Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial.

AIM: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. MATERIALS AND METHODS: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 ). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed. RESULTS: Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m2 , glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants. CONCLUSION: SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD.

Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide.

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the "established CV disease" (CVD) and "CV risk factor" subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P-interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum.

The effect of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across baseline blood pressure categories: Analysis of the LEADER and SUSTAIN 6 trials.

It is unknown if the cardioprotective and renal effects of glucagon-like peptide-1 receptor agonists are consistent across blood pressure (BP) categories in patients with type 2 diabetes and at high risk of cardiovascular events. Using data from the LEADER (9340 patients) and SUSTAIN 6 (3297 patients) trials, we evaluated post hoc the cardiorenal effect of liraglutide and semaglutide on major adverse cardiovascular events (MACE) and nephropathy by baseline BP categories using a Cox proportional hazards model (treatment and subgroup as factors; adjusted for cardiorenal risk factors). Data from the two trials were analysed separately. In the LEADER and SUSTAIN 6 trials, the prevalence of stage 1 hypertension was 30% and 31%, respectively, and of stage 2 hypertension 41% and 43%, respectively. There was no statistical heterogeneity across the BP categories for the effects of liraglutide (P = .06 for MACE; P = .14 for nephropathy) or semaglutide (P = .40 for MACE; P = .27 for nephropathy) versus placebo. This implies that liraglutide and semaglutide may be beneficial for patients with type 2 diabetes, irrespective of their baseline BP.

Correlation of ST changes in leads V4-V6 to area of ischemia by CMR in inferior STEMI.

OBJECTIVE: We aim to determine the correlation between ST-segment changes in leads V4-V6 and the extent of myocardial injury by cardiac magnetic resonance (CMR) in patients with inferior ST elevation (STE) myocardial infarction (iSTEMI). DESIGN: Admission electrocardiogram and CMR data from the MITOCARE trial were used. Differences in mean myocardium at risk, infarct size, ejection fraction and myocardial segment involvement by CMR were compared in patients with first iSTEMI with STE, ST depression (STD) or no ST changes (NST) in V4-V6. Myocardial segment involvement was further evaluated by comparing proportion of patients in each group with ≥25% and ≥50% segment involvement. RESULTS: Fifty-four patients were included. Patients with STE (n = 22) and STD (n = 16) in V4-V6 had significantly lower ejection fraction compared to NST (n = 16) (48% vs 48% vs 54%, p = .02). STE showed more apical, apical lateral and mid-inferolateral involvement but less basal inferior involvement than NST. STD exhibited greater basal inferoseptal involvement compared to STE. There were more patients with STE that had ≥25% and ≥50% apical lateral involvement compared with STD and NST groups. Patients with STD were more likely to have ≥25% and ≥50% basal inferoseptal involvement compared with STE and NST groups. CONCLUSION: Our study suggests that in iSTEMI, ST changes in the precordial leads V4-V6 correlates with greater myocardial injury and distribution of myocardium at risk.

The significance of ST-elevation in aVL in anterolateral myocardial infarction: An assessment by cardiac magnetic resonance imaging.

BACKGROUND: Anterolateral myocardial infarction (MI) is traditionally defined on the electrocardiogram by ST-elevation (STE) in I, aVL, and the precordial leads. Traditional literature holds STE in lead aVL to be associated with occlusion proximal to the first diagonal branch of the left anterior descending coronary artery. However, concomitant ischemia of the inferior myocardium may theoretically lead to attenuation of STE in aVL. We compared segmental distribution of myocardial area at risk (MaR) in patients with and without STE in aVL. METHODS: We identified patients in the MITOCARE study presenting with a first acute MI and new STE in two contiguous anterior leads from V1 to V6 , with or without aVL STE. Patients underwent cardiac magnetic resonance imaging 3-5 days after acute infarction for quantitative assessment of MaR. RESULTS: A total of 32 patients met inclusion criteria; 13 patients with and 19 without STE in lead aVL. MaR > 20% at the basal anterior segment was seen in 54% of patients with aVL STE, and 11% of those without (p = 0.011). MaR > 20% at the apical inferior segment was seen in 62% and 95% of patients with and without aVL STE, respectively (p = 0.029). The total MaR was not different between groups (44% ± 10% and 39% ± 8.3% respectively, p = 0.15). CONCLUSION: Patients with anterior STEMI and concomitant STE in aVL have less MaR in the apical inferior segment and more MaR in the basal anterior segment.

Correlation of anteroseptal ST elevation with myocardial infarction territories through cardiovascular magnetic resonance imaging.

BACKGROUND: Anteroseptal ST elevation myocardial infarction (STEMI) is traditionally defined on the electrocardiogram (ECG) by ST elevation (STE) in leads V1-V3, with or without involvement of lead V4. It is commonly taught that such infarcts affect the basal anteroseptal myocardial segment. While there are suggestions in the literature that Q waves limited to V1-V4 represent predominantly apical infarction, none have evaluated anteroseptal ST elevation territories. We compared the distribution of the myocardium at risk (MaR) in STEMI patients presenting with STE limited to V1-V4 and those with more extensive STE (V1-V6). METHODS: We identified patients in the MITOCARE study presenting with a first acute STEMI and new STE in at least two contiguous anterior leads from V1 to V6. Patients underwent cardiac magnetic resonance (CMR) imaging three to five days after acute infarction. RESULTS: Thirty-two patients met inclusion criteria. In patients with STE in V1-V4 (n = 20), myocardium at risk (MaR) > 50% was seen in 0%, 85%, 75%, 100%, and 90% in the basal anteroseptal, mid anteroseptal, apical anterior, apical septal segments, and apex, respectively. The group with STE in V1-V6 (n = 12), MaR > 50% was seen in 8%, 83%, 83%, 92%, and 83% of the same segments. CONCLUSIONS: Patients with acute STEMI and STE in leads V1-V4, exhibit MaR in predominantly apical territories and rarely in the basal anteroseptum. We found no evidence to support existence of isolated basal anteroseptal or septal STEMI. "Anteroapical" infarction is a more precise description than "anteroseptal" infarction for acute STEMI patients exhibiting STE in V1-V4.

Clinical characteristics and lipid lowering treatment of patients initiated on proprotein convertase subtilisin-kexin type 9 inhibitors: a nationwide cohort study.

OBJECTIVES: Given the novelty of proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), little is known regarding overall implementation or clinical characteristics among patients who initiate treatment. We aimed to assess the total number of patients initiated on PCSK9i along with a description of the clinical characteristics and lipid lowering treatment (LLT) of such patients. SETTING: A register-based descriptive cohort study of patients receiving a PCSK9i in the time period from 01 January 2016 to 31 March 2017 using a cross linkage between three nationwide Danish registers. Information regarding PCSK9i prescriptions, patient demographics, concurrent pharmacotherapy, comorbidities and previous coronary procedures was identified. RESULTS: Overall, 137 patients initiated treatment with PCSK9i in the study period from 11 in the first quarter of 2016 to 40 in the first quarter of 2017. The majority had a history of ischaemic heart disease (IHD) (67.9%) with ischaemic stroke and diabetes mellitus being present in 7.3% and 16.8% of patients, respectively. All patients initiated on PCSK9i had been previously prescribed statin treatment with atorvastatin and simvastatin being most frequently prescribed in 53% and 36% of patients, respectively. The majority of patients had received both statins and ezetimibe (94.9%) and approximately half of these patients had also received bile acid sequestrant (45.3%). Clinical characteristics mainly differed in patients receiving triple LLT compared with patients not receiving triple LLT in the regards of heart failure. CONCLUSION: Patients treated with PCSK9i were rare, characterised by having IHD and had received various and intensive conventional LLT prior to PCSK9i initiation in agreement with current international guidelines.

The ECG as decision support in STEMI.

The electrocardiogram (ECG) can be used for determining the presence, location and extent of jeopardized myocardium during acute coronary occlusion. Accordingly, the ECG has become essential in the treatment of patients with acute coronary syndrome (ACS). This thesis aims at optimizing the decision support, provided by the ECG, for choosing the best treatment strategy in the individual patient with ST-segment elevation acute myocardial infarction (STEMI). ECG recorded in the prehospital setting has become the standard of care in many communities, but to achieve the full advantage of this early approach it is important that the ECG is recorded from accurately placed electrodes to produce an ECG that resembles the standard 12-lead ECG. Accurate electrode placement is difficult especially in the acute setting, and we investigated an alternative lead system with fewer electrodes in easily identified positions. We showed that the system produced waveforms similar to the standard 12-lead ECG. However, occasional diagnostic errors were seen, compromising general acceptance of the system. Once the ECG has been recorded a decision regarding triage must be made on the basis of a correct ECG diagnosis. We found that trained paramedics can diagnose STEMI correctly in patients without ECG confounding factors, while the presence of ECG confounding factors decreased their ability substantially. Consequently, since many patients do present with ECG confounding factors, transmission to an on-call cardiologist for an early correct diagnosis is needed. We showed that time to pPCI was reduced by more than 1 hour by transmitting prehospital ECG to a cardiologist's handheld device for diagnosis, triage, and activation of the catheterization laboratory when needed. The optimal treatment strategy is dependent on the duration of ischemia however patient information is often inaccurate. Accordingly, it would be advantageous if the first available ECG can help identify patients who will benefit greatly from acute reperfusion therapy versus patients with modest effect. We showed that by recognizing the acuteness of the infarction process the initial ECG can identify a group of patients with no potential for myocardial salvage despite short symptom duration. Urgent transport for pPCI may then not be necessary in this group of patients, and conservative treatment may be an option. Conversely, we also identified a group of patients with a large potential for myocardial salvage with acute reperfusion therapy despite long symptom duration. We also investigated whether ST-segment elevation on the initial ECG could provide prognostic information and thereby decision support for appropriate triage. All patients regardless of ST-segment elevation seemed to have most clinical benefit from pPCI. However, only patients with the greatest amount of ST-segment elevation had a reduced mortality rate with pPCI suggesting that patients with minor infarcts may achieve similar benefit from fibrinolysis followed by transfer to angiography and PCI. Once the triage decision is settled, STEMI patients must undergo ECG monitoring and receive antithrombotic therapy for optimal prehospital care. STEMI patients transported over even short distances are in danger of developing arrhythmic complications, but appropriate treatment is available when primary ambulances are supported by physician-manned ambulances in urban areas. Prehospital antithrombotic therapy must be effective in preparing the patient for pPCI without causing bleeding. Heparin is currently the standard therapy, but we showed that the direct thrombin inhibitor bivalirudin may be an attractive alternative by causing less bleeding events, and a higher frequency of preprocedure thrombolysis in myocardial infarction (TIMI) 3 flow. After reperfusion therapy a decision regarding the need for further treatment is desirable. By determining ST-segment resolution in the post-reperfusion ECG we showed that the degree of ST-segment resolution at 90 minutes and 4 hours is important for risk stratification after fibrinolysis, but not after pPCI. Interestingly, we found that patients with compete ST-segment resolution treated with fibrinolysis had the highest risk of reinfarction. Consequently, transfer to a PCI-facility should be considered in all patients treated with fibrinolysis as the initial reperfusion therapy. Based on the findings in the present thesis we conclude that the ECG is an important tool for decision support in every step from symptom onset to post-reperfusion therapy in STEMI patients.

[Telemedicine in the transmission of prehospitalisation ECGs of patients with suspected acute myocardial infarction]. / Telemedicinsk elektrokardiogramtransmission i den praehospitale fase hos patienter, der er under mistanke for at have akut myokardieinfarkt.

INTRODUCTION: Time to reperfusion is critical to the outcome of patients with ST-elevation myocardial infarction (MI). Other studies have indicated that wireless transmission of prehospital ECGs can reduce the time to reperfusion. This study evaluated the effect on time to treatment using prehospitalisation ECG transmission to a cardiologist's handheld device in patients with acute chest pain, as well as the potential effect of direct transfer of patients to the closest appropriate cardiological facility. MATERIALS AND METHODS: During a one-year study period, prehospitalisation ECGs were transmitted for all patients with symptoms indicative of acute coronary syndrome. The ECGs were received on a handheld device by an attending cardiologist, and the patient was referred to PCI treatment if ST-elevation was found. RESULTS: 152 transmissions were registered; 27 of these patients underwent primary PCI treatment. 135 (89%) of the attempted transmissions were successful. Compared to historic controls, there was an increased on-scene time usage of 7 minutes, including transfer. The median time spent from arrival at the hospital to the start of invasive treatment was low, 22 minutes. Compared to historic controls, we found a total reduction in time spent of 72 minutes (p< 0.01). DISCUSSION: The results indicate that it is possible to minimize the time delay to primary PCI treatment by direct transfer through consultation and use of wireless transmission of prehospitalisation-acquired ECGs to a handheld device carried by an attending cardiologist.