| 1. |
- Adingupu, D. D., et al.
(författare)
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Radial artery intima-media thickness regresses after secondary prevention interventions in patients' post-acute coronary syndrome and is associated with cardiac and kidney biomarkers
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:32, s. 53419-53431
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Tidskriftsartikel (refereegranskat)abstract
- Background: Radial artery intima-media thickness (rIMT) measured by ultra-high-resolution ultrasound is associated with increased cardiovascular risk and predicts outcomes. We performed non-invasive high-resolution ultrasound of the radial artery to investigate vascular changes in subjects presenting with acute coronary syndrome (ACS) and who had undergone percutaneous coronary intervention (PCI). Purpose: In the present work, we aimed to follow rIMT change over time post-acute coronary syndrome as a tool to monitor potential response to intensified medical therapy. Methods: We examined 256 subjects who underwent PCI due to ACS and healthy controls (n= 39) and we measured a number of biomarkers, which are known to be associated with cardiovascular disease. Images of radial artery were acquired bilaterally in the longitudinal view using a 50 MHz transducer (Vevo 2100 VisualSonics, Inc, Toronto, Ontario, Canada). Carotid IMT (cIMT) and rIMT were measured at <1 month after index PCI followed by a repeated measurement of rIMT at 4 months from the ACS in a sub-set (n= 117). Results: rIMT measured within 1 month post ACS was significantly higher than rIMT after 4 months from ACS, (p < 0.0001), mean +/- SD (rIMT right 0.35 +/- 0.08; rIMT left 0.37 +/- 0.08) vs. (rIMT right 0.29 +/- 0.08; rIMT left 0.31 +/- 0.09) respectively. There was no statistically significant change in cIMT. In healthy controls there were no changes in rIMT or cIMT overtime. High levels of CX3CL1 and myeloperoxidase measured within one month post ACS are associated with increase of rIMT, r=0.38 (p< 0.0001) and r=0.41 (p< 0.0001) respectively. Conclusions: rIMT seem to decrease systemically after ACS and is accompanied with corresponding biomarker change. The cause and clinical implications of the observed decrement in rIMT after ACS need further studies.
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| 2. |
- Berger, J. S., et al.
(författare)
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Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial
- 2016
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703. ; 175, s. 86-93
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Tidskriftsartikel (refereegranskat)abstract
- Background Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y(12) receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events. Study design EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1: 1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur. Conclusions The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.
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| 3. |
- Blomster, Juuso I., et al.
(författare)
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Coronary flow reserve as a link between exercise capacity, cardiac systolic and diastolic function
- 2016
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 217, s. 161-166
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Tidskriftsartikel (refereegranskat)abstract
- Background: Decreased coronary flow reserve (CFR) is associated with increased risk of adverse cardiovascular events. We sought to investigate how CFR from left anterior descending (LAD) coronary artery reflects clinical markers of cardiac function. Methods: We enrolled 400 patients referred for myocardium perfusion scintigraphy due to chest pain at Sahlgrenska University Hospital in Gothenburg, Sweden. Transthoracic echocardiography including adenosine-assisted CFR in LAD was performed at a separate occasion. Results: Median age was 62 years (range 32-83) and 47% were female. Prior myocardial infarction had occurred in 28% of the population. In adjusted multivariate models, CFR in LAD was associated with echocardiography left ventricle ejection fraction at rest (beta = 0.97, p = 0.033) as well as under stress (beta = 1.52, p = 0.0056) and maximum exercise capacity (beta = 6.27, p = 0.026). CFR in LAD outweighed left ventricle ejection fraction as the determinant of maximum exercise capacity. Hyperaemic diastolic mitral annulus peak velocity measured by vector velocity imaging was inversely associated with LAD CFR (beta = -0.39, p = 0.0077). In subgroup analyses these findings were associated with normal coronary perfusion in myocardium perfusion scintigraphy. Conclusions: In patients with angina-like symptoms CFR measured in LAD reflects well both systolic and diastolic cardiac function emphasizing the essential role of myocardial microvascular circulation in cardiac physiology. (C) 2016 Published by Elsevier Ireland Ltd.
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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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. ; 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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| 8. |
- Utkovic Westergren, Helena, et al.
(författare)
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Determinants of coronary flow reserve in non-diabetic patients with chest pain without myocardial perfusion defects
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Background Microvascular dysfunction could be responsible for chest pain in patients without myocardial perfusion defects. We evaluated microvascular function using ultrasound-assessed coronary flow reserve (CFR) in patients with chest pain and normal myocardial perfusion scintigram. Secondly, we investigated association between cardiovascular parameters and decreased CFR in a sex specific manner. A total of 202 (128 women) non-diabetic patients with chest pain and suspected myocardial ischemia, but without myocardial perfusion defects on myocardial perfusion scintigram, were enrolled and underwent CFR examination and blood sampling. All patients were followed- up for cardiovascular events. We used a supervised principal component analysis including 66 variables such as clinical parameters, ongoing medication, coronary artery disease history, lipids, metabolic parameters, inflammatory and other cardiovascular parameters. During a median follow-up time of 5.4 years, 25 cardiovascular events occurred; (men; 18, women; 7). Average CFR of the study cohort was 2.7 +/- 1.2 and 14% showed impaired CFR< 2.0. In an adjusted Cox regression analysis, CFR< 2.0 independently predicted eventfree survival (HR: 2.5, p = 0.033). In the supervised principal component analysis high insulin resistance assessed by Homeostatic model assessment for insulin resistance was the strongest biochemical marker associated with decreased CFR. Interestingly, upon sex specific multivariable linear regression analysis, the association was only significant in men (beta = -0.132, p = 0.041) while systolic blood pressure remained an independent predictor in women (beta = -0.009, p = 0.011). In non-diabetic patients with chest pain without myocardial perfusion defects, low CFR has prognostic value for future cardiovascular events. Insulin resistance appears to be a marker for decreased CFR in men. Indeed, in the context of contribution of traditional risk factors in this patient population, the value of systolic blood pressure seems to be important in the women.
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| 9. |
- 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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| 10. |
- Westergren, Helena, 1977, et al.
(författare)
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Insulin resistance, endothelial function, angiogenic factors and clinical outcome in non-diabetic patients with chest pain without myocardial perfusion defects
- 2016
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Ingår i: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 15:36
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with angina-like symptoms without myocardial perfusion scintigram (MPS)-verified abnormality may still be at risk for cardiovascular events. We hypothesized that insulin resistance could play a role in this population even without diagnosed diabetes. We further explored physiological and blood biomarkers, as well as global gene expression patterns that could be closely related to impaired glucose homeostasis to deepen our mechanistic understanding. Methods: A total of 365 non-diabetic patients with suspected myocardial ischemia referred to MPS were enrolled and followed up regarding event-free survival with a median time of 5.1 years. All patients underwent endothelial function assessment by reactive hyperemic index (RHI) using EndoPAT and extensive biomarker analysis. Whole blood global gene expression pathway analysis was performed in a subset of patients. Results: Homeostasis model assessment of insulin resistance (HOMA-IR) added independent prognostic value in patients without myocardial perfusion defects. In a multivariable analysis, HOMA-IR was inversely associated with low RHI. Furthermore, elevated HOMA-IR was associated with decreased levels of vascular endothelial growth factor D, stem cell factor and endocan as well as to increased level of interleukin-6. Global gene expression pathway analysis of whole blood cells showed that high HOMA-IR and impaired endothelial function were associated with upregulated pro-inflammatory pathways and down-regulated eukaryotic initiation factor-2 pathway. Conclusions: Insulin resistance measured by HOMA-IR is associated with endothelial dysfunction and confers independent prognostic information in non-diabetic patients with chest pain without myocardial perfusion defects. Increased systemic pro-inflammatory state and decreased levels of pro-angiogenic vascular growth factors may be important underlying molecular mechanisms.
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