15 research outputs found
Influence of intenesive coronary care acoustics on the quality of care and phyiological state of patients
No full textThe Glycoprotein IIb/IIIa Platelet Receptor Blocker Tirofiban, but Not Heparin, Counteracts Platelet Aggregation in Unstable Angina Pectorisfn1fn1This study was supported by the Swedish Heart and Lung Foundation and the Foundations of the Karolinska Institute, Stockholm, Sweden.
No full textInfluence of intensive coronary care acoustics on the quality of care and physiological state of patients
No full textThe Na+/H+exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction11This manuscript is dedicated to the memory of Karl-Ludwig Neuhaus (1944–2000). Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial
No full textAbstractOBJECTIVESWe conducted an international, prospective, randomized, double-blind, placebo-controlled phase 2 trial in patients undergoing thrombolytic therapy or primary angioplasty for acute ST-elevation myocardial infarction (MI) to investigate the effect of eniporide on infarct size and clinical outcome.BACKGROUNDExperimental studies suggest that the activity of the Na+/H+exchange (NHE) plays an important role in the unfavorable sequels of myocardial ischemia and reperfusion. Eniporide specifically inhibits the NHE-1 isoform and has been shown to limit infarct size in experimental models.METHODSThe primary efficacy end point was the infarct size measured by the cumulative release of alpha-hydroxybutyrate dehydrogenase (alpha-HDBH) (area under the curve [AUC] 0 to 72 h). In stage 1, 50, 100, 150 or 200 mg eniporide given as a 10-min infusion before start of reperfusion therapy were compared with placebo in 430 patients, and in stage 2, 100 and 150 mg eniporide were compared with placebo in 959 patients.RESULTSIn stage 1, the administration of 100 mg and 150 mg eniporide resulted in smaller infarct sizes (mean alpha-HBDH AUC in U/ml × h, placebo: 44.2, 100 mg eniporide: 40.2, 150 mg eniporide: 33.9), especially in the angioplasty group. In contrast, in stage 2 there was no difference in the enzymatic infarct size between the three groups (placebo: 41.2, 100 mg eniporide: 43.0, 150 mg eniporide: 41.5). Overall there was no effect of eniporide on clinical outcome (death, cardiogenic shock, heart failure, life-threatening arrhythmias). However, there was a significant reduction of the incidence of heart failure in patients reperfused late (>4 h).CONCLUSIONSIn this large study administration of the NHE-1 inhibitor eniporide, before reperfusion therapy in patients with acute ST elevation MI, did not limit infarct size or improve clinical outcome
Studies on platelet function and microvesicles in acute coronary syndrome
No full textINTRODUCTION: The cornerstone of treatment of acute coronary syndrome (ACS) is percutaneous coronary intervention (PCI) and dual antiplatelet therapy (DAT) with aspirin and the ADP-receptor inhibitor clopidogrel. However, some ACS patients will suffer from recurrent cardiovascular events, and it has been shown that this may partly be due to an insufficient antiplatelet response to DAT. In this thesis, we investigated platelet function in ACS. The overarching aim was to further investigate clopidogrel non-responsiveness with established and new methods to assess platelet function.METHODS AND RESULTS: In study I, we investigated if arterial and venous sampling give comparable results with respect to detection of poor antiplatelet responsiveness to clopidogrel and aspirin with the established method multiple electrode whole blood impedance aggregometry (MEA). Twenty-eight patients with coronary artery disease were investigated in connection to PCI. Identical number of patients with poor responsiveness to clopidogrel (7/28; i.e. 25 %) and aspirin (3/28; i.e. 11 %) were detected in arterial and venous blood samples with MEA. Thus, arterial and venous sampling can be used interchangeably in the detection of poor responsiveness to clopidogrel and aspirin when MEA is used to study platelet function. In study II, we investigated ADP-induced platelet aggregation by MEA in 183 patients with ACS on DAT at discharge (3–5 days after admission). We also measured circulating microvesicles (MVs) and platelet derived MV (PMVs) in 154 of the ACS patients. Of note, MVs are small membrane buds released from various cells in response to activation or apoptosis. We found that around 20 % (36/183) of ACS patients were nonresponders (“high on-treatment platelet reactivity”; HPR) to clopidogrel. Flow cytometry measurements showed that circulating PMV levels were significantly higher in HPR compared to those with “sufficient” clopidogrel responsiveness (“normal on-treatment platelet reactivity”; NPR). Furthermore, in patients with strong inhibition to clopidogrel (low on-treatment platelet reactivity; LPR) PMV levels were significantly lower than in NPR patients. Thus, levels of circulating PMVs reflect platelet responsiveness to clopidogrel. Study III was performed to elucidate if MVs from ACS patients on DAT influence platelet aggregation. Thus, we added MVs from samples of patients with ACS with HPR and from patients with Non-HPR (i.e, LPR or NPR) to clopidogrel, to platelet rich plasma obtained from healthy volunteers. Results showed that MVs from HPR patients significantly enhanced spontaneous platelet aggregation as compared to MVs from patients with Non-HPR. In addition, we could also show that MVs from ACS patients with diabetes and DAT, enhanced platelet aggregation compared to MVs from ACS patients on DAT without diabetes. MVs have the potential to enhance platelet aggregation, supporting the idea that MVs may not only be “markers” but also “makers” of physiological or pathophysiological processes. In study IV, we investigated if circulating MVs expose a molecule of the humoral immune system pentraxin-3 (PTX3). Thus, we measured the presence of PTX3+--MVs in plasma in patients with acute myocardial infarction (AMI). We found that PTX3+--MVs were elevated at admittance in patients with acute ST-elevation myocardial infarction (STEMI; n=23) and that levels decreased after PCI. Further, the circulating PTX3+--MVs levels were even lower in AMI patients at discharge (3–5 days after admission; n=153), but not as low as in healthy subjects (n=15). Thus, PTX3 is exposed on circulating MVs in the acute setting of AMI, and the levels fall significantly over the days after the acute event. The PTX3+--MVs should be further phenotyped with our flow cytometry method to elucidate the origin of PTX3 and its possible role in acute coronary artery disease.CONCLUSION: Clopidogrel non-responsiveness is present in every fourth to every fifth ACS patient on clopidogrel. This can be detected either in arterial or venous samples by MEA. The number of circulating MVs reflect platelet responsiveness to clopidogrel, and circulating MVs in ACS patients have the capacity to enhance platelet aggregation, indicating a possible functional role of circulating MVs in the setting of ACS. In acute AMI, MVs exposing PTX3 circulate in an elevated concentration. The role of these PTX3+--MVs deserves to be further investigated.List of scientific papersI. Sam Kafian, Fariborz Mobarrez, Majid Kalani, Håkan Wallén & Bassem A. Samad. Comparison of venous and arterial blood sampling for the assessment of platelet aggregation with whole blood impedance aggregometry. Scand J Clin Lab Invest. 2011;71(8):637–40. https://doi.org/10.3109/00365513.2011.604731 II. Sam Kafian, Fariborz Mobarrez, Håkan Wallén & Bassem Samad. Association between platelet reactivity and circulating platelet-derived microvesicles in patients with acute coronary syndrome. Platelets. 2015;26(5):467–73. https://doi.org/10.3109/09537104.2014.940304 III. Sam Kafian, Håkan Wallén, Bassem A. Samad, Fariborz Mobarrez. Microvesicles from patients with acute coronary syndrome enhance platelet aggregation. [Manuscript]IV. Sam Kafian, Håkan Wallén, Gundars Rasmanis, Charlotte Thålin, Bassem A. Samad, Fariborz Mobarrez. Exposure of pentraxin-3 on microvesicles in patients with acute myocardial infarction. [Manuscript]</p
Safety of the PCSK9 inhibitor alirocumab: insights from 47 296 patient-years of observation /
No full textThe ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years
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Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment.
No full textIn observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor.In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data.Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02-1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment-baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03-1.12; P = 0.0002) for incident type 2 diabetes.In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined
Lipoprotein(a) and benefit of PCSK9 inhibition in patients with nominally controlled LDL cholesterol
No full textBACKGROUND Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains >= 70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.OBJECTIVES In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.METHODS ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was = 70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL).RESULTS In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (P-interaction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or <= 13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with P-interaction = 0.43.CONCLUSIONS In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402) (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.Cardiolog
Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab.
No full textApolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain.The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACE; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACE were assessed in adjusted Cox proportional hazards and propensity score-matched models.Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, ≥90 mg/dL, respectively; Ptrend<0.0001) and after adjustment for low-density lipoprotein cholesterol (Ptrend=0.035). Higher baseline apoB stratum was associated with greater relative (Ptrend<0.0001) and absolute reduction in MACE with alirocumab versus placebo. In the alirocumab group, the incidence of MACE after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata ≥50, >35-<50, and ≤35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACE after adjustment for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol but not vice versa.In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACE increased across baseline apoB strata. Alirocumab reduced MACE across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACE, even after accounting for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of apoB levels as low as ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome.URL: https://www.gov; Unique identifier: NCT01663402
Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment
No full textOBJECTIVE: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODS: In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTS: Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02-1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment-baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03-1.12; P = 0.0002) for incident type 2 diabetes. CONCLUSIONS: In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined
