| 1. |
- Alfredsson, Joakim
(författare)
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Management and Outcome in Non ST-Elevation Acute Coronary Syndromes : Similarities and Differences Between Women and Men
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Non ST-elevation Acute Coronary Syndromes are the most frequent manifestations of acute ischemic heart disease. Gender differences in treatment intensity, including differences in level of care, have been reported. Also differences in benefit from certain treatments, especially invasive treatment, have been discussed. Finally, difference in outcome between men and women, have been proposed. Results have been inconsistent, partly depending on if and how adjustment for differences in background characteristics has been made. The aims of the studies in this thesis were to assess differences between the genders in baseline characteristics, level of care, medical treatment and non-invasive and invasive cardiac procedures. The aims were also to determine gender differences in short and long-term mortality, including impact of level of care, and to determine differences between the genders in benefit from an invasive strategy, with special reference to benefit in women.Method: We used prospectively collected data from the RIKS-HIA registry in two studies (Paper I and IV). In one study we merged data from patients admitted to general wards in the south-east region of Sweden (The AKUT registry), with data from patients admitted to CCU´s (RIKS-HIA) at participating hospitals during the same time (Paper II). We also randomly assigned women to a routine invasive or a selective invasive treatment strategy, and performed a meta-analysis, to determine gender differences in benefit from a routine invasive strategy (Paper III).Results: Women were older than men and more likely to have a history of diabetes and hypertension, while men were more likely to have a history of myocardial infarction and revascularisation. Women were also more likely to have normal coronary arteries on the angiogram. After adjustment for baseline differences there were only minor, and directionally inconsistent, differences between women and men in pharmacological treatment. Men were more often referred for coronary angiography, even after adjustment. While CABG-rate was lower in women, after adjustment PCI-rate was similar or even higher compared to men. After adjustment for differences in age, longterm outcome was better in women. In our small but randomised trial there was no benefit from a routine invasive strategy in women. A meta-analysis indicated interaction between gender and treatment strategy, with lack of benefit in women, in contrast to in men. However, our large observational study indicated no gender difference with an invasive strategy. Moreover, benefit was similar in women and men with invasive treatment.Conclusion: There are substantial differences between women and men in baseline characteristics that affect management and outcome more than gender per se. After adjustment women have better long-term outcome than men. There appear to be a difference in benefit from a routine invasive strategy between the genders, with less benefit in women, but in routine clinical management there was no difference between women and men managed with an invasive strategy.
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| 2. |
- Arinell, Karin, 1982-
(författare)
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Immobilization as a risk factor for arterial and venous thrombosis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: Immobilization and a sedentary lifestyle are correlated with an elevated risk of both arterial and venous thrombosis. The goal of this research was to investigate whether markers associated with cardiovascular disease risk are altered during long term immobilization in a human model and in the brown bear, which survives annual cycles of long-term immobilization.Methods: In study populations assigned to 20-60 days of strict head-down-tilt bed rest 24h a day, we analysed blood levels of the emerging cardiovascular disease marker cystatin C, soluble markers of in vivo platelet activation P-selectin and PDGF-BB, and platelet aggregation. Blood samples were taken from free-ranging brown bears in summer and again during hibernation for analysis of lipid profile and platelet aggregation. Histological examination was performed on the left anterior descending coronary artery and aortic arches of bears harvested during the hunting season.Results: During prolonged bed rest in humans, levels of cystatin C and platelet aggregation remained unchanged, but we observed a significant decrease in platelet activation markers. Brown bear plasma lipids were elevated during hibernation compared with the active state and cholesterol levels were generally considerably higher than normal human values. The arterial specimens showed no signs of atherosclerosis. Platelet aggregation was halved during hibernation compared to the active state.Conclusions: Long-term immobilization has effects on several cardiovascular risk factors in both humans and bears. Increased knowledge and understanding of the protective mechanisms that allows the brown bear to survive repeated periods of immobilization could contribute to new strategies for prevention and treatment of cardiovascular disease in humans.
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| 3. |
- Graipe, Anna, 1973-
(författare)
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Bleeding complications after acute coronary syndrome with special reference to intracranial hemorrhage
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Bleeding complications following acute coronary syndrome (ACS) have attracted considerable attention in recent years. The gradual implementation of new evidence-based treatments in patients with ACS, with a focus on anti-ischemic therapy, has reduced the risk of ischemic events (new myocardial infarction or ischemic stroke) but at the expense of increased bleeding risk. Bleeding is associated with both increased morbidity and mortality and, with major bleeding, the risk of death is comparable to that seen in myocardial infarction. Avoidance of bleeding is one possible way to further improve post-ACS outcomes. During the 1990s reperfusion approaches shifted from thrombolysis, with its increased risk of bleeding and intracranial hemorrhage (ICH), to percutaneous coronary intervention (PCI), with an expected lower risk. Treatment recommendations are derived from randomized controlled trials in which high-risk patients are excluded, and observational studies are needed to assess outcomes. Antithrombotic treatment is associated with increased risk of serious bleeding and even more so with the new potent P2Y12 inhibitors. However, their association with ICH is not well studied, and knowledge is limited regarding temporal trends in ICH after ACS. Furthermore, few studies have long-term follow-up for serious bleedings and associated risk factors.Aims: The aims of this thesis were to assess the incidence, temporal trends and factors associated with ICH after acute myocardial infarction (AMI); investigate the impact on ICH risk of changing the treatment regimen from clopidogrel to ticagrelor; estimate the risk of serious bleeding (bleeding requiring hospitalization) after ACS and characterize the type of bleeding; identify factors associated with increased bleeding risk; and assess if serious bleeding is associated with increased mortality. Method: In studies I–III, patients with AMI were identified using the Register of Information and Knowledge About Swedish Heart Intensive Care Admission (RIKS-HIA), and the data were combined with information from the Swedish National Patient Register, 1998–2013 to identify ICH. In study II, we included a matched reference group from Statistics Sweden. Study IV included all patients who were identified with an ACS during the inclusion period of the Nurse-Based Age-Independent Intervention to Limit Evolution of Disease After Acute Coronary Syndrome risk factor trial (2010–2014), and patients were followed until December 2017. Serious bleedings were identified in the local diagnosis registry, and scrutinizing of the medical records validated all diagnoses. Baseline characteristics in all studies were evaluated using the student t-test, Mann–Whitney U test, or the chi-square test as appropriate. In studies I and II, the observational time was divided into periods and in study I the chi-square test for trend was used to evaluate the trend over time. Temporal trends in study II were assessed by Kaplan–Meier analysis and evaluated using log-rank test. To reduce selection bias related to the choice of antiplatelet treatment in study III, the date of the first prescription of ticagrelor was identified in the RIKS-HIA registry and used as a cutoff point, and the study period was divided into two periods of similar length to create two cohorts. The risk in the first with respect to the second cohort was assessed by Kaplan–Meier analysis, and cohorts were compared with the log-rank test. Kaplan–Meier analysis was also used in study IV to assess serious bleeds. Predictors were assessed by Cox regression analyses. Results: The 30-day risk of hemorrhagic stroke decreased from 0.2% in 1998 to 0.1% in 2008. The decrease can be explained by the shift in reperfusion method from thrombolysis to PCI in patients with a ST-elevation myocardial infarction. Age, hypertension and previous hemorrhagic stroke were associated with increased risk. The cumulative incidence of ICH within one year of AMI was 0.35%, which did not change during the 13-year follow-up (1998–2010) despite a considerable increase in the use of dual antiplatelet therapy. The incidence of ICH in the AMI cohort was twice that of a matched reference group. Age, decreased kidney function and previous ischemic and hemorrhagic stroke were associated with increased ICH risk. None of the medications included in the analysis were associated with a significant change in ICH risk. For antiplatelets, ticagrelor is a more potent P2Y12 inhibitor compared to clopidogrel and has previously been associated with increased bleeding risk; however, in this work ticagrelor was not associated with increased risk of ICH compared to clopidogrel. In study IV, during a median follow-up of 4.6 years, 8.6% of patients had a serious bleed after their ACS. This rate was 13.4% in patients aged ≥75 years. The most common location was gastrointestinal, followed by ICH. Risk factors associated with serious bleeding were age ≥75 years, hypertension, and previous heart failure. Bleeding per se was not associated with increased mortality.Conclusion: The shift in reperfusion method from thrombolysis to PCI likely explained the decrease in ICH in the acute phase after an AMI. The incidence of ICH post-discharge was stable over the study period despite increased use of antithrombotic therapy, and the use of more potent P2Y12 inhibitor did not increase the ICH risk. Serious bleeding was relatively frequent in the long term after ACS, and bleeding recurrence was common. Important risk factors for bleeding were age, hypertension, previous ischemic or hemorrhagic stroke, decreased renal function and previous heart failure. Individualized assessment of risk factors and comorbidity and individualized intensity and duration of antithrombotic treatment may further improve outcome in ACS patients. Continuous re-evaluation of bleeding risk is needed.
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| 4. |
- Holm, Anna, 1973-
(författare)
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Acute coronary syndrome : bleeding, platelets and gender
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUNDBleeding complications increase mortality in patients with acute coronary syndrome (ACS). Potential gender difference in bleeding regarding prevalence, location, severity and prognostic impact is still controversial and not well investigated. In regard to this aspect the relevance of triple antithrombotic therapy (TAT) is questioned. There is an ongoing debate on the clinical implications of TAT and furthermore assumed that bleeding complications, except impact on outcome, also are associated with great influence on health economy.The main focus of this thesis was to further investigate the incidence and impact of bleeding complications in patients treated for ACS, with special reference to gender disparities, TAT and health economics. The thesis will highlight the importance of improved bleeding prevention strategies for both men and women.METHODPaper I, II and IIIObservational studies from the SWEDEHEART register.In paper I we investigated patients hospitalised with myocardial infarction (MI) during 2006–2008. Outcomes were in-hospital bleedings, in-hospital mortality and one-year mortality in hospital survivors.In paper II, all patients with MI, in the County of Östergötland, Sweden during 2010 were included and followed for one year. The patients' medical records were evaluated, in relation to short and long-term bleeding complications, bleeding location, withdrawal of platelet inhibiting drugs and nonfatal MI and death.Paper III included all patients discharged with (TAT) in the County of Östergötland 2009-2015. Information about bleeds and ischemic complications during one-year follow-up were retrieved from the medical records. Estimation of the health care costs associated with bleeding episodes were added to the evaluation.Paper IVPatients with MI, scheduled for coronary angiography were recruited. All patients received clopidogrel and aspirin. A subgroup of patients received GP IIb/IIIa-inhibitor. Outcomes were platelet aggregation assessed at several time points, using a Multiplate impedance aggregometer, measurement of P-selectin in plasma, evaluation of high residual platelet reactivity (HRPR) and low residual platelet reactivity (LRPR) respectively and incidence of bleeding complications. A comparison between women and men was performed.RESULTSPaper IA total number of 50.399 patients were included, 36.6% women. In-hospital bleedings were more common in women (1.9% vs. 3.1%, p<0.001) even after multivariable adjustment (OR 1.17, 95%, CI 1.01–1.37). The increased risk for women was found in STEMI (OR 1.46, 95% CI 1.10–1.94) and in those who underwent PCI (OR 1.80, 95% CI 1.45–2.24).In contrast the risk was lower in medically treated women (OR 0.79, 95% CI 0.62–1.00). After adjustment, in-hospital bleeding was associated with higher risk of oneyear mortality in men (OR 1.35, 95% CI 1.04–1.74), whereas this was not the case in women (OR 0.97, 95% CI 0.72–1.31).Paper IIIn total 850 consecutive patients were included. The total incidence of bleeding events was 24.4% (81 women and 126 men, p=ns). The incidence of all in hospital bleeding events was 13.2%, with no gender difference. Women had significantly more minor nonsurgery related bleeding events than men (5% vs 2.2%, p=0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p=0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p=0.03). Women also had more access site bleeding complications (4% vs 1.7%, p=0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p≤0.001). Increased mortality was found only in men with non-surgery related bleeding events (p=0.008).Paper IIIAmong 272 identified patients, 156 bleeds occurred post-discharge, of which 28.8% were of gastrointestinal origin. In total 54.4% had at least one bleed during or after the index event and 40.1% bled post-discharge of whom 28.7% experienced a TIMI major or minor bleeding. Women discontinued TAT prematurely more often than men (52.9 vs 36.1%, p=0.01) and bled more (48.6 vs. 37.1%, p=0.09). One-year mean health care costs were EUR 575 and EUR 5787 in non-bleeding and bleeding patients, respectively.Paper IVWe recruited 125 patients (37 women and 88 men). We observed significantly more inhospital bleeding events in women as compared to men (18.9% vs 6.8%, p=0.04). There were no differences in platelet aggregation using three different agonists, reflecting treatment of GPIIb/IIIa inhibitors, clopidogrel and aspirin, at four different time-points nor were there any differences in p-selectin in plasma 3 days after admission.CONCLUSIONThere is a remarkably high bleeding incidence among patients treated with DAPT and even more so if treated with TAT. Female gender is an independent risk factor of inhospital bleeding after myocardial infarction, this higher bleeding risk in women appears to be restricted to invasively treated patients and STEMI patients. Even if women had higher short- and long-term mortality, there was no difference between the genders among those who bled. After multivariable adjustment the prognostic impact of bleeding complications was higher in menWomen seem to experience more minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome.In contrast men with non-surgery related bleeding complications had higher mortality. There is a lack of differences between the genders concerning platelet aggregation. Our results do not support gender disparities in platelet reactivity and excess dosing as a major explanation for increased bleeding risk in women. Improved bleeding prevention strategies are warranted for both men and women.
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| 5. |
- Olsson, Anki
(författare)
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Hemostatic function and inflammatory activation after weaning from cardio pulmonary bypass
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiopulmonary bypass (CPB) contributes to perioperative platelet dysfunction, increased fibrinolysis and impaired coagulation, which can have an impact on postoperative bleeding. During CPB the blood is exposed to foreign surfaces leading to activation of the coagulation system and a systemic inflammatory response with complement and leukocyte activation. Anticoagulation with heparin is used to prevent immediate blood clotting within the circuit. The heparin effect is reversed with protamine sulfate after weaning from CPB. Protamine has been suggested to impair platelet function in high doses although the mechanism is incompletely understood. Platelet dysfunction can promote bleeding which can necessitate transfusion and sometimes surgical re-exploration.After weaning from CPB the residual blood in the heart lung machine is usually retransfused to the patient in order to reduce the need for blood transfusion. The most common technique to transfuse residual blood is to collect the blood from the CPB circuit in an infusion bag (IB). An alternative way to re-transfuse the residual blood is by chasing it through the heart lung machine with Ringers solution, the Ringer chase technique (RC).The aim of this thesis was to examine a possible inhibitory effect of protamine on platelet aggregation. A second aim was to evaluate different techniques for retransfusion after weaning from CPB.Study I and II in this thesis are focused on the protamine effect on platelet aggregation and study III and IV on the quality of the blood in relation to the two different retransfusion techniques.In Study I we found that platelet aggregation evaluated by impedance aggregometry was reduced by approximately 50% after in vivo protamine administration. Protamine added in vitro also reduced platelet aggregation, by itself or in combination with heparin. Study II showed that protamine induces a marked but transient decrease in platelet aggregation already at a protamine-heparin ratio of 0.7:1, which also was sufficient to reverse the heparin anticoagulation as measured by activated clotting time (ACT). No further decrease was observed when additional protamine was given within three minutes. Platelet aggregation had begun to recover 20 minutes after protamine administration.In study III and IV we evaluated possible differences in quality of the retransfused residual blood from the heart-lung machine depending on if it is returned to the patient by the RC-technique or by an IB. Study III focused on biochemical markers of hemostasis, coagulation and fibrinolysis. Study IV concerns biochemical markers of inflammatory activity characterizing the inflammatory response during cardiac surgery with CPB including heparin binding protein (HBP) a new marker of neutrophil activation. CPB is associated with a marked systemic inflammatory response and levels of HBP indicates a pronounced neutrophil activation as part of a systemic inflammatory process. HBP levels during CPB was much higher than previously found during severe inflammatory conditions. We also concluded that the handling of the blood after weaning from CPB reduces platelet function, activates coagulation and fibrinolysis, increases hemolysis and the inflammatory response. Retransfusion of pump blood with the RC-technique was associated with better preserved platelet function, less hemolysis, less signs of activation of coagulation and fibrinolysis and less pronounced inflammatory activity than the commonly used IB technique. In the event of cell salvage technique not being feasible, we suggest that the RC technique is preferable to the IB technique but acknowledge that the clinical importance of this finding in terms of outcomes warrants further investigation
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| 6. |
- Sandstedt, Mårten, 1972-
(författare)
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Computed Tomography of the Coronary Arteries : Developmental and Prognostic Investigations
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Computed tomography (CT) is an increasingly used modality for investigations of patients with suspected coronary artery disease (CAD). Technical advances could improve diagnostic accuracy and lead to clinical workflow improvements. Also, more prognostic information can optimize clinical follow-up strategies and treatments.The general aim of this thesis was to explore the use of CT for CAD investigations. Three studies aimed to examine new technologies, including the evaluation of an on-site, computed tomography-based fractional flow reserve (CT-FFR) software (study I), the evaluation of an AI-based, calcium scoring computed tomography (CSCT) software (study III), and the evaluation of an photon-counting detector (PCD)-CT (study IV). One study aimed to evaluate the long-term prognostic value of coronary computed tomography angiography (CCTA) in symptomatic patients with no history of CAD (study II).The software evaluation studies (study I and III) and the prognostic study (study II) utilized CT data from clinical patients, while the PCD-CT evaluation study (study IV) used CT data from cadaveric specimens. The performances of both software programs were compared with standard references, being represented by fractional flow reserve (FFR) measurements (study I), and coronary artery calcification (CAC) scores from a semi-automatic software (study III), respectively. The PCD-CT performance on CAC quantification was compared with corresponding results from an energy integrating detector (EID)-CT, using micro-CT as the standard reference (study IV). The prognostic study merged registries to identify major adverse cardiac events (MACE), having a follow-up time of up to 7.5 years (study II).The CT-FFR and CSCT software correlation and agreement to corresponding standard references were good and excellent, respectively. Also, both software programs had time-saving potential (study I and III). The CAC quantification was more accurate using PCD-CT than EID-CT (study IV). The prognosis was excellent in patients with normal coronary arteries, and progressively impaired in non-obstructive and obstructive CAD (study II).The results in this thesis convey developmental, technical CT technology advances for CAD investigations. In addition, prognostic follow-up data is communicated. The results may benefit patients by an increased accuracy in the CT evaluation of CAD and can contribute to improve clinical follow-up strategies. Furthermore, the results suggest possibilities to improve the workflow in clinical radiology, which potentially could impact health care costs.
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| 7. |
- Sederholm Lawesson, Sofia
(författare)
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Management and Outcome in ST-Elevation Myocardial Infarction from a Gender Perspective
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to evaluate baseline characteristics, management and outcome in real life ST-elevation myocardial infarction [STEMI] cohorts from a gender perspective. We aimed to evaluate the total STEMI population as well as certain subgroups, such as the youngest. Moreover we aimed to analyse gender differences in renal function, and the prognostic impact of reduced renal function in men and women with STEMI.In Paper I all STEMI patients registered in RIKS-HIA between 1st Jan 1995 and 31st Dec 2006 were included, in total 54 146 patients, 35% women. Women were 7 years older than men, with 30 min longer median symptomto-door time. They had higher prevalence of co-morbidities such as diabetes, hypertension and heart failure whereas men were more often smokers, had a previous myocardial infarction [MI] or were previously revascularised. During hospital care, fewer women than men, 63% vs. 72%, p<0.001, received acute reperfusion therapy, odds ratio [OR] 0.83 (95% confidence interval [CI] 0.79 – 0.88) after multivariable adjustment. Inhospital mortality was 13% vs. 7%, women vs. men, p<0.001. After multivariable adjustments women had 22% higher risk of in-hospital death, OR 1.22 (95% CI 1.11 – 1.33). Adding reperfusion therapy to the adjustment model did not change the odds of death, OR 1.21 (1.11 – 1.32). Stratifying the cohort into four age-groups revealed increased mortality with increasing age as well as higher mortality in women than in men in all groups. The multivariable adjusted risk in women relative to men was highest amongst the youngest, OR 1.45 (95% CI 0.98 – 2.14). The long term prognosis was assessed in women vs. men with Cox proportional regression analyses, follow-up time 1 to 13 years. Women had 8% lower risk of long term mortality after multivariable adjustments, and after age-stratifying, women had better long term survival in all age-groups, except the youngest.Previous studies based on mixed MI cohorts had found a gender-age interaction with higher risk of death women relative to men in the youngest group. In Paper II we included all STEMI patients <46 years old registered in RIKS-HIA between 1st Jan 1995 and 31st Dec 2006, 1748 men and 384 women. Cardiovascular risk factors were common, and women had more often clustering of risk factors compared to men. The most prevalent risk factor was smoking, 64% of the women compared to 58% of the men were current smokers. There was no gender difference in delay times or in rate of reperfusion. Almost 60% of both women and men underwent coronary angiography within one week. There was no gender difference in prevalence of non-obstructive disease, (p=0.64), but men had had multi-vessel/left main disease much more often than women (33.6% vs. 19.2%; p<0.001). In-hospital mortality was low, 3% in women vs. 1% in men, crude OR women vs. men 2.83 (95% CI 1.32 – 6.03). Female gender appeared as an independent predictor in the multivariable model of in-hospital mortality, OR 2.85 (95% CI 1.31– 6.19). When the cohort was followed up to 10 years (mean 5.4 years) the risk of mortality was not higher in women (hazard ratio [HR] 0.93, 95% CI 0.60 – 1.45; p=0.75), and men had significantly higher risk of a second new MI during the following 10 years, HR 1.82 (95% CI 1.25 – 2.65; p=0.002).In the beginning of the 21st century there was a shift in reperfusion strategy with a decline in use of fibrinolytic therapy and an increase in use of primary PCI. We hypothesised that the gender differences noticed during the fibrinolytic era with lower chance of receiving reperfusion therapy and higher risk of early mortality in women, would have diminished during the new primary PCI era, as this is a better reperfusion strategy, especially for women. In Paper III we included STEMI patients from two time periods with different dominating reperfusion strategies in order to compare management and outcome between genders in both periods. Patients in the early period (n=15 697, 35% women) were registered in RIKS-HIA between 1st Jan 1998 and 31st Dec 2000 and those in the late period (n=14 380, 35% women) between 1st Jan 2004 and 31st Dec 2006. Among patients treated with reperfusion therapy 9% in the early compared to 68% in the late period were treated with primary PCI. The use of reperfusion therapy increased between the two periods, in men from 70.9% to 75.3%, in women from 63.1% to 63.6%. After multivariable adjustment, women were 14% and 20% less likely than men to receive reperfusion therapy, early and late periods, respectively. Heart failure, cardiogenic chock and major bleedings were more common in women compared to men. Evidence-based secondary preventive therapies were prescribed more often in the late compared to the early period in both genders, but more seldom to women in both periods. After multivariable adjustments women still had less chance of receiving ACE-inhibitors/ARBs but higher chance of receiving statins in the early period. In the late period women had 14 – 25% less chance of receiving any of the evidence-based secondary preventive therapies.In Paper IV all consecutive patients who fulfilled the criteria for ST-elevation or bundle branch block on admission ECG and who were planned to undergo immediate coronary angiography with the intention to perform primary PCI at the Department of Cardiology in Linköping were included, 98 women and 176 men. Estimated glomerular filtration rate [eGFR] according to Modification of Diet in Renal Disease study [MDRD] was calculated for all patients and they were staged into CKD stages 1-5. Estimated GFR was lower in women than in men, mean eGFR 54 vs. 68 mL/min/1.73m2, p<0.001. Ten men but no woman were classified belonging to the best CKD stage 1(eGFR >90 mL/min/1.73m2). In total 67% of women compared to 27% of men were classified as having renal insufficiency [RI] (eGFR <60 mL/min/1.73m2) and female sex was a strong independent factor associated with RI, OR 5.06 (95% CI 2.66 – 9.59). Reduced eGFR per 10 mL/min decline was independently associated to higher risk of death and MACE (death, new MI or stroke) within one year in women whereas we found no such associations in men. There was a borderline significant interaction between gender and eGFR regarding one year mortality (p=0.08) but not regarding MACE (p=0.11).As we found a remarkable gender difference in RI prevalence in Paper IV, we analysed an updated SWEDEHEART database including the years since S-creatinine became a mandatory variable to register. In Paper V all STEMI patients registered between 1st of Jan 2003 and 31st of Dec 2009 were included, in total 37 991 patients (36% women). RI was present in 38% in women vs. 19% in men according to MDRD and in 50% of men vs. 22% of men according to Cockcroft Gault [CG] (p<0.001 for both comparisons). Female gender was independently associated with RI regardless of used formula. In both genders, RI patients were older, had higher co-morbidity, suffered from more complications and had lower chance of receiving reperfusion therapy and evidence-based therapy at discharge compared to non RI patients. Among both RI and non RI patients, men had significantly higher chance than women of getting these therapies. In-hospital mortality was four to five times higher in RI vs. non RI patients. RI compared to non RI patients had approximately doubled risk of inhospital mortality in women and 2.5 times higher risk in men after multivariable adjustment. Regardless of used formula, the risk of dying at hospital increased with approximately 30% and the risk of long term mortality with approximately 10% in both genders per 10 mL/min decline of eGFR. There was no significant interaction between gender and eGFR regarding short- or long term outcome according to any of the formulas. Women had twice as high in-hospital and also higher cumulative long term mortality than men. After multivariable adjustments including all confounders except kidney function women had 7% lower risk of long term mortality but still 11% higher risk of in-hospital mortality. If eGFR according to any of the formulas was also included, there was no longer a gender difference regarding in-hospital mortality and women had lower risk of long term mortality. This was also the case if only adjusting for eGFR according to CG.Conclusion: In the real life STEMI setting, women were older with higher co-morbidity, longer delay, more complications and twice as high in-hospital mortality. They had significantly less chance of receiving acute reperfusion therapy, also after adjusting for possible confounders. During the fibrinolytic era women had higher risk of severe bleedings. We hypothesised that the gap in management would have decreased during the new primary PCI era, with a less time-dependent regime with less risk of fatal complications. Our hypothesis failed, and future studies ought to further scrutinise this gender difference in management. The less chance of reperfusion therapy did anyhow not explain the higher in-hospital mortality in women, which was 10-20% higher after multivariable adjustments, consistent with previous findings. Moderate to severe chronic kidney disease was very common in women with STEMI, 50% according to the Cockcroft Gault formula. Estimated GFR has seldom been taken into account in studies evaluating gender differences in outcome. If adjustment for eGFR was done, alone or added to the all other co-variates, women had no longer higher risk of in-hospital mortality. Adjusted long term outcome was better in women than in men, which was also the case in the youngest cohort when studied separately.
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| 8. |
- Törnudd, Mattias, 1974-
(författare)
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Protamine, Platelet Function and Coagulation in Cardiac Surgery
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bleeding is a serious and common complication in cardiac surgery. Complicated surgery together with alterations in hemostatic conditions from the use of cardiopulmonary bypass (CPB), presents challenges in how to preserve hemostasis in the patient. CPB is thought to affect platelet function and coagulation in many ways. Before connecting the patient to the CPB system, heparin is used as anticoagulation. With the connection between the patient and the CPB tubing there is a dilution of platelets and coagulation proteins and despite anticoagulation there is an activation of coagulation and inflammation resulting in consumption of coagulation factors and triggering of fibrinolysis. After disconnection of the CPB system, protamine is used to reverse the effect of heparin and restore the coagulation capacity of the patient. When protamine binds to heparin, the anticoagulant effect of heparin is removed but protamine is known to affect both platelet function and coagulation. There is uncertainty about how to best dose protamine to limit the negative effects from protamine without risking remaining heparin effect. A lot is known about how and to what extent cardiac surgery with the use of CPB affect the hemostasis in the patient, but there are still many uncertainties. The aims of this thesis were to examine how platelets are affected by CPB and protamine and to investigate if dosing of protamine had an impact on the risk of remaining or reappearing heparin after cardiac surgery. We also wanted to investigate whether sampling site matters when studying platelet function. In paper I, we found that protamine in vitro interacts with platelets by both a direct activating effect and by a secondary impairment of function when exposed to other activators. The impairment of platelet function from protamine could also be seen in vivo and is described in paper III. In paper III, we also conclude that, in contrast to prior studies, there was no increase in activation in platelets, nor net loss of platelets, during moderate CPB times. After CPB we found no impairment of platelet function compared with before surgery. In paper II, we found no differences in platelet aggregability between venous and arterial blood when measured with impedance aggregometry. Also, with flow cytometry most of our parameters showed no differences between venous and arterial blood. However, there were some differences. For example, the level of monocyte-platelet-aggregates was higher in venous- compared with arterial blood, which raises questions whether platelet function changes with oxygenation and flow conditions. In paper IV, we found a dose dependent risk of remaining heparin activity in the first postoperative period. We also found reappearance of heparin activity that was independent of the protamine dose in almost all our patients. We did not find any correlation between remaining or reappearing heparin activity and bleeding. In conclusion, this thesis describes that moderate CPB times do not have the severe impairment on platelet function earlier described in the literature. The thesis also increases the knowledge regarding how protamine affects platelet function and how dosing of protamine does and does not affect the risk of remaining and reappearing heparin activity. Finally, we conclude that in most cases platelet function can be studied in venous and arterial blood interchangeably, but there might be some differences in platelet function depending on whether they are in the venous our arterial system.
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| 9. |
- Venetsanos, Dimitrios
(författare)
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Improving management of STEMI patients treated with primary PCI : Pharmacotherapy, renal function estimation and gender perspective
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focused on the acute management of patients with ST-segment elevation myocardial infarction (STEMI) in an effort to provide information that may improve outcome. The aim was to evaluate the efficacy and safety of bivalirudin versus unfractionated heparin (UFH) in STEMI patients during primary PCI. Furthermore, to provide pharmacodynamic data of novel ways of ticagrelor administration compared to standard tivcagrelor. Additionally, to identify subgroups of patients, such as women who may derive greater benefit from specific antithrombotic strategies due to their risk/benefit profile. Finally, to evaluate current formulas for estimation of renal function in the acute phase of STEMI.In Paper I, all STEMI patients in Sweden between 2008 and 2014, treated with primary PCI and UFH or bivalirudin were included in our analysis. Of the total population of 23 800 patients, 8 783 (36.9%) were included in the UFH group and 15 017 (63.1%) in the bivalirudin group. Concomitant GPI administration was 68.5% in the UFH arm compared to 3.5% in the bivalirudin arm (p<0.01).The adjusted incidence of 30-day mortality was not significant different between the two groups (UFH vs bivalirudin, adjusted HR 0.94; 95% CI 0.82 -1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between the two groups. In contrast, patients treated with UFH had a significantly higher incidence of major in-hospital bleeding (adjusted OR 1.62; 95%CI 1.30 -2.03).In Paper II pharmacodynamic data of chewed or crushed ticagrelor compared to standard ticagrelor loading dose (LD) was assessed in 99 patients with stable angina. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60 minutes after LD. High Residual platelet reactivity (HRPR) was defined as > 208 P2Y12 reaction units (PRU). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60 minutes. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20 minutes whereas no difference was observed at 60 minutes. At 20 minutes, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01).In Paper III we presented a pre-specified gender analysis of the ATLANTIC trial including 1 862 STEMI patients that were randomly assigned to pre-hospital versus in-hospital administration of 180mg ticagrelor. Women were older and had higher TIMI risk score. Women had a 3-fold higher risk for all-cause mortality compared to men (5.7% vs 1.9%, HR 3.13, 95% CI 1.78 – 5.51). However, after adjustment for baseline characteristics, the difference was lesser and no longer significant (HR 1.98, 95% CI 0.97 – 4.04). Female gender was not an independent predictor of risk for bleeding after multivariable adjustments (BARC type 3-5 HR 1.52, 95% CI 0.74-3.09). There was no interaction between gender and efficacy or safety of randomised treatment.In Paper IV, forty patients with PCI- treated STEMI were included between November 2011 and February 2013. We validated the performance of the Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease Epidemiology (CKD-EPI) and the Grubb relative cystatin C (rGCystC) equations for estimation of GFR against measured GFR (mGFR) during the index hospitalisation for STEMI.MDRD-IDMS and CKD-EPI demonstrated a good performance to estimate GFR with accuracy within 30% (P30) 82.5% vs 82.5%, respectively. CKD was best classified by CKD-EPI (Kappa 0.83). CG showed the worst performance with the lowest P30. The rG-CystC equation had a marked bias of -17.8% and significantly underestimated mGFR (p=0.03).Conclusions – In STEMI patients treated with primary PCI, bivalirudin should be preferred in patient at high risk for bleeding. With crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared with standard integral tablets. In STEMI patients, fast and potent platelet inhibition with chewed ticagrelor may reduce the risk of early stent thrombosis and patients treated with a less aggressive antithrombotic strategy, such as UFH or bivalirudin monotherapy, may derive a greater benefit. Although gender differences in adverse outcomes could mainly be explained by older age and clustering of comorbidities in women, a bleedreduction strategy in women with high risk characteristics is warranted in order to improve their outcome. Regardless the choice of antithrombotic strategy, dose adjustment of drugs cleared by kidneys based on GFR estimation is of crucial importance. MDRD and CKD-EPI should be the formulas used for estimation of GFR in STEMI patients
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