| 1. |
- Govsyeyev, Nicholas, et al.
(författare)
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Etiology and outcomes of amputation in patients with peripheral artery disease in the EUCLID trial
- 2022
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Ingår i: Journal of Vascular Surgery. - : Elsevier. - 0741-5214 .- 1097-6809. ; 75:2, s. 660-670e3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Amputation remains a frequent and feared outcome in patients with peripheral artery disease (PAD). Although typically characterized as major or minor on the extent of tissue loss, the etiologies and outcomes after amputation by extent are not well-understood. In addition, emerging data suggest that the drivers and outcomes of amputation in patients with PAD may differ in those with and without diabetes mellitus (DM).Methods: The EUCLID trial randomized 13,885 patients with symptomatic PAD, including 5345 with concomitant diabetes, to ticagrelor or clopidogrel and followed them for long-term outcomes. Amputations were prospectively reported by trial investigators. Their primary and contributing drivers were adjudicated using safety data, including infection, ischemia, or multifactorial etiologies. Outcomes following major and minor amputations were analyzed, including recurrent amputation, major adverse limb events, adverse cardiovascular events, and mortality. Multivariable logistic regression models were used to identify independent predictors of minor amputations. Analyses were performed overall and stratified by the presence or absence of DM at baseline.Results: Of the patients randomized, 398 (2.9%) underwent at least one lower extremity nontraumatic amputation, for a total of 511 amputations (255 major and 256 minor) over a median of 30 months. A history of minor amputation was the strongest independent predictor for a subsequent minor amputation (odds ratio, 7.29; 95% confidence interval, 5.17-10.30; P <.001) followed by comorbid DM (odds ratio, 4.60; 95% confidence interval, 3.16-6.69; P <.001). Compared with patients who had a major amputation, those with a minor amputation had similar rates of subsequent major amputation (12.2% vs 13.6%), major adverse limb events (15.1% vs 14.9%), and major adverse cardiovascular events (17.6% vs 16.3%). Ischemia alone was the primary driver of amputation (51%), followed by infection alone (27%), and multifactorial etiologies (22%); however, infection was the most frequent driver in those with DM (58%) but not in those without DM (15%).Conclusions: Outcomes after amputation remain poor regardless of whether they are categorized as major or minor. The pattern of amputation drivers in PAD differs by history of DM, with infection being the dominant etiology in those with DM and ischemia in those without DM. Greater focus is needed on the prognostic importance of minor amputation and of the multifactorial etiologies of amputation in PAD. Nomenclature with anatomical description of amputations and eliminating terms "major" or "minor" would seem appropriate.
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| 2. |
- Hiatt, William R, et al.
(författare)
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Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease
- 2017
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Ingår i: The New England journal of medicine. - 0028-4793 .- 1533-4406. ; 376, s. 32-40
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease.METHODS: In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months.RESULTS: The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49).CONCLUSIONS: In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).
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| 3. |
- Norgren, Lars, et al.
(författare)
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Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial
- 2018
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : W B SAUNDERS CO LTD. - 1078-5884 .- 1532-2165. ; 55:1, s. 109-117
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established.Design, Materials, Methods: The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss.Results: In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 +/- 0.21 (mean +/- SD) for those with CLI versus 0.63 +/- 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI.Conclusions: Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI.
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| 4. |
- Szarek, Michael, et al.
(författare)
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Total Cardiovascular and Limb Events and the Impact of Polyvascular Disease in Chronic Symptomatic Peripheral Artery Disease
- 2022
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Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980 .- 2047-9980. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories.Methods and Results: In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle-brachial index ≤0.80) were randomized to treatment with ticagrelor or clopidogrel. Relative effects on total events (cardiovascular death; nonfatal myocardial infarction and ischemic stroke; acute limb ischemia, unstable angina, and transient ischemic attack requiring hospitalization; coronary, carotid, and peripheral revascularization procedures; and amputation for symptomatic PAD) were summarized by hazard ratios (HRs), whereas absolute risks were estimated by incidence rates and mean cumulative functions. Among 13 885 randomized patients, 7600 total cardiovascular and limb events occurred during a median 2.7 years of follow-up, translating to 60.0 and 62.5 events per 100 patients through 3 years for the ticagrelor and clopidogrel groups, respectively (HR, 0.96; 95% CI, 0.89-1.03; P=0.27). Among 1393 patients with disease in 3 vascular territories, event accrual rates through 3 years for the ticagrelor and clopidogrel groups were 87.3 and 97.7 events per 100 patients, respectively. Absolute risk reductions for ticagrelor relative to clopidogrel at 3 years were -0.2, 6.7, and 10.3 events per 100 patients for 1, 2, and 3 affected vascular territories, respectively (Pinteraction=0.09).Conclusions: Patients with symptomatic PAD have nearly double the number of total events than first events, with rates reflecting the number of affected vascular territories. These findings highlight the clinical relevance of quantifying disease burden in terms of total events and the need for long-term preventive treatments in high-risk patient populations. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT01732822.
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| 5. |
- Weissler, E. Hope, et al.
(författare)
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Understanding Study Drug Discontinuation Through EUCLID
- 2022
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Ingår i: Frontiers in Cardiovascular Medicine. - : Frontiers Media S.A.. - 2297-055X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Disparities in the care and outcomes of peripheral artery disease (PAD) have been well-established. In part this is due to disparities in enrollment of PAD trial cohorts. However, less attention has been paid to non-random protocol non-adherence after enrollment, which may lead to inaccurate estimates of treatment effects and reduce generalizability of study results. We aimed to ascertain characteristics associated with premature study drug discontinuation in a PAD cohort.Methods: Using data from EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease), factors associated with study drug discontinuation were assessed using univariable and multivariable Cox proportional hazards models with time to study drug discontinuation as the outcome of interest. Relationships between study drug discontinuation and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, ischemic stroke), major adverse limb events (MALE; acute limb ischemia, major amputation, and lower extremity revascularization), and all-cause hospitalization were assessed.Results: Of 13,842 eligible EUCLID participants, 3,886 (28.1%) prematurely and permanently discontinued study drug over a maximum follow-up of 42 months (annualized rate of 13.2 discontinuations per 100 patient-years). In a multivariable model, premature study drug discontinuation was associated with older age (aHR 1.16, 95%CI 1.14-1.19), eligibility based on prior lower extremity revascularization rather than ABI/TBI criteria (aHR 1.14, 95%CI 1.06-1.23), CLI status (aHR 1.23, 95%CI 1.06-1.42), COPD (aHR 1.36, 95%CI 1.24-1.49), and geographic region. In a multivariable analysis, study drug discontinuation was significantly associated with MACE (aHR 3.27, 95%CI 2.90-3.67, p < 0.001), MALE (aHR 1.84, 95%CI 1.63-2.07, p < 0.001), and all-cause hospitalization (aHR 2.37, 95%CI 2.21-2.54) following study drug discontinuation.Conclusions: This analysis of EUCLID demonstrates that premature, permanent discontinuation of study drug is relatively common in more than a quarter of PAD patients, is unevenly distributed based on geography and other baseline characteristics, and is associated with worse outcomes in a clinical trial context. Study teams leading future PAD trials may want to address the possibility of study drug discontinuation prospectively, as a proactive approach may help investigators to maintain study cohort diversity and representativeness without sacrificing power and precision.
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| 6. |
- Govsyeyev, Nicholas, et al.
(författare)
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Rivaroxaban in Patients with Symptomatic Peripheral Artery Disease after Lower Extremity Bypass Surgery with Venous and Prosthetic Conduits
- 2023
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Ingår i: Journal of Vascular Surgery. - : Elsevier. - 0741-5214 .- 1097-6809. ; 77:4, s. 1107-1118.e2
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Tidskriftsartikel (refereegranskat)abstract
- 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 with an overall favorable net benefit in patients undergoing surgical revascularization; however, the efficacy and safety in those treated by surgical bypass including stratified by bypass conduit (venous or prosthetic) has not been described.METHODS: In the VOYAGER PAD trial, patients with PAD after surgical and endovascular infrainguinal LER were randomized to rivaroxaban 2.5 mg twice daily or placebo and followed for a median of 28 months. The primary endpoint was a composite of acute limb ischemia (ALI), major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Index procedure details including conduit type (venous or prosthetic) were collected at baseline.RESULTS: Among 6564 randomized, 2185 (33%) underwent surgical LER. Of these, surgical bypass was performed in 1448 (66%), using prosthetic conduit in 773 (53%) and venous in 646 (45%). Adjusting for baseline differences and anatomic factors, the risk for unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving prosthetic versus venous conduits (adjHR 2.53, 95% CI 1.65-3.90; p<0.001) while the risk for ALI was 3 times greater (adjHR 3.07, 95% CI 1.84-5.11; p<0.001). Rivaroxaban reduced the primary outcome in patients treated with bypass surgery (HR 0.78, 95% CI 0.62-0.98) with consistent benefits in those receiving venous (HR 0.66, 95% CI 0.49-0.96) and prosthetic (HR 0.87, 95% CI 0.66-1.15) conduits (pinteraction 0.254). In the overall trial, TIMI major bleeding was increased with rivaroxaban; however, numbers in those treated with bypass surgery were low (5 with rivaroxaban, 9 with placebo, HR 0.55, 95% CI 0.18-1.65) and not powered to show statistical significance.CONCLUSIONS: Surgical bypass with prosthetic conduit is associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjusting for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduces this risk, increases bleeding, but has a favorable benefit risk in patients treated with bypass surgery and regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain.
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| 7. |
- Norgren, Lars, 1942-, et al.
(författare)
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PACE : randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial
- 2024
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Ingår i: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 111:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Revascularization is the primary treatment modality for chronic limb-threatening ischaemia (CLTI), but is not feasible in all patients. PLX-PAD is an off-the-shelf, placental-derived, mesenchymal stromal cell-like cell therapy. This study aimed to evaluate whether PLX-PAD would increase amputation-free survival in people with CLTI who were not candidates for revascularization.METHODS: People with CLTI and minor tissue loss (Rutherford 5) who were unsuitable for revascularization were entered into a randomized, parallel-group, placebo-controlled, multinational, blinded, trial, in which PLX-PAD was compared with placebo (2 : 1 randomization), with 30 intramuscular injections (0.5 ml each) into the index leg on days 0 and 60. Planned follow-up was 12-36 months, and included vital status, amputations, lesion size, pain and quality-of-life assessments, haemodynamic parameters, and adverse events.RESULTS: Of 213 patients enrolled, 143 were randomized to PLX-PAD and 70 to placebo. Demographics and baseline characteristics were balanced. Most patients were Caucasian (96.2%), male (76.1%), and ambulatory (85.9%). Most patients (76.6%) reported at least one adverse event, which were mostly expected events in CLTI, such as skin ulcer or gangrene. The probability of major amputation or death was similar for placebo and PLX-PAD (33 and 28.6% respectively; HR 0.93, 95% c.i. 0.53 to 1.63; P = 0.788). Revascularization and complete wound healing rates were similar in the two groups. A post hoc analysis of a subpopulation of 121 patients with a baseline haemoglobin A1c level below 6.5% showed improved 12-month amputation-free survival (HR 0.46, 0.21 to 0.99; P = 0.048).CONCLUSION: Although there was no evidence that PLX-PAD reduced amputation-free survival in the entire study population, benefit was observed in patients without diabetes mellitus or whose diabetes was well controlled; this requires confirmation in further studies. Trial registration: NCT03006770 (http://www.clinicaltrials.gov); 2015-005532-18 (EudraCT Clinical Trials register - Search for 2015-005532-18).
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