| 1. |
- Himmelmann, Anders, et al.
(författare)
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The impact of smoking on inhaled insulin
- 2003
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 26:3, s. 677-682
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study, one of the first to address issues of pulmonary insulin delivery in smokers, compared pharmacokinetics of inhaled insulin delivered via the AERx insulin Diabetes Management System (iDMS) in nondiabetic cigarette smokers and nonsmokers.RESEARCH DESIGN AND METHODS: In this randomized two-period crossover efficacy and safety trial in 27 nondiabetic smokers and 16 nonsmokers (18 men/25 women, mean age 28 years, mean BMI 23.0 kg/m(2)), subjects received single doses of inhaled insulin (33.8 IU) following overnight fasting on consecutive dosing days. On one dosing day, smokers smoked three cigarettes immediately before insulin administration ("acute smoking"); on the other dosing day, smokers had not smoked since midnight ("nonacute smoking"). After inhalation, 6-h serum insulin and serum glucose profiles were determined.RESULTS: Pharmacokinetic results for evaluable subjects were derived from serum insulin profiles. The amount of insulin absorbed during the first 6 h after dosing (area under the exogenous serum insulin curve from 0 to 6 h [AUC((0-6 h))]) was significantly greater in smokers (63.2 vs. 40.0 mU l(-1) x h(-1), P = 0.0017); peak concentration was both higher and earlier in the smokers (maximal serum concentration of insulin [C(max)] 42.0 vs. 13.9 mU/l, P < 0.0001; time to maximal serum concentration of insulin [t(max)] 31.5 vs. 53.9 min, P = 0.0003). The estimated intrasubject variability of AUC((0-6 h)) was 13.7 and 16.5% for nonsmokers and smokers, respectively. No safety issues arose.CONCLUSIONS: Absorption of inhaled insulin via the AERx iDMS was significantly greater in smokers, with a higher AUC((0-6 h)) and C(max) and a shorter t(max). Intrasubject variability of AUC((0-6 h)) was low and similar in nonsmokers and smokers. These data prompt more extensive investigation of inhaled insulin in diabetic smokers.
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| 2. |
- Åkerblom, Axel, 1977-, et al.
(författare)
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Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome : Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
- 2013
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 59:9, s. 1369-1375
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Tidskriftsartikel (refereegranskat)abstract
- Background: The estimated glomerular filtration rate (eGFR) independently predicts cardiovascular (CV) death or myocardial infarction (MI), and can be estimated by creatinine and cystatin C concentrations. We evaluated two different cystatin C assays, alone or combined with creatinine, in patients with acute coronary syndromes.Methods: Plasma cystatin C, measured with assays from Gentian and Roche, and serum creatinine was analyzed in 16279 patients from the PLATelet inhibition and patient Outcomes trial. Pearson’s correlation and agreement (Bland–Altman) between methods was evaluated. Prognostic value in relation to CV death or MI during one year of follow up was evaluated by multivariable logistic regression analysis including clinical variables and biomarkers, c-statistics and relative Integrated Discrimination Improvement (IDI).Results: Median cystatin C concentrations (interquartile intervals) were 0.83 (0.68 - 1.01) mg/L (Gentian) and 0.94 (0.80 - 1.14) mg/L (Roche). Overall correlation was 0.86 (95% confidence interval 0.85-0.86). The level of agreement was ±0.39mg/L (±2 standard deviations) (n=16279).The area under curve (AUC) in the multivariable risk prediction model with cystatin C (Gentian, Roche) or Chronic Kidney Disease - Epidemiology (CKD-EPI) added was 0.6914, 0.6913 and 0.6932. Corresponding relative IDIs were 2.96%, 3.86% and 4.68%, respectively (n=13050). Addition of eGFR by the combined creatinine-cystatin C equation yielded AUC of 0.6923(Gentian) and 0.6924(Roche) with relative IDIs of 3.54% and 3.24% respectively.Conclusions: Despite differences in cystatin C concentrations, overall correlation between the Gentian and Roche assays was good while agreement was moderate. The combined creatinine-cystatin C equation did not outperform risk prediction compared to CKD-EPI.
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| 3. |
- Almgren, Torbjörn, 1959, et al.
(författare)
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Diabetes in treated hypertension is common and carries a high cardiovascular risk: results from a 28-year follow-up.
- 2007
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Ingår i: Journal of hypertension. - 0263-6352. ; 25:6, s. 1311-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The objective of this study was to analyse predictive factors for development of type 2 diabetes during life-long therapy for hypertension and the alleged additional cardiovascular risk this constitutes. METHODS: The study group (n = 754) comprised the hypertensive subgroup of a randomized population sample of 7500 men, aged 47-54 years, screened for cardiovascular risk factors and followed for 25-28 years. The patients were treated with thiazide diuretics and beta-adrenergic blocking drugs with the addition of hydralazin during the first decade. Calcium antagonists were substituted for hydralazin and, if needed, angiotensin-converting enzyme inhibitors were added when these drugs became available. RESULTS: A total of 148 (20.4%) treated hypertensive patients developed diabetes during 25 years, and in multivariate Cox regression analysis body mass index, serum triglycerides and treatment with beta-blockers were positively related with this complication. New-onset diabetes implied a significantly increased risk for stroke [hazard ratio (HR): 1.67; 95% confidence interval (95% CI): 1.1-2.6; P < 0.05], myocardial infarction (OR: 1.66; 95% CI: 1.1-2.5; P < 0.05) and mortality (OR: 1.42; 95% CI: 1.1-1.9; P < 0.05). The greatest risk for stroke was new-onset diabetes, followed by smoking (OR: 1.46; 95% CI: 1-2.2; P = 0.07) and the greatest risk for myocardial infarction was new-onset diabetes, followed by smoking (HR: 1.64; 95% CI: 1.1-2.4; P < 0.01). The greatest risk for mortality was smoking (HR: 1.73; 95% CI: 1.3-2.2; P < 0.005). Achieved systolic and diastolic blood pressure were not predictive of cardiovascular complications or death. The mean observation time from onset of diabetes mellitus to a first stroke was 9.1 years and to a first myocardial infarction 9.3 years. CONCLUSION: Diabetes in treated hypertensive patients is alarmingly common and carries a high risk for cardiovascular complications and mortality.
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| 4. |
- Amarenco, Pierre, et al.
(författare)
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Ticagrelor Added to Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack in Prevention of Disabling Stroke : A Randomized Clinical Trial
- 2020
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 78:2, s. 177-185
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Reduction of subsequent disabling stroke is the main goal of preventive treatment in the acute setting after transient ischemic attack (TIA) or minor ischemic stroke.Objective: To evaluate the superiority of ticagrelor added to aspirin in preventing disabling stroke and to understand the factors associated with recurrent disabling stroke.Design, Setting, and Participants: The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) was a randomized clinical trial conducted between January 22, 2018, and December 13, 2019, with a 30-day follow-up, at 414 hospitals in 28 countries. The trial included 11 016 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk TIA, including 10 803 with modified Rankin Scale score (mRS) recorded at 30 days.Interventions: Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for days 2-30) or placebo within 24 hours of symptom onset. All patients received aspirin, 300 to 325 mg on day 1 followed by 75 to 100 mg daily for days 2 to 30.Main Outcomes and Measures: Time to the occurrence of disabling stroke (progression of index event or new stroke) or death within 30 days, as measured by mRS at day 30. Disabling stroke was defined by mRS greater than 1.Results: Among participants with 30-day mRS greater than 1, mean age was 68.1 years, 1098 were female (42.6%), and 2670 had an ischemic stroke (95.8%) as a qualifying event. Among 11 016 patients, a primary end point with mRS greater than 1 at 30 days occurred in 221 of 5511 patients (4.0%) randomized to ticagrelor and in 260 of 5478 patients (4.7%) randomized to placebo (hazard ratio [HR], 0.83; 95% CI, 0.69-0.99, P = .04). A primary end point with mRS 0 or 1 at 30 days occurred in 70 of 5511 patients (1.3%) and 87 of 5478 patients (1.6%) (HR, 0.79; 95% CI, 0.57-1.08; P = .14). The ordinal analysis of mRS in patients with recurrent stroke showed a shift of the disability burden following a recurrent ischemic stroke in favor of ticagrelor (odds ratio, 0.77; 95% CI, 0.65-0.91; P = .002). Factors associated with disability were baseline National Institutes of Health Stroke Scale score 4 to 5, ipsilateral stenosis of at least 30%, Asian race/ethnicity, older age, and higher systolic blood pressure, while treatment with ticagrelor was associated with less disability.Conclusions and Relevance: In patients with TIA and minor ischemic stroke, ticagrelor added to aspirin was superior to aspirin alone in preventing disabling stroke or death at 30 days and reduced the total burden of disability owing to ischemic stroke recurrence.Trial Registration: ClinicalTrials.gov Identifier: NCT03354429.
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| 5. |
- Amarenco, Pierre, et al.
(författare)
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Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin
- 2020
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 51:12, s. 3504-3513
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose:Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events.Methods:In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–30) or placebo added to aspirin (300–325 mg on day 1 followed by 75–100 mg daily for days 2–30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days.Results:Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56–0.96], P=0.023) resulting in a number needed to treat of 34 (95% CI, 19–171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74–1.08]; P=0.23, Pinteraction=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (P=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04–16.9], P=0.001).Conclusions:In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19–171).
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| 6. |
- Andell, Pontus, et al.
(författare)
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Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and Chronic Obstructive Pulmonary Disease : An Analysis From the Platelet Inhibition and Patient Outcomes (PLATO) Trial
- 2015
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Ingår i: Journal of the American Heart Association. - 2047-9980 .- 2047-9980. ; 4:10
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Tidskriftsartikel (refereegranskat)abstract
- Background-Patients with chronic obstructive pulmonary disease (COPD) experiencing acute coronary syndromes (ACS) are at high risk for clinical events. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor versus clopidogrel reduced the primary endpoint of death from vascular causes, myocardial infarction, or stroke after ACS, but increased the incidence of dyspnea, which may lead clinicians to withhold ticagrelor from COPD patients. Methods and Results-In 18 624 patients with ACS randomized to treatment with ticagrelor or clopidogrel, history of COPD was recorded in 1085 (5.8%). At 1 year, the primary endpoint occurred in 17.7% of patients with COPD versus 10.4% in those without COPD (P<0.001). The 1-year event rate for the primary endpoint in COPD patients treated with ticagrelor versus clopidogrel was 14.8% versus 20.6% (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.54 to 0.97), for death from any cause 8.4% versus 12.4% (HR=0.70; 95% CI: 0.47 to 1.04), and for PLATO-defined major bleeding rates at 1 year 14.6% versus 16.6% (HR=0.85; 95% CI: 0.61 to 1.17). Dyspnea occurred more frequently with ticagrelor (26.1% vs. 16.3%; HR=1.71; 95% CI: 1.28 to 2.30). There was no differential increase in the relative risk of dyspnea compared to non-COPD patients (HR=1.85). No COPD status-by-treatment interactions were found, showing consistency with the main trial results. Conclusions-In this post-hoc analysis, COPD patients experienced high rates of ischemic events. Ticagrelor versus clopidogrel reduced and substantially decreased the absolute risk of ischemic events (5.8%) in COPD patients, without increasing overall major bleeding events. The benefit-risk profile supports the use of ticagrelor in patients with ACS and concomitant COPD.
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| 7. |
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| 8. |
- Bellavia, Andrea, et al.
(författare)
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Time-based measures of treatment effect : reassessment of ticagrelor and clopidogrel from the PLATO trial
- 2017
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Ingår i: Open heart. - : BMJ. - 2053-3624. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Treatment effects to binary endpoints using time-to-event data in randomised controlled trials are typically summarised by reporting HRs derived with Cox proportional hazard models. Alternative and complementary methods include summarising the between-treatment differences on the metric time scale, quantifying the effect as delay of the event (DoE). The aim of this study was to reassess data from the PLATO study expressing the effects as the time by which the main outcomes are delayed or hastened due to treatment.METHODS: PLATO was a randomised controlled double-blind multicentre study (n=18,624), conducted between 2006 and 2008, which demonstrated superiority of the antiplatelet treatment ticagrelor over clopidogrel in reducing risk of several cardiovascular events. In the present study, four of the main PLATO outcomes were reassessed by calculating the time by which an event may be delayed due to the treatment.RESULTS: The effects of ticagrelor, as compared with clopidogrel, consisted of a substantial delay of the evaluated outcomes, ranging from 83 to 98 days over 400-day follow-up. The Delay of Events Curves showed that the effects progressively increased over time, and the significant findings were concordant with those presented in the original PLATO study.CONCLUSIONS: This study confirmed evidence of a beneficial effect of ticagrelor over clopidogrel, and provided the magnitude of such effects in terms of delayed event time. Investigating time-to-event data with a percentile approach allows presenting treatment effects from randomised controlled studies as absolute measures of the time by which an event may be delayed due to the treatment.TRIAL REGISTRATION NUMBER: PLATO (www.clinicaltrials.gov; NCT00391872); Results.
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| 9. |
- Bhatt, Deepak L., et al.
(författare)
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Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study
- 2019
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Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 42:5, s. 498-505
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Tidskriftsartikel (refereegranskat)abstract
- In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients >= 50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of >= 50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.
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| 10. |
- Bhatt, Deepak L., et al.
(författare)
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Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial
- 2019
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 394:10204, s. 1169-1180
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Tidskriftsartikel (refereegranskat)abstract
- Background Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor.Methods The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria:a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population).Findings Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3.3 years (IQR 2.8-3.8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7.3%] of 5558 vs 480 [8.6%] of 5596; HR 0.85 [95% CI 0.74-0.97], p=0.013). The same effect was not observed in patients without PCI (p=0.76, p(interaction)=0.16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3.1%] with ticagrelor vs 183 (3.3%) with placebo; HR 0.96 [95% CI 0.78-1.18], p=0.68), as well as all-cause death (282 [5.1%] vs 323 [5.8%]; 0.88 [0.75-1.03], p=0.11). TIMI major bleeding occurred in 111 (2.0%) of 5536 patients receiving ticagrelor and 62 (1.1%) of 5564 patients receiving placebo (HR 2.03 [95% CI 1.48-2.76], p<0.0001), and fatal bleeding in 6 (0.1%) of 5536 patients with ticagrelor and 6 (0.1%) of 5564 with placebo (1.13 [0.36-3.50], p=0.83). Intracranial haemorrhage occurred in 33 (0.6%) and 31 (0.6%) patients (1.21 [0.74-1.97], p=0.45). Ticagrelor improved net clinical benefit:519/5558 (9.3%) versus 617/5596 (11.0%), HR=0.85, 95% CI 0.75-0.95, p=0.005, in contrast to patients without PCI where it did not, p(interaction)=0.012. Benefit was present irrespective of time from most recent PCI.Interpretation In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk.
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