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The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = −0.142/−0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
Background: Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin–kexin type 9 inhibition in such patients is undetermined.
Objectives: This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.
Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint.
Results: Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6% to 2.3%), 1.9% (95% CI: −2.4% to 6.2%), and 13.0% (95% CI: −2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: −0.1% to 1.0%), 1.3% (95% CI: −1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%).
Conclusions: In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402)
Alirocumab reduces total nonfatal cardiovascular and fatal events: The ODYSSEY OUTCOMES trial
(2018)
Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.
Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.
Methods: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.
Results: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.
Conclusions: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.
Background: Patients with chronic kidney disease (CKD) have considerable cardiovascular morbidity and mortality. Aortic stiffness is an independent predictor of cardiovascular risk and related to left ventricular remodeling and heart failure. Myocardial fibrosis is the pathophysiological hallmark of the failing heart.
Methods and results: An observational study of consecutive CKD patients (n = 276) undergoing comprehensive clinical cardiovascular magnetic resonance imaging. The relationship between aortic stiffness, myocardial fibrosis, left ventricular remodeling and the severity of chronic kidney disease was examined. Compared to age-gender matched controls with no known kidney disease (n = 242), CKD patients had considerably higher myocardial native T1 and central aortic PWV (p ≪ 0.001), as well as abnormal diastolic relaxation by E/e′ (mean) by echocardiography (p ≪ 0.01). A third of all patients had LGE, with similar proportions for the presence and the (ischaemic and non-ischaemic) pattern between the groups. PWV was strongly associated with and age, NT-proBNP and native T1 in both groups, but not with LGE presence or type; the associations were amplified in severe CKD stages. In multivariate analyses, PWV was independently associated with native T1 in both groups (p ≪ 0.01) with near two-fold increase in adjusted R2 in the presence of CKD (native T1 (10 ms) R2, B(95%CI) CKD vs. non-CKD 0.28, 0.2(0.15–0.25) vs. 0.18, 0.1(0.06–0.15), p ≪ 0.01).
Conclusions: Aortic stiffness and interstitial myocardial fibrosis are interrelated; this association is accelerated in the presence of CKD, but independent of LGE. Our findings reiterate the significant contribution of CKD-related factors to the pathophysiology of cardiovascular remodeling.
Bone marrow and plasma FGF‐23 in heart failure patients : novel insights into the heart–bone axis
(2019)
Aims: Fibroblast growth factor 23 (FGF‐23) is known to be elevated in patients with congestive heart failure (CHF). As FGF‐23 is expressed in the bone but can also be expressed in the myocardium, the origin of serum FGF‐23 in CHF remains unclear. It is also unclear if FGF‐23 expressed in the bone is associated with outcome in CHF. The aim of the present study was to investigate FGF‐23 levels measured in bone marrow plasma (FGF‐23‐BM) and in peripheral blood (FGF‐23‐P) in CHF patients to gain further insights into the heart–bone axis of FGF‐23 expression. We also investigated possible associations between FGF‐23‐BM as well as FGF‐23‐P and outcome in CHF patients.
Methods and results: We determined FGF‐23‐P and FGF‐23‐BM levels in 203 CHF patients (85% male, mean age 61.3 years) with a left ventricular ejection fraction (LVEF) ≤45% and compared them with those of 48 healthy controls (48% male, mean age 39.2 years). We investigated the association between FGF‐23‐BM and FGF‐23‐P with all‐cause mortality in CHF patients, 32 events, median follow‐up 1673 days, interquartile range [923, 1828]. FGF‐23‐P (median 60.3 vs. 22.0 RU/mL, P < 0.001) and FGF‐23‐BM (median 130.7 vs. 93.1 RU/mL, P < 0.001) levels were higher in CHF patients compared with healthy controls. FGF‐23‐BM levels were significantly higher than FGF‐23‐P levels in both CHF patients and in healthy controls (P < 0.001). FGF‐23‐P and FGF‐23‐BM correlated significantly with LVEF (r = −0.37 and r = −0.33, respectively), N terminal pro brain natriuretic peptide levels (r = 0.57 and r = 0.6, respectively), New York Heart Association status (r = 0.28 and r = 0.25, respectively), and estimated glomerular filtration rate (r = −0.43 and r = −0.41, respectively) (P for all <0.001) and were independently associated with all‐cause mortality in CHF patients after adjustment for LVEF, estimated glomerular filtration rate, New York Heart Association status, and N terminal pro brain natriuretic peptide, hazard ratio 2.71 [confidence interval: 1.18–6.20], P = 0.018, and hazard ratio 2.80 [confidence interval: 1.19–6.57], P = 0.018, respectively.
Conclusions: In CHF patients, FGF‐23 is elevated in bone marrow plasma and is independently associated with heart failure severity and all‐cause mortality. The failing heart seems to interact via FGF‐23 within a heart–bone axis.
Background: Patients with chronic kidney disease (CKD) are at high risk of myocardial infarction. Cardiac troponins are the biomarkers of choice for the diagnosis of acute myocardial infarction (AMI) without ST‐segment elevation (NSTE). In patients with CKD, troponin levels are often chronically elevated, which reduces their diagnostic utility when NSTE‐AMI is suspected. The aim of this study was to derive a diagnostic algorithm for serial troponin measurements in patients with CKD and suspected NSTE‐AMI.
Methods and Results: Two cohorts, 1494 patients from a prospective cohort study with high‐sensitivity troponin I (hs‐cTnI) measurements and 7059 cases from a clinical registry with high‐sensitivity troponin T (hs‐cTnT ) measurements, were analyzed. The prospective cohort comprised 280 CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m2). The registry data set contained 1581 CKD patients. In both cohorts, CKD patients were more likely to have adjudicated NSTE‐AMI than non‐CKD patients. The specificities of hs‐cTnI and hs‐cTnT to detect NSTE‐AMI were reduced with CKD (0.82 versus 0.91 for hs‐cTnI and 0.26 versus 0.73 for hs‐cTnT) but could be restored by applying optimized cutoffs to either the first or a second measurement after 3 hours. The best diagnostic performance was achieved with an algorithm that incorporates serial measurements and rules in or out AMI in 69% (hs‐cTnI) and 55% (hs‐cTnT) of CKD patients.
Conclusions: The diagnostic performance of high‐sensitivity cardiac troponins in patients with CKD with suspected NSTE‐AMI is improved by use of an algorithm based on admission troponin and dynamic changes in troponin concentration.
Background: Kidney transplant recipients (KTR) reflect a high-risk population for coronary artery disease (CAD). CAD is the most common cause for morbidity and mortality in this population. However, only few data are available on the favourable revascularization strategy for these patients as they were often excluded from studies and not mentioned in guidelines.
Methods: This retrospective single-centre study includes patients with a history of kidney transplantation undergoing myocardial revascularization for multivessel or left main CAD by either percutaneous coronary intervention (PCI, n = 27 patients) or coronary artery bypass grafting (CABG, n = 24 patients) at University Hospital Frankfurt, Germany, between 2005 and 2015.
Results: In-hospital mortality was higher in the CABG group (20.8% vs. 14.8% PCI group; p = 0.45). In Kaplan-Meier analysis, one-year-survival showed better outcome in the PCI group (85.2% vs. 75%). After four years, outcome was comparable between both strategies (PCI 66.5% vs. CABG 70.8%; log-rank p = 0.94).
Acute kidney injury (AKI), classified by Acute Kidney Injury Network, was observed more frequently after CABG (58.3% vs. 18.5%; p < 0.01). After one year, graft survival was 95.7% in the PCI group and 94.1% in the CABG group. Four year follow-up showed comparable graft survival in both groups (76.8% PCI and 77.0% CABG; p = 0.78).
Conclusion: In this retrospective single-centre study of KTR requiring myocardial revascularization, PCI seems to be superior to CABG with regard to in-hospital mortality, acute kidney injury and one-year-survival. To optimise treatment of these high-risk patients, larger-scaled studies are urgently warranted.
Aim: Patients with advanced systolic chronic heart failure frequently suffer from progressive functional mitral regurgitation. We report our initial experience in patients with an implanted pulmonary artery pressure (PAP) sensor, who developed severe mitral regurgitation, which was treated with the MitraClip system. We non‐invasively compared changes in PAP values in patients after MitraClip with PAP changes in patients without MitraClip.
Methods and results: Among 28 patients with New York Heart Association III heart failure with implanted PAP sensor for haemodynamic telemonitoring from a single centre, four patients (age 66 ± 6 years, left ventricular ejection fraction 21 ± 3%, and cardiac index 1.8 ± 0.3) received a MitraClip procedure and were compared with 24 patients (age 72 ± 8 years, left ventricular ejection fraction 26 ± 9.9%, and cardiac index 2.0 ± 1.0) without MitraClip procedure in a descriptive manner. Ambulatory PAP values were followed for 90 days in both groups. In comparison with the PAP values 4 weeks before MitraClip procedure, PAP was profoundly reduced in all four patients after 30 days (ΔPAPmean −11 ± 5, ΔPAPdiast −7 ± 3 mmHg, P < 0.02) as well as after 90 days (ΔPAPmean −6.3 ± 6, ΔPAPdiast −1 ± 3 mmHg). Reductions in PAP were accompanied by a profound reduction in N terminal pro brain natriuretic peptide as well as clinical and echocardiographic improvement. When analysing the dynamics with a regression model, reductions in all PAP values were significantly greater after MitraClip compared with conservative haemodynamic monitoring (P < 0.001).
Conclusions: The efficacy of the interventional MitraClip procedure on clinical symptoms can be confirmed by haemodynamic telemonitoring. Thus, daily non‐invasive haemodynamic telemonitoring allows, for the first time, for a continuous assessment of the haemodynamic efficacy of novel therapies in patients with chronic heart failure.
Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome.
Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death.
Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend).
Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low.
Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.
Background: Treatment of patients presenting with possible acute myocardial infarction (AMI) is based on timely diagnosis and proper risk stratification aided by biomarkers. We aimed at evaluating the predictive value of GDF-15 in patients presenting with symptoms suggestive of AMI.
Methods: Consecutive patients presenting with suspected AMI were enrolled in three study centers. Cardiovascular events were assessed during a follow-up period of 6 months with a combined endpoint of death or MI.
Results: From the 1818 enrolled patients (m/f = 1208/610), 413 (22.7%) had an acute MI and 63 patients reached the combined endpoint. Patients with MI and patients with adverse outcome had higher GDF-15 levels compared with non-MI patients (967.1pg/mL vs. 692.2 pg/L, p<0.001) and with event-free patients (1660 pg/mL vs. 756.6 pg/L, p<0.001). GDF-15 levels were lower in patients with SYNTAX score ≤ 22 (797.3 pg/mL vs. 947.2 pg/L, p = 0.036). Increased GDF-15 levels on admission were associated with a hazard ratio of 2.1 for death or MI (95%CI: 1.67–2.65, p<0.001) in a model adjusted for age and sex and of 1.57 (1.13–2.19, p = 0.008) adjusted for the GRACE score variables. GDF-15 showed a relevant reclassification with regards to the GRACE score with an overall net reclassification index (NRI) of 12.5% and an integrated discrimination improvement (IDI) of 14.56% (p = 0.006).
Conclusion: GDF-15 is an independent predictor of future cardiovascular events in patients presenting with suspected MI. GDF-15 levels correlate with the severity of CAD and can identify and risk-stratify patients who need coronary revascularization.