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Early administration of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with acute coronary syndrome: a systematic review and meta-analysis

BMC Cardiovascular Disorders volume 24, Article number: 395 (2024) Cite this article

Abstract

Background

High-intensity statin therapy is currently recommended initial guideline therapy in ACS treatment. However, only a minority of patients are achieving LDL-C attainment goal at 6 months. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are on recommended guideline therapy post-ACS if LDL-C goal attainment is not achieved after high-intensity statin (4–6 weeks) and after the addition of ezetimibe if guideline goal attainment is not achieved after an additional 4–6 weeks. Thus, it has been recommended that PCSK9 inhibitors be considered earlier post-ACS. However, the efficacy of early PCSK9 inhibitors initiation in ACS patients remains uncertain.

Methods

This systematic review and meta-analysis was conducted following PRISMA guidelines. Randomized controlled trials (RCTs) and observational studies involving ACS patients who received PCSK9 inhibitors within 48 h of hospitalization were included. Common and random effects models were used to evaluate the pooled effect of early PCSK9 inhibitor administration. Nine RCTs and three cohort studies were included.

Results

Early PCSK9 inhibitor administration reduced the incidence of MI, ACS hospitalization, and revascularization at 6–18 months post-ACS. Although there was a drift towards reduced stroke, all-cause mortality, and cardiovascular death, no statistically significant reduction was observed. Additionally, PCSK9 inhibitors significantly enhanced lipid control at 4–12 weeks after index hospitalization.

Conclusion

Early PCSK9 inhibitors initiation in ACS patients reduces MACE and improves lipid profiles. While the results propose promising benefits in terms of stroke and mortality, further research with longer follow-up is required for more decisive evidence.

Peer Review reports

Introduction

Acute coronary syndrome (ACS) is a high-risk medical condition that requires rapid and effective treatment to prevent potential complications and reduce mortality rates [1]. Early initiation of intensive lipid-lowering treatment with greater LDL-C lowering is recommended in ACS patients to diminish the risk of additional complications [2,3,4].

This has long included high-intensity statin therapy, but several additional classes of lipid-lowering agents are also available to provide additional LDL-C lowering or as alternatives for individuals unable to take statins [5]. This includes proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

While chronic use of PCSK9 inhibitors in individuals with stable IHD is well-known to improve outcomes [6], whether early initiation of these agents (in the setting of ACS) might also reduce early events is less clear [7]. We aimed to address this area of uncertainty with a systematic review and meta-analysis of randomized controlled trials (RCTs) and cohort studies testing the efficacy of early administration of the PCSK9 inhibitors evolocumab and alirocumab, in patients hospitalized with ACS.

Methods

This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [8] and the study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) – PROSPERO ID: CRD42023443823 [9, 10].

Criteria for Considering Studies for this Review.

Types of studies

Randomized Controlled Trials (RCTs) and observational studies including adult patients with a diagnosis of ACS reporting head-to-head comparison of PCSK9 inhibitors started in the first 48 h after presentation to the hospital (early administration strategy) to usual care were included. Case reports, review articles, trial design protocols, non-comparative studies, and conference abstracts were dismissed.

Participants and interventions

Patient exclusion criteria differed across studies but generally included known allergies to PCSK9 inhibitors, conditions likely to change the clinical course independent of ACS, or conditions that could jeopardize their safety or limit their participation in the respective trial.

Outcome measures

Primary outcomes of the study included major adverse clinical events (MACE), including mortality (all-cause or cardiovascular), stroke, non-fatal MI, ACS hospitalization, and need for revascularization at 24 to 72 weeks post-index hospitalization. Secondary outcomes included laboratory measurements of lipid profile including apolipoprotein B (Apo B), apolipoprotein A-I (Apo A), lipoprotein(a) (Lp(a)), total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglycerides (TG) at 4–12 weeks post-index hospitalization.

Search strategy

After identifying relevant keywords and search terms (Supplementary Material), we performed a systematic search of the following electronic databases: PubMed, EMBASE, Cochrane Library, Clinicaltrials.gov, and WHO’s International Clinical Trials Registry Platform, from January 1, 2014, until July 11, 2023. Only English language studies were included. Reference lists of eligible studies and relevant reviews on the topic were also screened.

Data collection and management

The process involved importing the findings of the systematic search into Endnote software version 20.0 (from Clarivate PLC in London, United Kingdom). Two independent authors, SM and AN, reviewed study titles and abstracts, and any discrepancies were addressed by a third reviewer, HS. The selected studies were then retrieved in full, and data was extracted using a pre-designed form which included: name of the first author, study location, study type, sample size for each comparison group, baseline characteristics, laboratory markers, and the presence/absence of clinical events.

Risk of bias assessment

The quality of RCTs included in the study was assessed using version 2.0 of the Cochrane Risk of Bias Assessment Tool for Randomized Trials (RoB2) [10, 11]. The Newcastle-Ottawa Scale (NOS) [12] was used to assess the quality of nonrandomized studies included in our meta-analyses. Selection, comparability, and ascertainment of exposure/outcome were assessed in each non-randomized study. Two authors (SM, AN) assigned stars in each category, and conflicts were resolved through consensus.

Data analysis and investigation of heterogeneity

All statistical analyses were conducted using R Programming language (R for Windows, version 4.1.3, Vienna, Austria) and R Studio version 1.1.463 (Posit PBC, Boston, MA, United States) utilizing the “tidyverse” and “meta” statistical packages. Risk ratios with 95% confidence intervals were calculated for binary variables, while mean and standard deviation (SD) were calculated for continuous variables, to compare treatment methods mean difference (MD) was calculated. In studies that reported median and interquartile (IQR) ranges, we used the method developed by Lou et al. [13] and Wan et al. [14] to calculate means and standard deviations. Heterogeneity was assessed using the I2 statistic, with significant heterogeneity defined as I2 > 70%. If heterogeneity was significant, we used a random effects model to estimate the effect size of the pooled data; otherwise, a fixed effects model was used. Sensitivity and subgroup analyses were conducted to identify sources of heterogeneity when possible. Funnel plots were not produced for this study as the number of included papers was less than 10.

Sensitivity analysis

We performed a leave-one-out sensitivity analysis to evaluate the robustness of our meta-analysis for the LDL-C outcome by iteratively removing one study at a time and recalculating the pooled estimate.

Results

Study selection

Figure 1 depicts the selection process for the study. The database search produced 1301 records in total. 1054 items were retrieved for preliminary screening after duplicates were removed. Under the guidance of a senior team member, two independent reviewers examined the entirety of 102 articles before determining their ultimate eligibility. Publications that did not include randomized clinical trials and cohort studies were disregarded (Fig. 1). Finally, nine randomized clinical trials comprising a total of 1268 participants and three cohort studies including 1982 participants, were included in this analysis (Table 1).

Fig. 1
figure 1

Flowchart of the study selection process. RCT, randomized controlled trial

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Table 1 Characteristic and demographic information of included studies
Full size table

Characteristics of included studies

All 12 studies included in our analyses were published between 2019 and 2023. The mean ± SD age range was similar in both RCTs and cohort studies and the majority of patients were male (Table 1). Seven RCTs and one cohort study enrolled patients with both non-ST-elevation (NSTE) ACS and ST Elevation Myocardial Infarction (STEMI) [15,16,17,18,19,20,21,22], one RCT and one cohort included only patients with STEMI [23, 24], and one RCT and one cohort study only included patients with NSTE-ACS [25, 26]. One RCT and three cohort studies reported MACE [16, 20, 23, 26] with at least 6 months of clinical follow-up. Table 1. Characteristic and demographic information of included studies.

Outcomes

Primary outcomes- clinical outcomes

In comparison to usual care, at 6–18 months post index hospitalization, early initiation of PCSK9 inhibitors in patients with ACS resulted in a lower incidence of MI, ACS hospitalization, and need for revascularization with risk ratios (RR) of 0.59 (95%CI 0.38–0.92), 0.53 (95% CI 0.34–0.83) and 0.71 (95%CI 0.50-1.00), and estimated numbers needed to treat of 35,38, and 37, respectively (Fig. 2A and B, and 2C). However, while RR for stroke (CVA) (0.94; 95%CI 0.51–1.72), all-cause mortality (0.66; 95%CI 0.31–1.40), and cardiovascular death (0.79; 95%CI 0.35–1.79), tended to be reduced with PCSK9 inhibitor use, the effects were not statistically significant at 6–18 months post-ACS (Fig. 2D and E, and 2F).

Fig. 2
figure 2

(A–F) Forest plot showing the observed outcomes and the estimate of the common effect models for MI, ACS hospitalization, Need for Revascularization, Cerebrovascular Accidents, all-cause mortality, and Cardiovascular Mortality [16, 21, 23, 26]

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Secondary outcomes -lipid profiles

The random effect model analysis showed significant reductions in total (MD: -39.27, 95%CI (-52.08; -26.46)) and LDL-C (MD: -37.58, 95% CI (-46.63; -28.530)) in patients receiving early PCSK9 inhibitor treatment vs. control groups (Fig. 3A, B), although there was high heterogeneity.

Fig. 3
figure 3

(A–D) Forest plot showing the observed outcomes and the estimate of the common and random effect models for Total cholesterol, LDL-C, Lipoprotein a, and Apo lipoprotein B, at Short-term Follow-up (4–12 weeks) [15, 17,18,19,20, 22, 24, 25]

Full size image

Common effects modeling revealed a significant difference between the PCSK9 inhibitor group and the placebo group in Lp(a) levels (MD: -10.91, 95% CI (-16.47; -5.35)), and random effects modeling demonstrated a significant difference in Apo B levels between the two groups (MD: -27.03, 95% CI (-27.03; -17.76)), respectively (Fig. 3C and D). The results of HDL-C, TG, and Apo A levels during short-term follow-up (4–12 weeks) are presented in Supplementary files (Figure S1).

Sensitivity analysis

Figure S2 shows the leave-one-out sensitivity analysis for the LDL-C outcome. The point estimates and confidence intervals are consistent across the iterative removal of each study, indicating that no single study had an undue influence on the overall result and confirming the robustness of our meta-analysis for this outcome.

The methodological risk of bias

The results of quality assessments, using the Cochrane Risk of Bias 2 (RoB 2) tool for RCTs and the Newcastle Ottawa scale (NOS) for cohort studies, are represented in Figs. 4 and 5; Table 2. Except for the study by Li et al. [20]. which was found to have a high risk of bias due to the high-risk randomization process, all other included RCTs and cohorts were deemed to be of high quality.

Fig. 4
figure 4

Risk of bias graph in RCTs

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Fig. 5
figure 5

Risk of bias summary in included RCTs [15,16,17,18,19,20, 22, 24, 25]

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Table 2 Quality assessment of cohort studies
Full size table

Discussion

Our pooled analyses reveal that, at 6–18 months following ACS, adverse clinical events are reduced with administration/initiation of PCSK9 inhibitors in the first 48 h after presentation to the hospital. In comparison to the control group receiving standard therapy, the PCSK9 antibody group saw decreased incidence of MI, ACS-related hospitalization, and revascularization. Early PCSK9 inhibitors therapy also suggested potential advantages in terms of CVA, cardiovascular mortality, and all-cause mortality. In addition, early implementation of PCSK9 inhibitors significantly reduced total cholesterol, LDL-C, Apo B, and Lp(a) levels within 4–12 weeks of initiation.

Our meta-analysis provides evidence supporting the use of early PCSK9 inhibitor administration in ACS patients to improve clinical outcomes and lipid profiles. Early administration of PCSK9 inhibitor therapies should be considered by physicians in patients with ACS, particularly those with high LDL-C levels or those who can’t accomplish acceptable LDL-C reduction with statin therapy alone. However, treatment decisions should be modified based on medical history, risk factors, and the presence of concurrent medical conditions. Further study is needed to identify the ideal timing and duration of PCSK9 inhibitor therapies in ACS patients in order to evaluate the long-term safety and efficacy of this treatment approach. Early PCSK9 inhibitor therapy could stabilize vulnerable plaques, reduce inflammation, and prevent recurrent cardiovascular events [27,28,29].

Primary outcomes- clinical outcomes

To our knowledge, no meta-analysis has been conducted so far that has evaluated the effects of early implementation of PCSK9 inhibitors in ASC patients. Our assessment of both observational studies and RCTs with a minimum follow-up duration of 6 months revealed that the prompt use of PCSK9 inhibitors in ACS patients resulted in lower rates of MI, hospitalization, and the need for revascularization at mid-term follow-up (6–18 months) in comparison to placebo or standard of care. The biological plausibility of these early clinical benefits is supported by studies showing PCSK9i in ACS patients reduces plaque burden and increases fibrous cap thickness [16, 30, 31].

While there is limited knowledge of early initiations of PCSK9 inhibitors in ACS management, many studies have assessed the efficacy and safety of these drugs in stable patients. Turgeon et al. [32] found that PCSK9 inhibitors lowered the risk of composite MACE by 17% in a meta-analysis encompassing 23 RCTs with a minimum follow-up of 6 months. The effects of PCSK9 inhibitors on all-cause and cardiovascular mortality, however, were not statistically significant. Furthermore, a recent meta-analysis assessing the efficacy of PCSK9 inhibitors on MACE in adults with atherosclerotic cardiovascular disease found that both alirocumab and evolocumab reduced MACE at a mean 1.56 years follow-up with the corresponding number needed to treat of 36. This reduction also included a decrease in CVA and coronary revascularization [33].

While our results demonstrated that early administration of PCSK9 inhibitors shows better effectiveness than conventional therapy in terms of CVA, cardiovascular mortality, and all-cause death, the difference was not statistically significant. There are three critical factors to consider in this situation. To begin with, it is conceivable that the period of follow-up was insufficient to appropriately assess these effects. Second, just one RCT investigated MACE outcomes for more than 6 months [16], stressing the need for further trials with longer follow-up lengths to offer greater clarification on this issue and finally the incidence of aforementioned adverse events was too low, so it might be possible that studies were not powered enough to detect a significant shift in these outcomes.

Secondary outcomes- lipid profiles

The aggressive and rapid reduction of LDL-C levels has been generally acknowledged as an important method to reduce rates of MACE in high-risk individuals [34,35,36]. According to previous guidelines, it was recommended to re-evaluate lipid profiles 4–6 weeks after initiation of lipid-lowering therapies in post-NSTE-ACS management [3, 37]. Additionally, as a general suggestion, 8 ± 4 weeks is an appropriate timeframe for assessing the effectiveness of lipid-lowering treatment [3]. Therefore, in this meta-analysis, we assessed lipid profiles in both treatment groups regarding lipid profile at 4–12 weeks post initial treatment.

In congruence with a previous network meta-analysis evaluating patients with hypercholesterolemia [38], our pooled analysis of patients with the diagnosis of ACS confirmed the superiority of early usage of PCSK9 inhibitors compared to the usual treatment group regarding LDL-C in the near term.

Researchers have recently investigated the impact of lipoproteins other than LDL-C in MACE reduction, including Lp(a) and Apo B [39,40,41]. The exact mechanisms associated with Lp(a) reduction through PCSK9 inhibition are not clearly understood, but LDL receptor, LDL receptor-related protein 1, and scavenger receptor class B type 1 are some potential targets affected by PCSK9 inhibitors in Lp(a) catabolism [42]. Additionally, increasing Intermediate Density Lipoprotein and LDL ApoB fractional clearance rate and reducing LDL ApoB production rate have both been proposed as potential mechanisms of ApoB decrease by PCSK9 inhibitors [43]. According to our findings, early treatment of PCSK9 inhibitors successfully lowered Lp(a) and Apo B levels. Furthermore, multiple observational studies have found that those with high Lp A levels had a greater risk of MACE [44, 45]. Similarly, the results of previous studies [46,47,48] indicate a positive correlation between Apo B and the occurrence of MACE. However, the residual cardiovascular risk factors are not well established and further studies with high levels of evidence are necessary to clarify this matter.

Limitations

We acknowledge that our study has limitations. First, in the assessment of MACE, we only have one RCT and three cohorts, which contributed to heterogeneity in our pooled analysis. Second, not enough studies have been conducted to provide preferred evidence of long-term assessment of early injection of evolocumab and alirocumab in ACS patients, probably due to the high cost of PCSK9 inhibitors. Third, considering the absence of data on composite MACE incidence in our included studies, we were unable to analyze it due to the possibility of overlapping MACE components; and finally, our findings could be biased due to the small sample sizes of included studies, especially relevant to MACE, which have a low incidence. Each study used different time frames for follow-up and evaluation of outcomes, so we did not have uniform definitions which add to the heterogeneity of our results.

Cost implications and cost-effectiveness

While the clinical benefits of early initiation of PCSK9 inhibitors in ACS patients are engaging, the cost of these drugs is an important barrier to widespread adoption. A study by Gragnano et al. [49] found the rates of patients with full adherence to PCSK9 inhibitors significantly higher than the statin group after mean period of 10.4 months after initiation of the PCSK9 inhibitors. A study by Cesaro et al. [50] found that PCSK9 inhibitor therapy significantly improved EuroQol 5D quality of life scores and visual analog scale health status scores at 1 year compared to baseline in high cardiovascular risk patients, with the greatest improvement seen in the anxiety/depression dimension. The authors postulated that the substantial LDL-C lowering achieved, attainment of recommended LDL goals, less pill burden with injectable therapy, and a sense of reassurance may have contributed to the favorable effects on quality-of-life measures. A recent systematic review by Azari et al. in 2019 highlighted the high cost of PCSK9 inhibitors, reaching $7000 and $15,000 in developed countries and the USA, respectively. However, the review suggested the usage of these drugs may be more cost-effective in different populations [51]. To clarify this knowledge gap further research is needed to assess the cost-effectiveness of early PCSK9 inhibitor use in the post-ACS setting, considering factors such as long-term cardiovascular event reduction, hospital readmissions, and overall healthcare costs.

Conclusions

Early initiation of PCSK9 inhibitors in ACS patients appears to significantly reduce the rate of MI, ACS hospitalization, and the need for revascularization at 6 to 18 months of follow-up. Additionally compared to standard lipid-lowering therapy, more improvement in lipid profile was seen in the PCSK9 inhibitors group. This data supports the utilization of PSCK9 inhibitors earlier in the treatment paradigm of post-ACS patients.

Data availability

The datasets obtained and analyzed in the current study are available from the corresponding author upon reasonable request.

Abbreviations

ACS:

Acute coronary syndrome

LDL-C:

Low-density lipoprotein cholesterol

PCSK9 inhibitors:

Proprotein convertase subtilisin/kexin type 9

IHD:

Ischemic heart disease

RCT:

Randomized controlled trial

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analysis

MACE:

Major adverse cardiovascular events

MI:

Myocardial infarction

HDL-C:

High-density lipoprotein cholesterol

TG:

Triglyceride

STEMI:

ST elevation myocardial infarction

NSTE:

Non ST elevation

RR:

Risk ratio

SD:

Standard deviation

IQR:

Inter-quartile range

CVA:

Cerebral vascular accident

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Funding

This research did not receive any specific grant from funding agencies.

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Author notes

  1. Saba Maleki and Amir Nasrollahizadeh contributed equally to this work.

Authors and Affiliations

  1. Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, 1419733141, Iran

    Kaveh Hosseini, Hamidreza Soleimani, Saba Maleki & Amir Nasrollahizadeh

  2. Cardiovascular Diseases Research Institute, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, 1419733141, Iran

    Kaveh Hosseini, Hamidreza Soleimani & Amir Nasrollahizadeh

  3. Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, 1411713139, Iran

    Hamidreza Soleimani

  4. School of Medicine, Guilan University of Medical Sciences (GUMS), Rasht, Guilan Province, Iran

    Saba Maleki

  5. Centre for Clinical Research Sormland, Uppsala University, Uppsala, SE, Sweden

    Sima Tayebi

  6. California Cardiovascular Institute, Fresno, CA, USA

    John Nelson

  7. Center for the Prevention of Cardiovascular Disease, Leon H. Charney Division of Cardiology, NYU Langone Health, New York University Grossman School of Medicine, New York, NY, USA

    Sean P. Heffron

Authors
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Contributions

Conceptualization, K.H. and H.S.; methodology, K.H.; software, H.S.; validation, S.M. and A.N.; formal analysis, H.S.; investigation, S.M.; data curation, A.N.; writing—original draft preparation S.M. and A.N.; writing—review and editing, K.H., S.T., J.N., and S.H.; visualization, S.M.; project administration S.M. and A.N.; revision J.N and S.H. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Hamidreza Soleimani.

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Hosseini, K., Soleimani, H., Maleki, S. et al. Early administration of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with acute coronary syndrome: a systematic review and meta-analysis. BMC Cardiovasc Disord 24, 395 (2024). https://doi.org/10.1186/s12872-024-04057-w

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Keywords

BMC Cardiovascular Disorders

ISSN: 1471-2261

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