Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an agg... more Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an aggressive form of breast cancer and is historically associated with poor outcomes compared with HER2-negative MBC. Since 1998, four drugs have been globally approved for the targeted treatment of HER2-positive MBC. Additional advances in patient care-such as improved breast cancer screening, HER2 testing, and supportive care-have also occurred. The objective of this systematic review and meta-analysis is to determine whether there has been a cumulative change in survival over time in patients with HER2-positive advanced breast cancer based on results from interventional clinical trials (ICTs) and observational studies and to compare outcomes across these types of studies. A systematic search of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials will be performed. Two investigators will independently assess each abstract for inclusion. English language reports of ICTs and observational studies that include patients with HER2-positive advanced breast cancer from 1987 onwards will be considered. The primary outcome of interest is overall survival; secondary outcomes include progression-free survival and safety. Data on clinical outcomes, as well as on study design, study population, treatment/intervention, methodological quality, and outcomes, will be extracted using a structured codebook developed by the authors for this study. Standard and cumulative random effects meta-analysis will be performed to derive pooled risk estimates, both overall and by study design, controlling for covariates such as aggregate demographic and clinical characteristics of patients, treatment/intervention, and study characteristics. Heterogeneity of studies will be evaluated using the I(2) statistic. Differences in risk estimates by quality characteristics will be performed using meta-regression. This study will evaluate current and evolving trends in survival associated with HER2-positive advanced breast cancer over nearly 30 years and will build upon prior, less comprehensive, systematic analyses. This information is important to patients, healthcare providers, and researchers, particularly in the advanced disease setting, in which new therapies have been recently approved. Including observational studies allows us to evaluate real-world effectiveness; useful information will be gained by comparing findings from observational studies with those from ICTs. PROSPERO CRD42014014345.
Refractory cardiogenic shock (RCS) is associated with significant morbidity and mortality, and cu... more Refractory cardiogenic shock (RCS) is associated with significant morbidity and mortality, and current mainstays of medical therapy appear inadequate. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) represents an increasingly accepted therapy for RCS. Demographics, past medical history, preoperative characteristics, outcomes, and adverse events were collected for consecutive patients who received VA-ECMO support for RCS at our institution from March 2007 to December 2013. One hundred and seventy-nine patients with a mean age of 56.9 ± 16.1 years were included. Etiologies of RCS included postcardiotomy shock in 70 patients (39%), acute myocardial infarction in 46 patients (26%), primary graft failure in 17 patients (10%), and acute decompensated heart failure in 24 patients (13%). Mean arterial pressure before VA-ECMO support was 59.4 ± 22.8 mm Hg and 30.7% (n = 55) were undergoing active cardiopulmonary resuscitation at the time of cannulation. Overall, 38.6% of patients (n = 69) survived to discharge and 44.7% of patients (n = 80) survived to 30 days. Myocardial recovery was achieved in 79.7% of survivors (n = 55) and 39.1% were transitioned to a more durable device. Univariate analysis identified age (p = 0.002) and etiology of RCS (p = 0.041) as the most significant predictors of in-hospital mortality. Venoarterial extracorporeal membrane oxygenation for RCS appears successful as salvage therapy. Age and etiology should be considered when evaluating patients for VA-ECMO.
Mathematical models of disease progression predict disease outcomes and are useful epidemiologica... more Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The 𝖱 package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death), displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multi...
Background. Hybrid percutaneous coronary intervention offers an alternative method of revasculari... more Background. Hybrid percutaneous coronary intervention offers an alternative method of revascularization for high-risk surgical populations. We report the outcomes of a single-stage hybrid strategy in valvular cardiac surgery and explore its effects on operative risk and bleeding.
The options for secondary prevention of cryptogenic embolism in patients with patent foramen oval... more The options for secondary prevention of cryptogenic embolism in patients with patent foramen ovale are administration of antithrombotic medications or percutaneous closure of the patent foramen ovale. We investigated whether closure is superior to medical therapy. We performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end points were unaware of the study-group assignments. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy. The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population. The mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary en...
Patients with severe aortic stenosis at increased surgical risk continue to experience compromise... more Patients with severe aortic stenosis at increased surgical risk continue to experience compromised long-term survival despite successful transcatheter aortic valve implantation. We used time-related pathways in a multistate analysis to identify predictors of adverse long-term outcome in patients who underwent transcatheter aortic valve implantation. In a cohort of 389 patients with a mean age of 82.4 ± 5.8 years and a STS score of 6.8 ± 5.3 undergoing transcatheter aortic valve implantation between 2007 and 2011, multistate analysis was used to estimate mortality and stroke taking into account intercurrent events including kidney injury and the composite of access site and bleeding complications (ABC). Transapical access emerged as a predictor of kidney injury (hazard ratio [HR], 2.12; 95% confidence interval [CI] 1.00-4.47) and ABC (HR, 1.78; 95% CI, 1.07-2.96), but had no impact on the risk of stroke or death. Body mass index ≤20 kg/m(2) increased the risk of stroke or death (HR, ...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, Jan 17, 2014
Aims: To compare clinical outcomes after percutaneous coronary intervention (PCI) between patient... more Aims: To compare clinical outcomes after percutaneous coronary intervention (PCI) between patients with acute coronary syndromes (ACS) and those with stable ischaemic heart disease (SIHD) stratified by anatomic disease complexity (SYNTAX score). Methods and results: Patient-level data from three all-comers PCI trials were pooled. Patients (n=4,204) were stratified by clinical presentation (i.e., ACS or SIHD) and by SYNTAX score (i.e., lowest vs. two highest tertiles). The major adverse cardiac event (MACE) rates of patients with low-risk SIHD (n=531) and high-risk SIHD (n=1,066) were compared with ACS patients (n=2,607), respectively. At two years, the risk of MACE was higher for high-risk SIHD patients (OR 1.34, 95% CI: 1.08-1.66) and lower for low-risk SIHD patients (OR 0.61, 95% CI: 0.43-0.87) compared with ACS patients, respectively. This difference between high-risk SIHD patients and ACS patients was primarily driven by a higher risk of myocardial infarction (OR 1.64, 95% CI: 1...
Patients with ischemic stroke or transient ischemic attack presumably related to patent foramen o... more Patients with ischemic stroke or transient ischemic attack presumably related to patent foramen ovale (PFO) are at risk for recurrent cerebrovascular events. Differences in long-term clinical outcome were investigated among patients with percutaneous PFO closure and those who received medical treatment. Between 1994 and 2000, 308 consecutive patients with cerebrovascular events presumably related to PFO underwent either percutaneous PFO closure (150 patients) or medical treatment (158 patients). Patients were followed up prospectively for up to 15 years. Seven patients were lost during follow-up. The primary outcome was a composite of stroke, transient ischemic attack, or peripheral embolism. We analyzed 103 propensity score-matched pairs of patients who underwent percutaneous PFO closure or medical treatment. At a median follow-up of 9 years, the primary composite outcome occurred in 11 patients slated to PFO closure (11%) and 22 patients slated to medical treatment (21%; hazard ra...
Anemia is frequent among patients with cardiovascular disease and adversely affects prognosis. Th... more Anemia is frequent among patients with cardiovascular disease and adversely affects prognosis. The objective of this analysis was to assess the impact of anemia on long-term clinical outcomes among patients undergoing percutaneous coronary intervention (PCI) with the unrestricted use of drug-eluting stents (DES). Between April 2002 to March 2009, 6528 consecutive patients underwent PCI with the unrestricted use of DES. Among patients with anemia according to the criteria by the World Health Organization (WHO) (hemoglobin <130 g/L for men and <120 g/L for women, respectively) patients below the 25(th) percentile separately for men and women were defined to have severe anemia. We compared clinical outcomes among patients with severe anemia and no/mild anemia during long-term follow-up through 4 years. Whereas 21.6% of patients were found to have anemia according to the WHO definition, 347 patients (5.5%) had severe anemia (mean hemoglobin, 98±11 g/L). Severe anemia was more prev...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, Jan 22, 2014
Early-generation drug-eluting stent (DES) overlap (OL) is associated with impaired long-term clin... more Early-generation drug-eluting stent (DES) overlap (OL) is associated with impaired long-term clinical outcomes whereas the impact of OL with newer-generation DES is unknown. Our aim was to assess the impact of OL on long-term clinical outcomes among patients treated with newer-generation DES. We analysed the three-year clinical outcomes of 3,133 patients included in a prospective DES registry according to stent type (sirolimus-eluting stents [SES; N=1,532] versus everolimus-eluting stents [EES; N=1,601]), and the presence or absence of OL. The primary outcome was a composite of death, myocardial infarction (MI), and target vessel revascularisation (TVR). The primary endpoint was more common in patients with OL (25.1%) than in those with multiple DES without OL (20.8%, adj HR=1.46, 95% CI: 1.03-2.09) and patients with a single DES (18.8%, adj HR=1.74, 95% CI: 1.34-2.25, p<0.001) at three years. A stratified analysis by stent type showed a higher risk of the primary outcome in SES ...
Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an agg... more Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an aggressive form of breast cancer and is historically associated with poor outcomes compared with HER2-negative MBC. Since 1998, four drugs have been globally approved for the targeted treatment of HER2-positive MBC. Additional advances in patient care-such as improved breast cancer screening, HER2 testing, and supportive care-have also occurred. The objective of this systematic review and meta-analysis is to determine whether there has been a cumulative change in survival over time in patients with HER2-positive advanced breast cancer based on results from interventional clinical trials (ICTs) and observational studies and to compare outcomes across these types of studies. A systematic search of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials will be performed. Two investigators will independently assess each abstract for inclusion. English language reports of ICTs and observational studies that include patients with HER2-positive advanced breast cancer from 1987 onwards will be considered. The primary outcome of interest is overall survival; secondary outcomes include progression-free survival and safety. Data on clinical outcomes, as well as on study design, study population, treatment/intervention, methodological quality, and outcomes, will be extracted using a structured codebook developed by the authors for this study. Standard and cumulative random effects meta-analysis will be performed to derive pooled risk estimates, both overall and by study design, controlling for covariates such as aggregate demographic and clinical characteristics of patients, treatment/intervention, and study characteristics. Heterogeneity of studies will be evaluated using the I(2) statistic. Differences in risk estimates by quality characteristics will be performed using meta-regression. This study will evaluate current and evolving trends in survival associated with HER2-positive advanced breast cancer over nearly 30 years and will build upon prior, less comprehensive, systematic analyses. This information is important to patients, healthcare providers, and researchers, particularly in the advanced disease setting, in which new therapies have been recently approved. Including observational studies allows us to evaluate real-world effectiveness; useful information will be gained by comparing findings from observational studies with those from ICTs. PROSPERO CRD42014014345.
Refractory cardiogenic shock (RCS) is associated with significant morbidity and mortality, and cu... more Refractory cardiogenic shock (RCS) is associated with significant morbidity and mortality, and current mainstays of medical therapy appear inadequate. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) represents an increasingly accepted therapy for RCS. Demographics, past medical history, preoperative characteristics, outcomes, and adverse events were collected for consecutive patients who received VA-ECMO support for RCS at our institution from March 2007 to December 2013. One hundred and seventy-nine patients with a mean age of 56.9 ± 16.1 years were included. Etiologies of RCS included postcardiotomy shock in 70 patients (39%), acute myocardial infarction in 46 patients (26%), primary graft failure in 17 patients (10%), and acute decompensated heart failure in 24 patients (13%). Mean arterial pressure before VA-ECMO support was 59.4 ± 22.8 mm Hg and 30.7% (n = 55) were undergoing active cardiopulmonary resuscitation at the time of cannulation. Overall, 38.6% of patients (n = 69) survived to discharge and 44.7% of patients (n = 80) survived to 30 days. Myocardial recovery was achieved in 79.7% of survivors (n = 55) and 39.1% were transitioned to a more durable device. Univariate analysis identified age (p = 0.002) and etiology of RCS (p = 0.041) as the most significant predictors of in-hospital mortality. Venoarterial extracorporeal membrane oxygenation for RCS appears successful as salvage therapy. Age and etiology should be considered when evaluating patients for VA-ECMO.
Mathematical models of disease progression predict disease outcomes and are useful epidemiologica... more Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The 𝖱 package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death), displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multi...
Background. Hybrid percutaneous coronary intervention offers an alternative method of revasculari... more Background. Hybrid percutaneous coronary intervention offers an alternative method of revascularization for high-risk surgical populations. We report the outcomes of a single-stage hybrid strategy in valvular cardiac surgery and explore its effects on operative risk and bleeding.
The options for secondary prevention of cryptogenic embolism in patients with patent foramen oval... more The options for secondary prevention of cryptogenic embolism in patients with patent foramen ovale are administration of antithrombotic medications or percutaneous closure of the patent foramen ovale. We investigated whether closure is superior to medical therapy. We performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end points were unaware of the study-group assignments. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy. The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population. The mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary en...
Patients with severe aortic stenosis at increased surgical risk continue to experience compromise... more Patients with severe aortic stenosis at increased surgical risk continue to experience compromised long-term survival despite successful transcatheter aortic valve implantation. We used time-related pathways in a multistate analysis to identify predictors of adverse long-term outcome in patients who underwent transcatheter aortic valve implantation. In a cohort of 389 patients with a mean age of 82.4 ± 5.8 years and a STS score of 6.8 ± 5.3 undergoing transcatheter aortic valve implantation between 2007 and 2011, multistate analysis was used to estimate mortality and stroke taking into account intercurrent events including kidney injury and the composite of access site and bleeding complications (ABC). Transapical access emerged as a predictor of kidney injury (hazard ratio [HR], 2.12; 95% confidence interval [CI] 1.00-4.47) and ABC (HR, 1.78; 95% CI, 1.07-2.96), but had no impact on the risk of stroke or death. Body mass index ≤20 kg/m(2) increased the risk of stroke or death (HR, ...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, Jan 17, 2014
Aims: To compare clinical outcomes after percutaneous coronary intervention (PCI) between patient... more Aims: To compare clinical outcomes after percutaneous coronary intervention (PCI) between patients with acute coronary syndromes (ACS) and those with stable ischaemic heart disease (SIHD) stratified by anatomic disease complexity (SYNTAX score). Methods and results: Patient-level data from three all-comers PCI trials were pooled. Patients (n=4,204) were stratified by clinical presentation (i.e., ACS or SIHD) and by SYNTAX score (i.e., lowest vs. two highest tertiles). The major adverse cardiac event (MACE) rates of patients with low-risk SIHD (n=531) and high-risk SIHD (n=1,066) were compared with ACS patients (n=2,607), respectively. At two years, the risk of MACE was higher for high-risk SIHD patients (OR 1.34, 95% CI: 1.08-1.66) and lower for low-risk SIHD patients (OR 0.61, 95% CI: 0.43-0.87) compared with ACS patients, respectively. This difference between high-risk SIHD patients and ACS patients was primarily driven by a higher risk of myocardial infarction (OR 1.64, 95% CI: 1...
Patients with ischemic stroke or transient ischemic attack presumably related to patent foramen o... more Patients with ischemic stroke or transient ischemic attack presumably related to patent foramen ovale (PFO) are at risk for recurrent cerebrovascular events. Differences in long-term clinical outcome were investigated among patients with percutaneous PFO closure and those who received medical treatment. Between 1994 and 2000, 308 consecutive patients with cerebrovascular events presumably related to PFO underwent either percutaneous PFO closure (150 patients) or medical treatment (158 patients). Patients were followed up prospectively for up to 15 years. Seven patients were lost during follow-up. The primary outcome was a composite of stroke, transient ischemic attack, or peripheral embolism. We analyzed 103 propensity score-matched pairs of patients who underwent percutaneous PFO closure or medical treatment. At a median follow-up of 9 years, the primary composite outcome occurred in 11 patients slated to PFO closure (11%) and 22 patients slated to medical treatment (21%; hazard ra...
Anemia is frequent among patients with cardiovascular disease and adversely affects prognosis. Th... more Anemia is frequent among patients with cardiovascular disease and adversely affects prognosis. The objective of this analysis was to assess the impact of anemia on long-term clinical outcomes among patients undergoing percutaneous coronary intervention (PCI) with the unrestricted use of drug-eluting stents (DES). Between April 2002 to March 2009, 6528 consecutive patients underwent PCI with the unrestricted use of DES. Among patients with anemia according to the criteria by the World Health Organization (WHO) (hemoglobin <130 g/L for men and <120 g/L for women, respectively) patients below the 25(th) percentile separately for men and women were defined to have severe anemia. We compared clinical outcomes among patients with severe anemia and no/mild anemia during long-term follow-up through 4 years. Whereas 21.6% of patients were found to have anemia according to the WHO definition, 347 patients (5.5%) had severe anemia (mean hemoglobin, 98±11 g/L). Severe anemia was more prev...
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, Jan 22, 2014
Early-generation drug-eluting stent (DES) overlap (OL) is associated with impaired long-term clin... more Early-generation drug-eluting stent (DES) overlap (OL) is associated with impaired long-term clinical outcomes whereas the impact of OL with newer-generation DES is unknown. Our aim was to assess the impact of OL on long-term clinical outcomes among patients treated with newer-generation DES. We analysed the three-year clinical outcomes of 3,133 patients included in a prospective DES registry according to stent type (sirolimus-eluting stents [SES; N=1,532] versus everolimus-eluting stents [EES; N=1,601]), and the presence or absence of OL. The primary outcome was a composite of death, myocardial infarction (MI), and target vessel revascularisation (TVR). The primary endpoint was more common in patients with OL (25.1%) than in those with multiple DES without OL (20.8%, adj HR=1.46, 95% CI: 1.03-2.09) and patients with a single DES (18.8%, adj HR=1.74, 95% CI: 1.34-2.25, p<0.001) at three years. A stratified analysis by stent type showed a higher risk of the primary outcome in SES ...
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