Cause of Death Among Patients With Peripheral Artery Disease

Background: Peripheral artery disease is common and associated with high mortality. There are limited data detailing causes of death among patients with peripheral artery disease. Methods: EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) was a randomized clinical trial that assigned patients with peripheral artery disease to clopidogrel or ticagrelor. We describe the causes of death in EUCLID using mortality end points adjudicated through a clinical events classification process. The association between baseline factors and cardiovascular death was evaluated by Cox proportional hazards modeling. The competing risk of noncardiovascular death was assessed by the cumulative incidence function for cardiovascular death and the Fine and Gray method to ascertain the association between baseline characteristics and cardiovascular mortality. Results: A total of 1263 out of 13 885 (9.1%) patients died (median follow-up: 30 months). There were 706 patients (55.9%) with a cardiovascular cause of death and 522 (41.3%) with a noncardiovascular cause of death. The most common cause of cardiovascular death was sudden cardiac death (20.1%); while myocardial infarction (5.2%) and ischemic stroke (3.2%) were uncommon. The most common causes of noncardiovascular death were malignancies (17.9%) and infections (11.9%). The factor most associated with a higher risk of cardiovascular death was age per 5 year increase (HR, 1.26 [95% CI, 1.20–1.32]). Female sex was associated with a lower risk of cardiovascular death (HR, 0.68 [95% CI, 0.56–0.82]). To evaluate the effect of noncardiovascular death as a competing risk, we superimposed the cumulative incidence function curve with the Kaplan-Meier curve. These curves closely approximated each other. After accounting for the competing risk of noncardiovascular death, the magnitude and direction of the factors associated with cardiovascular death were minimally changed. Conclusions: Among patients with symptomatic peripheral artery disease, noncardiovascular causes of death reflected a high proportion (40%) of deaths. Accounting for noncardiovascular deaths as a competing risk, there was not a significant change in the risk estimation for cardiovascular death. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01732822.

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Cardiovascular consequences of discontinuing low-dose rivaroxaban in people with chronic coronary or peripheral artery disease

Heart ◽

10.1136/heartjnl-2020-318758 ◽

2021 ◽

pp. heartjnl-2020-318758

Author(s):

Gilles R Dagenais ◽

Leanne Dyal ◽

Jacqueline J Bosch ◽

Darryl P Leong ◽

Victor Aboyans ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Low Dose ◽

Cardiovascular Death ◽

Stroke Rate ◽

Early Stopping ◽

Peripheral Artery ◽

Once Daily ◽

Registration Number ◽

Artery Disease

ObjectiveIn patients with chronic coronary or peripheral artery disease enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, randomised antithrombotic treatments were stopped after a median follow-up of 23 months because of benefits of the combination of rivaroxaban 2.5 mg two times per day and aspirin 100 mg once daily compared with aspirin 100 mg once daily. We assessed the effect of switching to non-study aspirin at the time of early stopping.MethodsIncident composite of myocardial infarction, stroke or cardiovascular death was estimated per 100 person-years (py) during randomised treatment (n=18 278) and after study treatment discontinuation to non-study aspirin (n=14 068).ResultsDuring randomised treatment, the combination compared with aspirin reduced the composite (2.2 vs 2.9/100 py, HR: 0.76, 95% CI 0.66 to 0.86), stroke (0.5 vs 0.8/100 py, HR: 0.58, 95% CI 0.44 to 0.76) and cardiovascular death (0.9 vs 1.2/100 py, HR: 0.78, 95% CI 0.64 to 0.96). During 1.02 years after early stopping, participants originally randomised to the combination compared with those randomised to aspirin had similar rates of the composite (2.1 vs 2.0/100 py, HR: 1.08, 95% CI 0.84 to 1.39) and cardiovascular death (1.0 vs 0.8/100 py, HR: 1.26, 95% CI 0.85 to 1.86) but higher stroke rate (0.7 vs 0.4/100 py, HR: 1.74, 95% CI 1.05 to 2.87) including a significant increase in ischaemic stroke during the first 6 months after switching to non-study aspirin.ConclusionDiscontinuing study rivaroxaban and aspirin to non-study aspirin was associated with the loss of cardiovascular benefits and a stroke excess.Trial registration numberNCT01776424.

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Dynamic prediction of competing risk events using landmark sub-distribution hazard model with multiple longitudinal biomarkers

Statistical Methods in Medical Research ◽

10.1177/0962280220921553 ◽

2020 ◽

Vol 29 (11) ◽

pp. 3179-3191

Author(s):

Cai Wu ◽

Liang Li ◽

Ruosha Li

Keyword(s):

Kidney Disease ◽

Cumulative Incidence ◽

Disease Risk ◽

Predictor Variable ◽

Cumulative Incidence Function ◽

Competing Risk ◽

Model Parameters ◽

Dynamic Prediction ◽

Risk Of Death ◽

Incidence Function

The cause-specific cumulative incidence function quantifies the subject-specific disease risk with competing risk outcome. With longitudinally collected biomarker data, it is of interest to dynamically update the predicted cumulative incidence function by incorporating the most recent biomarker as well as the cumulating longitudinal history. Motivated by a longitudinal cohort study of chronic kidney disease, we propose a framework for dynamic prediction of end stage renal disease using multivariate longitudinal biomarkers, accounting for the competing risk of death. The proposed framework extends the local estimation-based landmark survival modeling to competing risks data, and implies that a distinct sub-distribution hazard regression model is defined at each biomarker measurement time. The model parameters, prediction horizon, longitudinal history and at-risk population are allowed to vary over the landmark time. When the measurement times of biomarkers are irregularly spaced, the predictor variable may not be observed at the time of prediction. Local polynomial is used to estimate the model parameters without explicitly imputing the predictor or modeling its longitudinal trajectory. The proposed model leads to simple interpretation of the regression coefficients and closed-form calculation of the predicted cumulative incidence function. The estimation and prediction can be implemented through standard statistical software with tractable computation. We conducted simulations to evaluate the performance of the estimation procedure and predictive accuracy. The methodology is illustrated with data from the African American Study of Kidney Disease and Hypertension.

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461Modulation of ischemic and bleeding risk by peripheral artery disease after an acute coronary syndrome

European Heart Journal ◽

10.1093/eurheartj/ehz747.0120 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M Cespon Fernandez ◽

S Raposeiras Roubin ◽

E Abu-Assi ◽

S Manzano-Fernandez ◽

F Dascenzo ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Peripheral Artery Disease ◽

Cumulative Incidence ◽

Bleeding Risk ◽

Peripheral Artery ◽

Data Set ◽

Coronary Syndrome ◽

Artery Disease ◽

The Impact

Abstract Introduction Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with acute coronary syndrome (ACS). With this study from real-life patients, we try to analyze the balance between ischemic and bleeding risk during treatment with dual antiplatelet therapy (DAPT) after an ACS according to the presence or not of PAD. Methods The data analyzed in this study were obtained from the fusion of 3 clinical registries of ACS patients: BleeMACS (2004–2013), CardioCHUVI/ARRITXACA (2010–2016) and RENAMI (2013–2016). All 3 registries include consecutive patients discharged after an ACS with DAPT and undergoing PCI. The merged data set contain 26,076 patients. A propensity-matched analysis was performed to match the baseline characteristics of patients with and without PAD. The impact of prior PAD in the ischemic and bleeding risk was assessed by a competitive risk analysis, using a Fine and Gray regression model, with death being the competitive event. For ischemic risk we have considered a new acute myocardial infarction (AMI), whereas for bleeding risk we have considered major bleeding (MB) defined as bleeding requiring hospital admission. Follow-up time was censored by DAPT suspension/withdrawal. Results From the 26,076 ACS patients, 1,600 have PAD (6.1%). Patients with PAD were older, and with more cardiovascular risk factors. DAPT with prasugrel/ticagrelor was less frequently prescribed in patients with PAD in comparison with the rest of the population (8.2% vs 22.8%, p<0.001). During a mean follow-up of 12.2±4.8 months, 964 patients died (3.7%), and 640 AMI (2.5%) and 685 MB (2.6%) were reported. After propensity-score matching, we obtained two matched groups of 1,591 patients. Patients with PAD showed a significant higher risk of both AMI (sHR 2.17, 95% CI 1.51–3.10, p<0.001) and MB (sHR 1.51, 95% CI 1.07–2.12, p=0.018), in comparison with those without PAD. The cumulative incidence of AMI was 63.9 and 29.8 per 1,000 patients/year in patients with and without PAD, respectively. The cumulative incidence of MB was 55.9 and 37.6 per 1,000 patients/year in patients with and without PAD, respectively. The rate difference per 1,000 patient-years for AMI between patients with and without PAD was +34.1 (95% CI 30.1–38.1), and for MB +18.3 (16.1–20.4). The net balance between ischemic and bleeding events comparing patients with and without PAD was positive (+15.8 per 1,000 patients/year, 95% CI 9.7–22.0). Conclusions PAD was associated with higher ischemic and bleeding risk after hospital discharge for ACS treated with DAPT. However, the balance between ischemic and bleeding risk was positive for patients with PAD in comparison with patients without PAD. As summary, ACS patients with PAD had an ischemic risk greater than the bleeding risk.

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Risk factors and clinical outcomes in chronic coronary and peripheral artery disease: An analysis of the randomized, double-blind COMPASS trial

European Journal of Preventive Cardiology ◽

10.1177/2047487319882154 ◽

2019 ◽

Vol 27 (3) ◽

pp. 296-307 ◽

Cited By ~ 11

Author(s):

Thomas Vanassche ◽

Peter Verhamme ◽

Sonia S Anand ◽

Olga Shestakovska ◽

Keith AA Fox ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Peripheral Artery Disease ◽

Low Dose ◽

Cardiovascular Death ◽

Peripheral Artery ◽

Double Blind ◽

Artery Disease ◽

Risk Factor Status ◽

Ischemic Events

Aims Secondary prevention in patients with coronary artery disease and peripheral artery disease involves antithrombotic therapy and optimal control of cardiovascular risk factors. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study, adding low-dose rivaroxaban on top of aspirin lowered cardiovascular events, but there is limited data about risk factor control in secondary prevention. We studied the association between risk factor status and outcomes, and the impact of risk factor status on the treatment effect of rivaroxaban, in a large contemporary population of patients with coronary artery disease or peripheral artery disease. Methods and results We reported ischemic events (cardiovascular death, stroke, or myocardial infarction) in participants from the randomized, double-blind COMPASS study by individual risk factor (blood pressure, smoking status, cholesterol level, presence of diabetes, body mass index, and level of physical activity), and by number of risk factors. We compared rates and hazard ratios of patients treated with rivaroxaban plus aspirin vs aspirin alone within each risk factor category and tested for interaction between risk factor status and antithrombotic regimen. Complete baseline risk factor status was available in 27,117 (99%) patients. Status and number of risk factors were both associated with increased risk of ischemic events. Rates of ischemic events (hazard ratio 2.2; 95% confidence interval 1.8–2.6) and cardiovascular death (hazard ratio 2.0; 1.5–2.7) were more than twofold higher in patients with 4–6 compared with 0–1 risk factors ( p < 0.0001 for both). Rivaroxaban reduced event rates independently of the number of risk factors ( p interaction 0.93), with the largest absolute benefit in patients with the highest number of risk factors. Conclusion More favorable risk factor status and low-dose rivaroxaban were independently associated with lower risk of cardiovascular events.

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Effect of Rivaroxaban and Aspirin in Patients with Peripheral Artery Disease Undergoing Surgical Revascularization: Insights from the VOYAGER PAD Trial

Circulation ◽

10.1161/circulationaha.121.054835 ◽

2021 ◽

Author(s):

E. Sebastian Debus ◽

Mark R. Nehler ◽

Nicholas Govsyeyev ◽

Rupert M. Bauersachs ◽

Sonia S. Anand ◽

...

Keyword(s):

Myocardial Infarction ◽

Placebo Group ◽

Peripheral Artery Disease ◽

Major Bleeding ◽

Cumulative Incidence ◽

Efficacy And Safety ◽

Peripheral Artery ◽

Safety Outcome ◽

Fatal Bleeding ◽

Artery Disease

Background: Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. VOYAGER PAD demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. Methods: The VOYAGER PAD trial randomized patients with PAD after surgical and endovascular LER to rivaroxaban 2.5mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary endpoint was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. International Society on Thrombosis and Haemostasis (ISTH) bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. Results: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared to placebo, rivaroxaban reduced the primary endpoint consistently regardless of LER method (p-interaction 0.43). Following surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (HR 0.81, 95% CI 0.67 - 0.98; p=0.026). In the overall trial, TIMI major bleeding and ISTH major bleeding were increased with rivaroxaban. There was no heterogeneity for TIMI major bleeding (p-interaction 0.17) or ISTH major bleeding (p-interaction 0.73) based on LER approach. Following surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence 1.3% and 1.4% respectively (HR 0.88, 95% CI 0.39-1.95; p=0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (p=0.95) and postprocedural bleeding requiring intervention (p=0.93) were not significantly increased. Conclusions: The efficacy of rivaroxaban is associated with a benefit in surgical LER patients. While bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage or postprocedural bleeds requiring intervention. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02504216

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Vorapaxar in the treatment of cardiovascular diseases

Future Cardiology ◽

10.2217/fca-2019-0090 ◽

2020 ◽

Vol 16 (5) ◽

pp. 373-384

Author(s):

Udaya S Tantry ◽

Kevin P Bliden ◽

Rahul Chaudhary ◽

Marko Novakovic ◽

Amit Rout ◽

...

Keyword(s):

Myocardial Infarction ◽

Peripheral Artery Disease ◽

Coronary Revascularization ◽

Bleeding Risk ◽

Cardiovascular Death ◽

Severe Bleeding ◽

Peripheral Artery ◽

Primary Hemostasis ◽

History Of ◽

Artery Disease

Vorapaxar specifically and effectively inhibits protease activated receptor-1 and may reduce thrombin-mediated ischemic events without interfering primary hemostasis. In the TRA-2P-TIMI 50 trial, vorapaxar reduced the risk of primary ischemic outcome but with increased bleeding risk. In the post hoc analysis, in patients with a history of myocardial infarction, peripheral artery disease, the net clinical outcome favored vorapaxar therapy with 10% reduction in cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization and moderate or severe bleeding. Based on these favorable results, vorapaxar was approved for the reduction of thrombotic cardiovascular events in patients with prior myocardial infarction or with peripheral artery disease on top of standard antiplatelet therapy. A careful patient selection is needed to balance efficacy versus safety.

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Association analysis of successive events data in the presence of competing risks

Statistical Methods in Medical Research ◽

10.1177/0962280216667645 ◽

2016 ◽

Vol 27 (6) ◽

pp. 1661-1682

Author(s):

Xiaotian Chen ◽

Yu Cheng ◽

Ellen Frank ◽

David J Kupfer

Keyword(s):

Bipolar Disorder ◽

Cumulative Incidence ◽

Manic Episode ◽

Cumulative Incidence Function ◽

Bivariate Distribution ◽

Dependent Censoring ◽

Competing Risk ◽

Incidence Function ◽

Event Times ◽

Events Data

We aim to close a methodological gap in analyzing durations of successive events that are subject to induced dependent censoring as well as competing-risk censoring. In the Bipolar Disorder Center for Pennsylvanians study, some patients who managed to recover from their symptomatic entry later developed a new depressive or manic episode. It is of great clinical interest to quantify the association between time to recovery and time to recurrence in patients with bipolar disorder. The estimation of the bivariate distribution of the gap times with independent censoring has been well studied. However, the existing methods cannot be applied to failure times that are censored by competing causes such as in the Bipolar Disorder Center for Pennsylvanians study. Bivariate cumulative incidence function has been used to describe the joint distribution of parallel event times that involve multiple causes. To the best of our knowledge, however, there is no method available for successive events with competing-risk censoring. Therefore, we extend the bivariate cumulative incidence function to successive events data, and propose non-parametric estimators of the bivariate cumulative incidence function and the related conditional cumulative incidence function. Moreover, an odds ratio measure is proposed to describe the cause-specific dependence, leading to the development of a formal test for independence of successive events. Simulation studies demonstrate that the estimators and tests perform well for realistic sample sizes, and our methods can be readily applied to the Bipolar Disorder Center for Pennsylvanians study.

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Predictive Value of Underweight Status for Patients With Peripheral Artery Disease With Claudication

Angiology ◽

10.1177/0003319717736627 ◽

2017 ◽

Vol 69 (6) ◽

pp. 513-522 ◽

Cited By ~ 4

Author(s):

Keisuke Senda ◽

Takashi Miura ◽

Masatoshi Minamisawa ◽

Yasushi Ueki ◽

Tomoaki Mochidome ◽

...

Keyword(s):

Cardiovascular Disease ◽

Peripheral Artery Disease ◽

Limb Ischemia ◽

Cardiovascular Death ◽

Peripheral Artery ◽

Reactive Protein ◽

Overweight Group ◽

Underweight Patients ◽

Artery Disease ◽

Cox Analysis

We evaluated whether underweight status is associated with poor prognosis in patients with peripheral artery disease (PAD) with claudication, excluding critical limb ischemia. We identified 441 claudicants hospitalized for cardiovascular disease between 2005 and 2012. Patients were divided into 4 groups according to body mass index (BMI): an underweight group (BMI < 18.5 kg/m2; n = 48), a normal group (BMI = 18.5-25.0 kg/m2; n = 286), an overweight group (BMI = 25.0-30.0 kg/m2; n = 92), and an obese group (BMI ≥ 30.0 kg/m2; n = 15). The mean follow-up period was 3.5 ± 1.9 years. The underweight group had significantly lower levels of hemoglobin, albumin, estimated glomerular filtration rate, triglycerides, and hemoglobin A1c; higher levels of C-reactive protein and B-type natriuretic peptide; and a higher prevalence of hemodialysis. The incidence of all-cause death and cardiovascular death was significantly higher in the underweight group (underweight vs normal, 77.1% vs 33.0%; P < .001 and 43.3% vs 14.4%; P < .001, respectively). In a multivariate Cox analysis, underweight status was an independent predictor of all-cause death (hazard ratio, 2.53; 95% confidence interval, 1.58-4.18; P < .001). Therefore, promoting weight gain, as well as managing cardiovascular disease, may be important for underweight patients with PAD.

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Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: The EUCLID trial

Vascular Medicine ◽

10.1177/1358863x19864172 ◽

2019 ◽

Vol 24 (5) ◽

pp. 422-430 ◽

Cited By ~ 1

Author(s):

Charles W Hopley ◽

Sarah Kavanagh ◽

Manesh R Patel ◽

Cara Ostrom ◽

Iris Baumgartner ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Ischemic Stroke ◽

Kidney Disease ◽

Peripheral Artery Disease ◽

Major Bleeding ◽

Cardiovascular Death ◽

Major Amputation ◽

Peripheral Artery ◽

Increased Risk ◽

Artery Disease

In patients with symptomatic peripheral artery disease (PAD), the impact of chronic kidney disease (CKD) on major adverse cardiovascular events has not been fully evaluated. The Examining Use of Ticagrelor In PAD (EUCLID) trial randomized 13,885 patients with PAD to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. This post hoc analysis compared the incidence of the primary composite endpoint (cardiovascular death, myocardial infarction (MI), or ischemic stroke) in patients with CKD (eGFR < 60 mL/min/1.73 m2) with those without CKD (eGFR ⩾ 60 mL/min/1.73 m2). The primary safety endpoint was thrombolysis in MI (TIMI) major bleeding. A total of 13,483 patients were included; 3332 (25%) had CKD, of whom 237 had stage 4/5 disease. Median follow-up was approximately 30 months. After statistical adjustment, patients with CKD had a higher rate of the primary endpoint compared with those without CKD (6.75 vs 3.72 events/100 patient-years; adjusted hazard ratio (HR) 1.45, 95% CI 1.30–1.63). CKD was not associated with increased risk of hospitalization for acute limb ischemia (ALI) (adjusted HR 0.96, 95% CI 0.69–1.34) or major amputation (adjusted HR 0.92, 95% CI 0.66–1.28). CKD was not associated with a significantly increased risk of major bleeding (adjusted HR 1.21, 95% CI 0.89–1.64), but minor bleeding was significantly increased (adjusted HR 1.51, 95% CI 1.07–2.15). In conclusion, patients with PAD and CKD had higher rates of cardiovascular death, MI, and ischemic stroke, but similar rates of ALI, major amputation, and TIMI major bleeding when compared with patients without CKD. ClinicalTrials.gov Identifier: NCT01732822

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Analysis of Survival Data with Competing Risks in ADRD (Alzheimer's Disease and Related Dementias) Research

Innovation in Aging ◽

10.1093/geroni/igab046.2430 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 645-645

Author(s):

Dianxu Ren ◽

Oscar Lopez ◽

Jennifer Lingler

Keyword(s):

At Risk ◽

Competing Risks ◽

Cumulative Incidence ◽

Hazard Model ◽

Cumulative Incidence Function ◽

Competing Risk ◽

Subdistribution Hazard ◽

Incidence Function ◽

Diabetes Status ◽

Conventional Methods

Abstract Competing risk is an event that precludes the occurrence of the primary event of interest. For example, when studying risk factors associated with dementia, death before the onset of dementia serve as a competing event. A subject who dies is no longer at risk of dementia. This issue play more important role in ADRD research given the elderly population. Conventional methods for survival analysis assume independent censoring and ignore the competing events. However, there are some challenge issues using those conventional methods in the presence of competing risks. First, no one-to-one link between hazard function and cumulative incidence function (CIF), and Kaplan-Meier approach overestimates the cumulative incidence of the event of interest. Second, the effect of covariates on hazard rate cannot be directly linked to the effect of cumulative incidence (the risk). We will discuss two types of analyses in the presence of competing risk: Cause-specific hazard model and Fine-Gray subdistribution hazard model. Cause-specific hazard model directly quantify the cause-specific hazard among subjects who are at risk of developing the event of interest, while Fine-Gray subdistribution hazard model directly model the effects of covariates on the cumulative incidence function. The type of research questions (Association vs. Prediction) may guide the choice of different statistical approaches. We will illustrate those two competing risk analyses using the large national dataset from National Alzheimer’s Coordinating Center (NACC). We will analyze the association between baseline diabetes status and the incidence of dementia, in which death before the onset of dementia is a competing event.

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