Randomized Clinical Trial Research Articles

Sub-Saharan Africa's contribution to clinical trials in international acute coronary syndromes and heart failure guidelines

Abstract Introduction There is a growing burden of acute coronary syndrome (ACS) and heart failure (HF) in sub-Saharan Africa (SSA), yet outcomes remain poor compared to high-income countries (HICs). Global clinical guidelines are pivotal to the delivery of evidence based cardiovascular care, however their applicability to populations in SSA remains unclear. Purpose To evaluate the extent to which populations from SSA contribute to pharmacotherapeutic randomised clinical trials informing international ACS and HF clinical guidelines. Methods We extracted details on pharmacotherapeutic randomised control trials (RCTs) contributing to Class I or II guideline recommendations from the 2023 European Society of Cardiology (ESC) guidelines for ACS and the 2021 ESC guidelines for HF. Data on RCTs contributing to these guidelines were extracted from the ClinicalTrials.gov or published articles. We analysed the proportion of RCTs which had a contribution from countries in each World Bank income group. Then we specifically assessed the contribution of SSA countries to clinical trials and analysed temporal trends. Results Of 119 RCTs from the ESC HF guidelines and the 343 pharmacotherapy RCTs from the ESC ASC guidelines 75.9% were exclusively conducted in high-income countries, 22.2% of the trials included at least one site from a middle-income country and none included sites from a low-income country (figure 1). The global distribution of HF (figure 2a) and ACS (figure 2b) pharmacotherapy guidelines is demonstrated in figure 2. The only country represented from SSA was South Africa which is an upper middle-income country. A site from South Africa was included in 17 (14.2%) HF RCTs and 28 (8.2%) ACS RCTs. There has been a significant increase in the proportion HF RCTs conducted in SSA, increasing from 2.6% between 1990 and 1999 to 50% since 2020 (OR 28.8, 95% CI 2.6 – 983.4, p-value for trend< 0.0001). For ACS RCTs, the proportion of trials conducted in SSA increased from 1.8% pre 1990 to 23.4% during 2000-2009 (OR 15.9, 95% CI 4.2 - 112.9, p value for trend = 0.003) then declined to 11.3% from 2010-2019. Conclusions There is a marked under-representation of SSA countries in ACS and HF pharmacotherapy RCTs, despite the region's escalating cardiovascular disease burden. South Africa is the sole contributor from the region, with all other SSA countries absent. This finding could potentially affect the applicability and generalisability of global guidelines to populations in SSA with distinct clinical presentations and healthcare challenges.Figure 1 Figure 2

Heterogeneous effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular events among people with type 2 diabetes: an application of machine learning to target trial emulation

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are widely used to reduce cardiovascular risk in patients with type 2 diabetes. However, certain patient subgroups, including younger individuals or those with lower body mass index (BMI), have been underrepresented in previous randomized clinical trials. Therefore, the consistency of the effectiveness of SGLT2i has not been thoroughly investigated. Purpose This research aims to investigate the individual benefit of SGLT2i on cardiovascular risk reduction across the diverse patient population with type 2 diabetes Methods We investigated the effectiveness of SGLT2i versus active comparators (dipeptidyl peptidase 4 inhibitors [DPP4i]) using a target trial emulation framework, prevalent new-user design, and a nationwide insurer-based database covering more than 30 million working-age citizens in Japan. Participants were identified using data from April 2015 to March 2022 and were followed until March 2023. The primary endpoint was the composite of all-cause death, myocardial infarction, stroke, or heart failure. We then applied the machine learning causal forest algorithm to the emulated trial cohort to predict the individualized benefit of SGLT2i in reducing cardiovascular outcomes. After describing the characteristics of patients with predicted benefits above the median (high-benefit group) and those with predicted benefits below the median (low-benefit group), we compared the long-term survival outcomes between the high-benefit group and the low-benefit group using adjusted Cox proportional hazard models. Results The study included 274,886 participants (SGLT2i, n=137,443; DPP4i, n=137,443) with a mean age of 55.7 years, 17.3% (n=47,517) female, and a mean BMI of 27.3kg/m2. Over a median follow-up of 36 months, 3.6% (n=9,896) experienced the primary outcome. SGLT2i were associated with a reduced incidence of the primary endpoint in the entire cohort (hazard ratio [HR] = 0.94 [95% confidence interval (95%CI): 0.90–0.97]). The causal forest model showed that the effects of SGLT2i were heterogeneous across individuals. Patients in the low-benefit group were characterized by older age, female gender, lower BMI, lower blood pressure, worse kidney function, and milder diabetes status than those in the high-benefit group. While we found the preventive effect of SGLT2i on long-term cardiovascular outcomes in the high-benefit group (HR [95%CI] = 0.86 [0.82–0.90]), the effect was not observed in the low-benefit group (HR [95%CI] = 1.05 [1.00–1.11]; p-for-interaction < 0.001). Conclusion By applying a machine-learning causal forest to a target trial emulation cohort in the general population, we found heterogeneity in the effect of SGLT2i on cardiovascular outcomes, and identified characteristics of patients who are less likely to benefit from SGLT2i. The findings suggest personalized treatment strategies for cardiovascular risk reduction in patients with type 2 diabetes.Graphical summary

Effects of Sacubitril/Valsartan on all-cause hospitalizations in heart failure: participant-level pooled analysis of PARADIGM-HF and PARAGON-HF

Abstract Background Sacubitril/valsartan is indicated to reduce the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with chronic HF. However, many of these patients are older and have multiple comorbidities that increase the risk of hospitalizations other than HF, yet the effects of sacubitril/valsartan on hospitalizations of any cause have not been well described. Methods PARADIGM-HF and PARAGON-HF were phase-3, global multicenter randomized clinical trials that evaluated sacubitril/valsartan versus enalapril (in PARADIGM-HF) or valsartan (in PARAGON-HF) across the spectrum of left ventricular ejection fraction (LVEF; ≤40% in PARADIGM-HF and ≥45% in PARAGON-HF). We pooled individual participant-level data from these 2 trials to examine the effects of sacubitril/valsartan on time-to-first investigator-reported all-cause and cause-specific hospitalization using Cox proportional hazards models, stratified by geographic region and trial. We additionally examined heterogeneity in treatment response by LVEF. Results Over 2.8 years median follow-up, among 13,194 participants in the pooled PARADIGM-HF/PARAGON-HF, sacubitril/valsartan significantly reduced the risk of all-cause hospitalizations compared with renin-angiotensin system inhibitor (HR 0.92; 95% CI 0.88-0.97; P=0.002); Figure 1 Panel A. The absolute risk reduction (ARR) was 2.1 per 100 patient-years corresponding to a number-needed-to-treat (NNT) of 48 patient-years of treatment exposure to prevent 1 all-cause hospitalization. Reductions in overall hospitalizations among patients with identifiable causes (N=5,783) seemed to be primarily driven by lower rates of cardiac and pulmonary hospitalizations associated with sacubitril/valsartan. Patients treated with sacubitril/valsartan did not have a higher rate of composite non-cardiac hospitalizations (Figure 1 Panel B). Similarly, sacubitril/valsartan reduced the risk of the composite of all-cause hospitalization or all-cause mortality (HR 0.92; 95% CI 0.87-0.96; P<0.001), with an ARR of 2.5 per 100 patients-years and an NNT of 40 patient-years. For all-cause hospitalization, we observed significant heterogeneity by LVEF as a continuous measure (Pinteraction=0.027); treatment effects were most apparent in those with an LVEF below 60% (HR 0.91 95% CI 0.86-0.96; Figure 2). Conclusions In a pooled analysis of >13,000 patients with chronic HF, sacubitril/valsartan reduced hospitalization for any reason with benefits most apparent among those with an LVEF below normal.

Clinical implications of atrial fibrillation recurrence vs. burden following catheter ablation: outcome data from 3 contemporary clinical trials using an insertable cardiac monitor

Abstract Background Recurrence of atrial fibrillation (AF) following catheter ablation is typically defined in clinical trials in a binary fashion, e.g. > 30 seconds or none. However, the clinical implications of this endpoint, adopted from formal guidelines, have been questioned. Purpose We hypothesized that assessment of AF burden can provide incremental clinical and management implications to the dichotomous definition of AF recurrence following ablation. Methods The study population comprised 147 patients enrolled in 3 ongoing multicenter randomized clinical trials (ICM REDUCE-AF [N=67]); HYBRID-AF (N=55] and DAPA-AF [N=25]), each employing an insertable cardiac monitor (ICM) to assess post-ablation AF recurrence and burden. The rate of cardiovascular (CV)-related healthcare utilization (CV-HCU, defined as the total number CV admissions, ED visits, cardioversions, procedures, and unplanned office visits) was compared based on AF recurrence (defined as >2 minutes of ICM-detected AF) vs. based on AF burden post-ablation (defined as time in AF divided by total monitoring time). Results Among the 147 study patients, mean age was 65 years; 53 (36%) were women; and 78 (53%) had persistent AF. At 12-months post-ablation (excluding blanking), the cumulative probability of AF recurrence was 60% (Figure 1A). However, 27% of AF recurrences were associated with a very low AF burden (≤0.1%) and low CV-HCU (10 events per 100 patient-months), similar to patients without AF recurrence (11 events per 100 patient-months). In contrast, recurrences with a higher AF burden (>0.1%; mean 17% ± 25%) were associated with a 3-fold higher rate of CV-HCU (31 events per 100 patient-months, p<0.001; Figure 1B). Findings were consistent regardless of AF-type, comorbidities or LVEF. Conclusions A substantial proportion of AF recurrences following contemporary AF ablation are associated with a very low AF burden without apparent effect on CV outcomes, whereas higher AF burden is associated with increased CV-HCU. These findings stress the need to move beyond a dichotomous definition of AF recurrence and to monitor AF burden post-ablation to guide management decisions in contemporary clinical practice.Figure 1

A new hydration strategy can reduce contrast-induced acute kidney injury after PCI in patients with chronic heart failure and chronic kidney disease: a two-center randomized controlled trial

Abstract Backgrounds Adequate hydration is crucial for preventing contrast-induced acute kidney injury (CI-AKI), particularly in patients with chronic kidney disease (CKD). The current guidelines recommend half-volume hydration for patients with chronic heart failure (CHF) to prevent pulmonary edema. Thus, it is challenging to administer hydration therapy in patients with CHF and CKD. This study was aimed to compare different hydration strategies in this subset of patients. Methods This two-center, open-label, randomized clinical trial enrolled 303 CHF (patients with elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion) patients with CKD (estimated glomerular filtration rate [eGFR] of 15-60 mL/min/1.73m2) undergoing selective coronary angiography (CAG) from two tertiary hospitals from October 2020 to December 2023. Patients were randomized into three groups: half-volume hydration group (HH group, 0.5 mL/Kg/h hydration), standard hydration group (SH group, 1 mL/Kg/h hydration), and standard hydration with diuretic group (SH+D group, 1 mL/Kg/h hydration + immediate postoperative intravenous injection of furosemide 20 mg). All patients received hydration from 6 to 12 hours before to 24 hours after the procedure. The primary endpoint was CI-AKI, defined as a serum creatinine (SCr) increase of more than 0.3 mg/dL or 1.5-1.9 times greater than the baseline 48-72 hours after CAG. Safety endpoints included pulmonary edema during hydration, perioperative mortality, and the need for dialysis. Results A total of 101 patients were included in each group. Baseline characteristics (mean age, proportion of males, left ventricular ejection fraction and eGFR) were similar among groups. SCr, cystatin C levels, and SCr level changes between 48 and 72 hours after procedure did not significantly differ among groups (P > 0.05). The incidence of CI-AKI was highest in the HH group (22.8%), lowest in the SH+D group (11.9%), and intermediate in the SH group (17.8%) (P = 0.041). Regarding safety endpoints, there were 2 patients in the HH group, 3 patients in the SH group and 1 patient in the SH+D group experienced heart failure or pulmonary edema during hydration, with no statistically significant differences among the groups (P = 0.874). Perioperative mortality occurred in 1 patient in the HH group and 2 patients in the SH+D group, with no statistically significant differences (P = 0.776). No patient required renal replacement therapy. Conclusions In CHF patients with CKD, the half-volume hydration regimen recommended by guidelines was associated with a higher incidence of CI-AKI compared to standard hydration. However, standard hydration combine with diuretic fails to reduce the risk of heart failure during hydration or perioperative mortality, even if this novel strategy does not increase the risk of CI-AKI compared to standard hydration therapy.

Effects of rivaroxaban on vascular endothelial function and circulating endothelial progenitor cells: a randomized controlled trial

Abstract Background Combination of low dose rivaroxaban with aspirin was shown to reduce major adverse cardiovascular events when compared to aspirin monotherapy in COMPASS trial. The beneficial effect of rivaroxaban beyond factor Xa inhibition remains unknown. Purpose This randomized controlled trial explored the effects of rivaroxaban on vascular endothelial function and circulating endothelial progenitor cells in patients with stable atherosclerotic disease. Methods An investigator-initiated, investigator-blinded, single-center randomized clinical trial was conducted from May 2021 to August 2023. 142 patients were randomized in 1:1 ratio to receive rivaroxaban 2.5mg twice daily plus aspirin 100mg once daily (Treatment Group) or aspirin 100mg once daily (Control Group) and had follow-up for 3 months. The primary outcome was change of flow mediated dilation (FMD) from baseline to 3-month follow-up. Key secondary outcomes included change of circulating endothelial progenitor cells (CD45+/34+/133+, CD45+/34+/KDR+), platelet activation marker (CD41+/62p+), inflammatory marker (CD14+/11b+) and thrombo-inflammatory maker (CD14+/42b+) measured by flow cytometry, as well as platelet function (aspirin reaction unit, ARU) measured by blood biochemistry. Intention-to-treat analysis was performed with analysis of covariance (ANCOVA) and P < 0.05 was considered statistically significant. Results Overall, 142 patients were enrolled in the study. One patient was excluded from analysis due to protocol deviation. Among the remaining 141 patients (78.8% male and mean age 69±9 years), there were 71 in Treatment Group and 70 in Control Group. The recruited patients had a high prevalence of cardiovascular comorbidities including 76.6% with hypertension, 50.4% with hyperlipidemia, 45.4% with diabetes, and 92.2% with percutaneous coronary intervention. At 3 months, Treatment Group had greater FMD improvements (+2.18±5.66% vs +1.57±5.07%, P=0.03), and more reduction in platelet activation marker (-0.33±13.55% vs +5.78±21.60%, P=0.01). There was no significant change in circulating endothelial progenitor cells, inflammatory marker, thrombo-inflammatory maker, and platelet function. Minor bleeding occurred in 2 patients (2.82%) in Treatment Group and none in Control Group (P>0.05). Conclusion In patients with stable atherosclerotic disease, addition of rivaroxaban to aspirin was well tolerated, and it improved vascular endothelial function and reduced platelet activation.

Acupuncture-assisted lifestyle intervention improve the metabolic status and spontaneous brain activity of type 2 diabetes Mellitus patients: a randomized, clinical trial

BackgroundAggressive weight management in patients with type 2 diabetes mellitus has demonstrated numerous metabolic advantages, however, existing therapies for weight control have not reached satisfactory results. This study aimed to evaluate the efficacy and safety of acupuncture in the weight management of type 2 diabetes mellitus (T2DM) patients by using a randomized, sham-controlled clinical trial design.MethodsIn this single-blind randomized clinical trial, 102 overweight adult T2DM patients were randomized into two groups. The control group receives diet, exercise, and sham acupuncture intervention, whereas the acupuncture group receives diet and exercise and acupuncture intervention, both for 1 month. Body weight and other anthropometric and laboratory indices were assessed at baseline and endpoint, meanwhile, the body fat content and spontaneous brain activity were measured by functional magnetic resonance imaging(fMRI)as the exploratory outcomes.ResultsNo significant difference was observed between the studied parameters at the baseline. The body weight and BMI were significantly reduced both in the control and acupuncture groups after intervention, without statistical difference between the two groups. What’s interesting is that compared to the control, the acupuncture group displayed a greater improvement in central fat tissue. It notes that the acupuncture group achieved significant liver fat content reduction than the sham acupuncture group. At the same time, the spontaneous brain activity in the occipital lobe and parietal lobe significantly increased in the acupuncture group.ConclusionOne month of acupuncture treatment preferentially improved ectopic fat deposition and was accompanied by changes in brain activity compared with the control group, even before significant changes in total body weight had occurred. further studies of longer duration are necessary for validation.Trial registration: The protocol of this clinical trial is registered at the Acupuncture-Moxibustion Clinical Trial Registry (AMCTR, http://www.acmctr.org/, No. AMCTR-IOR-20000341).

Applicability of VICTORION-1 PREVENT Criteria to the US Population

Abstract Background VICTORION-1 PREVENT (V-1P) is an ongoing randomized clinical trial comparing inclisiran sodium 300mg every six months with placebo for primary prevention in patients with high cardiovascular (CV) risk. Purpose We evaluated the generalizability of V-1P trial enrollment criteria to the US population to understand the demographic and CV health characteristics of the trial target population. Methods We included data from the National Health and Nutrition Examination Survey (N=25,531, 2015-March 2020), a nationally representative sample of the US population. Enrollment criteria similar to V-1P were applied. Nonpregnant adults 40-79 years with low-density lipoprotein cholesterol (LDL-C) of 70-189 mg/dL were included. 10-year risk for CV disease was determined using the American Heart Association race-free 10-year PREVENT risk equations. Individuals with 10-year risk >20% or 7.5%-19.9% with two risk enhancing factors at baseline were included. Risk enhancing factors included elevated high sensitivity C-reactive protein (≥2 mg/L), inflammatory arthritis, estimated glomerular filtration rate <60 ml/min/1.73 m2, metabolic syndrome, or early family history of CV disease. Patients with history of atherosclerotic CV disease or liver disease were excluded. Estimates of demographics and health characteristics were nationally representative using survey weights. Results Among US adults, 21,576,506 (standard error [SE]: ±1,258,255) meet eligibility criteria for V-1P (weighted estimate). This represents 8.8% of all US adults or 15.1% of US adults 30-79 years. The V-1P eligible population had a mean age of 65.3 years (SE: ±0.5 years), and 55.0% (SE: ±2.5%) were female. Compared with the US adult population (≥18 years), V-1P eligible population had a higher mean body mass index (32.6 ± 0.3 kg/m2 vs 29.5 ± 0.2 kg/m2) and higher rates of obesity (61.0% ± 2.1% vs 40.0% ± 1.1%) (Table). V-1P eligible population also had higher mean systolic blood pressure (133.9 ± 1.0 mmHg vs 121.7 ± 0.3 mmHg), similar mean diastolic blood pressure (72.6 ± 0.8 mmHg vs 71.8 ± 0.2 mmHg), and higher rates of hypertension (85.8% ± 2.0% vs 45.9% ± 1.1%). Mean hemoglobin A1c percent (6.3 ± 0.1 vs 5.7 ± 0.02), fasting blood sugar (127.7 ± 1.9 mg/dL vs 109.2 ± 0.6 mg/dL), and diabetes rates (39.7% ± 2.6% vs 13.1% ± 0.7%) were higher in the V-1P eligible population. Mean low-density lipoprotein cholesterol (115.8 ± 1.5 mg/dL vs 110.2 ± 0.8 mg/dL) and fasting triglycerides (137.6 ± 5.0 mg/dL vs 110.4 ± 1.7 mg/dL) were higher, while mean high-density lipoprotein cholesterol was lower (49.9 ± 0.8 mg/dL vs 54.8 ± 0.4 mg/dL). The distribution of key CV risk factors is shown in the Figure. Conclusion V-1P enrollment criteria apply to many patients. These patients have significant cardiometabolic risk factor burden, and effective preventive therapies could have substantial health impact.

Evaluation of concordance and association with clinical outcomes across eGFR values calculated with eight different formulas in a large cohort of european patients with atrial fibrillation

Abstract Background In randomized clinical trials of Direct Oral Anticoagulants (DOACs), the assessment of renal function impairment glomerular filtration rate (eGFR) in patients with Atrial Fibrillation (AF) has predominantly utilized the Cockroft-Gault (CG) formula for estimating Creatinine clearance (CrCl). However, in clinical practice, several other formulas for estimating glomerular filtration rate (eGFR) are employed. Limited data exist regarding the evaluation and comparison of eGFR/CrCl in AF patients. Objectives This study aimed to assess the concordance in the categorisation of renal function in in 6 classes taking into account eight different formulas for eGFR/CrCl (CG, CKD-EPI, CG/body surface area [BSA], BIS1, LMK, EKFC, FAS, MDRD) and their associations with a composite outcome (Major Adverse Cardiovascular Events [MACE] and all-cause death) in AF patients. Methods A contemporary European AF patient registry was utilized, and eGFR/CrCl were calculated using CG, CKD-EPI, CG/BSA, BIS1, LMK, EKFC, FAS, and MDRD formulas. eGFR was categorized according to KDIGO classes, with CKD patients defined as having eGFR/CrCl <60 ml/min/m2. Concordance was estimated using weighted Cohen’s kappa. Associations were evaluated through adjusted Cox regression analyses for the composite outcome, and results were plotted as spline curves. Results: A total of 8516 patients were included in the analysis (Median [IQR] age: 70 [63-77] years; 3518 women, 41.3%). Among the formulas, EKFC exhibited the highest median values of eGFR and the lowest prevalence of CKD patients, while BIS1 had the lowest median eGFR values, and the FAS formula led to the highest prevalence of CKD patients [Figure 1]. In the concordance analysis, CKD-EPI demonstrated the highest concordance with all other formulas, even if Cohen’s kappa for measuring the degree of concordance ranged from 0.61 to 0.88 [Figure 1]. In adjusted Cox regression analyses, all formulas were associated with an increased risk for the composite outcome, progressively as eGFR decreased. When plotted as spline curves, the associations with the composite outcome visually showed a similar behaviour of risks across eGFR values in all formulas compared to the CG spline [Figure 2]. Conclusions Among AF patients, the CKD-EPI formula exhibited variable, but substantially good concordance with CG, CG/BSA, BIS1, LMK, EKFC, FAS, and MDRD formulas. All calculated eGFR values showed a strong association with the composite outcomes, similarly to the CG formula, with higher risk when renal function decreased.FIGURE 1FIGURE 2

Cardioprotection with transcoronary saline infusion during primary angioplasty for ST-elevation myocardial infarction: design and rationale of the STEMI-Cool pilot study

Abstract Background Prompt restoration of blood flow in ST-segment elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (pPCI) improves outcomes, but is associated with myocardial stunning, increased infarct size, and microvascular dysfunction. To date, there is no effective therapy to reduce this ischaemia-reperfusion injury (IRI). Mild systemic hypothermia has demonstrated potential but is difficult to achieve and poorly tolerated. Transcoronary hypothermia delivers rapid and effective myocardial cooling, is well tolerated, but not effective when commenced after flow restoration. Coronary haemodilution during reperfusion has shown cardioprotective effects in preclinical studies but has not been fully assessed. Purpose STEMI-Cool is a pragmatic, registry-based randomised clinical trial to assess recruitment rate, feasibility, and safety of a simple protocol which we have reported in a proof-of-concept study. The study has commenced recruitment and aims to overcome the limitations of previous negative studies by combining the beneficial effects of transcoronary cooling and dilution, initiating the infusion prior to wire insertion - therefore avoiding initial unprotected reperfusion (likely to be the critical time for IRI), and avoiding significant delays in reperfusion. Moreover, we will explore mechanistic endpoints and an original method to quantify the intracoronary dilution (with a thermodilution-derived "haemodilution constant ratio"). Lastly, we will investigate ways to "engineer out" the thermistor wire so that the method could be applied to routine pPCI with conventional equipment. Methods Pragmatic broad eligibility criteria allow potential recruitment of all STEMI cases clinically eligible for pPCI. Sixty patients will be randomised 1:1 to standard of care or protected reperfusion with continuous infusion of room temperature saline through the guiding catheter, to achieve intracoronary temperature reduction of 6-8°C. The infusion commences prior to crossing the occlusion with a thermistor wire, which is used as guidewire, and continues for 10 minutes after flow restoration (i.e., TIMI flow≥2). Invasive coronary physiology studies are undertaken after pPCI. Novel and established biomarkers of myocardial damage and inflammation (including dipeptidyl peptidase 3, tumor necrosis factor α, and interleukins 1β, 6, 10) are measured in the preprocedural arterial blood. Cardiac imaging and clinical outcomes are assessed at 48h and 6-12 months. Nesting STEMI-Cool in our local registry Heart-ACS facilitates blood sampling and follow-up. Conclusions STEMI-Cool will primarily investigate recruitment rate, feasibility and safety of an innovative, simple cooling and diluting strategy for cardioprotection during pPCI. Mechanistic outcomes will explore inflammatory, microvascular, structural and functional changes. Finally, we will aim to simplify further the protocol for future research and potential clinical use.STEMI-Cool method schematicSTEMI-Cool protocol timeline

Outcomes of CT- or CMR-guided TAVR according to sex: a secondary analysis of the randomized TAVR-CMR trial

Abstract Background Previous studies have reported sex differences in pre-procedural imaging characteristics of patients undergoing transcatheter aortic valve replacement (TAVR) evaluation. Whether these differences affect the outcome of computed tomography (CT)-guided or cardiac magnetic resonance (CMR)-guided TAVR has not been studied. Objectives This analysis aimed to evaluate sex-based differences in imaging findings and outcomes in patients undergoing TAVR for severe aortic valve stenosis. Methods This was a secondary analysis of the TAVR-CMR trial, a randomized clinical trial comparing TAVR planning by CT or CMR. Outcomes (based on the Valve Academic Research Consortium (VARC)–2 definition) with each imaging strategy were compared according to sex. Results Of 380 patient randomized into the TAVR-CMR trial, 194 (51.1%) were female and 186 (48.9%) were male. Of these, 267 patients eventually underwent TAVR (133 women (49.8%) and 134 men (50.2%), p=0.457). Imaging findings differed between the sexes for both imaging modalities. The comparison between CT and CMR to assess the access route and landing zone showed no difference in both women and men (all p>0.05). Implantation success was not significantly different between imaging strategies for both women (84.7% (CT group) vs. 93.2% (CMR group), p=0.11) and men (95.7% (CT group) vs. 93.8% (CMR group), p=0.61). All-cause mortality at 6 months was not significantly different between imaging strategies for both women (10.2% (CT group) vs. 8.1% (CMR group), p=0.68) and men (4.3% (CT group) vs. 9.4% (CMR group), p=0.24). Conclusions This secondary analysis has confirmed sex-related differences in pre-procedural imaging characteristics, with no influence of the imaging modality used. Similar outcomes were observed in both female and male patients when the TAVR was guided by either a CMR or a CT scan.

Race in heart failure: a pooled participant-level analysis of the global PARADIGM-HF and PARAGON-HF trials

Abstract Background Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF). Early experiences with neprilysin inhibition suggested possible increased risks of angioedema, especially among Black individuals. We aimed to examine the safety and efficacy profile of sacubitril/valsartan in a pooled participant-level dataset of 2 large cohorts of patients with HF by self-reported race. Methods PARADIGM-HF and PARAGON-HF were multicenter, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor (RASi, enalapril or valsartan, respectively) in patients with HF and LVEF ≤40% (PARADIGM-HF) or LVEF ≥45% (PARAGON-HF). We included all patients with available data on self-reported race and categorized patients as White, Asian, or Black. We assessed adjudicated outcomes including the composite of first HF hospitalization (HFH) or cardiovascular (CV) death, its components, and angioedema by racial group. Results Among 12,097 included participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Asian participants were from 19 countries, with highest enrollment from India, China, and the Philippines. Black participants were from 18 countries, with highest enrollment from the US, South Africa, and Brazil. Black patients had the worst baseline health status (adjusted KCCQ-OSS mean 70.3), while White (71.4) and Asian patients (76.4) had better health status; P<0.001. Over 2.4-years of median follow-up, Black (adjusted HR 1.67; 95% CI 1.37-1.89; P<0.001) and Asian patients (adjusted HR 1.32; 95% CI 1.16-1.50; P<0.001) experienced higher risks of the primary outcome compared with White patients (Figure 1). The treatment effects of sacubitril/valsartan vs. RASi on the primary endpoint were consistent among White (HR 0.84; 95% CI: 0.77-0.91), Asian (HR 0.92; 95% CI: 0.78-1.10), and Black patients (HR 0.79; 95% CI: 0.58-1.07; Pinteraction = 0.39). In light of higher baseline risks, Black patients accrued the greatest absolute risk reduction with sacubitril/valsartan (Figure 2). Consistent treatment benefits by race were also observed for the individual components (CV death alone and first HFH alone). Rates of any adjudicated angioedema were numerically higher with sacubitril/valsartan vs. RASi across race groups (White 0.4% vs. 0.2%; Asian 0.6% vs. 0.2%; Black 2.3% vs. 0.8%), however no patient in either trial experienced airway compromise or required mechanical airway protection. Conclusions In a pooled experience of over 12,000 participants enrolled in 2 trials conducted across 56 countries, Black and Asian patients exhibited a higher risk of CV events than White patients. Rates of non-serious angioedema were numerically higher with sacubitril/valsartan across race groups. The relative CV benefits of sacubitril/valsartan were consistent across races, with greatest absolute benefits observed in Black patients.

Intracardiac leadless pacemaker: long term safety over traditional pacemakers. a systematic review and meta-analysis

Abstract Introduction Leadless pacemaker (LP) is a novel technology designed to reduce lead-related, including pocket infections, associated with traditional pacemakers. LP can be used in patients with high-degree AV block, sinus node dysfunction, and bradycardia with syncope. We conducted a systematic review and meta-analysis to examine the long-term safety of intra-cardiac leadless pacemakers compared with traditional pacemakers. Methods Our protocol was registered in advance on PROSPERO. Studies were eligible if they compared complications, revision, cardiac perforation, infections, and all-cause mortality between patients who received leadless pacemakers versus traditional pacemakers. The systematic search was conducted in five databases (MEDLINE, EMBASE, CENTRAL, Web of Science, Scopus) without restriction. The random-effect model was implemented to calculate pooled odds ratio (OR) with a 95% confidence interval (CI). Also, the Mantel-Haenszel method, Paule-Mandel estimator for tau^2, Q-Profile method for the confidence interval of tau^2 and tau, and Hartung-Knapp adjustment for random effects model methods were used for the prediction of data extracted directly from the curves. ROBINS-I tool was used for the risk of bias assessment, and the certainty of the evidence was evaluated with the GRADE approach. Results Of 6450 studies screened, we identified 21 observational studies of Nanostim and Micra leadless pacemakers. The pooled incidence of complications of leadless versus traditional pacemakers at 1, 6, 12-24 months show the odds are clinically and statistically different (OR=0.66, 95% CI: 0.42–1.02; OR=0.44, 95% CI: 0.22–0.86; OR=0.41, 95% CI: 0.32–0.53 respectively). The pooled incidence of infection rate at 6, 12-24 months is lower in patients with LP (OR=0.37, 95% CI: 0.31–0.44; OR=0.20, 95% CI: 0.00–97.31). The studies comparing all-cause mortality during 6, 12-24 months in leadless versus traditional pacemakers did not show statistically significant differences in these outcomes (OR=1.26, 95% CI: 0.88–1.81; OR=0.86, 95% CI: 0.25–2.92 respectively. Conclusion Our results show that complications and infections occur less frequently in patients with leadless pacemakers than in patients with conventional pacemakers with no difference in all-cause mortality. However, there is a need for high-quality randomized clinical trials and propensity score-matched studies focusing on this clinically relevant question.Complication Forest plotsInfection Forest plots

Persistent angina following revascularization for chronic coronary syndromes: a systematic review and meta-analysis of randomized controlled trials

Abstract Introduction Recent randomized clinical trials (RCTs) have demonstrated that revascularization plus optimal medical therapy for patients with chronic coronary syndromes (CCS) results in greater reduction in angina than medical therapy alone. However, the frequency of persistent angina following revascularization for CCS is not well understood. Purpose To quantify the frequency of persistent angina following revascularization in contemporary RCTs of revascularization plus medical therapy vs. medical therapy alone among patients with CCS. Methods A literature search through January of 2024 was conducted in PubMed and Cochrane Central Register of Controlled Trials for contemporary RCTs reporting angina frequency following randomization to revascularization plus medical therapy vs. medical therapy alone. The primary outcome of interest was the frequency of persistent angina in the revascularization arms of these studies at early (3-12 months) and late (3-5 years) time points. A random effects model was used to combine results from individual studies. Results From a total of 5287 citations, the search yielded 7 RCTs that met inclusion criteria. These studies randomized 5719 patients to an invasive or revascularization strategy. Revascularization was exclusively by percutaneous coronary intervention (PCI) in 4 studies and by coronary artery bypass grafting or PCI in 3 studies. At the early time point, the combined frequency of persistent angina was 39.6% (95% CI: 30.6-49.4). For the two blinded, sham-controlled studies, the rate of persistent angina was significantly greater at 67.2% (95%CI: 54.9-77.4) compared to 30.5% (95% CI: 23.1-39) in the unblinded studies (P<0.001). In the 5 studies with 3-5 years of follow-up, the frequency of persistent angina was 33.3% (95% CI: 19.2-51.2). Conclusion Persistent angina is common after revascularization for CCS and suggests alternative causes and treatments of residual angina should be considered.

Relapse of infective endocarditis after cardiac implantable electronic device removal compared to a conservative strategy

Abstract Background According to current guidelines, complete removal of cardiac implantable electronic device (CIED) should be considered in patients with valvular infective endocarditis (IE), accounting for the identified pathogen and need for valve surgery (Class IIa recommendation). Unselected longitudinal data are needed to assess this strategy. Purpose To examine IE readmission after IE discharge according to status of CIED removal in patients with conservatively treated IE. Methods Using Danish nationwide registries, we identified patients aged ≥18 years with first-time IE from 2010-2021. We included patients with conservatively treated IE and a CIED, who were alive at IE discharge. Patients who underwent CIED removal during IE admission were compared to those without removal, examining the study outcome of IE readmission within six months after IE discharge. An initial blanking period of 14 days was applied after IE discharge. The Aalen-Johanson estimator and multivariable Cox regression models were used to determine cumulative incidences and adjusted hazard ratios (HRs) of IE readmission according to status of CIED removal, respectively. Results Among 6,843 patients with first-time IE, 5,731 (83.7%) were conservatively treated. Of these, 1,201 (21.0%) had a CIED, of which 205 (17.1%) died during IE admission. Thus, the final study population comprised 996 patients alive at IE discharge. The median age of the study population was 75.5 years (interquartile range [IQR]: 67.9-82.0), and 753 (75.6%) were males. In total, 574 (57.6%) patients underwent CIED removal during IE admission. Patients who underwent CIED removal were younger, compared to patients without CIED removal, 73.1 years (IQR: 65.7-79.1) versus 79.0 years (IQR: 71.3-85.1), respectively. The six-month cumulative incidence of IE readmission was 2.0% (95% confidence interval [CI]: 1.1-3.5%) in patients who underwent CIED removal versus 6.1% (95% CI: 4.0-8.9%) in patients without CIED removal (P-value=0.001) (Figure 1). CIED removal was associated with a significantly lower six-month rate of IE readmission, compared to no CIED removal (HR: 0.36 [95% CI: 0.17-0.77]). Relapse bacteraemia (including IE) with the same microorganism as first-time IE occurred in 2.2% of patients who underwent CIED removal and in 5.4% of patients without CIED removal. Staphylococcus aureus was the most common microorganism in 33.3% of patients with relapse bacteraemia who underwent CIED removal. Conclusions In this nationwide study, the six-month rate of infective endocarditis (IE) readmission was three-fold lower in patients who underwent cardiac implantable electronic device (CIED) removal, compared to patients without CIED removal. The current findings suggest that CIED removal is associated with lower risk of relapse of IE in patients with conservatively treated IE. These results are in line with current guideline recommendations. However, more randomized clinical trial data are needed.

Efficacy of acetazolamide as adjunct therapy in improving fluid management in patients with acute congestive heart failure: a systematic review and meta-analysis of randomized controlled trials

Abstract Introduction Persistent congestion in acute congestive heart failure despite conventional treatments highlights the need for innovative therapeutic approaches. Evaluating acetazolamide as adjunctive therapy for reducing volume overload is significant. Our meta-analysis examines randomized clinical trials to assess acetazolamide's efficacy in improving fluid management in acute congestive heart failure. Methods We systematically searched Embase, PubMed, and the Cochrane Library in January 2024 for randomized controlled trials comparing the addition of acetazolamide to diuretic therapy versus standard diuretic therapy in patients with acute congestive heart failure. Article selection was conducted independently by two authors. Statistical analyses, including the weighted mean differences (MD) and assessment of heterogeneity using the I² statistic, were performed using R software version 5.4.1. Results Three studies comprising 596 patients were included. Of these, 297 (50%) received acetazolamide as adjunctive diuretic therapy, while 299 (50%) received standard diuretic therapy with a loop diuretic. Among participants, 385 (65%) were male, with a mean age of 72.76 years (±11.13). Acetazolamide adjunctive therapy led to an increase in natriuresis at day 2, expressed in milimoles (mmol), (MD 80.30; 95% CI [45.10-115.51]; p<0.00001; I2=29%), and a trend towards higher natriuresis volume, expressed in liters (L), at day 2 (MD 0.56; 95% CI [-0.37-1.48]; p=0.24; I2=87%), although the latter lacked statistical significance. Conclusions Our findings suggest that acetazolamide adjunctive therapy may have potential benefits in improving fluid management and possibly enhancing clinical outcomes in patients with acute congestive heart failure. Further research is warranted to validate these findings and explore the long-term effects of acetazolamide therapy.

Non-invasive imaging to guide percutaneous coronary revascularization in chronic total occlusion: a systematic review and meta-analysis

Abstract Background and aims Whether recanalization of coronary chronic total occlusions (CTO) leads to improved patient outcomes is uncertain. We set out to investigate the use of noninvasive imaging modalities to guide patient selection for percutaneous recanalization of coronary chronic total occlusions (CTO-PCI) and its association with outcomes. Methods Systematic review and meta-analysis of studies involving patients undergoing CTO-PCI to detail use of preprocedural non-invasive imaging, change in clinical endpoints and the occurrence of clinical events in these patient cohorts. PubMed and Embase, the Cochrane Database of Systematic Reviews, the PROSPERO database and the Clinical Trials Registry were searched for relevant randomized and observational studies up to May 2023. This study is registered with PROSPERO. The study primary endpoint was a composite of all-cause death and nonfatal myocardial infarction (MI), with a secondary composite endpoint of cardiovascular death, nonfatal MI and target vessel revascularization (TVR). Additional endpoints were individual components of the composite endpoints along with changes in angina burden, LV ejection fraction, ischemic burden, and infarct extent after PCI. Results Of 1264 publications retrieved, 31 studies (26 observational and 5 randomized) were finally included for a total of 7260 patients. Guidance to CTO-PCI varied greatly among included studies, with only a minority implementing routine preprocedural inducible ischemia and myocardial viability assessment. At a median of 3.1 years (range 1-5 years), the primary endpoint occurred at a rate of 3.1 events per 100 patient-years (95%CI: 2.4-3.7). When non-invasive imaging was used to guide CTO-PCI, patients with myocardial ischemia and/or viability, a reduced risk for the primary endpoint was observed (OR 0.3 95%CI 0.2-0.5) compared to CTO-PCI without evidence of myocardial ischemia and/or viability. CTO-PCI was associated with improvements in SAQ summary score, LVEF, reduction of ischemic burden, improvement in myocardial perfusion (all P-values < 0.01), with no change in the burden of myocardial scarring. At meta-regression analysis, a greater improvement in LVEF was observed in studies enrolling patients with lower average baseline LVEF (≤ 45%) (R2 = 63%, p < 0.0001). Conclusions CTO-PCI led to a significant improvement in symptom status (reduction of chest pain) and LV ejection fraction. CTO-PCI guided by the presence of ischemia and/or viability was associated with improved patient outcomes compared with CTO-PCI in the absence of ischemia and/viability, or in patients where non-invasive imaging testing was not performed. Future randomized clinical trials testing whether ischemia and viability-guided CTO-PCI improves clinical outcomes are lacking and warranted.PRISMA Flow diagramGraphical abstract

Ex-vivo evaluation of clinically-set hydraulic sealers used with different canal dryness protocols and obturation techniques: a randomized clinical trial

ObjectivesThis 2-part randomized parallel triple-blind clinical trial adopts a unique model assessing clinically-set hydraulic calcium silicate-based sealers (HCSBS) after different root canal dryness protocols and obturation techniques.MethodsFor the first phase of the study, 24 teeth scheduled for orthodontic extractions were allocated into four groups according to the canal dryness protocol and the obturation technique. G1 (CLC-AHP): cold lateral compaction (CLC) with AH Plus sealer, G2 (CLC-ES-SD): CLC with Endosequence (ES) after standard canal(s) dryness (SD); G3 (SC-ES-SD): matching single-cone (SC) with ES after SD; G4 (SC-ES-PD): as G3 but after partial canal(s) dryness (PD). Teeth were extracted after one month of clinical service and examined for intracanal voids by micro-CT (2D & 3D). For the 2nd phase, another 24 teeth were allocated into four groups according to the root canal dryness protocol and the HCSBS used (ES or CeraSeal (CeS)). Teeth were extracted after one month and sectioned vertically for energy dispersive X-ray (EDX)/scanning electron microscope (SEM) examination. One-way ANOVA with Games-Howell post-hoc test and Chi-square test with multiple z-tests were used for statistical analysis.ResultsSC-PD showed the highest percentage of voids (p < 0.05). MicroCT scans as well as EDX/SEM examination showed that PD resulted in significantly larger interfacial gaps (p < 0.001) with more hydration products at the sealer/dentin interface than SD.ConclusionsBoth tested dryness protocols allowed the hydration of HCSBS and the formation of hydration products, thus standard dryness is recommended to reduce the incidence of intracanal voids.Clinical relevanceWhen using the single-cone obturation technique, intentional root canal moisture negatively affects the performance of HCSBS.Protocol Registrationhttp://www.clinicaltrials.gov, ID: NCT05808062.

Microaxial Flow Pump Hemodynamic and Metabolic Effects in Infarct-Related Cardiogenic Shock

Mechanical circulatory support with a microaxial flow pump (MAFP) has been shown to improve survival in ST-elevation myocardial infarction-induced cardiogenic shock (STEMI-CS). Understanding the impact on hemodynamic stability over time is crucial for optimizing patient treatment. To determine if an MAFP reduces the need for pharmacological circulatory support without compromising hemodynamics compared with standard care in STEMI-CS. This was a substudy of the Danish-German (DanGer) Shock trial, an international, multicenter, open-label randomized clinical trial. Patients from 14 heart centers across Denmark, Germany, and the UK were enrolled. Inclusion criteria for the trial were STEMI and systolic blood pressure less than 100 mm Hg or ongoing vasopressor treatment, left ventricular ejection fraction less than 45%, and arterial lactate level greater than 2.5 mmol/L. Of the enrolled patients, after exclusions from death in the catheterization laboratory or immediately on intensive care unit (ICU) admission, the remaining patients had serial recordings of hemodynamics, arterial lactate, and use of vasoactive drugs. Patients who were in comas after cardiac arrest and patients with mechanical complications or right ventricular failure were excluded. Data were analyzed from May to September 2024. MAFP and standard of care or standard of care alone. Hemodynamic status in terms of heart rate and blood pressure, metabolic status in terms of arterial lactate concentration, and vasoactive-inotropic score (VIS). The clinical events during the first 72 hours were as follows: death from all causes, escalation of mechanical circulatory support, and discharge alive from the ICU. From 355 enrolled patients, 324 (mean [IQR] age, 68 [58-75] years; 259 male [80%]) underwent ICU treatment (169 [52%] in the MAFP group, 155 [48%] in the standard-care group). Baseline characteristics were balanced. There was no difference in heart rate between groups, and mean arterial pressure was above the treatment target of 65 mm Hg in both groups but was achieved with a lower VIS in the MAFP group. No difference in arterial lactate level was found between groups at randomization, but on arrival to the ICU, the MAFP group had significantly lower arterial lactate levels compared with the standard-care group (mean difference, 1.3 mmol/L; 95% CI, 0.7-1.9 mmol/L), a difference that persisted throughout the first 24 hours of observation. The MAFP group achieved lactate normalization (<2 mmol/L) 12 hours (95% CI, 5-18 hours) before the standard-care group. Use of a MAFP reduces the use of vasopressors and inotropic medication while maintaining hemodynamic stability and achieving faster normalization of lactate level in patients with STEMI-CS. ClinicalTrials.gov Identifier: NCT01633502.

Driving pressure during general anesthesia for minimally invasive abdominal surgery (GENERATOR)—study protocol of a randomized clinical trial

BackgroundIntraoperative driving pressure (ΔP) has an independent association with the development of postoperative pulmonary complications (PPCs) in patients receiving ventilation during general anesthesia for major surgery. Ventilation with high intraoperative positive end–expiratory pressure (PEEP) with recruitment maneuvers (RMs) that result in a low ΔP has the potential to prevent PPCs. This trial tests the hypothesis that compared to standard low PEEP without RMs, an individualized high PEEP strategy, titrated to the lowest ΔP, with RMs prevents PPCs in patients receiving intraoperative protective ventilation during anesthesia for minimally invasive abdominal surgery.Methods“DrivinG prEssure duriNg gEneRal AnesThesia fOr minimally invasive abdominal suRgery (GENERATOR)” is an international, multicenter, two–group, patient and outcome–assessor blinded randomized clinical trial. In total, 1806 adult patients scheduled for minimally invasive abdominal surgery and with an increased risk of PPCs based on (i) the ARISCAT risk score for PPCs (≥ 26 points) and/or (ii) a combination of age > 40 years and scheduled surgery lasting > 2 h and planned to receive an intra–arterial catheter for blood pressure monitoring during the surgery will be included. Patients are assigned to either an intraoperative ventilation strategy with individualized high PEEP, titrated to the lowest ΔP, with RMs or one with a standard low PEEP of 5 cm H2O without RMs. The primary outcome is a collapsed composite endpoint of PPCs until postoperative day 5.DiscussionGENERATOR will be the first adequately powered randomized clinical trial to compare the effects of individualized high PEEP with RMs versus standard low PEEP without RMs on the occurrence of PPCs after minimally invasive abdominal surgery. The results of the GENERATOR trial will support anesthesiologists in their decisions regarding PEEP settings during minimally invasive abdominal surgery.Trial registrationGENERATOR is registered at ClinicalTrials.gov (study identifier: NCT06101511) on 26 October 2023.