Background/Introduction N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a marker of ventricular wall stress and a potent predictor of death and heart failure (HF) across multiple populations (from healthy insurance applicants to various disease entities). Purpose To evaluate the prognostic importance of NT-proBNP in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction, pulmonary congestion, or both and ≥1 of 8 predefined risk-augmenting factors (age ≥70 years, diabetes, previous MI, eGFR <60 ml/min/1.73 m2, atrial fibrillation, LVEF <30%, Killip class III/IV, or ST elevation MI without reperfusion) enrolled in PARADISE-MI. Methods Patients were randomized to sacubitril/valsartan 200mg or ramipril 5mg twice daily within 0.5 to 7 days of presenting with an AMI. Patients with prior HF were excluded. NT-proBNP and high-sensitivity troponin T (hsTnT) were collected at randomization in a prespecified sub-study of 1129 patients. The primary endpoint of PARADISE-MI was a time-to-first composite of cardiovascular (CV) death or incident HF (hospitalization or outpatient symptomatic HF); secondary endpoints included all-cause death and the composite of fatal or non-fatal MI or stroke. Results Median NT-proBNP was 1757 pg/ml [interquartile range, 896–3462 pg/ml] at randomization (4.0±1.8 days after presentation with the index MI). Patients with higher NT-proBNP levels at baseline were older, more commonly women and more frequently had hypertension, atrial fibrillation, renal dysfunction, and pulmonary congestion at randomization (all p<0.001). NT-proBNP concentrations were only weakly correlated with levels of hsTnT at randomization (r=0.38, p<0.001). NT-proBNP at baseline was strongly associated with the primary composite endpoint (adjusted HR 1.45 per doubling NT-proBNP; 95% CI, 1.23–1.70), independent of clinical variables as well as hsTnT (Figure). NT-proBNP was also independently associated with all-cause death (aHR 1.74; 95% CI, 1.38–2.21) and fatal or non-fatal MI or stroke (aHR 1.24; 95% CI, 1.05–1.45). The relative effect of sacubitril/valsartan versus ramipril on the primary composite endpoint was not statistically different across the spectrum of NT-proBNP (p-interaction = 0.46). Conclusions When assessed within the first week of a high risk AMI NT-proBNP is not only associated with incident HF and death but also with atherosclerotic events and provides prognostic information that is independent of hsTnT in this post AMI population. Funding Acknowledgement Type of funding sources: None.
Background Although multiple novel biomarkers have individually been shown to predict outcomes in patients with HFrEF, the value of these over and above conventional clinical and laboratory variables, plus natriuretic peptides, is uncertain. Purpose To test the incremental predictive value of 11 novel biomarkers added to a recent prognostic model 1 (PREDICT-HF) derived in PARADIGM-HF and validated in ATMOSPHERE and the Swedish heart failure registry. The PREDICT-HF model includes clinical variables, standard laboratory variables, and BNP or NT-proBNP. Methods 1559 participants enrolled in PARADIGM-HF had all 11 biomarkers of interest measured. These reflected different pathophysiological pathways: (i) myocyte injury (high sensitivity cardiac troponin T), (ii) cardiac remodelling and inflammation (growth stimulation expressed gene 2, growth differentiation factor-15 and galectin-3), (iii) extracellular matrix remodelling (matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1), (iv) neurohormonal pathways (aldosterone) and (v) renal dysfunction and injury (cystatin C, kidney injury molecule-1 and urinary albumin to creatinine ratio). The incremental prognostic value of these biomarkers was evaluated using Harrell's C statistic. Results The mean age of participants studied was 67.3 (SD 9.9) years, 1254 (80%) were men and 1103 (71%) were in NYHA class II. During a median follow-up of 31 months, 197 patients died and 300 experienced the primary composite outcome (cardiovascular death or heart failure hospitalization). When each candidate biomarker (log unit) was added individually to the PREDICT-HF base model, GDF-15, ST2, TIMP1, cystatin C, hsTnT and UACR were independent predictors of all-cause mortality (Table 1). GDF-15, TIMP1, hs-TnT and cystatin C consistently increased the risk of both all-cause mortality and the primary outcome. Individuals who had all 4 biomarkers elevated (compared to none elevated) had the highest risk: HR for all-cause mortality 3.65 (2.01–6.64), p<0.0001. Adding these 4 biomarkers to the baseline PREDICT HF model improved the C statistic for all-cause mortality from 0.726 to 0.745. Conclusion Several novel biomarkers provide meaningful additional prognostic information in patients with HFrEF. A multimarker approach incorporating biomarkers reflecting different pathophysiological pathways added most information. This approach may be useful in refining risk and targeting treatment. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The PARADIGM-HF trial was funded by Novartis.J.J.V.M is supported by a British Heart Foundation Centre of Excellence Grant
Background Mineralocorticoid receptor antagonists (MRAs) reduce the risk of cardiovascular death or heart failure admission in patients with myocardial infarction (MI) and left ventricular systolic dysfunction (LVSD) combined with either heart failure (HF) or diabetes. Whether use of MRA and initiation of sacubitril/valsartan are safe and whether MRAs modify the effect of sacubitril/valsartan initiation in high-risk MI patients is unknown. Purpose This analysis examined whether background treatment with a MRA modifies the treatment effect and safety of sacubitril/valsartan in patients with a MI and LVSD and/or pulmonary congestion. Methods In the PARADISE MI Trial (Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) N=5661 patients were randomized to either sacubitril/valsartan (97/103 mg twice daily) or ramipril (5 mg twice daily) within 7 days of their MI. The primary outcome in this analysis was the composite of worsening HF (HF hospitalization or outpatient worsening) or cardiovascular death evaluated by the clinical endpoint committee (CEC-adjudicated) or the investigators. Safety was defined as symptomatic hypotension, hyperkalemia >5.5 mmol/L or permanent drug discontinuation. Results A total of 2338 patients (41%) were treated with an MRA and they were more often Caucasian (79% vs. 73%), had worse left ventricular ejection fraction (34±8 vs. 38±10%), a higher KILLIP Class (63% vs. 55% in class II or more) and a lower estimated Glomerular filtration rate (71 vs. 73 ml/min/1.73 m2), than patients not taking an MRA. Age (63 years), sex (24% females), and frequency of diabetes (42%) did not differ. The treatment effect of sacubitril/valsartan compared with ramipril was similar in patients taking or not taking an MRA: hazard ratio (MRA): (95% confidence interval [CI]): 0.96 (0.77, 1.19) versus (95% CI: 0.87 (0.71, 1.05), respectively, for the primary endpoint (p value for interaction = 0.51) (CEC adjudicated) (Figure 1); similar findings were observed if investigator reported endpoints were evaluated (P=0.61 for interaction). Safety of sacubitril/valsartan compared to ramipril initiation was not changed by +/−MRA use, but an increase in symptomatic hypotension was observed (HR(MRA): 1.37 and HR: 1.39, P<0.001) in both groups (P=0.968 for interaction), whereas an increased risk of hyperkalemia or permanent drug discontinuation was not observed in the sacubitril/valsartan group (P>0.05 for all comparisons). Conclusions As expected, patients taking MRAs had a higher risk. Use of a MRA did not modify the treatment effect and safety of initiation of sacubitril/valsartan compared to ramipril in the post MI setting in patients with LVSD and/or congestion. Our analyses support that sacubitril/valsartan and MRAs can be used simultaneously. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis sponsored Randomized clinical trial
Background Large randomized controlled trials (RCT) have shown that COVID-19 vaccines are effective at preventing severe COVID-19. However, the RCT's are not powered to detect rare adverse events. It has been reported that the new mRNA based COVID-19 vaccines may increase the risk of thromboembolic and ischemic events. Likewise, thromboembolic and ischemic events are also known complications to infection with SARS-CoV-19. Currently, less is known about the risk-reward relationship of receiving an mRNA-based COVID-19 vaccine versus contracting COVID-19 infection with respect to thromboembolic and ischemic outcomes. Purpose To compare the risk of thromboembolic and ischemic events following COVID-19 vaccination to the risk following infection with SARS-CoV-19. Methods The study period was from March 2020 to August 2021. All individuals were >18 years old. The population was stratified into two different groups. The vaccinated group consisted of recipients of the first dose of either Moderna (mRNA-1273, n=488,220) or Pfizer-BioNTech (BNT162b2 mRNA, n=3,186,164) vaccines. Individuals who had previously tested positive for SARS-CoV-19 were excluded. The other group consisted of individuals who had tested positive for SARS-CoV-19 in the same period who had not yet received their first vaccination dose (n=233,926). The exposure period for both groups was set to 28 days following vaccination/testing positive for SARS-CoV-19 (Figure 1). Patient level data were obtained on all included individuals using nationwide registries. Primary outcomes were acute myocardial infarction (AMI), ischemic stroke, pulmonary embolism (PE), and deep venous thrombosis (DVT). Odds ratios were obtained from logistic regression models with the vaccinated group acting as reference. Multivariable models were adjusted for demographics and comorbidities. Results In the vaccinated group, mean age was 53±19 years and 50.3% were female. In the group of participants testing positive for SARS-CoV-19, mean age was 42.1±17.4 years and 50.2% were female. In total, 773 suffered a stroke, 472 suffered a PE, 500 suffered an AMI, and 484 suffered a DVT during the 28-day exposure period. We observed an increased absolute risk of all outcomes for participants testing positive for SARS-CoV-19 as compared to participants being vaccinated (stroke: 0.049% vs 0.019%, p<0.001), (PE: 0.91% vs 0.0072%, p<0.001), (AMI: 0.021 vs 0.013, p=0.0004), and (DVT: 0.037% vs 0.011%, p<0.001). In multivariable models, participants testing positive for SARS-CoV-19 had a significantly increased risk of all outcomes compared to participants being vaccinated: (stroke: OR: 4.0, 95% CI: [2.9–5.6], p<0.001), (PE: OR: 38.6 95% CI: [30.3–48.5], p<0.001), (AMI: OR: 3.3, 95% CI: [2.1–5.00], p<0.001), and (DVT: OR: 5.3, 95% CI: [3.8–7.5], p<0.001) (Figure 2). Conclusion The risks of thromboembolic and ischemic events were substantially higher after SARS-CoV-19 infection than after vaccination in the Danish population. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Gentofte University Hospital
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