Publications by authors named "Warren H Capell"

21 Publications

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Reduction in Acute Limb Ischemia with Rivaroxaban versus Placebo in Peripheral Artery Disease after Lower Extremity Revascularization: Insights from VOYAGER PAD.

Circulation 2021 Oct 12. Epub 2021 Oct 12.

Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO; CPC Clinical Research, Aurora, CO.

Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Prior lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking. VOYAGER PAD (NCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan Meier estimates, and Cox proportional-hazards models were used to generate hazard ratios and associated confidence intervals. Analyses were performed as intention-to-treat. Among 6,564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, prior LER, baseline ABI <0.50, surgical LER, and longer target lesion length were associated with increased risk of ALI. Incident ALI was associated with subsequent all-cause mortality (HR 2.59, 95% CI 1.98-3.39) and major amputation (HR 24.87, 95% CI 18.68-33.12). Rivaroxaban reduced ALI relative to placebo by 33% (absolute risk reduction 2.6% at 3 years, HR 0.67, 95% CI 0.55-0.82, P=0.0001), with benefit starting early (HR 0.45, 95% CI 0.24-0.85, P=0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and ICU stay, HR 0.58, 95% CI 0.40-0.83, P=0.003) and regardless of LER type (surgical vs endovascular revascularization, p-interaction=0.42) or clopidogrel use (p-interaction=0.59). After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055146DOI Listing
October 2021

Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial.

Eur Heart J 2021 10;42(39):4040-4048

CPC Clinical Research, 2115 N Scranton Street, Suite 2040, Aurora, CO, USA.

Aims: In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described.

Methods And Results: The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding).

Conclusion: Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.
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http://dx.doi.org/10.1093/eurheartj/ehab408DOI Listing
October 2021

Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial.

Circulation 2021 Oct 12;144(14):1104-1116. Epub 2021 Aug 12.

CPC Clinical Research, Aurora, CO (M.R.N., N.G., W.H.C., T.B., N.J., C.N.H., W.R.H., M.P.B.).

Background: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for 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 peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point 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 major bleeding. International Society on Thrombosis and Haemostasis 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 with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (-interaction, 0.43). After 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 (hazard ratio, 0.81 [95% CI, 0.67-0.98]; =0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding (-interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding (-interaction, 0.73) on the basis of the LER approach. After 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 was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; =0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (=0.95) and postprocedural bleeding requiring intervention (=0.93) was not significantly increased.

Conclusions: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although 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. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054835DOI Listing
October 2021

Total Ischemic Event Reduction With Rivaroxaban After Peripheral Arterial Revascularization in the VOYAGER PAD Trial.

J Am Coll Cardiol 2021 Jul 16;78(4):317-326. Epub 2021 May 16.

CPC Clinical Research, Aurora, Colorado, USA; Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA. Electronic address:

Background: Patients with peripheral artery disease (PAD) undergoing lower extremity revascularization (LER) are at high risk of major adverse limb and cardiovascular events. The VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trial demonstrated that rivaroxaban 2.5 mg twice daily reduced first events by 15%. The benefit of rivaroxaban on total (first and subsequent) events in this population is unknown.

Objectives: This study sought to evaluate the total burden of vascular events in patients with PAD after LER and the efficacy of low-dose rivaroxaban on total events.

Methods: VOYAGER PAD randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily plus aspirin or aspirin alone. The primary endpoint was time to first event of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The current analysis considered all events (first and subsequent) for components of the primary endpoint as well as additional vascular events including peripheral revascularizations and venous thromboembolism. HRs were estimated by marginal proportional hazards models.

Results: Among 6,564 randomized events, there were 4,714 total first and subsequent vascular events including 1,614 primary endpoint events and 3,100 other vascular events. Rivaroxaban reduced total primary endpoint events (HR: 0.86; 95% CI: 0.75-0.98; P = 0.02) and total vascular events (HR: 0.86; 95% CI: 0.79-0.95; P = 0.003). An estimated 4.4 primary and 12.5 vascular events per 100 participants were avoided with rivaroxaban over 3 years.

Conclusions: Patients with symptomatic PAD who are undergoing LER have a high total event burden that is significantly reduced with rivaroxaban. Total event reduction may be a useful metric to quantify the efficacy of rivaroxaban in this setting. (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities [VOYAGER PAD]; NCT02504216).
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http://dx.doi.org/10.1016/j.jacc.2021.05.003DOI Listing
July 2021

Exercise Training and Revascularization in the Management of Symptomatic Peripheral Artery Disease.

JACC Basic Transl Sci 2021 Feb 22;6(2):174-188. Epub 2021 Feb 22.

Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Exercise therapy and lower extremity revascularization both improve walking performance in symptomatic patients with peripheral artery disease. The combination of therapies provides greater benefit than either alone and may reduce the need for subsequent revascularization procedures, but further trials with longer follow-up are needed for the outcome of subsequent revascularization.
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http://dx.doi.org/10.1016/j.jacbts.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907537PMC
February 2021

Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study.

Am Heart J 2021 05 9;235:12-23. Epub 2021 Feb 9.

CPC Clinical Research, Aurora, CO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.

Background: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established.

Study Design: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events.

Conclusions: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.
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http://dx.doi.org/10.1016/j.ahj.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871775PMC
May 2021

Should Participants in Clinical Trials Be Able to Withdraw from Passive Follow-Up?

Ethics Hum Res 2021 Jan;43(1):32-36

Professor of medicine at CPC Clinical Research at the University of Colorado Anschutz Medical Campus in the Department of Medicine.

A research participant's right to withdraw from all research procedures is widely accepted, but there can be justifiable limits to a participant's exercise of autonomy to withdraw from some procedures. Clinical outcomes trials depend on complete subject follow-up for accurate assessment of the safety and efficacy of investigational therapies. Subjects' refusal to complete follow-up, even through passive medical record review, can cause failure to detect safety signals, inaccurate estimation of efficacy, or lack of acceptance of trial results, which alters the study's benefit-risk ratio. Allowing participant refusal of follow-up data collection therefore creates tension between respect for persons and beneficence. With minimal risk study procedures that can help preserve trial benefit, such as passive data collection, we argue that the importance of upholding the principle of beneficence outweighs individual autonomy concerns. Furthermore, a consent process that prospectively informs participants of mandatory passive follow-up is ethically justified and optimizes the balance between autonomy and beneficence.
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http://dx.doi.org/10.1002/eahr.500077DOI Listing
January 2021

Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.

Circulation 2020 12 3;142(23):2219-2230. Epub 2020 Nov 3.

Department of Vascular Medicine, Klinikum Darmstadt GmbH, Germany (R.B.).

Background: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described.

Methods: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization.

Results: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity ( for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel; for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel ( for trend=0.06).

Conclusions: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050465DOI Listing
December 2020

Rivaroxaban in Peripheral Artery Disease after Revascularization.

N Engl J Med 2020 05 28;382(21):1994-2004. Epub 2020 Mar 28.

From Colorado Prevention Center (CPC) Clinical Research (M.P.B., M.R.N., W.H.C., L.D., N.J., C.N.H., W.R.H.), the Department of Medicine, Division of Cardiovascular Medicine (M.P.B., C.N.H., W.R.H.), the Department of Surgery, Division of Vascular Surgery (M.R.N.), and the Department of Medicine, Division of Endocrinology (W.H.C.), University of Colorado Anschutz Medical Campus, and the Department of Biostatistics and Informatics, Colorado School of Public Health (J.M.K.) - all in Aurora; the Department of Vascular Medicine, Klinikum Darmstadt, Darmstadt, and Center for Thrombosis and Hemostasis, University of Mainz, Mainz (R.M.B.), the Department of Vascular Medicine, Vascular Surgery-Angiology-Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg (E.S.D.), and Bayer, Wuppertal (A.F.P., E.M.) - all in Germany; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada (S.S.A.); Duke Clinical Research Institute, Division of Cardiology, Duke University, Durham, NC (M.R.P.); the Vascular and Interventional Radiology Department, Careggi University Hospital, University of Florence, Florence, Italy (F.F.); Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine (I.G.); B-A-Z County University Teaching Hospital, Miskolc, Hungary (L.M.); University of Latvia, Pauls Stradins University Hospital, Riga (D.K.K.); ECLA (Estudios Clínicos Latino América), ICR (Instituto Cardiovascular de Rosario), Rosario, Argentina (R.D.); the Division of Angiology, Medical University Graz, Graz, Austria (M.B.); and Janssen Research and Development, Raritan (L.P.H.), and Thrombosis Group Head, Clinical Development, Bayer U.S., Whippany (S.D.B.) - both in New Jersey.

Background: Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain.

Methods: In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome.

Results: A total of 6564 patients underwent randomization; 3286 were assigned to the rivaroxaban group, and 3278 were assigned to the placebo group. The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan-Meier estimates of the incidence at 3 years were 17.3% and 19.9%, respectively (hazard ratio, 0.85, 95% confidence interval [CI], 0.76 to 0.96; P = 0.009). TIMI major bleeding occurred in 62 patients in the rivaroxaban group and in 44 patients in the placebo group (2.65% and 1.87%; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P = 0.07). ISTH major bleeding occurred in 140 patients in the rivaroxaban group, as compared with 100 patients in the placebo group (5.94% and 4.06%; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P = 0.007).

Conclusions: In patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the groups. The incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone. (Funded by Bayer and Janssen Pharmaceuticals; VOYAGER PAD ClinicalTrials.gov number, NCT02504216.).
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http://dx.doi.org/10.1056/NEJMoa2000052DOI Listing
May 2020

Rationale and design for the Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD).

Am Heart J 2018 05 3;199:83-91. Epub 2018 Feb 3.

CPC Clinical Research, Aurora, CO; University of Colorado School of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO. Electronic address:

Background: Patients with peripheral artery disease (PAD) undergoing a lower-extremity revascularization are at heightened risk for ischemic cardiac and limb events. Although intensification of antithrombotic therapy after revascularization has demonstrated benefit in coronary disease populations, this approach has not been well studied or shown consistent benefit in PAD. Recent trial evidence demonstrated that a treatment strategy of rivaroxaban added to background antiplatelet therapy reduced ischemic risk in patients following recent acute coronary syndromes, as well as in patients with stable atherosclerotic vascular disease. Whether these benefits extend to the population of patients with symptomatic lower-extremity PAD undergoing revascularization is the objective of the VOYAGER PAD trial.

Study Design: VOYAGER PAD is an international randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rivaroxaban in symptomatic PAD patients undergoing a peripheral surgical and/or endovascular revascularization. Patients are randomized in a 1:1 ratio to either rivaroxaban 2.5 mg twice daily or placebo, on a background of low-dose aspirin (100 mg daily). In addition, the use of a limited course of P2Y inhibition is allowed at the discretion of the site investigator. The primary efficacy end point is a novel composite of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, and major amputation of vascular etiology. The primary safety end point is major bleeding according to the Thrombolysis in Myocardial Infarction definition. Enrolment began in August 2015 and will complete randomization of at least 6,500 patients by January 2018. This event-driven trial is expected to observe outcomes over a mean patient follow-up of 30 months.

Conclusions: VOYAGER PAD is evaluating the efficacy of rivaroxaban added to background antiplatelet therapy to reduce major cardiovascular and limb ischemic vascular outcomes in the high-risk population of PAD patients undergoing peripheral revascularization.
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http://dx.doi.org/10.1016/j.ahj.2018.01.011DOI Listing
May 2018

A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative.

Circulation 2017 Jun;135(25):2534-2555

From Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora (C.N.H., W.R.H.); CPC Clinical Research, Aurora, CO (C.N.H., W.H.C., W.R.H.); Department of Surgery, Faculty of Medicine and Health, Örebro University, Sweden (L.N.); Ohio Health, Columbus (G.M.A.); Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Colorado School of Medicine, Aurora (W.H.C.); University of Sydney, Westmead Hospital, Australia (J.P.F.); Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, UK (F.G.R.F.); Department of Vascular Diseases, Lund University, Skåne University Hospital, Malmö, Sweden (A.G.); Department of Surgery, University of Sydney, Westmead Hospital, Australia (K.H.); Harvard Medical School, Boston, MA (M.R.J.); and Department of Vascular Surgery and Institute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital and Academy, Gothenburg University, Sweden (J.N.).

Peripheral artery disease affects >200 million people worldwide and is associated with significant limb and cardiovascular morbidity and mortality. Limb revascularization is recommended to improve function and quality of life for symptomatic patients with peripheral artery disease with intermittent claudication who have not responded to medical treatment. For patients with critical limb ischemia, the goals of revascularization are to relieve pain, help wound healing, and prevent limb loss. The baseline risk of cardiovascular and limb-related events demonstrated among patients with stable peripheral artery disease is elevated after revascularization and related to atherothrombosis and restenosis. Both of these processes involve platelet activation and the coagulation cascade, forming the basis for the use of antiplatelet and anticoagulant therapies to optimize procedural success and reduce postprocedural cardiovascular risk. Unfortunately, few high-quality, randomized data to support use of these therapies after peripheral artery disease revascularization exist, and much of the rationale for the use of antiplatelet agents after endovascular peripheral revascularization is extrapolated from percutaneous coronary intervention literature. Consequently, guideline recommendations for antithrombotic therapy after lower limb revascularization are inconsistent and not always evidence-based. In this context, the purpose of this structured review is to assess the available randomized data for antithrombotic therapy after peripheral arterial revascularization, with a focus on clinical trial design issues that may affect interpretation of study results, and highlight areas that require further investigation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.024469DOI Listing
June 2017

A randomized trial of heart failure disease management in skilled nursing facilities (SNF Connect): Lessons learned.

Clin Trials 2017 Jun 31;14(3):308-313. Epub 2017 Jan 31.

GRECC Denver VA Eastern Colorado Health System and Division of Geriatric Medicine, Department of Internal Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.

Background/aims: Conducting clinical trials in skilled nursing facilities is particularly challenging. This manuscript describes facility and patient recruitment challenges and solutions for clinical research in skilled nursing facilities.

Methods: Lessons learned from the SNF Connect Trial, a randomized trial of a heart failure disease management versus usual care for patients with heart failure receiving post-acute care in skilled nursing facilities, are discussed. Description of the trial design and barriers to facility and patient recruitment along with regulatory issues are presented.

Results: The recruitment of Denver-metro skilled nursing facilities was facilitated by key stakeholders of the skilled nursing facilities community. However, there were still a number of barriers to facility recruitment including leadership turnover, varying policies regarding research, fear of litigation and of an increased workload. Engagement of facilities was facilitated by their strong interest in reducing hospital readmissions, marketing potential to hospitals, and heart failure management education for their staff. Recruitment of patients proved difficult and there were few facilitators. Identified patient recruitment challenges included patients being unaware of their heart failure diagnosis, patients overwhelmed with their illness and care, and frequently there was no available proxy for cognitively impaired patients. Flexibility in changing the recruitment approach and targeting skilled nursing facilities with higher rates of admissions helped to overcome some barriers.

Conclusion: Recruitment of skilled nursing facilities and patients in skilled nursing facilities for clinical trials is challenging. Strategies to attract both facilities and patients are warranted. These include aligning study goals with facility incentives and flexible recruitment protocols to work with patients in "transition crisis."
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http://dx.doi.org/10.1177/1740774517690529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690185PMC
June 2017

Ethical conduct of palliative care research: enhancing communication between investigators and institutional review boards.

J Pain Symptom Manage 2014 Dec 28;48(6):1211-21. Epub 2014 May 28.

University of Colorado School of Medicine, Aurora, Colorado, USA. Electronic address:

Palliative care has faced moral and ethical challenges when conducting research involving human subjects. There are currently no resources to guide institutional review boards (IRBs) in applying standard ethical principles and terms-in a specific way-to palliative care research. Using as a case study a recently completed multisite palliative care clinical trial, this article provides guidance and recommendations for both IRBs and palliative care investigators to facilitate communication and attain the goal of conducting ethical palliative care research and protecting study participants while advancing the science. Beyond identifying current challenges faced by palliative care researchers and IRBs reviewing palliative care research, this article suggests steps that the palliative care research community can take to establish a scientifically sound, stable, productive, and well-functioning relationship between palliative care investigators and the ethical bodies that oversee their work.
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http://dx.doi.org/10.1016/j.jpainsymman.2014.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247357PMC
December 2014

Fatty acids increase glucose uptake and metabolism in C2C12 myoblasts stably transfected with human lipoprotein lipase.

Am J Physiol Endocrinol Metab 2010 Oct 13;299(4):E576-83. Epub 2010 Jul 13.

Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA.

Cellular effects of FFA might differ from those of lipoprotein triglyceride (TG)-derived fatty acids (TGFA). The aim of the current study was to examine the relationship between lipoprotein lipase (LPL) expression, TGFA, or FFA availability and glucose metabolism in the absence of insulin in C2C12 myoblasts. Control myoblasts or myoblasts stably transfected with human lipoprotein lipase (C2/LPL; 15-fold greater LPL activity) were incubated for 12 h in fetal bovine serum-free medium in the absence or presence of Intralipid-20. Intracellular retention of labeled medium glucose was assessed in a subset of experiments. In the presence of Intralipid, medium glucose disappearance was increased in C2/LPL cells but not in control cells. In both cell types, glucose label retention in cellular TG was increased in the presence of Intralipid; incubation with albumin-bound oleate produced similar results. In the presence of Intralipid, the LPL hydrolytic inhibitor tetrahydrolipstatin blocked excess glucose retention in cellular TG but did not significantly decrease glucose disappearance in C2/LPL cells. Changes in glucose transport or hexokinase II did not explain the altered glucose disappearance in C2/LPL cells. Our results suggest that LPL overexpression in these cells leads to chronic metabolic adaptations that alter glucose uptake and retention.
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http://dx.doi.org/10.1152/ajpendo.00618.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957863PMC
October 2010

Lack of suppression of circulating free fatty acids and hypercholesterolemia during weight loss on a high-fat, low-carbohydrate diet.

Am J Clin Nutr 2010 Mar 27;91(3):578-85. Epub 2010 Jan 27.

University of Colorado, Aurora, CO, USA.

Background: Little is known about the comparative effect of weight-loss diets on metabolic profiles during dieting.

Objective: The purpose of this study was to compare the effect of a low-carbohydrate diet (< or =20 g/d) with a high-carbohydrate diet (55% of total energy intake) on fasting and hourly metabolic variables during active weight loss.

Design: Healthy, obese adults (n = 32; 22 women, 10 men) were randomly assigned to receive either a carbohydrate-restricted diet [High Fat; mean +/- SD body mass index (BMI; in kg/m(2)): 35.8 +/- 2.9] or a calorie-restricted, low-fat diet (High Carb; BMI: 36.7 +/- 4.6) for 6 wk. A 24-h in-patient feeding study was performed at baseline and after 6 wk. Glucose, insulin, free fatty acids (FFAs), and triglycerides were measured hourly during meals, at regimented times. Remnant lipoprotein cholesterol was measured every 4 h.

Results: Patients lost a similar amount of weight in both groups (P = 0.57). There was an absence of any diet treatment effect between groups on fasting triglycerides or on remnant lipoprotein cholesterol, which was the main outcome. Fasting insulin decreased (P = 0.03), and both fasting (P = 0.040) and 24-h FFAs (P < 0.0001) increased within the High Fat group. Twenty-four-hour insulin decreased (P < 0.05 for both groups). Fasting LDL cholesterol decreased in the High Carb group only (P = 0.003). In both groups, the differences in fasting and 24-h FFAs at 6 wk were significantly correlated with the change in LDL cholesterol (fasting FFA: r = 0.41, P = 0.02; 24-h FFA: r = 0.52, P = 0.002).

Conclusions: Weight loss was similar between diets, but only the high-fat diet increased LDL-cholesterol concentrations. This effect was related to the lack of suppression of both fasting and 24-h FFAs.
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http://dx.doi.org/10.3945/ajcn.2009.27909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132068PMC
March 2010

Plant sterols added to combination statin and colesevelam hydrochloride therapy failed to lower low-density lipoprotein cholesterol concentrations.

J Clin Lipidol 2007 Dec 18;1(6):626-33. Epub 2007 Oct 18.

Department of Clinical Pharmacy, University of Colorado-Denver, 12631 East 17th Ave, PO Box 6511, Aurora, CO 80045, USA.

Background: The purpose of this study was to evaluate the effects on LDL-cholesterol (LDL-C) from addition of plant sterol treatment to patients with dyslipidemia already taking a statin and colesevelam hydrochloride (HCl). Current cholesterol treatment guidelines recommend use of plant stanols/sterols to help reach LDL-C goals in patients taking other lipid-lowering therapies. Previous data demonstrate LDL-C lowering by adding stanols/sterols to statins. However, data are conflicting regarding the benefit from combination stanols/sterols with bile acid sequestrants.

Methods: Fifty-five subjects on a stable dose of statin completed a 10-week, double-blind, randomized study of colesevelam HCl 3.75 g/day alone for 4 weeks, then 6 weeks of additional 2 g/day plant sterol-fortified orange juice (S-OJ) or placebo orange juice (P-OJ). Serum total cholesterol (TC), LDL-C, HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline, 4 weeks, and 10 weeks.

Results: Baseline LDL-C measurements (mean ± SD) were similar between S-OJ and P-OJ groups (122 ± 20 vs 126 ± 24 mg/dL, respectively). Four weeks of colesevelam HCl in combination with a statin significantly reduced TC, LDL-C, and ApoB (9.6%, P < 0.001; 21.9%, P < 0.001; and 8.5%, P = 0.001, respectively), and significantly increased HDL-C (6.2%, P = 0.002) and TG (18.8%, P = 0.002). However, compared to P-OJ, 10 weeks of S-OJ produced no effect on any outcome parameter beyond that of colesevelam HCl.

Conclusion: Plant S-OJ appears to be ineffective at further reducing LDL-C when added to statin and colesevelam HCl combination therapy in patients with dyslipidemia.
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http://dx.doi.org/10.1016/j.jacl.2007.10.004DOI Listing
December 2007

Time course of C-reactive protein reduction with simvastatin therapy in patients with type 2 diabetes mellitus.

Am J Cardiol 2006 Dec 25;98(12):1656-9. Epub 2006 Oct 25.

Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver & Health Sciences Center, Denver, CO, USA.

The aim of this study was to investigate the time course of C-reactive protein (CRP) reduction with simvastatin in patients with type 2 diabetes mellitus. Thirty-five subjects (mean +/- SEM body mass index 32.8 +/- 1 kg/m(2), mean +/- SEM glycated hemoglobin 7.3 +/- 0.2%) were studied using a randomized, crossover, double-blind design. Patients were treated with simvastatin 40 mg or placebo for 28 days, with a minimum 28-day intervening washout. On entry, all subjects had low-density lipoprotein cholesterol >100 mg/dl and/or non-high-density lipoprotein cholesterol >130 mg/dl. High-sensitivity CRP (hs-CRP) was measured on days 0, 1, 3, 7, 14, 21, and 28 of each phase; fasting lipids were measured weekly. The mean hs-CRP level was 4.2 +/- 0.6 mg/L at baseline (>3.0 mg/L represents high risk). After simvastatin administration, there was a significant reduction in levels of log(hs-CRP) (p = 0.001). This effect of simvastatin was seen by day 7 (p = 0.008), with maximal reduction seen at day 14 (p = 0.004; hs-CRP in original units 3.1 +/- 0.5 mg/L with simvastatin and 4.1 +/- 0.6 mg/L with placebo). As expected, the change in hs-CRP was not related to low-density lipoprotein cholesterol reduction. By day 28 with simvastatin, hs-CRP had returned to near baseline levels. In conclusion, in patients with type 2 diabetes mellitus, simvastatin reduced hs-CRP within 7 days. However, this potentially beneficial effect was lost within 28 days.
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http://dx.doi.org/10.1016/j.amjcard.2006.07.047DOI Listing
December 2006

Severe hypertriglyceridemia with a history of treatment failure.

Nat Clin Pract Endocrinol Metab 2005 Nov;1(1):53-8; quiz 59

Division of Endocrinology, Metabolism, and Diabetes at the University of Colorado at Denver and Health Sciences Center, CO, USA.

Background A 53-year-old man with a history of hypertension and gout was referred to our clinic for severe hypertriglyceridemia, diagnosed 3 years previously. He was asymptomatic and had no history of abdominal pain, pancreatitis or diabetes, but consumed six cans of beer per night. Over the previous 2 years, he had been treated unsuccessfully with multiple medications; during this period his fasting triglycerides ranged from 5.41 mM to 55.04 mM (479 to 4,871 mg/dl). Investigations Physical examination including fundoscopy, medication review, and laboratory tests.Diagnosis Severe hypertriglyceridemia due to a genetic combined hyperlipidemia, exacerbated by persistent excessive alcohol intake and metabolic syndrome. Management Cessation of alcohol intake, initiation of a fat-restricted diet, and fibrate therapy, with close follow-up. Once serum triglycerides were controlled, attention was turned to lowering LDL-cholesterol concentration according to The National Cholesterol Education Program, Adult Treatment Panel III guidelines.
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http://dx.doi.org/10.1038/ncpendmet0025DOI Listing
November 2005

Treatment of hypertriglyceridemia.

Curr Diab Rep 2006 Jun;6(3):230-40

Hypertriglyceridemia is a disorder commonly encountered in clinical practice. Treatment of this condition aims to prevent the major complications of hypertriglyceridemia, which differ depending on whether triglyceride elevations are moderate or severe. This review discusses the pathophysiology and clinical consequences of hypertriglyceridemia and outlines treatment approaches based on the degree of triglyceride elevation. Special consideration is given to clinical trials using medications that primarily target triglycerides.
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http://dx.doi.org/10.1007/s11892-006-0040-9DOI Listing
June 2006

Increased expression of the SNARE accessory protein Munc18c in lipid-mediated insulin resistance.

J Lipid Res 2003 Jun 16;44(6):1174-81. Epub 2003 Apr 16.

Department of Medicine, Division of Endocrinology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.

Fatty acids inhibit insulin-mediated glucose metabolism in skeletal muscle, an effect largely attributed to defects in insulin-mediated glucose transport. Insulin-resistant mice transgenic for the overexpression of lipoprotein lipase (LPL) in skeletal muscle were used to examine the molecular mechanism(s) in more detail. Using DNA gene chip array technology, and confirmation by RT-PCR and Western analysis, increases in the yeast Sec1p homolog Munc18c mRNA and protein were found in the gastrocnemius muscle of transgenic mice, but not other tissues. Munc18c has been previously demonstrated to impair insulin-mediated glucose transport in mammalian cells in vitro. Of interest, stably transfected C2C12 cells overexpressing LPL not only demonstrated increases in Munc18c mRNA and protein but also in transcription rates of the Munc18c gene. To confirm the relevance of fatty acid metabolism and insulin resistance to the expression of Munc18c in vivo, a 2-fold increase in Munc18c protein was demonstrated in mice fed a high-fat diet for 4 weeks. Together, these data are the first to implicate in vivo increases in Munc18c as a potential contributing mechanism to fatty acid-induced insulin resistance.
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http://dx.doi.org/10.1194/jlr.M300003-JLR200DOI Listing
June 2003

Short-term triglyceride lowering with fenofibrate improves vasodilator function in subjects with hypertriglyceridemia.

Arterioscler Thromb Vasc Biol 2003 Feb;23(2):307-13

Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.

Objective: The objective of this study was to investigate the effects of lowering plasma triglycerides (TGs) on endothelial function and gain insight into the role played by free fatty acids (FFAs) in hypertriglyceridemia-associated vascular dysfunction.

Methods And Results: Eleven hypertriglyceridemic subjects without coronary artery disease, diabetes, elevated low-density lipoprotein cholesterol, tobacco use, or hypertension were studied using a randomized, double-blinded, crossover design (fenofibrate and placebo, 14 days). After each regimen, forearm blood flow was assessed by plethysmography in response to arterial acetylcholine, nitroprusside, and verapamil infusion. Hourly plasma TGs, FFA, glucose, and insulin were measured during a 24-hour feeding cycle to characterize the metabolic environment. Changes in plasma FFA after intravenous heparin were used to estimate typical FFA accumulation in the luminal endothelial microenvironment. Fenofibrate lowered plasma TG (P<0.001), total cholesterol (P<0.01), and apolipoprotein B (P<0.01) without altering high-density lipoprotein or low-density lipoprotein cholesterol concentrations. Forearm blood flow in response to acetylcholine (P<0.0001), nitroprusside (P<0.001), and verapamil (P<0.0001) improved after fenofibrate. Fenofibrate lowered 24-hour (P<0.0001) and post-heparin (P<0.001) TG and tended to lower 24-hour (P=0.054) and post-heparin (P=0.028) FFA.

Conclusions: Vascular smooth muscle function significantly improves after lowering plasma TG without changes in confounding lipoproteins or insulin resistance. The data raise additional questions regarding the role of FFA in hypertriglyceridemia-associated vascular dysfunction.
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http://dx.doi.org/10.1161/01.atv.0000046230.02211.b4DOI Listing
February 2003
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