Publications by authors named "Lloyd P Haskell"

8 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 and aspirin among patients with peripheral artery disease: a meta-analysis of the COMPASS and VOYAGER trials.

Eur J Prev Cardiol 2021 Aug 31. Epub 2021 Aug 31.

Department of Cardiology, University of Colorado School of Medicine, 13001 E 17th Pl, Boulder, Colorado 80045, USA.

Aims: Peripheral artery disease (PAD) patients suffer a high risk of major cardiovascular (CV) events, with athero-thrombo-embolism as the underlying pathophysiologic mechanism. Recently, two large randomized clinical trials evaluated the efficacy and safety of low-dose rivaroxaban twice daily plus aspirin in stable PAD outpatients and those immediately after peripheral revascularization. We sought to determine if the effects of low-dose rivaroxaban and aspirin compared to aspirin alone are consistent across this broad spectrum of PAD patients.

Methods And Results: We conducted a random-effects meta-analysis of the COMPASS and VOYAGER randomized trials among 11 560 PAD patients (4996 from COMPASS and 6564 from VOYAGER) in the primary analysis and 9332 (2768 from COMPASS and 6564 from VOYAGER) with lower extremity (LE)-PAD in the secondary analysis. The hazard ratio (HR) for the composite of CV death, myocardial infarction, ischaemic stroke, acute limb ischaemia, or major vascular amputation was 0.79 (95% confidence interval, CI: 0.65-0.95) comparing low-dose rivaroxaban plus aspirin to aspirin alone. While the risk of major bleeding was increased with low-dose rivaroxaban plus aspirin compared to aspirin alone [HR: 1.51 (95% CI: 1.22-1.87)], there was no significant increase in severe bleeding [HR: 1.18 (95% CI: 0.79-1.76)]. Similar effects were observed in the subset with symptomatic LE-PAD.

Conclusions: Among PAD patients, low-dose rivaroxaban plus aspirin is superior to aspirin alone in reducing CV and limb outcomes including acute limb ischaemia and major vascular amputation. This reduction is offset by a relative increase in major bleeding, but not by an excess of fatal or critical organ bleeding. The consistency of findings of these trials supports the use of combination low-dose rivaroxaban plus aspirin in PAD patients across a broad spectrum of disease.
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http://dx.doi.org/10.1093/eurjpc/zwab128DOI Listing
August 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

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

Optimizing dose selection with modeling and simulation: application to the vasopeptidase inhibitor M100240.

J Clin Pharmacol 2004 Jun;44(6):621-31

Aventis Pharmaceuticals, 1041 Route 202-206, Bridgewater, NJ 08807, USA.

Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) has gained increasing interest in the treatment of hypertension, heart failure, and renoprotection. Specifically, M100240, the thioester of the dual ACE/NEP inhibitor MDL100,173, has been evaluated in the management of hypertension. A model-based analysis, including simulations, was employed to characterize the relationship between individual M100240 drug exposure and neurohormonal response and to optimize the dose selection for future clinical studies. Sixty-two healthy subjects and 189 hypertensive patients were studied after oral once-daily administration of 2.5, 5, 10, 25, or 50 mg M100240. Pharmacokinetic-biomarker and blood pressure response models were fitted to the data with the computer program NONMEM. A direct inhibitory E(max) model adequately described the relationship between MDL100,173 concentration and ACE activity. No clear concentration or dose-dependent NEP or blood pressure responses were evident. Given a target 90% ACE inhibition, simulation reveals that (1). 50 mg M100240 once daily produces adequate ACE inhibition 24 hours postdose in only 20% of subjects, and (2). higher and/or more frequent doses on the order of 25 mg three times daily or 50 mg twice daily are required to achieve the target ACE inhibition in at least 50% of patients over 24 hours. Insufficient blood pressure-lowering effects were observed in healthy subjects and hypertensive patients due to inadequate ACE and NEP inhibition with once-daily oral doses of up to 50 mg of M100240. Divided doses might provide target ACE inhibition in more patients.
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http://dx.doi.org/10.1177/0091270004265365DOI Listing
June 2004
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