This was a real-world single-center cohort study that included a retrospective analysis of 317 patients with acute anterior wall MI after HF who underwent PCI. The main findings were as follows. 1. In terms of the application of GDMT in this study, the application rates of RAAS inhibitors, β receptor blockers, MRAs, and SGLT2i were relatively low in patients with acute anterior wall MI after HF (35.0%, 53.9%, 38.2%, and 1.6%, respectively). 2. For patients with acute anterior wall MI after HF who underwent PCI, the use of GDMT was the main influencing factor for the occurrence of the patient's endpoint events, mainly reflected in the reduction in the patient's readmission rate. Compared to patients who did not receive GDMT, patients who initiated GDMT in the hospital had a lower incidence of readmission events. 3. The analysis of each subgroup (sex, age, BMI, HF subtype, and MI subtype) revealed that in the > 65-year-old subgroup, BMI ≤ 30 subgroup, and HFpEF subgroup (LVEF ≥ 50%), the incidence of endpoint events in patients who underwent GDMT was lower than that in the non-GDMT group. 4. Compared with the application of certain guideline-directed medicines, the combined use of guideline-directed medicines reduced the incidence of the above events.
The implications of this study for the application of GDMT in HF after acute anterior wall MI in the real world
The DELEVER study included patients with LVEF > 40%, and the application rates of RAAS inhibitors, β receptor blockers and MRAs were 71.7%, 76.1%, and 38.7%, respectively.[11] In our study, the application rates of RAAS inhibitors, β receptor blockers, MRAs, and SGLT2i were relatively low, with rates of 35.0%, 53.9%, 38.2%, and 1.6%, respectively. Unlike the DELEVER study, our study focused on patients with HF after acute anterior wall MI. Acute anterior wall MI may cause short-term onset of ventricular arrhythmias or hemodynamic changes in patients, making the clinical decision-making regarding the use of GDMT more complex than in patients with heart failure caused by other reasons, which may lead to a decrease in the proportion of patients receiving GDMT. In addition, blood pressure, heart rate, the eGFR, and a congested state during hospitalization can all affect the initiation of GDMT. Patients who cannot tolerate GDMT for the above reasons are not uncommon in clinical practice. Heart rate and blood pressure are important monitoring indicators for patients with HF after MI. The current guidelines recommend a target heart rate of approximately 60 beats/minute for HF patients after AMI. If patients have concomitant arrhythmias, clinical physicians cannot apply β receptor blockers to patients with heart rates ≤ 60 beats/minute;[12] for patients with hypertension and heart failure, it is recommended that the patient’s blood pressure be ≤ 130/80 mmHg.[13, 14] However, ARNI is not recommended when the patient's systolic blood pressure is less than 100 mmHg, and ACEI/ARB and β receptor blockers are not recommended when the patient's systolic blood pressure is less than 90 mmHg.[14] For the eGFR, patients treated with ACEI/ARB/ARNI and MAR should have an eGFR greater than 30 ml/min/1.73 m2. The eGFR of patients treated with empagliflozin and dapagliflozin should be greater than 20 ml/min/1.73 m2 and 30 ml/min/1.73 m2, respectively. In addition, due to the short launch time of SGLT2is, the application rate of SGLT2is in this study was relatively low, only 2.3%. Considering that the GDMT regimen for patients at discharge may be influenced by their predischarge blood pressure, heart rate, and eGFR, this study analyzed the blood pressure, heart rate, and eGFR of two groups of patients at discharge. The results showed no statistically significant differences in blood pressure, heart rate, or eGFR between the two groups of patients at discharge. Therefore, we found in this study that the subjective decision-making of clinical physicians was an important factor affecting the initiation of GDMT, and the results of this study precisely highlight the importance of applying GDMT in the clinic to improve the prognosis of HF patients after acute anterior wall MI. In addition, the baseline data of this study showed that the majority of patients had an LVEF ≥ 40%, with HFpEF + HFmrEF accounting for 90.7% and 96.3% of the patients in the GDMT group and non-GDMT group, respectively. For patients with HFpEF or HFmrEF, the current guidelines for HF and MI have different recommendations for four guideline-directed medicines to improve ventricular remodeling, which may be one of the reasons why physicians hesitate to initiate GDMT as shown by their lower recommendation level compared to that of HFrEF. [1, 7] On the other hand, awareness of the application of GDMT in the real world still needs to be improved, and there is still a considerable gap in the recommendations of the guidelines. Retrospective studies in the real world reflect the practical application of GDMT, which is also of great significance and reference value for improving clinical treatment.
GDMT application can improve the prognosis of patients with HF after acute anterior wall MI who receive PCI, with patients in the HFpEF subgroup (LVEF ≥ 50%) benefitting more
In most cases, the development of HF after MI is due to poor remodeling of the left ventricle (LV), possibly because the LV has a much greater advantage in cardiac pumping function than does the right ventricle (RV), and poor remodeling of the LV is more likely to lead to HF and a lower ejection fraction.[15] Compared with MI at other sites, anterior wall MI causes greater LV damage, resulting in a greater risk of HF. The degree of LV dysfunction in patients with inferior MI is relatively mild. Although some patients with inferior MI may experience early hemodynamic changes and complications due to concomitant RV infarction, long-term LV systolic function may not be significantly impaired.[16] Another study showed that approximately 30% of patients with anterior wall MI experience ventricular remodeling, while only approximately 17% of patients with nonanterior wall MI experience ventricular remodeling.[8] Therefore, for patients with acute anterior wall MI, GDMT should be initiated more actively. The endpoint events of this study confirmed this conclusion. In addition, a decrease in LVEF is associated with a greater risk of HF. Previous studies have shown that a 5% reduction in LVEF measured by ventricular angiography during hospitalization increases the risk of developing HF after hospitalization by 12–18%.[6, 17] However, all the patients included in this study were STEMI patients, and currently, the evaluation method for ventricular imaging is rarely used. Another study showed that a 5% decrease in LVEF measured by echocardiography 5 to 20 months after MI increases the risk of developing HF by 20%. In that study, thrombolytic patients accounted for 35% of all patients, whereas anterior and inferior wall MI patients accounted for 59.4% and 34.4% of patients, respectively,[18] which is different from the characteristics of all anterior wall MI patients who received PCI in this study. The baseline LVEF in this study was measured by echocardiography during hospitalization, and although the LVEF of the majority of patients was above 40%, the baseline LVEF in patients with HF after acute anterior wall MI is still a predictor of poor prognosis, which can provide a certain warning and reference for clinical practice. In addition, we divided all patients into three subgroups according to HF guidelines: HFpEF, HFmrEF, and HFrEF. The results showed that the use of GDMT in the HFpEF group could significantly benefit patients. A total of 4834 AMI patients who received PCI were screened in the PROMETHEUS study subgroup. GDMT was defined as the use of aspirin, P2Y12 inhibitors, statins, ACEIs/ARBs (70.8%), and β receptor blockers (92.2%); no data on the application of MRAs and SGLT2is was included in this study. The research results showed that the use of GDMT could benefit patients in both the LVEF ≥ 40% and LVEF < 40% subgroups, but the benefit was greater in the LVEF < 40% subgroup.[19] The reasons for the differences between this study and the PROMETHEUS study may be as follows. On the one hand, the overall sample size of this study was relatively small, with a small proportion of HFmrEF and HFrEF in all patients, accounting for 10.4% (33/317) and 7.9% (25/317), respectively. On the other hand, the patient characteristics of this study were anterior wall MI combined with HF, and the types of guideline-directed medicines used were slightly different. Based on the results of this study, we believe that GDMT for the prevention and treatment of ventricular remodeling should also be actively applied in HFpEF patients with acute anterior wall MI after PCI to improve patients’ prognosis. At the same time, studies with larger sample sizes should be conducted in the future to evaluate the different benefits of GDMT in these three groups of patients: HFpEF, HFmrEF, and HFrEF, after acute anterior wall MI.
In addition, for AMI patients, there may be myocardial stunting.[20] Although normal blood flow is restored through reperfusion, mechanical dysfunction may take several hours, days, or weeks to fully recover from. Therefore, some patients may have low blood pressure and decreased systolic function during hospitalization, but their blood pressure and myocardial systolic function may recover after discharge. Therefore, compared to patients with heart failure caused by other reasons, patients with HF after AMI are likely to experience dynamic changes in LVEF after discharge. HFrEF may gradually progress to heart failure with improved ejection fraction (HFimpEF) or heart failure with recovered ejection fraction (HFrecEF) due to the recovery process after surviving myocardial contractile function. Patients with HFpEF and HFmrEF may also experience heart failure with a decreased ejection fraction (HFdecEF) due to severe myocardial injury and a lack of standardized treatment. Therefore, dynamic evaluation and follow-up of HF patients after AMI are particularly important for adjusting treatment strategies in a timely manner. However, it should be noted that HFimpEF or HFrecEF only represents a certain degree of relief in cardiac function or structure and is not a true cure or complete normalization. The use of GDMT should continue to be applied to improve disease prognosis.
Early initiation of GDMT in the hospital can improve the prognosis of HF patients after acute anterior wall MI
For the timing of GDMT initiation, the current 2021ESC and 2022AHA guidelines for HF have optimized the GDMT initiation process. Early initiation of treatment is recommended for HFrEF patients.[1, 21] In addition, guidelines related to MI suggest that if there are no contraindications, the early use of ACE inhibitors (IIa, A) is recommended for all ACS patients; the early application of β receptor blockers is recommended for ACS patients with an LVEF ≤ 40% (IIa, B).[7] Early ventricular remodeling after MI mainly occurs at the site of infarction, within a few hours of acute coronary artery occlusion, and lasts for nearly a week. Acute long-term ischemia can lead to irreversible damage and poor ventricular remodeling. Timely reperfusion can restore the function of the stunned myocardium within hours or days, which is the most important means to save dying myocardium and prevent poor ventricular remodeling.[22] However, myocardial reperfusion itself may also lead to cellular damage and an increase in the infarct size.[22] The above basic research not only clarifies the role of timely revascularization in preventing and treating ventricular remodeling after AMI but also suggests the importance of early initiation of GDMT in patients with HF after MI who undergo PCI. A meta-analysis of clinical studies, such as CONSENSUS II, GISSI3, ISIS4 and CCS1, confirmed that ACEI treatment within 24 or 36 hours after the onset of AMI can reduce mortality within 30 days and the incidence rate of HF, and 80% of the benefits occurred in the first week of AMI.[23] The CAPRICORN trial confirmed that early application of carvedilol can reduce mortality in patients with AMI and an LVEF ≤ 40% and improve ventricular remodeling indicators in patients 6 months after MI.[24] The REMINDER study confirmed that the use of MRAs within 24 hours in STEMI patients without a history of HF can reduce cardiac mortality, readmission for heart failure, and NT-proBNP levels.[25] The above research confirms the significance of the early application of ACEI, β receptor blockers and MRAs in the prevention and treatment of HF after MI, but at that time, the rate of PCI was relatively low. The EMMY trial[26] showed that the early application of empagliflozin after PCI for AMI can significantly reduce NT-proBNP levels and improve ventricular remodeling to a certain extent, but the results of the subgroup analysis on the site of MI were not mentioned. The PARADISE-MI study[27] suggested that compared to ACEI, the early application of ARNI can improve ventricular remodeling and reduce the cumulative incidence of HF. However, this study included high-risk populations with an LVEF less than 40% and/or evidence of pulmonary congestion. The background of this study was all patients with HF after acute anterior wall MI who had undergone PCI, and the majority of patients had an LVEF ≥ 40%, which is different from the findings of the above studies to varying degrees. Therefore, the results of this study could serve as a reference for clinical treatment.
This study grouped patients with HF after acute anterior wall MI according to whether GDMT was used before discharge in clinical practice to explore the prognostic effect of early hospital initiation of GDMT on patients with HF after acute anterior wall MI who received PCI. The 1-year follow-up results showed that the use of GDMT had a lower incidence of all-cause mortality and all-cause readmission composite endpoint events; cardiac mortality and cardiac readmission composite endpoint events; all-cause readmission events; and cardiac readmission events. The main benefit was from reducing the incidence of readmission events. The initiation of GDMT to prevent ventricular remodeling in the hospital has a significant effect on improving the prognosis of HF patients after acute anterior wall MI. This study grouped patients based on whether GDMT was used before discharge, without examining whether there were any changes in GDMT initiation within one year after discharge in either group. This is also a limitation of using GDMT in a real-world cohort study. On the other hand, the use of GDMT during follow-up may be influenced by changes in the patient’s blood pressure, heart rate, eGFR, and LVEF, which are dynamic processes. Therefore, this study mainly emphasizes the timing of initiating GDMT in the hospital rather than the long-term impact of GDMT on HF patients after acute anterior wall MI.
The follow-up results of this study showed that the incidence of all-cause death and all-cause readmission composite endpoints; cardiac death and cardiac readmission composite endpoints; all-cause readmission; and cardiac readmission within one year after PCI were 12.62% (40/317), 9.15% (29/317), 11.99% (38/317), and 8.52% (27/317), respectively. GDMT significantly reduced the incidence of the above endpoints. Further analysis showed that the benefits of GDMT mainly come from reducing the readmission rate of patients. In the EMPEROR-Preserved study,[28] the incidence of all-cause readmission within 1 year was 5.93% (355/5988). The higher incidence of all-cause readmission in this study may be because the patients included in this study had HF after acute anterior wall MI. Compared to patients with HF caused by other factors, acute anterior wall MI causes greater myocardial damage to patients, resulting in more all-cause readmissions within 1 year after PCI. In addition, studies have shown that the proportion of primary PCI in AMI patients is approximately 80%,[29] but in this study, the proportion of primary PCI was approximately 60%, which may also increase the incidence of clinical events one year after PCI. As a single-center cohort study, although there were significant differences in some indicators of the baseline data, Cox regression analysis was used to correct for these factors. The incidence of primary endpoint events in patients in the GDMT group was lower than that in patients in the non-GDMT group, indicating that early initiation of GDMT in the hospital was significantly beneficial for patients with HF after acute anterior wall MI who received PCI.
Influence of the subgroup on the prognosis of patients with HF after acute anterior wall MI following in-hospital initiation of GDMT
Previous studies have shown that for HF patients after MI, factors such as sex, age, BMI, and myocardial infarction type may lead to differences in patient prognosis.[17] The population included in this study was HF patients after acute anterior wall MI. Therefore, subgroup analyses based on the above factors were also conducted. The results showed that in the age > 65 years subgroup and the BMI ≤ 30 subgroup, the incidences of all-cause mortality and all-cause readmission composite endpoints; all-cause readmission; cardiac death and cardiac readmission composite endpoints; and cardiac readmission of patients in the GDMT group were lower than those in the non-GDMT group (P < 0.05). Subgroup analysis of the PARADISE-MI trial also revealed that for individuals aged ≥ 65 years, ANRI can reduce cardiac death or first HF attack events.[27] Previous studies have shown that the incidence rate of HF during hospitalization of AMI patients aged 75–85 years is three times that of AMI patients aged 25–54 years.[30] After discharge, the incidence rate of HF in the elderly group is six times that of AMI patients aged 25–54 years. After multivariate correction, the results showed that for every 10-year increase in age, the risk of HF during hospitalization increased by approximately 50%, and the risk of HF after discharge increased by 20–50%.[15] Combined with the results of this study, it is suggested that for patients older than 65 years with HF after acute anterior MI, GDMT should also be more actively initiated to improve the prognosis of patients, which is consistent with a previous RCT showing that GDMT is more beneficial for high-risk patients. Most previous studies have revealed an obesity paradox in which the survival rate of HF patients with elevated BMI actually increases.[31, 32] In addition, Zamora et al.[33] showed that BMI is related to the survival benefits of HF patients with diabetes. There is an obesity paradox in patients without diabetes, but there is no obesity paradox in patients with diabetes. Similarly, the obesity paradox was not shown in this study, which showed that GDMT in the BMI ≤ 30 subgroup could benefit patients more. However, the proportions of patients with T2DM in the two groups of patients in this study were 23.7% and 18.5%, respectively, and there was no statistically significant difference between the two groups. Due to the prevalence of the "obesity paradox" in most heart failure studies, further exploration should be conducted to determine whether HF patients with acute anterior wall MI still exhibit the "obesity paradox" after excluding T2DM factors. In addition, studies have shown that weight loss is beneficial for reducing the incidence of HF and improving exercise tolerance.[34] Based on the results of this study, we believe that patients with HF after acute anterior wall MI should avoid having an excessive BMI while actively using GDMT to improve their prognosis. For patients of different sexes and with different MI subtypes, this study revealed that there was no significant difference in the incidence of endpoint events between patients in the GDMT group and those in the non-GDMT group. This may indicate that for HF after acute anterior wall MI, factors such as age, size of the MI, and location of the MI have a significant impact on the research results. On the other hand, it may also indicate that GDMT can significantly benefit patients with acute anterior wall MI after receiving optimized treatments such as PCI and standardized antithrombotic and statin therapy. The differences in sex and type of myocardial infarction may have had relatively small impacts on this study, but there are still limitations because of the relatively small sample size in this study; further exploration of these two aspects is needed.
Although the MI size of the two groups of patients was not analyzed in this study, the MI size of acute MI patients is considered to be related to the early implementation of PCI. Therefore, the baseline data of this study included the “door-to-balloon time” and the “first medical contact-to-balloon time”. The results showed no statistically significant difference between the two groups. In the future, more objective indicators are still needed to measure the MI area of patients to explore its impact on the effectiveness of GDMT in patients with HF after MI.
The impact of combined initiation of GDMT on the prognosis of patients with HF after acute anterior wall MI
Previous studies have shown that for HFrEF patients, the optimal treatment regimen using a combination of four guideline-directed medicines can reduce mortality by more than 70%.[35] The latest ACC decision consensus on GDMT in HFrEF patients also suggests that initiating guideline-directed medicines with a low-dose combination may be more beneficial than using one or two medicines at the maximum tolerable dose.[36] However, there is still no clear recommendation for HF patients with an LVEF > 40% after AMI; therefore, the relevant benefits are worth exploring. This study conducted subgroup analyses based on whether patients were using RAAS inhibitors, β receptor blockers, MRAs, or SGLT2is. The results suggested that the combined use of guideline-directed medicines has certain significance in improving the clinical prognosis of patients with HF after acute anterior wall MI. On the one hand, this may be related to the small sample size in this study, especially the low proportion of patients receiving SGLT2is in this study. On the other hand, it also suggests that for patients with HF after acute anterior wall MI, the combined initiation of GDMT is more effective. The pathophysiology of HF after MI involves multiple mechanisms, and different guideline-directed medicines can improve ventricular remodeling by exerting their respective pharmacological effects. Therefore, combination therapy may significantly improve the prognosis of patients with HF after MI. In addition, initiating SGLT2is and MRAs may alleviate the patient's congestion, enabling them to accept β receptor blockers more quickly; SGLT2is reduce the risk of hyperkalemia in patients, enabling the application of MRAs. In addition, various guidelines and consensuses suggest that after the combined initiation of GDMT, further titration of the medicines to the target dose or maximum tolerable dose to achieve optimal medicine treatment status is still necessary to improve patient prognosis. It is worth noting that the above recommendations are still mainly aimed at HFrEF and HFpEF patients after MI. There are still differences in various studies on the long-term (time > 1 year) application of β receptor blockers and the optimal dosage, which also suggests that a large number of RCTs are needed in the future to confirm such issues. However, this study has preliminarily shown that for patients with HF after acute anterior wall MI, initiating GDMT in the hospital and combined GDMT medicine application can benefit patients more. In addition, the author believes that early combined initiation of GDMT, on the one hand, follows the recommendations of optimizing the GDMT initiation process in the guidelines and, on the other hand, may increase patient compliance. Compared to gradually increasing multiple medicines during outpatient follow-up, in-hospital combined initiation of GDMT may improve patient compliance with GDMT outside of the hospital, which may be a potential improvement factor for patient prognosis. Notably, various guidelines and consensuses provide corresponding guidance on the administration sequence and principles of GDMT in clinical practice. For example, a low-dose drug combination is preferred, and it is generally recommended to increase the dose to the target dose or maximum tolerable dose within 4 weeks. Step-by-step initiation: Using the minimum dose, if some patients still cannot tolerate the simultaneous initiation of the "new quadruple" drug, they can start with 1–2 drugs first. If patients can tolerate this dose, then it should be gradually increased. According to the individualization principle, clinical decisions should be made according to the patient's individual condition (combined with diabetes, MI, renal insufficiency, hyperkalemia, arrhythmia, etc.) and the drugs’ characteristics.[36, 37] In summary, the current guidelines recommend prioritizing low-dose combined GDMT, and our research findings also support early initiation of GDMT to improve the prognosis of HF patients after acute anterior wall MI.