Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the ...effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event.
We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina.
The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval CI, 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo.
In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.).
The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence ...for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT).
In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death.
After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval CI, 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29).
In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).
To investigate the association between SARS-CoV-2 vaccination and myocarditis or myopericarditis.
Population based cohort study.
Denmark.
4 931 775 individuals aged 12 years or older, followed from 1 ...October 2020 to 5 October 2021.
The primary outcome, myocarditis or myopericarditis, was defined as a combination of a hospital diagnosis of myocarditis or pericarditis, increased troponin levels, and a hospital stay lasting more than 24 hours. Follow-up time before vaccination was compared with follow-up time 0-28 days from the day of vaccination for both first and second doses, using Cox proportional hazards regression with age as an underlying timescale to estimate hazard ratios adjusted for sex, comorbidities, and other potential confounders.
During follow-up, 269 participants developed myocarditis or myopericarditis, of whom 108 (40%) were 12-39 years old and 196 (73%) were male. Of 3 482 295 individuals vaccinated with BNT162b2 (Pfizer-BioNTech), 48 developed myocarditis or myopericarditis within 28 days from the vaccination date compared with unvaccinated individuals (adjusted hazard ratio 1.34 (95% confidence interval 0.90 to 2.00); absolute rate 1.4 per 100 000 vaccinated individuals within 28 days of vaccination (95% confidence interval 1.0 to 1.8)). Adjusted hazard ratios among female participants only and male participants only were 3.73 (1.82 to 7.65) and 0.82 (0.50 to 1.34), respectively, with corresponding absolute rates of 1.3 (0.8 to 1.9) and 1.5 (1.0 to 2.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 1.48 (0.74 to 2.98) and the absolute rate was 1.6 (1.0 to 2.6) per 100 000 vaccinated individuals within 28 days of vaccination. Among 498 814 individuals vaccinated with mRNA-1273 (Moderna), 21 developed myocarditis or myopericarditis within 28 days from vaccination date (adjusted hazard ratio 3.92 (2.30 to 6.68); absolute rate 4.2 per 100 000 vaccinated individuals within 28 days of vaccination (2.6 to 6.4)). Adjusted hazard ratios among women only and men only were 6.33 (2.11 to 18.96) and 3.22 (1.75 to 5.93), respectively, with corresponding absolute rates of 2.0 (0.7 to 4.8) and 6.3 (3.6 to 10.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 5.24 (2.47 to 11.12) and the absolute rate was 5.7 (3.3 to 9.3) per 100 000 vaccinated individuals within 28 days of vaccination.
Vaccination with mRNA-1273 was associated with a significantly increased risk of myocarditis or myopericarditis in the Danish population, primarily driven by an increased risk among individuals aged 12-39 years, while BNT162b2 vaccination was only associated with a significantly increased risk among women. However, the absolute rate of myocarditis or myopericarditis after SARS-CoV-2 mRNA vaccination was low, even in younger age groups. The benefits of SARS-CoV-2 mRNA vaccination should be taken into account when interpreting these findings. Larger multinational studies are needed to further investigate the risks of myocarditis or myopericarditis after vaccination within smaller subgroups.
Patients with infective endocarditis on the left side of the heart are typically treated with intravenous antibiotic agents for up to 6 weeks. Whether a shift from intravenous to oral antibiotics ...once the patient is in stable condition would result in efficacy and safety similar to those with continued intravenous treatment is unknown.
In a randomized, noninferiority, multicenter trial, we assigned 400 adults in stable condition who had endocarditis on the left side of the heart caused by streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci and who were being treated with intravenous antibiotics to continue intravenous treatment (199 patients) or to switch to oral antibiotic treatment (201 patients). In all patients, antibiotic treatment was administered intravenously for at least 10 days. If feasible, patients in the orally treated group were discharged to outpatient treatment. The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from the time of randomization until 6 months after antibiotic treatment was completed.
After randomization, antibiotic treatment was completed after a median of 19 days (interquartile range, 14 to 25) in the intravenously treated group and 17 days (interquartile range, 14 to 25) in the orally treated group (P=0.48). The primary composite outcome occurred in 24 patients (12.1%) in the intravenously treated group and in 18 (9.0%) in the orally treated group (between-group difference, 3.1 percentage points; 95% confidence interval, -3.4 to 9.6; P=0.40), which met noninferiority criteria.
In patients with endocarditis on the left side of the heart who were in stable condition, changing to oral antibiotic treatment was noninferior to continued intravenous antibiotic treatment. (Funded by the Danish Heart Foundation and others; POET ClinicalTrials.gov number, NCT01375257 .).
Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We ...compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.
After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.
After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval CI, 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).
In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).
Objectives The purpose of this study was to investigate the risk of thrombosis and bleeding according to multiple antithrombotic treatment regimens in atrial fibrillation (AF) patients after ...myocardial infarction (MI) or percutaneous coronary intervention (PCI). Background The optimal antithrombotic treatment strategy is unresolved in patients with multiple indications. Methods A total of 12,165 AF patients hospitalized with MI and/or undergoing PCI between 2001 and 2009 were identified by nationwide registries (60.7% male; mean age 75.6 years). Risk of MI/coronary death, ischemic stroke, and bleeding according to antithrombotic treatment regimen was estimated by Cox regression models. Results Within 1 year, MI or coronary death, ischemic stroke, and bleeding events occurred in 2,255 patients (18.5%), 680 (5.6%), and 769 (6.3%), respectively. Relative to triple therapy (oral anticoagulation OAC plus aspirin plus clopidogrel), no increased risk of recurrent coronary events was seen for OAC plus clopidogrel (hazard ratio HR: 0.69, 95% confidence interval CI: 0.48 to 1.00), OAC plus aspirin (HR: 0.96, 95% CI: 0.77 to 1.19), or aspirin plus clopidogrel (HR: 1.17, 95% CI: 0.96 to 1.42), but aspirin plus clopidogrel was associated with a higher risk of ischemic stroke (HR: 1.50, 95% CI: 1.03 to 2.20). Also, OAC plus aspirin and aspirin plus clopidogrel were associated with a significant increased risk of all-cause death (HR: 1.52, 95% CI: 1.17 to 1.99 and HR: 1.60, 95% CI: 1.25 to 2.05, respectively). When compared to triple therapy, bleeding risk was nonsignificantly lower for OAC plus clopidogrel (HR: 0.78, 95% CI: 0.55 to 1.12) and significantly lower for OAC plus aspirin and aspirin plus clopidogrel. Conclusions In real-life AF patients with indication for multiple antithrombotic drugs after MI/PCI, OAC and clopidogrel was equal or better on both benefit and safety outcomes compared to triple therapy.
Patients undergoing surgical aortic valve replacement (SAVR) are considered at high risk of infective endocarditis (IE). However, data on the risk of IE following transcatheter aortic valve ...replacement (TAVR) are sparse and limited by the lack of long-term follow-up as well as a direct comparison with patients undergoing SAVR.
This study sought to investigate the long-term incidence of IE in patients undergoing TAVR and to compare the long-term risk of IE with patients undergoing isolated SAVR.
In this nationwide observational cohort study, all patients undergoing TAVR and isolated SAVR from January 1, 2008, to December 31, 2016, with no history of IE and alive at discharge were identified using data from Danish nationwide registries.
A total of 2,632 patients undergoing TAVR and 3,777 patients undergoing isolated SAVR were identified. During a mean follow-up of 3.6 years, 115 patients (4.4%) with TAVR and 186 patients (4.9%) with SAVR were admitted with IE. The median time from procedure to IE hospitalization was 352 days (25th to 75th percentile: 133 to 778 days) in the TAVR group and 625 days (25th to 75th percentile: 209 to 1,385 days) in the SAVR group. The crude incidence rates of IE were 1.6 (95% confidence interval CI: 1.4 to 1.9) and 1.2 (95% CI: 1.0 to 1.4) events per 100 person-years in TAVR and SAVR patients, respectively. The cumulative 1-year risk of IE was 2.3% (95% CI: 1.8% to 2.9%) and 1.8% (95% CI: 1.4% to 2.3%) in TAVR and SAVR patients, respectively. Correspondingly, the cumulative 5-year risk of IE was 5.8% (95% CI: 4.7% to 7.0%) and 5.1% (95% CI: 4.4% to 6.0%), respectively. In multivariable Cox proportional hazard analysis, TAVR was not associated with a statistically significant different risk of IE compared with SAVR (hazard ratio: 1.12; 95% CI: 0.84 to 1.49).
The 5-year incidence of IE following TAVR was 5.8% and not significantly different than the incidence following SAVR.
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The effect of bystander interventions on long-term functional outcomes among survivors of out-of-hospital cardiac arrest has not been extensively studied.
We linked nationwide data on out-of-hospital ...cardiac arrests in Denmark to functional outcome data and reported the 1-year risks of anoxic brain damage or nursing home admission and of death from any cause among patients who survived to day 30 after an out-of-hospital cardiac arrest. We analyzed risks according to whether bystander cardiopulmonary resuscitation (CPR) or defibrillation was performed and evaluated temporal changes in bystander interventions and outcomes.
Among the 2855 patients who were 30-day survivors of an out-of-hospital cardiac arrest during the period from 2001 through 2012, a total of 10.5% had brain damage or were admitted to a nursing home and 9.7% died during the 1-year follow-up period. During the study period, among the 2084 patients who had cardiac arrests that were not witnessed by emergency medical services (EMS) personnel, the rate of bystander CPR increased from 66.7% to 80.6% (P<0.001), the rate of bystander defibrillation increased from 2.1% to 16.8% (P<0.001), the rate of brain damage or nursing home admission decreased from 10.0% to 7.6% (P<0.001), and all-cause mortality decreased from 18.0% to 7.9% (P=0.002). In adjusted analyses, bystander CPR was associated with a risk of brain damage or nursing home admission that was significantly lower than that associated with no bystander resuscitation (hazard ratio, 0.62; 95% confidence interval CI, 0.47 to 0.82), as well as a lower risk of death from any cause (hazard ratio, 0.70; 95% CI, 0.50 to 0.99) and a lower risk of the composite end point of brain damage, nursing home admission, or death (hazard ratio, 0.67; 95% CI, 0.53 to 0.84). The risks of these outcomes were even lower among patients who received bystander defibrillation as compared with no bystander resuscitation.
In our study, we found that bystander CPR and defibrillation were associated with risks of brain damage or nursing home admission and of death from any cause that were significantly lower than those associated with no bystander resuscitation. (Funded by TrygFonden and the Danish Heart Foundation.).
Summary Background Patients with acute ST-segment elevation myocardial infarction (STEMI) and multivessel coronary disease have a worse prognosis compared with individuals with single-vessel disease. ...We aimed to study the clinical outcome of patients with STEMI treated with fractional flow reserve (FFR)-guided complete revascularisation versus treatment of the infarct-related artery only. Methods We undertook an open-label, randomised controlled trial at two university hospitals in Denmark. Patients presenting with STEMI who had one or more clinically significant coronary stenosis in addition to the lesion in the infarct-related artery were included. After successful percutaneous coronary intervention (PCI) of the infarct-related artery, patients were randomly allocated (in a 1:1 ratio) either no further invasive treatment or complete FFR-guided revascularisation before discharge. Randomisation was done electronically via a web-based system in permuted blocks of varying size by the clinician who did the primary PCI. All patients received best medical treatment. The primary endpoint was a composite of all-cause mortality, non-fatal reinfarction, and ischaemia-driven revascularisation of lesions in non-infarct-related arteries and was assessed when the last enrolled patient had been followed up for 1 year. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov , number NCT01960933. Findings From March, 2011, to February, 2014, we enrolled 627 patients to the trial; 313 were allocated no further invasive treatment after primary PCI of the infarct-related artery only and 314 were assigned complete revascularisation guided by FFR values. Median follow-up was 27 months (range 12–44 months). Events comprising the primary endpoint were recorded in 68 (22%) patients who had PCI of the infarct-related artery only and in 40 (13%) patients who had complete revascularisation (hazard ratio 0·56, 95% CI 0·38–0·83; p=0·004). Interpretation In patients with STEMI and multivessel disease, complete revascularisation guided by FFR measurements significantly reduces the risk of future events compared with no further invasive intervention after primary PCI. This effect is driven by significantly fewer repeat revascularisations, because all-cause mortality and non-fatal reinfarction did not differ between groups. Thus, to avoid repeat revascularisation, patients can safely have all their lesions treated during the index admission. Future studies should clarify whether complete revascularisation should be done acutely during the index procedure or at later time and whether it has an effect on hard endpoints. Funding Danish Agency for Science, Technology and Innovation and Danish Council for Strategic Research.
Abstract
Aims
In observational studies, non-alcoholic fatty liver disease (NAFLD) is associated with high risk of ischaemic heart disease (IHD). We tested the hypothesis that a high liver fat content ...or a diagnosis of NAFLD is a causal risk factor for IHD.
Methods and results
In a cohort study of the Danish general population (n = 94 708/IHD = 10 897), we first tested whether a high liver fat content or a diagnosis of NAFLD was associated observationally with IHD. Subsequently, using Mendelian randomization, we tested whether a genetic variant in the gene encoding the protein patatin-like phospholipase domain containing 3 protein (PNPLA3), I148M (rs738409), a strong and specific cause of high liver fat content and NAFLD, was causally associated with the risk of IHD. We found that the risk of IHD increased stepwise with increasing liver fat content (in quartiles) up to an odds ratio (OR) of 2.41 (1.28–4.51)(P-trend = 0.004). The corresponding OR for IHD in individuals with vs. without NAFLD was 1.65 (1.34–2.04)(P = 3×10−6). PNPLA3 I148M was associated with a stepwise increase in liver fat content of up to 28% in MM vs. II-homozygotes (P-trend = 0.0001) and with ORs of 2.03 (1.52–2.70) for NAFLD (P = 3×10−7), 3.28 (2.37–4.54) for cirrhosis (P = 4×10−12), and 0.95 (0.86–1.04) for IHD (P = 0.46). In agreement, in meta-analysis (N = 279 013/IHD = 71 698), the OR for IHD was 0.98 (0.96–1.00) per M-allele vs. I-allele. The OR for IHD per M-allele higher genetically determined liver fat content was 0.98 (0.94–1.03) vs. an observational estimate of 1.05 (1.02–1.09)(P for comparison = 0.02).
Conclusion
Despite confirming the known observational association of liver fat content and NAFLD with IHD, lifelong, genetically high liver fat content was not causally associated with risk of IHD. These results suggest that the observational association is due to confounding or reverse causation.
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