*For medical professionals only
Statins reduce cardiovascular events in most patients and play a cardiovascular preventive role. But in two large clinical trials of patients with a history of heart failure (heart failure), statin therapy failed to show a clear benefit.
The ODYSSEY OUTCOMES and FOLIER studies confirmed that pro-protein invertase subtilinolysin 9 (PCSK9) inhibitors reduce the risk of cardiovascular events in patients with stable or acute atherosclerotic cardiovascular disease.
It is unclear whether PCSK9 inhibitors reduce major cardiovascular adverse events (MACE) in patients with a history of heart failure, or reduce the risk of hospitalization for heart failure.
Recently, the European Journal of The Heart published a post-mortem analysis of the ODYSSEY OUTCOME study evaluating the prognosis effect of randomized treatment with PCSK9 inhibitors (aliszeumab) or placebo in patients with ACS with or without heart failure. Let's take a look.
Research design
The ODYSSEY OUTCOMES trial included patients aged ≥40 years, randomized with 1-12 months hospitalization due to ACS, receiving atorvastatin 40-80 mg/day, rosuvastatin 20-40 mg/day, or the maximum tolerated dose of one of the statins for more than 2 weeks, LDL-C ≥ 1.81 mmol/L, non-HDL cholesterol ≥ 2.59 mmol/L, or apolipoprotein B≥80 mg/dL.
Patients are randomly assigned to receive alizemab 75 mg or placebo therapy;
Patients assigned to the Aliciclizumab group were given a dose-adjusting regimen specified in the protocol to achieve LDL-C levels in the range of 0.65-1.29 mmol/L.
The primary endpoint was MACE, the secondary endpoint was hospitalization for heart failure, and the composite endpoints of overall mortality and all-cause death, nonfatal MI, and nonfatal ischemic stroke.
Studies compared the effects of aliciclizumab on MACE and MACE components (including MI types, hospitalizations and deaths due to heart failure) in patients with and without a history of heart failure. Changes in highly sensitive C-reactive protein (hs-CRP) in both groups of patients were analyzed simultaneously.
Research results
A total of 18 924 patients were enrolled in the study, including 2815 patients with a history of heart failure (14.9%) and 16 109 patients without a history of heart failure (85.1%). Patients with or without a history of co-heart failure had the same median follow-up time, all of which were 2.8 (2.3, 3.4) years.
In terms of baseline data, patients with a history of heart failure had higher median baseline status values and lower lipoprotein (a) levels compared with patients without a history of heart failure.
In the subgroup of patients with and without heart failure, the proportion of patients randomized to receive alizemab or placebo was roughly equal.
Effects on lipid levels and highly sensitive C-reactive proteins: In a subgroup of patients with either concomitant or arrhythmia, alizemab reduced LDL-C levels by similar amounts, as well as lipoprotein (a) and HS-CRP reductions.
1. Effect on major adverse cardiovascular events (MACE).
MACE event rate: higher than in patients with a history of heart failure (6.34 vs. 3.43 cases/100 person-years).
MACE Risk:
In the overall trial cohort and subgroup without history of heart failure, alioxeizumab significantly reduced the incidence of MACE.
In patients with a history of heart failure, aliciclizumab did not reduce MACE.
In terms of the effect on the incidence of MACE, random grouping had a significant interaction with the history of heart failure. Further validation was made using the Fine–Gray competitive risk model, and the results were consistent with the Cox model.
Figure 1 Effect of aliciclizumab and placebo on the cumulative incidence of major adverse cardiovascular events, classified by history of heart failure.
In the overall trial cohort, alizeliumab treatment reduced the risk of non-fatal MI;
In patients without a history of heart failure, the conclusion remains consistent;
However, in patients with a history of heart failure, the risk of nonfatal MI in the aliciclizumab group was higher than in the placebo group.
2. Effect on the risk of hospitalization for heart failure
Risk of hospitalization for heart failure:
Patients with a history of heart failure have a higher risk of hospitalization for heart failure compared with patients without a history of heart failure,
In the overall trial cohort and in patients with/non-coordinated heart failure, alioximab did not reduce the risk of hospitalization for heart failure.
In patients with/without a history of heart failure, aliciclizumab had a similar effect on hospitalizations for total heart failure (first and relapse) and on hospitalizations for first heart failure.
Figure 2 Effect of alisciclizumab and placebo on the cumulative incidence of hospitalization for heart failure, classified by history of heart failure
3. Effect on the risk of death
Risk of all-cause death:
In the overall trial population and in patients without heart failure, aliciclizumab reduced the risk of all-cause death.
In patients with a history of heart failure, aliciclizumab had no effect on the risk of all-cause death.
4. Effect on cardiovascular death or hospitalization due to heart failure
Risk of combined endpoint of cardiovascular death or hospitalization due to heart failure:
In the overall trial population, there was no significant decrease in the aliciclizumab group.
In patients without a history of heart failure, the reduction effect was not significant (0.95 vs. 1.13/100 patients·year),
In patients with a history of heart failure, the increase was not significant (4.48 vs. 3.94/100 patients· year);
Risk of death, nonfatal myocardial infarction, or nonfatal ischemic stroke complex endpoint:
In the overall trial population and patients without heart failure, the risk of occurrence of the compound endpoint in the alioxeizumab group was significantly reduced,
In patients with a history of heart failure, the risk of compound endpoint events in the Alicisumab group was not significantly increased.
5. Effect on patients with previous coronary events, surgery or coronary angiography
Based on a history of previous MI, PCI, or CABG, or coronary artery stenosis recorded ≥ 70%, the role of aliciclizumab in patients with a possible heart failure ischemic matrix was evaluated.
Alizeliumab reduces the risk of MACE in patients without a history of heart failure, previous coronary events, previous surgery, or contrast-confirmed disease;
In patients with a history of heart failure, the protective effect of alioximab disappears.
Adverse events: the overall incidence of adverse events was similar in patients with or without a history of heart failure, but the incidence of serious adverse events was higher in patients with a history of heart failure. In each subgroup of heart failure, the incidence of overall and serious adverse events was similar in the alisciumab and placebo groups.
Research discussion
The results of the ODYSSEY OUTCOMES trial showed that alisciclimab reduced atherosclerotic lipoprotein to a similar extent in patients with or without a history of heart failure.
Further data analysis of this study found that alioxeizumab significantly reduced MACE across the trial cohort and in patients without a history of heart failure, but in patients with a history of heart failure, the risk of MACE development was not reduced and the risk of nonfatal MI was significantly increased.
Alisciclizumab had no significant effect on the risk of hospitalization for heart failure for the overall population studied or for patients with or without prior heart failure.
Aliciyuzumab reduces all-cause death for the overall population studied and in patients without a history of heart failure, but not in patients with a history of heart failure.
Figure 3 MacE decreased in patients without a history of heart failure, but not in patients with a history of heart failure
Given the large decrease in LDL-C in alizetimab, alizeumab therapy did not benefit from reducing MACE, hospitalization for heart failure, or death risk of mace, heart failure, and may be explained as follows:
First, patients with a history of heart failure may have a competitive risk due to underlying conditions that PCSK9 inhibitors cannot regulate, such as heart pump failure or arrhythmias.
Second, there are differences in baseline features in patients with a history of concomitant and non-concomitant heart failure, suggesting that patients with a history of concomitant heart failure may have a more difficult course of disease progression to change after lipid-lowering therapy.
Third, lower lipoprotein concentrations in patients with chronic heart failure have been shown to be associated with impaired survival, but this may also be the possibility of reverse causation and inadequate correction of unknown confounding factors.
source:
Alirocumab after acute coronary syndrome in patients with a history of heart failure. Eur Heart J. 2021:ehab804. doi: 10.1093/eurheartj/ehab804.
Author: Li Yukun Beijing Anzhen Hospital affiliated to Capital Medical University