bluuebunny/crossref_metadata_2025 huggingface dataset:
Bradycardia associated with ALK inhibitors in the treatment of non-small cell lung cancers: a systematic review and meta-analysis
Authors: Zhou S , Cirne F , Kappel C , El-Kadi A , Ellis P , Leong D P
Published: October 2021

Introduction

Anaplastic Lymphoma Kinase (ALK) inhibitors represent a major therapeutic advance in the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). Bradycardia was initially observed with crizotinib, the first ALK inhibitor. The risk of bradycardia and whether it differs among various generations of ALK inhibitors has not been systematically described.

Purpose

The primary objective of this systematic review is to compare the risk of bradycardia in patients who received an ALK inhibitor or standard chemotherapy for the treatment of NSCLC in randomized controlled trials.

Methods

We conducted a systematic literature search in MEDLINE, EMBASE, Cochrane Central, Web of Science, and Clinical Trials registry. We included randomized controlled trials that compared two different ALK inhibitors, or an ALK inhibitor with standard chemotherapies in patients with NSCLC. The primary outcome of interest was the number of bradycardia events. Because bradycardia was not systematically reported in many trials, we also documented reports of dizziness (as a potential symptom of bradycardia) in a secondary analysis.

Results

We identified 12 eligible studies including 2915 participants. Bradycardia was reported as a treatment-emergent adverse event in 9 trials; dizziness was reported in the remaining 3 trials. The type of bradycardia and use of heart rate-slowing medications were not documented in most studies. The incidence of bradycardia among 1080 individuals prescribed crizotinib in 8 trials was 13% (95% CI 9–17%) during a mean follow-up of 1.26 years. A meta-analysis of four trials that compared crizotinib with standard chemotherapies (Figure 1) showed a higher risk of bradycardia with crizotinib (RR 19.33; 95% CI 5.40–69.22). Newer generations of ALK inhibitors (alectinib, brigatinib and lorlatinib) showed similar rates of bradycardia compared to crizotinib (RR 0.51; 95% CI 0.21–1.26; Figure 2). Dizziness was more common in ALK inhibitors than standard chemotherapies (RR 1.83; 95% CI 1.38–2.42).

Conclusions

Our findings suggest that crizotinib is associated with a higher rate of bradycardia than standard chemotherapies, while no difference was found between crizotinib and newer generations of ALK inhibitors. The higher rate of dizziness in ALK inhibitors could represent a symptom of bradycardia. Further research is needed to evaluate the incidence and types of ALK inhibitor-associated bradycardia and its relationship with patient symptoms.

Funding Acknowledgement

Type of funding sources: None. Figure 2
Ventricular arrhythmias in patients with immune checkpoint inhibitor myocarditis
Authors: Hassan M , Fradley M G , Drobni Z D , Mahmood S S , Nohria A , Thuny F , Michel C , Mahmoudi M , Thavendiranathan P , Garcia De Yebenes Castro M , Afilalo J , Nicolas E Z , Yang E H , Lyon A R , Neilan T
Published: October 2021

Background

Immune checkpoint inhibitor (ICI)-associated myocarditis is associated with a markedly increased risk of morbidity and mortality. The occurrence of ventricular arrhythmias (VA) in patients with ICI-associated myocarditis has not been well characterized.

Purpose

The aim of this study was to determine the characteristics and risk factors for severe VA in patients with ICI myocarditis.

Methods

The cohort consisted of 202 patients with ICI myocarditis. Ventricular arrhythmias were defined as a composite of sustained ventricular tachycardia and ventricular fibrillation. We used a multivariable logistic regression model to test the association between clinical variables and the development of VA.

Results

From a cohort of 202 patients with ICI myocarditis (67±13 years, 35% female, 60% hypertension, 23% diabetes mellitus), 41 (20.3%) developed VA, of which, 33 had VT and 8 had VF. The median time from admission to VF was 144 hours and to VT was 72 hours. A VA occurred in 17.5% of patients with a normal LVEF, and 25% of patients with reduced LVEF. On univariate analysis, a QRS duration >110ms (OR 2.88, 95% CI 1.40 to 6.16, P=0.005) and a QTc duration >470ms were associated with an increased probability of VA (OR 2.58, 95% CI 1.23, 5.41, P=0.012). The association remained significant after adjustment for age and gender. Additionally, a longer time from admission to initiation of corticosteroids was associated with a higher probability of VA (OR 1.06, 95% CI 1.01 to 1.13, P=0.027). The association between the time from admission to administration of corticosteroids and probability of VA remained significant after adjustment for age, gender, and LVEF on admission (OR, 1.06, 95% CI 1.00, 1.13, P=0.037) where each 6-hour delay in the initiation of corticosteroids was associated with a 4% increase in the risk for VA.

Conclusions

Ventricular arrhythmias are common in the setting of ICI myocarditis and are observed in patients presenting with both a preserved and a reduced LVEF. Wider QRS and longer QT at presentation and longer time from admission to initiation of corticosteroids were associated with an increased risk of VA.

Funding Acknowledgement

Type of funding sources: None.
Sensitivity and specificity of strain rate for the early detection of left ventricular dysfunction in breast cancer patients receiving adjuvant treatment with adriamycin with or without trastuzumab
Authors: Tettamanti M E , Gimenez I , Chacon C , Nadal J , Costanzo V , Nervo A , Losco F , Chacon R , Santos D A
Published: October 2021

Background

Medical literature states that a global longitudinal strain rate (GLS) <−19% and further reductions in relation with baseline GLS may predict long term left ventricular dysfunction in breast cancer patients receiving adjuvant treatment with Adriamycin (A) with or without trastuzumab (T). However, there is not strong evidence to support the use of this technique in daily clinical practice.

Purpose

To analyze the sensitivity (S) and specificity (Sp) of GLS <−19% or its relative 10, 15 and 20% reduction form baseline, for the early detection of left ventricular dysfunction in breast cancer patients receiving adjuvant treatment with A with or without T.

Methods

Patients were prospectively assessed with a cardiac echoDoppler + GLS at baseline, every 3 months during the first year and every 4 months thereafter. We assessed the S and Sp of GLS <−19% or its relative >10%, >15% and >20% reduction form baseline after treatment with A with or without T as predictors of cardiotoxicity (defined as a >10 percentage points decrease of left ventricular ejection fraction to a value below the lower normal limit with respect to baseline).

Results

136 out of 884 patients (16%) had GLS measured at each visit: 83 patients (60%) and 53 patients (40%) treated with A or A+T respectively. Patients were followed up to 31±6 months. Mean age was 51±12 years. The table shows the baseline characteristics of both groups. 10 out of 83 patients in group A (12%) and 18 out of 53 P in group A+T (34%) developed cardiotoxicity. Baseline left ventricular ejection fraction and GLS were 61±4,7% and −20,18±2,6% in group A, and 58,7±5,8% and −19,5±2,6 post treatment. In this group, GLS S and Sp were 50 and 80%, respectively. In the group A+T, the best GLS cutoff was −19%, with a 60% sensitivity and 78% specificity.

Conclusions

In our non-selected cohort of patients, nor GLS or its percentage reductions along follow up predicted the reduction of left ventricular ejection fraction and the developing of cardiotoxic ventricular dysfunction in breast cancer patients receiving adjuvant treatment with A with or without T. The systematic use of this tool should be further investigated and validated at each center to help establish its usefulness in daily practice.

Funding Acknowledgement

Type of funding sources: None. Baseline characteristics
Impact of active and stable cancer on survival in patients undergoing percutaneous coronary intervention
Authors: Kang M G , Kim K H , Park H W , Koh J S , Park J R , Park Y H , Hwang S J , Jeong Y H , Kwak C H , Ahn J H , Song H N , Hwang J Y
Published: October 2021

Background

With advances in treatment of ischemic heart disease and cancer treatment, use of percutaneous coronary intervention (PCI) in cancer survivors and patients with active cancer (AC) is expanding.

Objectives

The purpose of this study was to determine the impact of cancer on survival and major cardiovascular events (MACE) in a long-term, single-center cohort of patients treated with PCI.

Methods

Patients treated with PCI between January 2010 and December 2017 were grouped as follows: controls (patients without cancer), stable cancer (SC), and AC. AC was included patients with cancer diagnosed within the past 6 months, patients who had cancer-related therapy within the past 6 months, active metastatic disease, or active recurrence of the cancer. The primary endpoints were 5-year survival and a secondary endpoint was 5-year MACE.

Results

A total of 6,743 patients (age 66±12 years, 68.4% men) treated with PCI were included: 6,404 (95.0%) controls, 245 (3.6%) SC, and 94 (1.4%) AC. Predominant malignancies were gastrointestinal (37.4%), lung (22.7%), and genitourinary cancer (14.7%). No differences were observed between patients with AC, SC and controls regarding 5-year MACE (total MACE, 33.2% vs. 28.1% vs. 17.5%, p=0.072; cardiac death, 13.6% vs. 9.1% vs. 6.7%, p=0.066; non-fatal myocardial infarction, 2.9% vs. 7.5% vs. 7.8%, p=0.820; revascularization, 17.9% vs. 17.6% vs. 11.6%, p=0.794, respectively). Patients with AC and SC had reduced 5-year survival compared with controls (62.0% vs. 81.5% vs. 89.8%, p<0.001) (Figure). AC was associated with a 1.76 (95% CI 1.22 to 2.54, p=0.002) fold increased risk of all-cause 5-year mortality in multivariable adjusted models.

Conclusions

Cumulative incidence of 5-year survival was discriminated by concurrent status of cancer following PCI. Individualized decision making is needed in the routine practice of PCI regarding concurrent cancer-specific treatment and prognosis.

Funding Acknowledgement

Type of funding sources: None.
Incident cardiovascular events among middle-age men are associated with increased risk of subsequent prostate cancer diagnosis
Authors: Fardman A , Tiosano S , Kaplan A , Kalstein M , Moshkovits Y , Segev S , Klempfner R , Segev A , Grossman E , Maor E
Published: October 2021

Introduction

Prostate cancer is the second most common malignancy in men worldwide, but incidence is highly dependent on screening.

Purpose

We aimed to examine whether incident cardiovascular disease (CVD) events are associated with increased risk of future prostate cancer in middle-aged men.

Methods

We evaluated asymptomatic self-referred men who participated in a screening program. All subjects were free of CVD and cancer at baseline. CVD was defined as the composite of acute coronary syndrome, percutaneous coronary intervention, or stroke. Study endpoint was the development of cancer during follow up. Cancer and mortality data were available for all subjects from national registries. Cox regression models were applied with CVD as a time-dependent covariate and death as a competing risk event.

Results

Final study population included 18,282 subjects. Median age was 47 years (Interquartile range [IQR] 41–54). During median follow up time of 12 years (IQR 4–17) 2,047 (11%) subjects developed CVD, 406 (2.2%) developed prostate cancer and 694 (4%) died. Compared with patients who were free of CVD or prostate cancer during follow up, risk of death was 4, 6 and 15 times higher for patients who developed CVD event, prostate cancer, or both during follow up, respectively (p <.001 for all). Time dependent survival analysis showed that subjects who developed CVD during follow up were 60% more likely to develop prostate cancer (95% Confidence Interval [CI] 1.2–2.1, p=.001). However, after multivariable adjustment, this association was no longer significant. Interaction analysis demonstrated that the association of incident CVD with the risk of future cancer diagnosis was age dependent such that in middle-aged men (age≤55 years; N=14,473) incident CVD was associated with a significant 70% increased risk of subsequent cancer diagnosis in multivariable model (95% CI 1.13–2.6, p=.011, p for interaction=.002). Exploratory analysis of men younger than 55 showed that independent association of incident CVD with subsequent cancer diagnosis was different among subjects with normal body mass index (BMI) (≤25 kg/m2) compared with those with increased BMI (HR 0.55; 95% CI [0.22–1.42]; p value=0.23 vs. 1.6; 95% CI [1.007–2.54]; p value=.047; p for interaction=.058, respectively).

Conclusion

Incident CVD is independently associated with increased risk of subsequent prostate cancer diagnosis among men ≤55 years. Routine prostate cancer surveillance should be considered after CVD event in this population.

Funding Acknowledgement

Type of funding sources: None.
Cardiovascular events among recipients of hematopoietic stem cell transplantation
Authors: Aghel N , Lui M , Mian H , Khalaf D , Hillis C , Petropoulos J , Wang V , Leber B , Lipton J , Walker I , Leong D
Published: October 2021

Background

Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) are potential curative treatments for several hematological malignancies (1). Survival after HSCT has improved over the last decade, but survivors remain at risk for health issues after transplantation. Cardiovascular complications after HSCT are increasingly recognized (2). Cardiovascular diseases may be an important cause of mortality and morbidity in patients after HSCT owing to the toxicities of the cancer therapies; however, the incidence of cardiovascular events (CVEs) in this population has not been completely characterized. The objective of this systematic review is to summarize the evidence on the incidence of CVEs in HSCT recipients.

Methods

Medline and Embase were searched from inception to December 2020 without language restriction. Two authors independently screened the titles and abstracts. Inclusion criteria were: cohort studies and phase 3 randomized controlled trials that reported CVEs (i.e., heart failure, arrythmias, acute coronary syndrome, and stroke) or cardiovascular death among adults who underwent HSCT for a hematological malignancy. All-cause mortality, relapse-related mortality, and non-relapse-related mortality (NRM) were also collected. Studies in which the follow up period was not started immediately after HSCT were excluded due to the risk of immortal bias.

Results

Of 8151 nonduplicate articles, 30 studies including 14019 individuals post autologous HSCT, and 22 studies including 31049 individuals post allogeneic HSCT met the inclusion criteria.

The cumulative incidence of CVEs in the first 100 days post autologous HSCT was 9% and arrhythmia (i.e., atrial fibrillation) was the most common CVE. In recipients of allogeneic HSCT, the 100-day cumulative incidence of CVEs was 3%, and heart failure (HF) was the most common reported CVE. In recipients of autologous and allogeneic HSCT, cardiovascular death was responsible for 43% and 10% of NRM within 100 days, respectively (Table 1).

The incidence of CVEs was 4.96 per 1000-person years (95% CI; 4.21–5.80) in long-term survivors (beyond 100-days) of autologous HSCT, and HF was the most common CVE in this population. In long-term survivors of allogeneic HSCT, the incidence of CVEs was 1.90 per 1000-person years (95% CI: 1.59–2.24). Cardiovascular death was the most frequently reported CVE in long-term survivors of allogeneic HSCT (Table 2).

Conclusion

CVEs remain a major cause of non relapse morbidity and mortality in recipients of HSCT, especially recipients of autologous HSCT within the first 100 days. Future studies are needed to identify the risk factors for CVEs that are specific to HSCT recipients.

Funding Acknowledgement

Type of funding sources: None.
Pregnancy in women with hypertrophic cardiomyopathy: observational data from the tertiary referral center registry
Authors: Karelkina E , Zaitsev V , Konasov K , Svistelnikova E , Bautin A , Li O , Irtyuga O , Moiseeva O
Published: October 2021

Introduction

The number of cases of hypertrophic cardiomyopathy (HCM) in pregnancy increases every year. In most cases the course of pregnancy is favorable, however in certain high–risk scenarios there is an increased risk of complications (e.g., increased ventricular ectopic activity, heart failure exacerbation). Management heavily relies on the severity of the outflow tract obstruction, extent of left ventricular hypertrophy and sudden cardiac death (SCD) risk stratification.

Purpose

The main objective of this study is to assess risk factors and complications during pregnancy, childbirth and the postpartum period in women with HCM.

Methods

In this retrospective study we included 60 pregnant women with HCM who were admitted to the tertiary referral center between October 2010 and December 2019 with a mean age of 29.1±5.19 years. ECHO was performed in all patients.

Results

Twenty patients (33%) have obstructive HCM (HOCM), 31 patients (51,6%) were nulliparous, 20 patients (33%) had no clinical symptoms prior to pregnancy. Since the third trimester of pregnancy we observed the onset or exacerbation of heart failure in 26 (43.3%) cases, half of these patients presented with NYHA class III–IV. SCD risk was 3.64% (2.66 –5.84) in the third trimester. Six patients (9.23%) were required ICD implantation. Caesarean section (CS) delivery was performed in 38 patients (63.3%). However, the CS proportion has decreased from 80% to 51% in the last 5 years. Despite frequent complications during pregnancy and the postpartum period, no maternal mortality has been reported. The newborns' weight in HOCM cases was significantly lower than in patients without LVOT obstruction.

Conclusion

Despite the favorable course of pregnancy in HCM patients, the third trimester of pregnancy was often accompanied by the onset and progression of heart failure, as well as an increase in the proportion of patients with ventricular arrhythmias. In patients with HOCM, a decrease in the weight of newborns was revealed.

Funding Acknowledgement

Type of funding sources: None. Characteristics of women with HCP
Arterial hypertension in pregnant women: the effect of body mass index and smoking
Authors: Rublevskaya A , Bichan N A
Published: October 2021

Aim

To evaluate the effect of body mass index (BMI) and smoking, as well as their combination on the development of arterial hypertension (AH) during pregnancy.

Materials

The study included 312 pregnant women with hypertension (group I), with an average age of 32 [28–36] years. The diagnosis of moderate and severe hypertension was established before pregnancy on the basis of the national guidelines. The control group consisted of 358 pregnant women without hypertension (group II), with an average age of 28 [24–32] years. The study included the assessment of anthropometric data at 6–8 weeks of pregnancy, questionnaires and assessment of the smoking status of pregnant women (pack-years), ambulatory blood pressure monitoring (ABPM).

Results

At admission, the mean systolic blood pressure (SBP) in group I was 147 [140–164] mmHg, and the diastolic blood pressure (DBP) was 95.8 [84–100] mmHg. According to the ABPM data, the mean SBP was 142 [135–164] mmHg, and the mean DBP was 95.8 [84–98] mmHg When registered for pregnancy in the group 1, the BMI was significantly higher compared to the control group, 30.2 (25–34,9) and 22.3 (20.2–25.6), p<0.001, respectively. Obesity and smoking were statistically more common in group I compared to the control group, p<0.001 and p=0.01, respectively. The index of the smoker in the group with AH was 7.5 [2.5–15] pack-years, in the control group – 1.9 [1.0–7.5], p<0.001.

Smoking pack-years ≥10, increased the chance of developing hypertension by 13.1 (5.5–29.9) times, in turn, with pack-years <10 (compared to non-smokers), the chance of developing hypertension increased by 2.6 (1.6–3.9) times. Obesity significantly increased the chance of hypertension, Odds Ratio=12 (7.6–19.1). Among women with a normal BMI, smoking increased the chance of developing hypertension by 5 (2.7–9.3) times compared to its absence. The combination of smoking and an above-normal BMI compared to no smoking and a normal BMI increased the chance of developing hypertension by 31 (15.3–62) times. In women with a normal BMI, smoking (pack-years <10) increased the chance of developing hypertension by 3.6 (1.8–6.8) times compared to its absence. Also in this group, smoking (pack-years ≥10) increased the chance of developing hypertension by 5 (1.2–21) times compared to IPL<10 and by 17.7 (4.7–67) times compared to no smoking. In women with normal BMI, smoking (pack-years <10), compared with non-smoking women, did not significantly affect the chance of developing hypertension. In obese women, pack-years did not significantly affect the chance of developing hypertension (p=0.07).

Conclusions

An increase in body mass index and smoking, either single or in combination, can increase the chance of developing hypertension.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): Russian Medical Academy of Continuous Professional Education, Novokuznetsk
Predictors of inappropriate dosing of direct oral anticoagulants in nonagenarian patients with atrial fibrillation
Authors: Dominguez Erquicia P , Raposeiras-Roubin S , Abu-Asi E , Cespon-Fernandez M , Alonso Rodriguez D , Camacho Freire S J , Curbelos Fernandez N , Lopez Masjuan Rios A , Melendo Viu M , Iniguez Romo A
Published: October 2021

Background

Direct oral anticoagulants (DOACs) are presented as a good option for older patients owing to their safety profile. However, the dosing can become challenging especially in this population.

Objective

Our aim is to evaluate the predictors of inappropriate dosing of DOACs.

Methods

The authors analyzed the use of DOACs in 726 patients aged ≥90 years with a diagnosis of atrial fibrillation (AF) from a retrospective multicenter registry from 3 health areas in Spain. We studied the dosing, differentiating between appropriate dose, underdosing or overdosing. To evaluate the best predictive model, the Akaike information criterion (AIC) was used.

Results

Follow-up was 27.7±18.3 months. Mean age was 93.0±5.2 years, and 60.1% of patients were female. 339 patients received rivaroxaban (47.3%), 237 apixaban (33.1%), 105 dabigatran (14.7%) and 35 edoxaban (4.9%). An important proportion of patients received a suboptimal dose (41.5%, n=297): 35.3% underdosed and 6.1% overdosed. The rate of suboptimal dosing was higher for apixaban and lower for dabigatran (Figure 1A). In our registry we found as a predictors of inappropriate dosing: kidney function (Chronic Kidney Disease Epidemiology Collaboration), odds Ratio (OR) 1.04; 95% CI: 1.03–1.05, P<0.001; weight measured in kilograms, OR 1.04; 95% CI: 1.01–1.07, P=0.012; and high blood pressure (HBP), OR 1.61; 95% CI: 1.02–2.53, P=0.041 (Figure 1B). Other variables such as HASBLED, CHADSVASc, anemia, prior bleeding, or concomitant use of antiplatelet therapy, were not significantly associated.

Conclusions

We want to highlight that the use of an inappropriate dose of DOAC in older patients is common, about 40% in our study. Apixaban was the most frequently underdosed DOAC. HBP, weight, and kidney function were associated with an inappropriate dosing prescription. Therefore, it is important to carefully evaluate the characteristics of the patient to prescribe the appropriate dose that guarantees a correct action.

Funding Acknowledgement

Type of funding sources: None. Dosing of DOACsPredictors of inappropriate dosing
Effect of prophylactic and therapeutic low molecular weight heparins on mortality in 15,704 COVID-19 patients. A systematic review and a meta-analysis
Authors: Pani A , Giossi R , Menichelli D , Tratta E , Romandini A , Roncato R , Nani A , Schenardi P , Diani E , Fittipaldo V A , Farcomeni A , Scaglione F , Pastori D
Published: October 2021

Background

Antithrombotic treatment, including low molecular weight heparin (LMWH), has been proposed as a potential therapy for Coronavirus disease 2019 (COVID-19), to counteract diffuse intravascular clotting activation. However, it is unclear whether prophylactic or therapeutic doses are similarly effective in reducing mortality.

Methods

We performed a systematic review and meta-analysis of clinical studies to evaluate the efficacy of heparin (either, LMWH or fondaparinux) compared to no anticoagulation in reducing overall mortality. A subgroup analysis comparing prophylactic or therapeutic regimen was performed. Secondary endpoints were major bleeding and length of hospital stay (LOS).

Results

12 studies were included, 2 prospective and 10 retrospective with 15,704 patients. Of these, 11,251 (71.6%) were on heparins. Ten studies reported data on all-cause mortality (figure), showing that both prophylactic and full dose reduced mortality (pooled Hazard Ratio [HR] 0.55, 95% confidence interval [CI] 0.48–0.63 and HR 0.49, 95% CI 0.41–0.59, respectively). The prophylactic dose was associated with a lower risk of major bleeding (Odds Ratio [OR] 0.60, 95% CI 0.41–0.87), while a non-significant trend towards an increased risk of bleeding for the therapeutic dose was noted (OR 1.55, 95% CI 0.98–2.43). Finally, LOS was evaluated in 3 studies; the mean difference for prophylactic heparin treatment was −2.38 (−3.14, −1.61) days.

Discussion

Heparin is effective in reducing mortality in COVID-19 patients, with therapeutic and prophylactic regimens showing a similar reduction in the mortality rate. Prophylactic dose may be considered as the first choice in all patients with COVID-19 requiring hospital admission.

Funding Acknowledgement

Type of funding sources: None.
Strategies to bridge therapeutic gap in low-density-lipoprotein cholesterol lowering among 90,590 Chinese population with atherosclerotic cardiovascular diseases on stable statin monotherapy
Authors: Sun H , Lai A , Yan B
Published: October 2021

Background

Current guideline recommends addition of PCSK9-inhibitor to achieve low-density-lipoprotein cholesterol (LDL-C) lowering by ≥50% to target LDL-C <1.4mmol/L for patients with established atherosclerotic cardiovascular disease (ASCVD) already on maximum tolerated dose of statin and ezetimibe.

Purpose

We aimed to evaluate the residual distance to target LDL-C (LDL-C lowered by ≥50% and <1.4mmol/L) in ASCVD patients on statin monotherapy and the proportion projected to reach target LDL-C by up-titration to high potency statin, addition of ezetimibe and PCSK9-inhibitor.

Methods

We retrospectively analyzed 90,590 patients with ASCVD on stable dose of statin monotherapy prior to lipid profile assessment from 43 public hospitals in Hong Kong between Aug 2016 and Jul 2020. Patients were divided into (i) high potency statin (HP-S; rosuvastatin ≥20mg, atorvastatin ≥40mg or simvastatin ≥80mg) and (ii) non-high potency statin (NHP-S; other statin doses) statin users. We calculated the mean percentage LDL-C reduction required to reach the target of LDL-C lowered by ≥50% and <1.4mmol/L. We assumed up-titration from NHP-S to HP-S would further reduce LDL-C by approximately 5–10%; addition of ezetimibe 15–20% and PCSK-9 inhibitor 50–60%.

Results

Of 90,590 patients (63.2% male, mean age 66.8±11.3), 80.5% had coronary artery, 1.6% had peripheral artery and 21% had cerebrovascular disease; 18.7% were on HP-S and 81.3% on NHP-S. LDL-C lowered by ≥50% and <1.4mmol/L were not achieved in 96.8% (n=71,333/73,655) patients on NHP-S and 93.9% (n=15,896/16,935) patients on HP-S. In these patients, mean LDL-C was 1.8±0.6 and 1.9±0.6mmol/L and mean percentage LDL-C reduction required to reach target LDL-C goal was 40.5±15.4% and 39.3±17.8%, respectively. The proportion of patients who required 5–10%, 10–30%, 30–60% and >60% further reduction to reach target LDL-C were 2.5%, 22.1%, 65.4% and 9%, respectively. Proportion of NHP-S patients projected to reach LDL-C goal by up-titrating to HP-S is 2.2% (n=1,569/71,333). Addition of ezetimibe is projected to achieve LDL-C target in 20.5% (n=17,519/85,660) patients on HP-S who are not at goal. Overall, 78.1% (n=68,141/87,229) of patients on HP-S and ezetimibe were expected to need PCSK-9 inhibitor and is projected to achieve LDL-C target in 98% of cases (n=66,806/68,141).

Conclusion

Our “real-world” study showed the use of HP-S in ASCVD patients was low and >90% did not reach LDL-C target. High potency statin plus ezetimibe was projected to bridge about one fifth of these patients to target LDL-C. PCSK-9 inhibitor is likely required in significant number of patients despite HP-S plus ezetimibe.

Funding Acknowledgement

Type of funding sources: None.
Risk of death with sodium-glucose co-transporter-2 inhibitors across the hallmark cardiovascular and renal outcome trials: an updated meta-analysis
Authors: Patoulias D , Boulmpou A , Tranidou A , Nikolaidis A , Mouselimis D , Papadopoulos C E , Vassilikos V , Doumas M
Published: October 2021

Background

Patients with type 2 diabetes mellitus (T2DM) experience a 15% increase in the risk for death compared to the general population, with age less than 55 years, insufficient glycemic control and albuminuria representing the major risk factors for all-cause and cardiovascular mortality. Despite progression in diagnosis and treatment, mortality remains elevated among affected individuals. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are considered as the optimal treatment option for patients with T2DM and concomitant cardiovascular or renal disease, while these regimens demonstrated a clear benefit in all-cause and cardiovascular mortality compared to placebo.

Purpose

As we recently welcomed the publication of large-scale randomized controlled trials (RCTs) with SGLT-2 inhibitors addressing surrogate, hard endpoints, we sought to perform an updated meta-analysis, investigating the effect of SGLT-2 inhibitors on all-cause, cardiovascular and renal death among the high- or very-high risk patients enrolled in those trials.

Methods

We pooled data from the relevant, recent hallmark RCTs; 10 trials were included in our analysis encompassing a total of 71,533 enrolled participants, assigned either to SGLT-2 inhibitor treatment or placebo. We set cardiovascular death as the primary efficacy outcome, while we assessed all-cause death and renal death as secondary efficacy outcomes.

Results

Treatment with SGLT-2 inhibitors resulted in a significant decrease in the risk of cardiovascular death, equal to 14% (RR = 0.86, 95% CI; 0.80 to 0.93, I2=22%). Only canagliflozin produced a significant result, while dapagliflozin led to a marginally non-significant reduction in cardiovascular mortality (Figure 1). Notably, SGLT-2 inhibitors led to a significant decrease in the risk for all-cause death, equal to 14% (RR=0.86, 95% CI; 0.81 to 0.92, I2=34%) the result was significant only for canagliflozin and dapagliflozin, while none of the rest SGLT-2 inhibitors resulted in a significant decrease in the risk for all-cause death (Figure 1). SGLT-2 inhibitors also produced a non-significant decrease in the risk for renal death (RR=0.36, 95% CI; 0.12 to 1.14, I2=0%). Neither canagliflozin nor dapagliflozin had a significant impact on risk reduction for renal death, while no cases of renal death were reported in VERTIS CV trial. No subgroup differences were identified for any of the three comparisons (Figure 2).

Conclusions

Antidiabetic treatment with SGLT-2 inhibitors provides a clear benefit in terms of cardiovascular and all-cause mortality for the very high-risk patients enrolled in the cardiovascular and renal outcome trials. Canagliflozin seems to be associated with the greatest impact on risk reduction for all-cause and cardiovascular death, followed by dapagliflozin.

Funding Acknowledgement

Type of funding sources: None. Figure 1Figure 2
SIRT1 improves endothelial function by suppressing oxidative stress in diabetic mice
Authors: Yang K , Velagapudi S , Camici G , Xu A , Luescher T F
Published: October 2021

Background

The activation of longevity gene and the intracellular expression of the protein SIRT1 in vivo shows beneficial effects in different organs including cardiovascular function [1]. However, it is not known whether extracellular SIRT1 plays a role and has favorable effects on endothelial and vascular function.

Purpose

The current study aimed to investigate the effects of in-vivo treatment of diabetic mice with recombinant mouse SIRT1 (rcSIRT1) on endothelial and vascular dysfunctions.

Methods

Db/db mice of 12 weeks of age and their lean controls were treated with vehicle or rcSIRT1 protein intraperitoneally for 4 weeks with a dose of 5μg/mouse /day. At the end of the treatment period, pulse wave velocity of carotid arteries was examined with echocardiology and the activities of mouse were recorded through metabolic cage housing system. Aorta, carotid arteries, and mesenteric arteries were isolated at sacrifice to assess endothelial and vascular function in myograph systems.

Results

The db/db mice treated with rcSIRT1 were more active in the dark cycle. Their vascular functions were improved as aortas exhibited reduced contractions to phenylephrine and increased relaxations to acetylcholine. Carotid arteries also performed better function as the pulse wave velocity was reduced and endothelium-dependent contracting factors were significantly decreased after treatment. Mesenteric resistance arteries had preserved endothelial dependent hyperpolarization compared to the controls. Incubation with different inhibitors showed that rcSIRT1 exerted beneficial effects on vascular function by supressing oxidative stress which were mediated by NADPH oxidase and COX-1 pathways.

Conclusions

Exogenous treatment of diabetic mice with recombinant SIRT1 significantly improves endothelial and vascular function. Circulating Sirt1 may be a novel therapeutic preventing diabetic vascular disease.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation
Differential effect of novel antidiabetic agents on the arterial stiffness and endothelial function in patients with type 2 diabetes mellitus
Authors: Stampouloglou P K , Bletsa E , Siasos G , Oikonomou E , Paschou S A , Gouliopoulos N , Katsianos E , Tsigou V , Kassi E , Tentolouris N , Tsioufis K , Tousoulis D
Published: October 2021

Background

Arterial stiffness and endothelial function markers flag increased cardiovascular disease risk in patients with type 2 Diabetes Mellitus (T2DM).

Purpose

To investigate the effects of novel antidiabaetic agents on arterial stiffness and endothelial function in T2DM patients.

Patients and methods

We enrolled 80 consecutive patients under stable antidiabetic therapy who did not reach therapeutic targets. Subjects were assessed to receive an additional antidiabetic agent to optimize glucose control; dipeptidyl peptidase-4 inhibitor (DPP-4i, n=24), glucagon like peptide-1 receptor agonist (GLP-1RA, n=26), sodium/glucose cotransporter-2 inhibitor (SGLT-2i, n=21) or long lasting insulin (n=9). Glycosylated hemoglobin (Hba1c) along with carotid-femoral pulse wave velocity (PWV), augmentation index (Alx) and flow-mediated dialatation (FMD), as biomarkers of arterial stiffness and endothelial function accordingly, were measured at baseline and 3 months after treatment intensification.

Results

There were no differences between the study groups in traditional risk factors, or baseline HbA1c, PWV, Alx and FMD levels (ps=NS for all). All groups achieved better glycemic control in terms of HbA1c values between baseline and follow-up, as seen in the paired differences of these values (for DPP4i: 0.7±0.3%, for GLP-1RA: 1.3±0.7%, for SGLT-2i: 0.8±0.5% and for insulin 2.0±0.8%, p<0.001 for all). PWV showed a decrease from 10.0±0.84 to 9.1±0.43 m/sec (p=0.092) in the DPP4-i group, from 11.7±0.72 to 10.2±0.74 m/sec (p<0.001) in the GLP-1RA group, from 10.3±0.54 to 9.6±0.59 m/sec (p=0.001) in the SGLT-2i group and from 11.6±1.04 to 11.1±1.02 m/sec (p=0.219) in the insoulin group, as presented in Figure 1. Alx was also decreased from 34.2±1.89 to 31.5±2.7% (p=0.023) in the DPP-4i group, from 29.1±1.52 to 25.6±2.09% (p<0.001) in the GLP-1RA group, from 29.9±1.44 to 24.2±1.48% (p<0.001) in the SGLT-2i group and from 28.2±2.33 to 26.2±1.64% (p=0.153) in the insulin group, as presented in Figure 1, as well. Regarding FMD, a reduction in the values between groups from baseline to follow-up was also observed; from 5.33±1.3 to 5.50±1.1% (p=0.004) for the DPP-4i group, from 5.54±0.8 to 5.99±0.8% (p=0,001) for the GLP-1RA group, from 5.59±0.9 to 5.77±1.2% (p=0.005) for the SGLT-2i group and from 5.76±0.8 to 5.83±0.9% for the insulin group, as demonstrated in Figure 2.

Limitations: Our results should be examined under the scope of limited data pool and its subsequent restrictions.

Conclusion

These preliminary data provide evidence that treatment intesification- particularly with GLP1-RA and SGLT-2i, benefits vascular properties, a finding which could partly explain the positive cardiovascular outcomes of recent randomized clinical trials in this field.

Funding Acknowledgement

Type of funding sources: None.
Gastrointestinal bleeding risk following concomitant treatment with oral glucocorticoids in patients with atrial fibrillation on direct-acting oral anticoagulants
Authors: Holt A , Blanche P , Zareini B , Rasmussen P V , Strange J E , Rajan D , Jensen M H , El-Sheikh M , Schjerning A M , Schou M , Gislason G H , Torp-Pedersen C , McGettigan P , Lamberts M K
Published: October 2021

Background

Oral glucocorticoids and direct-acting oral anticoagulants (DOAC) have both been associated with a risk of gastrointestinal (GI) bleeding. However, drug safety, especially regarding the risk of bleeding, in relation to concomitant treatment with oral glucocorticoids and DOACs is insufficiently explored.

Purpose

We aimed to investigate the short-term risk of GI bleeding in patients with atrial fibrillation (AF) following concomitant treatment with DOACs and oral glucocorticoids.

Methods

Register-based, retrospective and nationwide Danish study including patients with AF and on DOAC treatment during 2012–2018. Patients were defined as exposed to oral glucocorticoids from the date of a redeemed prescription and 60 days forward. We associated concomitant treatment with GI bleeding and reported hazard ratios (HR) via a nested case-control design and standardized 60-day absolute risk adjusted for comorbidities using a cohort design. In both analyses, exposed were compared to non-exposed controls matched on age, sex, calendar year, follow-up time and DOAC agent.

Results

We included 98,376 patients (age [interquartile range]: 75 [68– 82], 44% females) with AF on DOAC treatment. The use of oral glucocorticoids among included patients was widespread with 16% redeeming at least one prescription within three years, 4% redeeming at least five (Figure 1A). Lung disease was the most frequent indication (Figure 1B). Concomitant treatment with DOACs and oral glucocorticoids was associated with an increased incidence of GI bleeding (total n=4,946) compared with only DOAC treatment, including a dose-response trend (<20mg daily dose, HR [95% confidence interval (CI)]: 1.64 [1.38–1.95]; ≥20mg daily dose, HR [95% CI]: 2.29 [1.90–2.77]). Likewise, the standardized 60-day absolute risk of GI bleeding from first oral glucocorticoid exposure was increased compared with non-exposed (Figure 2).

Conclusion

Caution should be exercised when prescribing even short-term oral glucocorticoid treatment for DOAC treated patients, most notably in high doses and for patients with elevated bleeding risk.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Ib Mogens Kristiansens Almene FondandHelsefonden
Ranolazine exerted cardioprotection against doxorubicin-induced cardiotoxicity through inhibiting excessive autophagy in rats
Authors: Arinno A , Maneechote C , Khuanjing T , Chunchai T , Prathumsap N , Ongnok B , Arunsak B , Jaiwongkam T , Kerdphoo S , Shinlapawittayatorn K , Chattipakorn S C , Chattipakorn N
Published: October 2021

Background

Doxorubicin (Dox) is a highly effective chemotherapeutic agent for several malignancies. However, its cardiotoxicity and progressive heart failure are the most serious adverse effects that compromised its clinical use. Recently, ranolazine, the late sodium (Na+) current inhibitor for patients with chronic angina, has been suggested as a potential agent to treat early cardiotoxicity induced by antitumor drugs. In that single report, pretreatment with ranolazine improved cardiac function and decreased mortality rates in the Dox-treated rats, by decreasing oxidative stress and apoptosis. Nevertheless, its protective mechanisms on autophagy in the Dox-treated rats have never been elucidated.

Purpose

We hypothesized that ranolazine exerts cardioprotection in the Dox-treated rats by improving left ventricular (LV) function and reducing cardiac injury though suppressing excessive autophagy.

Methods

Male Wistar rats (n=24) received either normal saline solution (NSS, n=8) or Dox (3 mg/kg/day, i.p.) for 6 doses. Then, the Dox-treated rats were assigned to orally administered with either saline (n=8) or ranolazine (305 mg/kg/day, n=8) for 30 consecutive days. Following the treatment, the LV function, cardiac injury, and autophagy were determined.

Results

Dox caused LV dysfunction as indicated by the decreased %LV ejection fraction (LVEF) and the increased serum cardiac troponin-I (cTn-I) levels (Fig. 1A). In addition, Dox induced excessive autophagy by increasing Beclin-1, p62, and light chain 3-II/I (LC3II/I) protein expressions (Fig. 1B). Treatment with ranolazine attenuated autophagic-related proteins (Beclin-1, p62, and LC3II/I), and improved LV function (Fig. 1A-B).

Conclusion

Ranolazine exerted cardioprotection in the Dox-treated rats through suppressing autophagic-regulatory proteins, suggesting its potential cardioprotective roles as a concomitant therapy for cancer patients receiving Dox.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): the NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand and the National Research Council of Thailand
Validity and utility of the questionnaire-based FRAIL scale in elderly patients with heart failure: findings from the FRAGILE-HF
Authors: Nozaki K , Kamiya K , Hamazaki N , Saitou H , Saitou K , Ogasawara Y , Maekawa E , Konishi M , Kitai T , Iwata K , Jujo K , Kagiyama N , Matsue Y
Published: October 2021

Introduction

The coexistence of heart failure (HF) and frailty leads to a worse prognosis. Frailty is generally diagnosed using the Fried criteria. To assess whether patients are frail according to the Fried scale, face-to-face physical examinations are required. However, with the COVID-19 pandemic, to avoid the spread of the virus in hospitals, it is important to screen hospitalized patients for frailty without contact. Therefore, non-contact measurement methods, such as questionnaires, should be used to screen for frailty in clinical practice. The FRAIL scale is a questionnaire used to screen for frailty. There are no studies regarding the consistency of the FRAIL scale with the Fried criteria, the impact on mortality, and physical dysfunction in elderly patients with HF.

Purpose

We investigated whether the FRAIL scale questionnaire is consistent with the Fried criteria, predicts all-cause mortality, and reflects physical dysfunction in patients with HF.

Methods

The present study was secondary analysis of FRAGILE-HF, a cohort study that enrolled participants from 2016 to 2018 and followed up for 1-year of discharge. A prospective multicenter cohort study in which 15 hospitals in Japan (8 university hospitals and 7 non-university teaching hospitals) participated. We prospectively enrolled 1332 consecutive hospitalized patients with HF ≥65 years old and analyzed 1028 patients after excluding 304 patients with missing data on the FRAIL scale. The FRAIL scale, the Fried model, and physical function were measured before discharge. The endpoint was all-cause mortality.

Results

According to the FRAIL scale, 459 (44.6%) and 491 (47.8%) were classified as frail and pre-frail, respectively. The Kappa coefficient between the FRAIL scale and the Fried criteria were 0.39 (95% confidence interval [CI]: 0.34–0.44; P value: <0.001). The area under the receiver-operating characteristic curves for frailty diagnosed by the Fried criteria of the FRAIL scale was 0.74 (95% CI: 0.71–0.76; P value: <0.001). A total of 118 deaths occurred during 1 year of follow-up. After adjusting for the MAGGIC score and log-BNP, The FRAIL scale predicted all-cause mortality (hazard ratio: 1.17; 95% CI: 1.01–1.36; P value = 0.035). The FRAIL scale was also associated with various physical dysfunction that correlated with poor prognosis.

Conclusions

The FRAIL scale had moderate consistency with the Fried criteria, predicted all-cause mortality, and reflected clinically important physical dysfunction.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): the Japan Society for the Promotion of Science Grant-in-Aid (JSPS KAKENHI, Grant Number 19K19884)
Determination of left ventricular diastolic dysfunction using machine learning methods
Authors: Kuznetsova N , Sagirova Z H , Dhif I , Gognieva D , Gogiberidze N , Chomakhidze P , Kopylov P
Published: October 2021

Introduction

Nowadays, more than 50% of new cases of heart failure (HF) are due to heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction of left ventricular underlies the development of HFpEF. Determination of diastolic function can be determinated using echocardiographic examination but not as a method of screening.

Purpose

Create a Machine Learning model to determinate severe (2nd or 3rd degrees) left ventricular diastolic dysfunction (LV DD) using single channel ECG.

Methods

The study prospectively included 375 patients aged between 18 and 88 years. Each of them underwent an assessment of left ventricular diastolic function using echocardiography based on ASE/EACVI guidelines and standard 2016. ECG was registered in I standard lead for 3 minutes. Then a spectral analysis of the ECG was performed using a wavelet transform based on the Fourier transform. Prediction of LV DD was implemented based on different machine learning methods.

Results

Based on the time intervals between the waves, the energy of the ECG signal in the target zones of the complexes, the amplitude at different points of the ECG complexes and the asymmetry indicators, different mathematical models were created to determine the severe (2nd or 3rd degree) LV DD. Lasso regression predicted the presence of severe LV DD with sensitivity 90% and specificity 80,6% (AUC- 0.856). The most significant for this method were the following variables: TA, SDNN, RonsF, ASEPMAX, B1, TpTe, ADP, SEPMAX, Sbeta, SEPF, RR, SRP-B0, Pan.1, QT/TQ, PpeakN, SA, SRP-B1. Random Forest also showed high sensitivity 80% and specificity 89, 3% (AUC- 0.860). For Random Forest model the most dignificant were: TpTe, VAT, QTc, QT/TQ, J80A, TA, Tenergy, Tpenergy, Beta, QRS11energy, Pan, Pan.1, RA, Pfi, QRSst, QRSfi, PpeakP, PpeakN, Rpeak, Speak, RonsF, B0-B1, SEP, SEP-B1, SEP-B0, SRP, SRP-B1, SRP-B0, ASEP. LV DD 1 degree did not have markers in our study.

Conclusion

Several machine learning methods have shown high sensitivity and specificity in identifying severe LV DD. Potentially ECG can be used as a screening method for determination of the LV DD.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): This work was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers “Digital biodesign and personalized healthcare” No. 075-15-2020-926