associated with high structural valve deterioration and reintervention rates and low, though not absent, hazards of thromboembolism and bleeding. Foremostly, most patients will require one or more reinterventions during their lifetime and survival is impaired in comparison with the age- and sex-matched general population. Prosthesis durability remains the main concern in nonelderly patients.

The Ross Procedure: A Systematic Review, Meta-Analysis, and Microsimulation.

BACKGROUND: To support decision-making in aortic valve replacement in children and adults, we provide a comprehensive overview of outcome after the Ross procedure. METHODS AND RESULTS: A systematic search was conducted for publications reporting clinical outcome after the Ross procedure, published between January 1, 2000, and November 22, 2017. Reported event rates and time-to-event data were pooled and entered into a microsimulation model to calculate life expectancy and lifetime event risk. Ninety-nine publications were included (13 129 patients; total follow-up: 93 408 patient-years, pooled mean follow-up: 7.9±5.3 years). Pooled mean age at surgery was 9.4±5.5 years for children and 41.9±11.4 for adults. For children and adults, respectively, pooled early mortality risk was 4.19% (95% CI, 3.21-5.46) and 2.01% (95% CI, 1.44-2.82), late mortality rate was 0.54%/y (95% CI, 0.42-0.70) and 0.59%/y (95% CI, 0.46-0.76), autograft reintervention 1.28%/y (95% CI, 0.99-1.66) and 0.83%/y (95% CI, 0.68-1.01), and right ventricular outflow tract reintervention 1.97%/y (95% CI, 1.64-2.36) and 0.47%/y (95% CI, 0.37-0.59). Pooled thromboembolism and bleeding rates were low and comparable to the general population. Lifetime risks of autograft and right ventricular outflow tract reintervention were, respectively, 94% and 100% for children and 49% and 19% for a 45-year-old. Estimated life expectancy after surgery was 59 years for children (general population: 64 years) and 30 years for a 45 years old (general population: 31 years). CONCLUSIONS: Through excellent survival and avoidance of the burden of anticoagulation, the Ross procedure provides a unique opportunity for patients whose preferences do not align with the outcome provided by mechanical valve replacement and for growing children who also benefit from autograft diameter increase along with somatic growth. On the downside, almost all pediatric and many adult Ross patients will require a reintervention in their lifetime.

Progression of Hearing Loss in the Aging Population: Repeated Auditory Measurements in the Rotterdam Study.

We quantified changes in the auditory acuity of 675 aging adults (mean age 71.1 years, 52.0% female, mean follow-up 4.4 years ± 0.2) of an ongoing cohort study with a pure-tone audiogram and a speech-in-noise test. Generalized estimating equation models were used to study the association between hearing loss and the progression with age, sex, education, cognition, BMI, blood pressure, having type 2 diabetes mellitus, cholesterol ratio, smoking and alcohol consumption. The mean progression of hearing loss was 0.29 and 1.35 dB/year (low and high frequencies). Progression of hearing loss was associated with baseline hearing thresholds. Besides, the presence of type 2 diabetes, smoking, age, sex and time were associated with worse hearing at baseline, but there was no statistical evidence that the tested determinants were associated with progression of hearing loss. This finding indicates that the 4-year progression of hearing loss in older adults in this study is not influenced by the measured determinants. More research with multiple follow-up rounds is desired.

Stroke Rates Following Surgical Versus Percutaneous Coronary Revascularization.

BACKGROUND: Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are used for coronary revascularization in patients with multivessel and left main coronary artery disease. Stroke is among the most feared complications of revascularization. Due to its infrequency, studies with large numbers of patients are required to detect differences in stroke rates between CABG and PCI. OBJECTIVES: This study sought to compare rates of stroke after CABG and PCI and the impact of procedural stroke on long-term mortality. METHODS: We performed a collaborative individual patient-data pooled analysis of 11 randomized clinical trials comparing CABG with PCI using stents; ERACI II (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Patients With Multiple Vessel Disease) (n = 450), ARTS (Arterial Revascularization Therapy Study) (n = 1,205), MASS II (Medicine, Angioplasty, or Surgery Study) (n = 408), SoS (Stent or Surgery) trial (n = 988), SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial (n = 1,800), PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) trial (n = 600), FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1,900), VA CARDS (Coronary Artery Revascularization in Diabetes) (n = 198), BEST (Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease) (n = 880), NOBLE (Percutaneous Coronary Angioplasty Versus Coronary Artery Bypass Grafting in Treatment of Unprotected Left Main Stenosis) trial (n = 1,184), and EXCEL (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial (n = 1,905). The 30-day and 5-year stroke rates were compared between CABG and PCI using a random effects Cox proportional hazards model, stratified by trial. The impact of stroke on 5-year mortality was explored. RESULTS: The analysis included 11,518 patients randomly assigned to PCI (n = 5,753) or CABG (n = 5,765) with a mean follow-up of 3.8 ± 1.4 years during which a total of 293 strokes occurred. At 30 days, the rate of stroke was 0.4% after PCI and 1.1% after CABG (hazard ratio [HR]: 0.33; 95% confidence interval [CI]: 0.20 to 0.53; p < 0.001). At 5-year follow-up, stroke remained significantly lower after PCI than after CABG (2.6% vs. 3.2%; HR: 0.77; 95% CI: 0.61 to 0.97; p = 0.027). Rates of stroke between 31 days and 5 years were comparable: 2.2% after PCI versus 2.1% after CABG (HR: 1.05; 95% CI: 0.80 to 1.38; p = 0.72). No significant interactions between treatment and baseline clinical or angiographic variables for the 5-year rate of stroke were present, except for diabetic patients (PCI: 2.6% vs. CABG: 4.9%) and nondiabetic patients (PCI: 2.6% vs. CABG: 2.4%) (p for interaction = 0.004). Patients who experienced a stroke within 30 days of the procedure had significantly higher 5-year mortality versus those without a stroke, both after PCI (45.7% vs. 11.1%, p < 0.001) and CABG (41.5% vs. 8.9%, p < 0.001). CONCLUSIONS: This individual patient-data pooled analysis demonstrates that 5-year stroke rates are significantly lower after PCI compared with CABG, driven by a reduced risk of stroke in the 30-day post-procedural period but a similar risk of stroke between 31 days and 5 years. The greater risk of stroke after CABG compared with PCI was confined to patients with multivessel disease and diabetes. Five-year mortality was markedly higher for patients experiencing a stroke within 30 days after revascularization.

Statistical primer: how to deal with missing data in scientific research?

Missing data are a common challenge encountered in research which can compromise the results of statistical inference when not handled appropriately. This paper aims to introduce basic concepts of missing data to a non-statistical audience, list and compare some of the most popular approaches for handling missing data in practice and provide guidelines and recommendations for dealing with and reporting missing data in scientific research. Complete case analysis and single imputation are simple approaches for handling missing data and are popular in practice, however, in most cases they are not guaranteed to provide valid inferences. Multiple imputation is a robust and general alternative which is appropriate for data missing at random, surpassing the disadvantages of the simpler approaches, but should always be conducted with care. The aforementioned approaches are illustrated and compared in an example application using Cox regression.

Downsized cryopreserved and standard-sized allografts for right ventricular outflow tract reconstruction in children: long-term single-institutional experience.

OBJECTIVES: The objective of this study was to determine long-term results with bicuspidalized allografts compared to non-bicuspidalized allografts in children under 2 years undergoing primary correction of the right ventricular outflow tract. METHODS: Thirty-five consecutive bicuspidalized allografts were compared to 45 consecutive non-bicuspidalized allografts implanted during the same period. Valve-related events were analysed with Kaplan-Meier and Cox-regression techniques. Mixed-effects modelling was used to analyse serial echocardiographic measurements of pulmonary gradient. In addition, a systematic review with meta-analysis of the published literature concerning implantation of bicuspidalized allografts was performed. RESULTS: Perioperative characteristics and in-hospital mortality [bicuspidalized 5 (14.3%), non-bicuspidalized 6 (13.3%)] were comparable (P = 0.902). Bicuspidalized allografts were smaller (14.7 vs 16.5 mm, P = 0.023) and always (100%) of pulmonary origin compared to 26 (57.8%) of the standard-sized allografts. There were no differences in late mortality between the bicuspidalized and non-bicuspidalized group (6.7% vs 7.7%, P = 0.798) or freedom from allograft replacement at 10 years (82 ± 10% and 71 ± 8%, for bicuspidalized and non-bicuspidalized allografts, respectively). Evolution of peak pulmonary gradient (P = 0.273) was comparable between bicuspidalized and non-bicuspidalized allografts. Meta-analysis showed a pooled early and late mortality for bicuspidalized allograft patients of 10.72% [95% confidence interval (CI) 6.13-18.75] and 1.6% per year (95% CI 0.99-2.79), respectively. Pooled estimated late reintervention and replacement rates were 5.94% per year (95% CI 3.42-10.30) and 3.78% per year (95% CI 2.69-5.32), respectively. CONCLUSIONS: Bicuspidalization seems to be a viable alternative to combat limited supply of small-sized allografts with acceptable survival and reintervention rates comparable to non-bicuspidalized allografts.

Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data.

BACKGROUND: Numerous randomised trials have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) for patients with coronary artery disease. However, no studies have been powered to detect a difference in mortality between the revascularisation strategies. METHODS: We did a systematic review up to July 19, 2017, to identify randomised clinical trials comparing CABG with PCI using stents. Eligible studies included patients with multivessel or left main coronary artery disease who did not present with acute myocardial infarction, did PCI with stents (bare-metal or drug-eluting), and had more than 1 year of follow-up for all-cause mortality. In a collaborative, pooled analysis of individual patient data from the identified trials, we estimated all-cause mortality up to 5 years using Kaplan-Meier analyses and compared PCI with CABG using a random-effects Cox proportional-hazards model stratified by trial. Consistency of treatment effect was explored in subgroup analyses, with subgroups defined according to baseline clinical and anatomical characteristics. FINDINGS: We included 11 randomised trials involving 11 518 patients selected by heart teams who were assigned to PCI (n=5753) or to CABG (n=5765). 976 patients died over a mean follow-up of 3·8 years (SD 1·4). Mean Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score was 26·0 (SD 9·5), with 1798 (22·1%) of 8138 patients having a SYNTAX score of 33 or higher. 5 year all-cause mortality was 11·2% after PCI and 9·2% after CABG (hazard ratio [HR] 1·20, 95% CI 1·06-1·37; p=0·0038). 5 year all-cause mortality was significantly different between the interventions in patients with multivessel disease (11·5% after PCI vs 8·9% after CABG; HR 1·28, 95% CI 1·09-1·49; p=0·0019), including in those with diabetes (15·5% vs 10·0%; 1·48, 1·19-1·84; p=0·0004), but not in those without diabetes (8·7% vs 8·0%; 1·08, 0·86-1·36; p=0·49). SYNTAX score had a significant effect on the difference between the interventions in multivessel disease. 5 year all-cause mortality was similar between the interventions in patients with left main disease (10·7% after PCI vs 10·5% after CABG; 1·07, 0·87-1·33; p=0·52), regardless of diabetes status and SYNTAX score. INTERPRETATION: CABG had a mortality benefit over PCI in patients with multivessel disease, particularly those with diabetes and higher coronary complexity. No benefit for CABG over PCI was seen in patients with left main disease. Longer follow-up is needed to better define mortality differences between the revascularisation strategies. FUNDING: None.