bluuebunny/crossref_metadata_2025 huggingface dataset:
Amiodarone induced thyroid dysfunction
Authors: Gudjonsson P , Ingolfsson A J , Gudnason T , Sigurdsson A F , Andersen K
Published: November 2023

Introduction

Amiodarone causes hypothyroidism in 12-25% of treated patients, depending on the classification of hypothyroidism. Amiodarone induced thyrotoxicosis is seen in 1.2%-12%. It is recommended to taper thyroid supplementation after discontinuing amiodarone.

Purpose

To investigate the prevalence of amiodarone induced thyroid dysfunction in Iceland and the effects of dosage and treatment duration.

Design

The study population comprised of all patients that were subscribed amiodarone in Iceland during the calendar year of 2014, a total of 1054 patients. Ten patients that never took amiodarone were excluded and there was missing data in 22. Hypothyroidism had been diagnosed in 91 patients before starting amiodarone and 59 took amiodarone for less than 90 days and were excluded from further analysis, leaving 871 patients. Follow up data was obtained from the national health care records both retrospectively and prospectively for first prescription of amiodarone and signs of thyroid related problems. Amiodarone induced hypothyroidism was defined as a raised TSH more than 90 days after starting treatment and further classified into subclinical (with normal T4) and overt (low T4). Amiodarone induced thyrotoxicosis was defined as low TSH with an elevated T4.

Results

Amiodarone induced hypothyroidism was seen in 22.2% of patients at a mean age of 74 years. 10.7% had overt AIH and 11.6% had subclinical hypothyroidism. Hypothyroidism occurred on average after 3.3 ±0.4 years of treatment. The incidence increased with treatment duration and peaked at 41.8% after 15 years of treatment. The risk did not change with dosage. Only 4.6% on thyroid supplementation therapy had stopped treatment after a mean follow-up of 4.5 years after discontinuing amiodarone.

Amiodarone induced thyrotoxicosis was seen in 10.0% with a mean age of 65.6 years. The mean duration of treatment at diagnosis of thyrotoxicosis was 3.9 ±0.6 years. The cumulative risk of thyrotoxicosis was highest (9.9%) during years 3 to 5 but persisted with ongoing treatment and peaked at 17.6% after 13 years of treatment. Higher dosage of amiodarone increased the risk in a dose dependent manner. It was 5% with <200 mg, 11.8% with 200 mg and 14.1% with >200mg (p<0.01). Hospital admission due to thyrotoxicosis was required in 35.3% of patients, 8.8% had thyroidectomies, 2.0% died and 26.5% had hypothyroidism following thyrotoxicosis. 48% were treated with carbimazole, of them 2.0% suffered agranulocytosis, 4.1% had hepatitis and 4.1% had pancreatitis.

Conclusion

In this nationwide study we found that long term users of amiodarone are at a higher risk of amiodarone induced hypothyroidism or thyrotoxicosis than previously described. Thyroid supplementation treatment is rarely stopped despite the pro-arrhythmic risk of overtreating hypothyroid patients. The high incidence of thyroid related adverse effects is a reminder of the serious side effects of amiodarone treatment.Amiodarone induced hypothyroidismAmiodarone induced Thyrotoxicosis
Targeting liver angiotensinogen using a GalNAc-siRNA improves cardiac remodeling in spontaneously hypertensive rats
Authors: Johannes Wikstrom J , Liang J , Cao H , Gao S , Gan L
Published: November 2023

Background

Dysregulation of the Renin-Angiotensin-Aldosterone System (RAAS) leads to hypertension and cardiac hypertrophy. Angiotensinogen (AGT) is the only precursor of all angiotensin peptide products. Liver-specific AGT silencing has been proven to be a promising treatment option in lowering blood pressure (BP) in patients, characterized by full RAAS inhibition and little RAAS escape phenomena. However, the long-term effects of AGT knockdown on cardiac remodeling is still unclear.

Purpose

To explore the long-term effects of a GalNAc-conjugated siRNA drug R0797070 on AGT inhibition, BP and cardiac functions in Spontaneously Hypertensive Rats (SHRs).

Methods

In vitro inhibitory activities of siRNAs were assessed in primary rat hepatocytes. The selected siRNA was conjugated with GalNAc based on RIBO-GALSTAR liver targeting system and named R0797070. In vivo effects of repeated doses of R0797070 were evaluated in SHR model. The animals were treated with R0797070 (3 mg/kg, every 8 weeks; subcutaneous injection) or PBS (5 ml/kg, every 8 weeks; subcutaneous injection) for 7 months with the first dose (day1) at the 3 months of age. Captopril (100 mg/kg per day; oral administration) was taken as a positive drug control and Wistar rats were used as normotensive control group. Blood pressure was monitored by tail-cuff method after an initial acclimatization training period. Serum AGT protein was measured by ELISA and liver mRNA expression was detected by qPCR. Echocardiography was used to determine the changes of cardiac morphology and functions，and wheat germ agglutinin (WGA) staining was used to measure myocyte cross-sectional size.

Results

R0797070 showed 90-99% inhibitory activities on hepatic AGT mRNA at different doses. In SHRs, a single dose of R0797070 at 3 mg/kg resulted in a maximum inhibition of 97% for serum AGT protein with 27 mmHg mean blood pressure (MBP) reduction on Day 15. Daily administration of Captopril could reduce MBP by 33 mmHg on average, while the duration of drug efficacy of R0797070 could reach 2 months with the average 25 mmHg MBP reduction. At the end of study, the echocardiographic results showed that R0797070 significantly reduced left ventricular hypertrophy in the 10-month-old SHRs. Consistently, R0797070 treatment reduced the heart weight by 10%，and LV myocyte size by 17%.

Conclusion

We showed the long-term effects of a GalNAc-siRNA R0797070 on silencing angiotensinogen expression, reducing blood pressure and left ventricular hypertrophy. Compared to daily oral administration of Captopril and its effect on blood pressure R0797070 demonstrated significant effect on cardiac hypertrophy.Figure 1Figure 2
Clinical characteristics and outcomes of super-low-dose edoxaban of 15 mg in patients with acute venous thromboembolism: insight from the COMMAND VTE Registry-2
Authors: Yamashita Y , Chatani R , Kaneda K , Nishimoto Y , Ikeda N , Kobayashi Y , Ikeda S , Kim K , Takase T , Tsuji S , Oi M , Takada T , Otsui K , Sakamoto J , Ogihara Y
Published: November 2023

Background/Introduction

The current guidelines recommend specific durations of anticoagulation therapy depending on the risks of recurrent venous thromboembolism (VTE), and prolonged anticoagulation therapy is recommended for patients at not-low risk of recurrence. However, clinicians are sometimes reluctant to continue anticoagulation therapy for patients with high-bleeding risk. A recent study reported that super-low-dose edoxaban of 15 mg was useful in preventing thromboembolic events for elderly patients with atrial fibrillation who were considered as high-bleeding risk patients. However, super-low-dose edoxaban of 15 mg is currently off-label for VTE all over the world, which could be a potential option for patient with VTE at high-bleeding risk.

Purpose

The current study aimed to investigate clinical characteristics and outcomes of VTE patients with super-low-dose edoxaban of 15 mg, using a large-scale multicenter observational database of patients with VTE.

Methods

The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. After excluding 3193 patients without edoxaban as oral anticoagulation therapy, the current study population was consisted of 2004 patients with edoxaban, who were divided into 3 groups according to initial dosage of edoxaban; 60 mg/day (N=664, 33%) 30 mg/day (N=1309, 65%) and 15 mg/day (N=31, 1.5%).

Results

Patients with edoxaban of 15 mg/day were oldest (60 mg/day: 62.3 years, 30 mg/day: 72.9 years and 15 mg/day: 79.2 years, P<0.001), were most often women (44%, 73% and 84%, P<0.001), showed a lowest mean body weight (68.4, 51.9 and 48.7 kg, P<0.001). Pulmonary embolism as initial presentation was least frequent in patients with edoxaban of 15 mg/day (58%, 44% and 13%, P<0.001). Patients with edoxaban of 15 mg/day most frequently had chronic kidney disease (10%, 22% and 26%, P<0.001) and anemia (45%, 66% and 74%, P<0.001). The discontinuation rates of anticoagulation therapy were not significantly different among the 3 groups (54.4%, 56.5% and 64.8% at 3-year, Log rank P=0.38). The cumulative incidences of recurrent VTE were not significantly different among the 3 groups (6.0%, 6.6% and 0.0% at 3-year, Log rank P=0.31). Similarly, the cumulative incidences of major bleeding were not significantly different among the 3 groups (9.2%, 11.6% and 15.3% at 3-year, Log rank P=0.11).

Conclusions

In the current real-world large VTE registry, a very minority of VTE patients received edoxaban of 15 mg/day, including patients at high-bleeding risk such as old age, low body weight and chronic kidney disease, who did not show significant worse outcomes in terms of recurrent VTE.
Comparisons of effectiveness and safety between different dosage strategy in patients with atrial fibrillation treated with rivaroxaban: a systemic review and meta-analysis
Authors: Chao T , Chan Y H , Lip G Y H , Chen S A
Published: November 2023

Background

Limited real world data show that rivaroxaban following dosage criteria from either ROCKET AF (15mg/day or 10mg/day if creatinine clearance (CrCl)<50ml/min) or J-ROCKET AF (15mg/day or 10mg/day if CrCl<50ml/min) are associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We aimed to study whether these observations differ between Asian and non-Asian subjects.

Methods

Databases were searched for adjusted observational study that compared relevant clinical outcomes of NVAF patients receiving off-label under-dosing rivaroxaban (10mg/day if CrCl>50ml/min), on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and off-label over-dosing rivaroxaban (20mg/day if CrCl<50ml/min).

Results

Eighteen studies were included. Rivaroxaban following J-ROCKET AF criteria (n=19,513) was associated with comparable risks of thromboembolism in the Asian subgroup (n=43,076), whereas rivaroxaban following J-ROCKET AF criteria (n=8555) was associated with higher risks of thromboembolism (hazard ratio (HR):1.27;[95% confidential interval (CI):1.05–1.53]) and all-cause mortality (HR:1.30;[95%CI:1.05–1.60]) compared with that of ROCKET AF criteria (n=23,139) in the non-Asian subgroup (n=31,694)(Figure). There was no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF versus ROCKET AF criteria either in the Asian or non-Asian subgroup (Figure). Off-label underdosed rivaroxaban 10mg (n=6305) was associated with a higher risk of thromboembolism (HR:1.64;[95%CI:1.28–2.11]) but lower risk of major bleeding (HR:0.72;[95%CI:0.57–0.90]) compared with eligible dosage criteria (n=11,673). Off-label overdosed rivaroxaban 20mg (n=7572) was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.42;[95%CI:1.14–1.79]), mortality (HR:1.41;[95%CI:1.15–1.73]) and major bleeding (HR:1.27; 95%CI:1.05–1.54; N=7 with I2=25%) compared with eligible dosage criteria (n=39,097).

Conclusions

Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET-AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favorable for the non-Asian population. Off-label underdosed rivaroxaban 10mg was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while off-label overdosed rivaroxaban 20mg was associated with worse outcome in most clinical events.
Ischemic and non-ischemic stroke reported in DOAC treated patients with atrial fibrillation and levetiracetam drug interaction: a real-world study
Authors: Abou Kaoud M , Orion D O , Nissan R N , Coster D C , Maor E M
Published: November 2023

Background

To date, the combination of direct oral anti coagulants and some anticonvulsants remain controversial. Therefore, the European Heart Rhythm recommendations do not support using levetiracetam with DOACs.

Objectives

This study sought to investigate reports on ischemic and hemorrhagic stroke with DOACs and the effect of levetiracetam on the rate of reporting in atrial fibrillation patients.

Methods

In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify adverse events associated with DOACs with and without concomitant use of levetiracetam. The authors evaluated disproportionate reporting by the reporting odds ratio adjusted to age and sex (adjROR) and the lower bound of the shrinkage 95% confidence interval (Ω025 > 0 is deemed significant).

Results

The authors identified 1723 (1.3%), 1841 (1.5%), and 3731 (5.3%) MedDRA preferred terms for ischemic stroke in AF patients treated with rivaroxaban, apixaban, and dabigatran, respectively. Whereas reports that described hemorrhagic stroke included, 3016 (2.2%), 1346 (1.1%), and 1256 (1.8%) for rivaroxaban, apixaban and dabigatran. Significant disproportionality signal was identified for ischemic stroke in dabigatran AF patients, (adjROR 3.10; 95%CI, 2.94-3.28). Rivaroxaban demonstrated the lowest adjROR for ischemic stroke when compared to apixaban and dabigatran, (adjROR 0.38; 95%CI, 0.36-0.41). A reciprocal image was noticed for hemorrhagic stroke with a higher reporting odds ratio for rivaroxaban (adjROR 1.46; 95%CI, 1.38-1.55) and a lower reporting odds ratio for dabigatran (adjROR 0.75; 95%CI 0.70-0.78). With regards to the DOAC-levetiracetam-ischemic stroke triplet; rivaroxaban, apixaban and dabigatran illustrated a significant signal in the regression and shrinkage analysis models. The exp(B) 95%CI for the interaction was highest with dabigatran, (exp(B) 3.92; 95%CI, 3.08-3.98).

Conclusions

In this large post-marketing study to date, the authors identified an interaction resulting in decreased effectiveness between levetiracetam and the DOACs. The greatest strength of association was found to be with dabigatran, supporting a P-glycoprotein induction mechanism. The interaction does not seem to influence the risk of hemorrhagic stroke. In line with current studies, ischemic stroke was lowest for rivaroxaban compared to dabigatran and apixaban on account of a higher risk for hemorrhagic stroke. Dabigatran demonstrated significantly lower reporting on hemorrhagic stroke but on account of a higher risk of ischemic stroke. We highly recommend pharmacodynamic monitoring, either anti-Xa for apixaban and rivaroxaban or plasma diluted thrombin time for dabigatran while concomitantly prescribing anticonvulsants with the DOACs.ResultsSensitivity Analysis
Inhibition of Factor XI using a GalNAc-siRNA RBD5049: a novel antithrombotic drug with high potency and long duration
Authors: Gan L , Li C , Sun Y , Wikstrom J , Guo Z , Yu H , Tong C , Zhang H , Liang Z , Gao S
Published: November 2023

Introduction

Bleeding risk remains a major concern of the existing anticoagulants. Inhibition Factor XI (FXI) using small molecule inhibitors, antibodies or antisense oligonucleotides (ASOs) to inactive intrinsic pathway of coagulation have been developed as a safer treatment option over the last decade. siRNA is a nucleic acid drug with class advantages of high selectivity, long duration and benign safety profiles. The current abstract summarizes key preclinical efficacy and safety data supporting the first-in-human study.

Purpose

To evaluate efficacy and safety, of a GalNAc-siRNA molecule RBD4059, for development of a novel antithrombotic treatment.

Methods

In vitro potency of several siRNAs were assessed and screened in HepG2 cells. Upon selection of the lead candidate, the siRNA was conjugated with a GalNAc molecule, using RIBO-GalSTAR liver targeting system. In vivo efficacy of RBD4059 was tested in C57BL/6J mice and cynomolgus non-human primates (NHPs). The antithrombotic effect of RBD4059 was determined in arterial and venous thrombosis models induced by FeCl3. Enoxaparin sodium (Lovenox) with clinical equivalent dose (4 mg/kg) was used as a control. Single- and repeated- dose GLP toxicology studies were performed in both CD-1 mice and NHPs.

Results

IC50 values of RBD4059 was 0.56 nM HepG2 cells. Dose-dependent and long-lasting effects of RBD4059 on the inhibition of plasma FXI activity (FXIa) were observed in mice and in NHPs. RBD4059 at a single dose of 9 mg/kg achieved a maximum of 89% plasma FXIa reduction and 1.38-fold APTT prolongation in mice, and the inhibitory effects could be maintained until Day 64. RBD4059 at 3 mg/kg or 9 mg/kg significantly prevented flow reduction due to FeCl3-induced thrombosis in both arterial and venous thrombosis models, and efficacy was superior than enoxaparin. In NHPs, the inhibitory effects of FXIa were maintained until Day 71 with the maximum effect of 77% FXIa reduction and 1.34-fold APTT prolongation. GLP toxicology studies showed good safety profile without any signs of increased bleeding despite supra-physiological doses and the NOAEL was considered 600 mg/kg in mice and 400 mg/kg in NHPs.

Conclusions

RBD4059 has demonstrated high potency/efficacy and long duration regarding FXI inhibition and with large safety margin. As the first siRNA based molecule targeting FXI, RBD4059 has now entered Phase 1 trial in human healthy volunteers.Figure 1
Clinical impact of switching or continuation of apixaban or rivaroxaban among patients with non-valvular atrial fibrillation
Authors: Deitelzweig S , Kang A , Jiang J , Gao C , Luo X , Atreja N , Han S , Cheng D , R S , Lip G
Published: November 2023

Background

Numerous studies have demonstrated varied clinical outcomes with initiation of different direct oral anticoagulants (DOACs) among patients with non-valvular atrial fibrillation (NVAF). Although switching of DOACs either for medical or non-medical reasons occurs among some NVAF patients in real-world clinical practice, there has been a lack of evidence on the clinical outcomes of those switchers.

Purpose

Assess the risk of stroke/systemic embolism (SE) and major bleeding (MB) among NVAF patients who switched from apixaban therapy to rivaroxaban or switched from rivaroxaban therapy to apixaban.

Methods

This retrospective study identified NVAF patients who initiated the most commonly used DOACs (apixaban or rivaroxaban) between 01 Jan 2013 and 31 December 2021 using a large US administrative claims database (Optum’s de-identified Clinformatics® Data Mart Database) representing patients in commercial or Medicare Advantage insurance plans. Patients who switched from one DOAC to the other within 30 days before or 90 days after discontinuation of initial DOAC and patients who continued receiving the initial DOAC were included. For switchers, the switch date was the index date. For continuers, a hypothetic index date was randomly assigned based on the distribution of the time from initial DOAC prescription to the switch date in the switchers group. Two final cohorts (switchers and continuers) within apixaban initiators and rivaroxaban initiators were further propensity score matched (PSM) based on pre-index characteristics up to a 1:5 ratio. The risks of stroke/SE and MB after the index date were compared between patients who continued the initial DOAC and patients who switched to the other DOAC.

Results

There were 167,868 apixaban initiators and 65,888 rivaroxaban initiators. After PSM, 2,884 patients who switched from apixaban to rivaroxaban were matched to 14,296 patients who continued apixaban, and 2,853 patients who switched from rivaroxaban to apixaban were matched to 13,330 patients who continued rivaroxaban. Patient characteristics were balanced between the continuers and switchers for both apixaban and rivaroxaban initiators. Patients who switched from apixaban to rivaroxaban were associated with a higher risk of stroke/SE (Hazard Ratio (HR):1.54, 95% Confidence Interval (CI): 1.06-2.24) and MB (HR: 1.73, 95% CI: 1.40-2.14) than those who continued apixaban. Patients who switched from rivaroxaban to apixaban were associated with a similar risk of stroke/SE (HR:0.75, 95% CI: 0.45-1.24) and a lower risk of MB (HR:0.58, 95%CI: 0.44-0.76) compared to those who continued rivaroxaban.

Conclusion

Bleeding outcomes associated with switching or continuation of apixaban or rivaroxaban in NVAF patients were consistent with existing evidence supporting a better safety profile for apixaban vs rivaroxaban.
Acetylsalicylic acid challenge or desensitization in sensitive patients with cardiovascular disease
Authors: Galli M , Cortellini G , Raiteri A , Lotrionte M , Fabio F , Romano A
Published: November 2023

Background

The use of acetylsalicylic acid (ASA) is problematic in subjects with histories of hypersensitivity reactions (HRs) to it or with cross-reactive types of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity.

Purpose

To evaluate the efficacy of low-dose ASA challenge (LDAC) and desensitization to allow ASA therapy at an antiplatelet dose in patients with atherosclerotic cardiovascular disease (ASCVD) or multiple related risk factors and histories of HRs to ASA or ≥ 2 chemically unrelated NSAIDs.

Methods

We studied prospectively all patients with such histories and ≥ 3 risk factors for ASCVD (group I), chronic coronary syndrome (CCS, group II), and acute coronary syndrome (ACS) with indication for ASA desensitization (group III). Patients from groups I and II underwent LDACs (cumulative dose of 110 mg), while those from group III were desensitized (cumulative dose of 100.1 mg).

Results

We evaluated 103 patients: 62 from group I, 24 from group II, and 17 from group III. Eighty-two of the 86 patients from the first two groups underwent LDACs and 2 reacted. Subsequently, 22 (27.5%) of the 80 patients with negative LDACs were administered dual antiplatelet therapy with ASA after successful percutaneous coronary interventions, thus sparing desensitizations. The remaining 4 patients with CCS and all 17 patients from group III were successfully desensitized.

Conclusions

LDAC proved to be a safe and reliable diagnostic tool for identifying patients with histories of HRs to ASA or ≥ 2 different NSAIDs who can tolerate ASA at antiplatelet doses. Routine LDAC is advisable in all patients at high risk for ASCVD or with CCS who report HRs to ASA or ≥ 2 NSAIDs. ASA desensitization remains a safe and effective option in patients with ACS.
Superiority of CS585 as a selective prostacyclin receptor agonist in prevention of thrombosis
Authors: Stanger L , Lambert S , Yamaguchi A , Yalavarthi P , Dahlof B , Bergh N , Holinstat M
Published: November 2023

Background

A major challenge with development of new targets for antithrombotic treatment is the sustained effect on the platelet and the target selectivity. While increasing cAMP in the platelet through activation of the prostacyclin (IP) receptor represents a viable antiplatelet target for prevention of thrombosis, current IP receptor agonists lack stability and selectivity. Development of a selective IP receptor agonist that is stable in the blood and selective for the IP receptor would represent a new approach for prevention of platelet activation and thrombosis in the blood and expand the utility of IP receptor agonists which are currently used for the treatment of pulmonary arterial hypertension (PAH).

Purpose

Develop an IV and oral IP receptor agonist, CS585, with sustained activity in vivo in the blood and eliminating the off-target effects observed with other IP agonists not having selective activation of the IP receptor. These characteristics would make CS585 an attractive new therapeutic approach for limiting platelet activation and thrombosis.

Methods

We assessed platelet activation and thrombosis in human blood ex vivo and mouse models in vivo. For mouse models, platelets and fibrin were labelled and accumulation at the site of injury was measured using intravital microscopy. Thrombosis in the vessel was assessed in the laser-induced cremaster thrombosis assay. Selectivity was assessed in human blood pharmacologically using prostaglandin receptor inhibitors and in mouse with an IP receptor knockout mouse. Flow cytometry, aggregometry, and western blot techniques were used to assess selectivity.

Results

IV and oral administration of CS585 resulted in sustained inhibited clot formation and fibrin formation at the site of injury in the laser-induced cremaster arteriole thrombosis assay in wild-type mice but was unable to alter platelet function in IP knockout mice. CS585 inhibition of platelet activation was fully prevented in platelets from IP knockout mice as assessed by flow cytometry (integrin activation and granule secretion) and by VASP phosphorylation. Inhibition of human platelet activation by CS585 was inhibited by pharmacological inhibition of the IP receptor, but not by inhibition of the DP1, EP2, or EP4 receptors as assessed by aggregation, flow cytometry, and VASP phosphorylation.

Conclusions

We have shown for the ﬁrst time that CS585, a novel IP receptor agonist, not only inhibits platelet activation and clot formation, but gives sustained inhibition through multiple routes of administration in an in vivo mouse model of thrombosis. Importantly, the challenge in selectivity observed with other IP receptor agonists is not observed with CS585 supporting its development for a number of diseases in the cardiovascular system including thrombosis, VTE, secondary prevention after MI and stroke, and PAH.CS585 inhibition of thrombosis in vivoCS585 selectively signals through IP
Variability of the antithrombotic effect of acetylsalicylic acid with the administration of different dosages: reality or myth?
Authors: Lima Lopes J , Passos M , Mateus C , Fialho I , De Oliveira V , Sousa Mendes D , Roque D
Published: November 2023

Introduction

We rely on the antithrombotic effect of acetylsalicylic acid (ASA) in a number of pathologies, although other beneficial effects are known, such as its anti-inflammatory properties, when administered in higher doses (500mg, 1000mg per os). However, whether the anti-inflammatory effect decreases the antithrombotic potency of ASA is not known. This gap in evidence may lead to an unnecessary use of two drugs (one antithrombotic and one anti-inflammatory) that could be replaced by ASA alone. This scenario presents frequently: post-infarct pericarditis or when in doubt between non-ST segment elevation myocardial infarction vs myopericarditis. In such cases, the use of ASA could assure both antithrombotic and anti-inflammatory effects. Since the antithrombotic effect of ASA is not scientifically proved for higher doses, currently we use ASA 100mg as an antithrombotic agent and ibuprofen as an anti-inflammatory. This experimental study intends to assess whether ASA maintains its antithrombotic effect when administered in an anti-inflammatory dose.

Methods

Twenty healthy volunteers were recruited. They all had their platelet function assessed in a qualitative manner, using PFA-200 Innovance technology. The volunteers were randomized into four groups, with 5 participants each. The participants of groups 1, 2, 3 and 4 ingested ASA 100mg, 300mg, 500mg and 1000mg respectively, in a blind experiment. One hour after ingestion (peak of action), the volunteers’ platelet function was reassessed. PFA-200 evaluates platelet function through platelet occlusion time (OT), which is measured in milliseconds (ms). Normal platelet function translates into OT of 82-150ms. If the OT is higher than 150ms, the patient is anti-aggregated.

Results

Prior to ASA administration, 19/20 volunteers had OT within the reference range. Afterwards, in all four groups, volunteers reached OT > 150ms, regardless of the ASA dose administered. Mean OT values for each group were 188ms [SD-23] , 205ms [SD-63], 262ms[SD-44] and 232ms [SD-47], respectively. Overall SD was 32ms.

Conclusion

ASA maintains its antithrombotic effect when administered in an anti-inflammatory dose. There is no clear correlation between the potency of antithrombotic effect and the ASA dose administered. This was a pilot study that supports the maintenance of the antithrombotic effect of ASA in higher doses, but further and larger studies are required to corroborate these results.
The effect of discontinuing long-term beta-blockers following acute myocardial infarction in optimally treated, stable patients without heart failure - a Danish, nationwide cohort study
Authors: Halili A , Holt A , Eroglu T E , Haxha S , Zareini B , Torp-Pedersen C , Bang C
Published: November 2023

Aims

We studied the effect of discontinuing beta-blockers following myocardial infarction in optimally treated, stable patients without heart failure.

Methods and results

Using nationwide registers, we identified first-time myocardial infarction patients treated with beta-blockers following percutaneous coronary intervention or coronary angiography.

The analysis was based on landmarks selected as 1, 2, 3, 4, and 5 years after the first redeemed beta-blocker prescription date. The outcomes included all-cause death, cardiovascular death, recurrent myocardial infarction, and a composite outcome of cardiovascular events and procedures. We used logistic regression and reported standardized absolute 5-year risks and risk differences at each landmark year. Among 21,220 first-time myocardial infarction patients, beta-blocker discontinuation was not associated with an increased risk of all-cause death, cardiovascular death, or recurrent myocardial infarction compared with patients continuing beta-blockers (landmark year 5; absolute risk difference [95% confidence interval]), correspondingly; -4.19% [-8.95%; 0.57%], -1.18% [-4.11%; 1.75%], and -0.37% [-4.56%; 3.82%]). Further, beta-blocker discontinuation within two years after myocardial infarction was associated with increased risk of the composite outcome but there was no risk difference associated with discontinuation hereafter.

Conclusion

Discontinuation of beta-blockers one year or later after myocardial infarction without heart failure was not associated with increased serious adverse events.
Impact of CYP2C19 genotype status on clinical outcomes in patients with symptomatic coronary artery disease, stroke, and peripheral arterial disease
Authors: Maas D , Willems L , Kranendonk J , Kramers C , Warle M
Published: November 2023

Background

Coronary artery disease (CAD), stroke, and peripheral arterial disease (PAD) are clinical manifestations of atherosclerosis. Clopidogrel is widely used for the secondary prevention of atherothrombotic events in these patients. CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results.

Purpose

To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD).

Methods

A comprehensive search in Pubmed, EMBASE and MEDLINE from their inception to April 8th 2022 was performed. For CAD, randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment were included. For stroke and PAD, cohort studies and post-hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke.

Results

Forty-two studies were identified: 11 studies on CAD, 27 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE (RR 0.60, 95% CI 0.43 – 0.83), myocardial infarction (RR 0.53, 95% CI 0.42 – 0.68), and stent thrombosis (RR 0.64, 95% CI 0.43 – 0.94) compared to standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70 – 1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.62, 95% CI 1.24 – 2.11) and recurrent ischemic stroke (RR 2.00, 95% CI 1.49 – 2.67) compared to non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43 – 1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events.

Conclusion

The available evidence in PAD is too limited to draw meaningful conclusions. In stroke patients, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI.
Empagliflozin restores autophagy and ameliorates ponatinib-induced cardiomyocyte death
Authors: Madonna R , Ghelardoni S , Moscato S , Mattii L , Barachini S , Novo G , Zucchi R , De Caterina R
Published: November 2023

Background

The tyrosine kinase inhibitor ponatinib has proven cardiovascular toxicity, for which no counteractive treatment is available at the moment. Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors are approved drugs treat patients with chronic heart failure of different aetiologies. They play direct anticancer activity in SGLT2-expressing cancer cells, independent of glucose metabolism and through inhibition of oxidative phosphorylation. Ongoing studies are now testing empagliflozin (EMPA) in the prevention of left ventricular dysfunction in patients receiving high cumulative doses of anthracyclines.

Aims

To determine the effect of EMPA on cardiomyocytes in an in vitro model of PON-induced cardiac toxicity, and to assess underlying cardioprotective mechanisms.

Methods and Results

We exposed cardiomyocytes to PON (1.7 nM) or vehicle (DMSO) in the presence or absence of EMPA (100 and 500 nM) for 24 hours. Compared with vehicle, incubations with PON significantly reduced cell viability at 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, decreased autophagic cells at immunofluorescence assay (1±0.5 vs 6±1 fluorescence intensity/total area, p=0.0006, Figure 1), and increased cell senescence (15±5 vs 4±2 β-gal positivity/tissue area, p<0.02), effects all reverted by EMPA (p<0.01). We observed no significant effects of PON or EMPA on formation of reactive oxygen species. Compared with vehicle, PON significantly reduced serum response factor (SRF)/serum response elements (SRE) binding activity (25±9 vs 218±15 SRE complex abundance, arbitrary units, p<0.001), in parallel with a reduction in cardiac actin expression (0.32±0.06 vs 0.98±0,12 cardiac actin/GAPDH ratio, arbitrary units, p=0.001), which was reversed by EMPA (p=0.001).

Conclusion

EMPA attenuates PON cardiotoxicity by reducing senescence and enhancing autophagy, apparently independent of antioxidant mechanisms. This study suggests the design of clinical studies aimed at assessing the effects of EMPA on PON-induced cardiotoxicity.Legend to Figure 1.CON, control (vehicle, DMSO); PON, ponatinib; EMPA 100, empagliflozin 100 nM; EMPA 500, empagliflozin 500 nM
Influence of cholesterol levels on NSAID-associated risks after myocardial infarction: a nationwide population-based cohort study
Authors: Abdallah M B , Bonnesen K , Pedersen L , Sorensen H T , Schmidt M
Published: November 2023

Introduction

Non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, fever, and inflammation, but they can increase the risk of recurrent myocardial infarction (MI), ischemic stroke, atrial fibrillation, and death in patients with MI. Consequently, the European Society of Cardiology warns against using NSAIDs in patients with manifest cardiovascular disease and in high-risk individuals, such as those with dyslipidemia. However, no study has investigated whether NSAID-associated cardiovascular risks differ according to patients’ low-density lipoprotein cholesterol (LDL-C) levels.

Purpose

To examine whether LDL-C levels influence the cardiovascular risk associated with NSAID use after first-time MI.

Methods

Using Danish health registries, we conducted a population-based cohort study of all adult patients with a first-time MI hospitalization during 2010–2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and high LDL-C group (<3 vs. ≥3 mmol/L). We used multivariate Cox regression to compute adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between NSAID use (modelled in time-varying manner) and a major adverse cardiovascular event (MACE), defined as a composite of recurrent MI, ischemic stroke, and all-cause death. We repeated the analysis by changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L.

Results

We followed 50,573 patient with a first-time MI for a mean of 3.5 years (66% males, median age of 68 years. During NSAID use, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11–1.32) overall, 1.19 (1.06–1.33) in the low LDL-C group, and 1.23 (1.07–1.41) in the high LDL-group. The HRs in the low and high LDL-C groups were 1.09 (0.88–1.34) vs. 0.94 (0.74–1.19) for recurrent MI, 0.97 (0.66–1.41) vs. 1.27 (0.86–1.87) for ischemic stroke, and 1.22 (1.07–1.39) vs. 1.54 (1.30–1.83) for all-cause death. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results.

Conclusion

In patients with a first-time MI, NSAID use was associated with an increased risk of MACE. The LDL-C level did not influence the association between NSAID use and MACE, but it might influence the association between NSAID use and all-cause death. Thus, healthcare providers should be mindful of the increased cardiovascular risk associated with NSAID use in patients with previous MI, regardless of LDL-C values.
Effects of nurse-led self-care interventions on health outcomes among people with heart failure: a systematic review and meta-analysis
Authors: Huang Z , Chair S , Liu T , Gao R
Published: November 2023

Background

Suboptimal self-care is associated with adverse patient outcomes. Nurse-led self-care interventions, strategies used to support self-care, are essential to heart failure management. However, research evidence of the effects of nurse-led heart failure self-care interventions on patient outcomes (quality of life, anxiety, symptom burden, sleep quality, healthcare service utilization, and mortality) is scant.

Purpose

To evaluate the effects of nurse-led self-care interventions on quality of life, anxiety, symptom burden, sleep quality, healthcare service utilization, and mortality in people with heart failure.

Methods

Six databases (MEDLINE, Embase, Web of Science, CENTRAL, CINAHL, and PsycINFO) were searched from the inception to December 2022 to identify eligible studies. Randomized controlled trials estimating the effectiveness of nurse-led self-care interventions on quality of life, anxiety, symptom burden, sleep quality, healthcare service utilization, and mortality in people with heart failure published in English were included. The risk of bias of included studies was assessed using RoB 2.0. We conducted data syntheses by means of R software and graded the quality of the evidence using the GRADE approach.

Results

Twenty-five studies with 2746 subjects were included. Our findings demonstrated that compared to the controls, nurse-led self-care interventions improved quality of life (standardized mean difference [SMD]: 0.83, 95% confidence interval [CI]: 0.50 to 1.15, moderate certainty of evidence), anxiety (mean difference [MD]: 1.83, 95% CI: 1.10 to 2.56, high certainty of evidence), and symptom burden (SMD: 0.81, 95% CI: 0.24 to 1.38, low certainty of evidence) in people with heart failure. No significant effects were found in all-cause hospital readmission and all-cause emergency department visit. Research evidence on sleep quality, cardiac-related hospital readmission, cardiac-related emergency department visit, and all-cause mortality remained unclear.

Conclusions

Our review suggests that nurse-led heart failure self-care interventions have favorable effects on the quality of life, anxiety, and symptom burden. Further well-designed randomized controlled trials are warranted to address the gaps identified in this review.
Experiences of informal caregivers taking care of heart surgery patients after discharge from hospital: a qualitative study
Authors: Lie I , Moons P , Tonnessen T , Halvorsen S , Blakoe M , Moller C H , Kaljusto M L , Parry M L , Bjornnes A K , Hojskov I E
Published: November 2023

Background/Introduction

Open heart surgery is still the main treatment option for severe coronary and heart valve disease. After discharge from hospital, caregivers of heart surgery patients are given the main responsibility for care of their next of kin at home. There is a lack of studies on caregivers’ experiences with information from health care professionals regarding the discharge to home.

Purpose

To explore the informal caregivers' information and communication experiences with health care professionals following discharge to home after heart surgery

Methods

In-depth interviews using a semi-structured interview guide during videotelephony (Facetime), phone or face-to-face onsite interview. The settings were university hospitals in Norway and Denmark respectively and were carried out between November 2022 – January 2023. Data was analyzed in the NVivo software tool following Braun and Clarke`s 6-step thematic analysis process.

Results

Twelve informal caregivers (10 women, 2 men, mean age 65 years) were interviewed two to four weeks after the heart surgery patient had been discharged to home.

Four main themes were identified: i) Lack of information ii) Insecurity, iii) Responsibility without knowledge and iv) Readmission to hospital is a challenge. Shortly after discharge the caregivers realized the consequences of lack of information and knowledge to facilitate for their next of kin` comfort, and how to manage if their symptoms worsened. Several caregivers were afraid, and especially if readmission to hospital due to serious complications were needed (Figure 1).

Conclusion(s)

Informal caregivers of heart surgery patients lack information from health care professionals, and communication with health care professionals at hospital discharge to gain knowledge, feel secured, and to be prepared for the responsibility for follow-up of their next of kin at home.Figure 1.Caregivers heart surgery pts.
Exploring the association between self-care behaviour, knowledge and cognition in patients with heart failure: a secondary analysis from the HF-Wii study
Authors: Stromberg A , Van Der Wal 'M , Jaarsma T
Published: November 2023

Background

Self-care is vital for patients with heart failure and is influenced by different factors, Knowledge and the ability to reflect on behaviors is important to make decisions on self-care. Cognition may also be an important factor in relation to both knowledge and self-care. It has been found that cognitive impairment in patients with heart failure is common, with a reported prevalence of 20–80%.

Aim

To explore association between self-care behaviour, knowledge and cognition in patients with heart failure.

Methods

This is a secondary analysis of the baseline measures from the HF-Wii study with data from 605 patients, mean age 70 ± 12, 29% female, 30 % in New York Heart Association Class III-IV. Data on self-care was collected with European Self-care Behaviour Scale (EHFScBS) (possible range 0-100). Knowledge was collected with the Dutch HF Knowledge Scale (possible range 0-15 points). Cognition was assessed Montreal Cognitive Assessment (MoCA). Knowledge was dichotomised into low vs. high knowledge (cut off 13) and cognition into mild, moderate or severe cognitive problems vs. no or light cognitive problems.

Results

The total score on the EHFScBS was 64.6 ± 21.0 with 41% (N=245) of the patients performing good self-care (score > 70). The mean score on the Dutch HF Knowledge Scale was 12.3 ± 1.9 and 308 patients had high knowledge (score > 13). The majority of the patients (61%; N=371) had mild cognitive problems and 195 (32%) had no or light cognitive problems with a mean MOCA score of 24.4 ± 3.8.

Self-care was significantly correlated to total knowledge (r = .23; p < .001), but it was not correlated to cognition. Furthermore, there was a positive correlation between total knowledge and cognition (r = .43; p <.001).

Out of the 308 patients with high level of knowledge (>13), 130 had mild, moderate or severe cognitive problems. The other 178 patients with high knowledge had no or only light cognitive problems. Patients with high knowledge had a significantly higher score on the self-care behavior scale, independently of their cognitive function.

In a multivariable logistic regression analysis, higher age [odds ratio (OR) 1.03; 95% confidence interval (CI) 1.02-1.06), better quality of life (OR .95; 95% CI .90 - .99) and higher levels of knowledge (OR 1.25; OR 1.13 – 1.38) were independently related to self-care.

Conclusion

HF knowledge and cognition are related in patients with heart failure, but only knowledge, not cognition, was independently related to self-care.
Evaluation of PHARM-HF, a pharmacist-led heart failure medication titration clinic
Authors: Turgeon R , Ladhar S , Hawkins N , Virani S
Published: November 2023

Background

Optimal medical therapy (OMT) is the bedrock of heart failure with reduced ejection fraction (HFrEF) management. The pharmacist-led PHARM-HF clinic provides rapid, pharmacist-led, telehealth-based initiation, titration, and optimization of medications for HFrEF. We evaluated OMT changes in patients from PHARM-HF referral to discharge.

Methods

This retrospective pre-post study evaluated patients attending PHARM-HF from January 2021 to February 2023. The primary outcome was a modified version of the OMT score, which integrates utilization and dosing of ACEi/ARBs/ARNI, beta-blockers, MRAs and SGLT2is. Secondary outcomes included OMT score categorized as suboptimal (score 0-4), acceptable (score 5-7) or optimal (score 8; all four drugs at max-tolerated dose); use of individual agents at 1 year follow-up; and change in left ventricular ejection fraction (LVEF) from baseline to 1-year follow-up. Change in modified OMT score from baseline to discharge was compared using the Wilcoxon signed rank test.

Results

We included 81 patients. Median age was 68 (interquartile range [IQR] 57-74), 21% were female, 44% in NYHA class 2, and median LVEF was 31% (IQR 25%-37%, range 0-8). Patients had a median 5 (IQR 4-7) encounters with the PHARM-HF clinic pharmacist. The median OMT score at baseline was 6 (IQR 4-7, range 0-8), which an improvement to a median score of 8 (IQR 8-8, range 2-8) at discharge (p<0.0001). At baseline, 7% of patients were categorized as optimal, which improved to 78% at discharge, with 16% of patients on target doses of all four medications. Medication use at 1 year follow-up was 83.4% for sacubitril-valsartan, 14.3% for ACEi/ARB, 97.6% for beta-blockers, 85.7% for MRA, 78.6% for SGLT2i. For 31 patients with baseline and 1-year LVEF, median LVEF improved from 30% (IQR 25%-37%) to 38% (IQR 34%-46%).

Conclusions

A pharmacist-led clinic increased prescription OMT uptake. Future multicentre studies should explore the role of pharmacists as collaborators and prescribers to optimize HFrEF care.