Addition of Ezetimibe to Intensive Lipid-Lowering Therapy Is Associated With a Lower Incidence of Heart Failure in Patients With Acute Coronary Syndrome

Abstract

Background: This study investigated whether intensive lipid-lowering therapy with pitavastatin and ezetimibe lowers the incidence of heart failure (HF) events in patients with acute coronary syndrome (ACS).

Methods and Results: In the HIJ-PROPER study, 1,734 patients with ACS were randomly assigned to either pitavastatin plus ezetimibe therapy (n=864) or pitavastatin monotherapy (n=857). We examined the incidence of HF between these 2 groups over a 3.9-year period after ACS. The primary endpoint of the study was hospitalization for HF. The mean low-density lipoprotein cholesterol levels during the follow-up period were 65.1 mg/dL in the pitavastatin plus ezetimibe group and 84.6 mg/dL in the pitavastatin monotherapy group. The incidence of HF hospitalization was significantly lower in the pitavastatin plus ezetimibe group than in the pitavastatin monotherapy group (19 [2.2%] vs. 40 [4.7%] patients; hazard ratio 0.47, 95% confidence interval 0.27–0.81; P<0.005). This trend was consistent after multivariable analysis using multiple models.

Conclusions: Intensive lipid-lowering therapy with pitavastatin and ezetimibe is associated with a lower incidence of hospitalization for HF in patients with ACS.

Lower levels of low-density lipoprotein cholesterol (LDL-C) are beneficial for patients with coronary artery disease, especially those with acute coronary syndrome (ACS), to prevent recurrent ischemic events.¹ Statins, which target cholesterol synthesis in the liver, lowered LDL-C levels and reduced the risk of death and recurrent ischemia in patients with ACS.^2,3 Some previous reports suggested that intensive statin therapy could reduce the incidence of hospitalization for heart failure (HF) compared with moderate statin therapy among patients with ACS.^4–7 There are reports that the positive effects of statins on HF cannot be explained solely by their LDL-C-lowering effect, and that their anti-inflammatory effects are also involved, preventing remodeling and improving endothelial function.^8,9 The use of ezetimibe, which has lowers LDL-C by inhibiting intestinal cholesterol absorption, is associated with a better prognosis in patients with ACS.¹⁰ A meta-analysis of clinical trials reported that ezetimibe may have an anti-inflammatory effect.¹¹ However, it remains unclear whether intensive LDL-C-lowering therapy with the addition of ezetimibe to a statin is associated with a reduction in HF events among patients with ACS.

In our previous randomized controlled trial, namely the Heart Institute of Japan–PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome (HIJ-PROPER), we tested the efficacy of intensive vs. conventional lipid-lowering therapy in ACS patients. In the parent HIJ-PROPER study, patients with ACS were randomized to receive intensive lipid-lowering therapy (pitavastatin+ezetimibe therapy) or conventional lipid-lowering therapy (pitavastatin monotherapy), and the incidence of the cardiovascular events was compared between groups.¹² The aim of the present study was to investigate whether intensive lipid-lowering therapy with pitavastatin+ezetimibe lowers the incidence of HF in patients with ACS.

Methods

Study Design and Participants

This was a subanalysis of the HIJ-PROPER study.¹² Briefly, HIJ-PROPER was a multicenter prospective randomized open-label blinded-endpoint trial with an active control design that compared 2 lipid-lowering treatment strategies in 19 Japanese hospitals between January 2010 and April 2013. The HIJ-PROPER study specifically targeted hospitalized patients with ACS and dyslipidemia. All participants had been hospitalized for ST-segment elevation myocardial infarction (MI), non-ST-segment elevation MI, or unstable angina within 72 h before randomization. As described above, in HIJ-PROPER, 1,734 patients with ACS were randomized to receive either intensive lipid-lowering therapy or conventional lipid-lowering therapy; 13 patients were lost to follow-up. Thus, 1,721 patients were included in the original study (864 in the pitavastatin+ezetimibe arm, 857 in the pitavastatin arm).

The primary endpoint of the present study was an HF event. We examined the incidence of HF events in the pitavastatin+ezetimibe and pitavastatin monotherapy groups. In the present study, we defined an HF event as an event requiring hospitalization and the presence of at least one of the following symptoms, physical findings, or X-ray findings: dyspnea on exertion, orthopnea, or paroxysmal nocturnal dyspnea; edema, third heart sound gallop, or elevated jugular venous pressure; and pulmonary congestion or cardiac enlargement.

Ethical Considerations

This study was conducted according to the principles of the Declaration of Helsinki. The present substudy has been registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (ID: UMIN000002742) as an international standard randomized controlled trial.

The institutional review board or relevant ethics committee of each participating medical center approved the study protocol, and all patients provided written informed consent for trial enrolment. A steering committee was responsible for the scientific conduct and publication of the trial results, and a working group was responsible for daily administration.

Statistical Analysis

Normally distributed data are presented as the mean±SD, data that are not normally distributed are presented as the median with interquartile range (IQR), and categorical data are presented as absolute values and percentages. Comparisons were made using the Welch t-test for normally distributed continuous variables, the Mann-Whitney U test for non-normally distributed continuous variables, and Pearson’s Chi-squared test for categorical variables. The time to the first occurrence of events was analyzed using the Kaplan-Meier method with a log-rank test and conventional Cox proportional hazards model.

Because of the small number of endpoints in this study, we avoided including all potential confounders in one multivariable model. Therefore, multivariable analysis was performed using the following 5 separate models to analyze whether ezetimibe use was an independent prognostic factor of HF event. The variables were included in the multivariable model if they had values of P<0.05 after the univariate analysis and according to clinical significance.

• Model 1 was adjusted for age, body mass index (BMI), estimated glomerular filtration rate (eGFR), history of HF, and MI.

• Model 2 was adjusted for age, eGFR, history of HF, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and the use of β-blockers.

• Model 3 was adjusted for age, the presence of diabetes, eGFR, history of HF, and previous percutaneous coronary interventions.

• Model 4 was adjusted for age, eGFR, BMI, history of HF, and percentage reduction in LDL-C.

• Model 5 was adjusted for age, eGFR, BMI, history of HF, and dose of pitavastatin.

Statistical significance was set at P<0.05, two-tailed test, unless stated otherwise. All statistical analyses were performed using JMP Pro 17 software (SAS Institute Inc., Cary, NC, USA).

Results

There were 864 (49.8%) patients in the pitavastatin+ezetimibe group and 857 (50.2%) patients in the pitavastatin monotherapy group. The baseline characteristics of patients in both groups are presented in Table 1; there were no significant differences between the 2 groups. Mean LDL-C levels during the follow-up period were 65.1 mg/dL in the pitavastatin+ezetimibe group and 84.6 mg/dL in the pitavastatin monotherapy group. During the study’s entire follow-up period of 3.9 years, 59 patients were hospitalized for HF.

Table 1.

Baseline Characteristics of the Study Population

	Pitavastatin monotherapy (n=857)	Pitavastatin+ezetimibe therapy (n=864)	P value
Age (years)	65.4±11.9	65.7±11.7	0.61
Male sex	661 (77.1)	639 (73.9)	0.12
BMI (kg/m2)	24.3±3.6	24.3±3.5	0.78
eGFR (mL/min/1.73 m2)	73.7±30.2	72.5±18.8	0.35
Hypertension	576 (67.2)	599 (69.3)	0.35
Diabetes	260 (30.3)	260 (30.1)	0.91
Current smoker	300 (35.0)	294 (34.0)	0.67
Previous MI	68 (7.9)	62 (7.6)	0.55
Previous revascularization	79 (9.2)	76 (8.8)	0.76
History of HF	15 (1.8)	21 (2.4)	0.32
Medication
β-blocker	91 (10.6)	87 (10.0)	0.71
ACEIs/ARBs	248 (28.9)	244 (28.2)	0.75
Calcium channel blocker	250 (29.2)	268 (31.0)	0.40
Aspirin	144 (16.8)	148 (17.1)	0.86
Mean dose of pitavastatin (mg)	2.02±9.91	2.36±0.90	<0.0001
Cholesterol metabolism
Total cholesterol	211±36.1	210±34.4	0.64
HDL-C	48.3±12.3	49.0±12.5	0.26
LDL-C	136±30.0	135±29.3	0.58
Triglyceride	132±72.8	129±69.3	0.33

Unless indicated otherwise, data are given as the mean±SD or n (%). ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; HF, heart failure; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction.

The incidence of HF hospitalization was significantly lower in the pitavastatin+ezetimibe than pitavastatin monotherapy group (19 [2.2%] vs. 40 [4.7%] patients; hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.27–0.81; P<0.005; Figure). Patient characteristics with or without HF and events other than HF are available in Supplementary Tables 1 and 2. As indicated in Table 2, factors associated with hospitalization for HF were age (HR 1.07; 95% CI 1.04–1.09; P<0.0001), BMI (HR 0.90; 95% CI 0.83–0.98; P=0.01), eGFR (HR 0.68; 95% CI 0.59–0.79; P<0.0001), diabetes (HR 1.83; 95% CI 1.10–3.07; P=0.02), smoking (HR 0.48; 95% CI 0.25–0.90; P=0.02), history of HF (HR 7.03; 95% CI 3.19–15.5; P<0.0001), previous MI (HR 3.61; 95% CI 1.95–6.68; P<0.0001), and previous revascularization (HR 3.30; 95% CI 1.81–6.02; P<0.0001). In addition, the use of β-blockers (HR 2.99; 95% CI 1.66–5.37; P=0.003), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (HR 1.99; 95% CI 1.19–3.33; P=0.009), calcium channel blockers (HR 1.98; 95% CI 1.19–3.30; P=0.009), and aspirin (HR 2.06; 95% CI 1.17–3.61; P=0.01) was associated with HF hospitalization (Table 2). As indicated in Table 3, the use of ezetimibe was associated with a lower incidence of the primary endpoint in the multivariable Cox proportional hazards models: Model 1, adjusted HR 0.47 (95% CI 0.27–0.80; P=0.006); Model 2, adjusted HR 0.45 (95% CI 0.26–0.78; P=0.005); Model 3, adjusted HR 0.47 (95% CI 0.27–0.81; P=0.007); Model 4, adjusted HR 0.46 (95% CI 0.25–0.85; P=0.013); and Model 5, adjusted HR 0.50 (95% CI 0.28–0.89; P=0.019). No correlation was observed between the percentage reduction in LDL-C levels from baseline to follow-up and the occurrence of hospitalization for HF (Supplementary Figure).

Figure.

Incidence of hospitalization for heart failure. The incidence of hospitalization for heart failure was significantly lower in the pitavastatin plus ezetimibe than pitavastatin monotherapy group.

Table 2.

Univariate Analysis of Factors Associated With Hospitalization for HF

	HR	95% CI	P value
AgeA	1.07	1.04–1.09	<0.0001
Male sex	0.65	0.38–1.13	0.13
BMIA	0.90	0.83–0.98	0.01
eGFRB	0.68	0.59–0.79	<0.0001
Hypertension	1.23	0.69–2.19	0.48
Diabetes	1.83	1.10–3.07	0.02
Current smoker	0.48	0.25–0.90	0.02
History of HF	7.03	3.19–15.5	<0.0001
Previous MI	3.61	1.95–6.68	<0.0001
Previous revascularization	3.30	1.81–6.02	<0.0001
Medication at enrollment
β-blocker	2.99	1.66–5.37	0.0003
ACEIs/ARBs	1.99	1.19–3.33	0.009
Calcium channel blocker	1.98	1.19–3.30	0.009
Aspirin	2.06	1.17–3.61	0.01
Use of ezetimibe	0.47	0.27–0.81	0.005
Mean dose of statin	0.81	0.58–1.10	0.19
HDL-CB	0.94	0.90–0.98	0.01
LDL-CB	1.04	0.96–1.12	0.28
TriglycerideB	0.94	0.90–0.98	0.01
hs-CRPB	1.01	0.91–1.08	0.90
% Reduction in HDL-C	1.00	0.99–1.01	0.56
% Reduction in LDL-C	1.01	0.99–1.02	0.13
% Reduction in triglyceride	1.00	0.99–1.00	0.37

^APer 1-unit increase; ^Bper 10-unit increase. CI, confidence interval; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive protein. Other abbreviations as in Table 1.

Table 3.

Multivariable Cox Analyses of Hospitalization for HF With Pitavastatin+Ezetimibe Therapy vs. Pitavastatin Monotherapy

	HR	95% CI	P value
Univariable analysis	0.47	0.27–0.80	0.006
Multivariable analysis
Model 1	0.47	0.27–0.80	0.006
Model 2	0.45	0.26–0.78	0.005
Model 3	0.47	0.27–0.81	0.007
Model 4	0.46	0.25–0.85	0.013
Model 5	0.50	0.28–0.89	0.019

Model 1 was adjusted for age, eGFR, BMI, history of HF, and previous MI. Model 2 was adjusted for age, eGFR, history of HF, the use of ACEIs or ARBs, and the use of β-blockers. Model 3 was adjusted for age, eGFR, the presence of diabetes, history of HF, and previous percutaneous coronary intervention. Model 4 was adjusted for age, eGFR, BMI, history of HF, and the percentage reduction in LDL-C levels. Model 5 was adjusted for age, eGFR, BMI, history of HF, and the dose of pitavastatin. CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.

Mean levels of high-sensitivity C-reactive protein (hs-CRP) in the 2 groups from baseline to follow-up are presented in Table 4. No differences were observed in hs-CRP levels between the 2 groups from baseline to 6 months. However, hs-CRP levels at the 12-month follow-up were significantly lower in the pitavastatin+ezetimibe group than in the pitavastatin monotherapy group (1,398±214 vs. 2,081±211; P=0.02).

Table 4.

hs-CRP Levels in the Pitavastatin+Ezetimibe and Pitavastatin Monotherapy Groups

	Pitavastatin monotherapy	Pitavastatin+ezetimibe therapy	P value
hs-CRP (ng/mL)
At baseline	20,960±1,067 (n=823)	21,212±1,069 (n=821)	0.87
At the 3-month follow-up	2,212±247 (n=758)	1,845±247 (n=758)	0.29
At the 6-month follow-up	1,732±276 (n=740)	1,967±278 (n=733)	0.55
At the 12-month follow-up	2,081±211 (n=711)	1,398±214 (n=693)	0.02

Unless indicated otherwise, data are presented as mean±SD. hs-CRP, high-sensitivity C-reactive protein.

Discussion

The primary findings of the present study are that: (1) intensive lipid-lowering therapy with pitavastatin and ezetimibe was associated with a reduction in the hospitalization rate for HF in patients with ACS; (2) a similar trend was observed when patient characteristics, medication, comorbidities, changes in LDL-C levels, and dose of pitavastatin were included as confounders in the multivariable analysis; and (3) there was no correlation between a reduction in LDL-C levels and a lower incidence of HF.

Ezetimibe inhibits cholesterol absorption from the intestinal tract and effectively lowers LDL-C levels. To date, no study has examined the effects of ezetimibe on HF events in patients with ACS. Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated that intensive lipid-lowering treatment with ezetimibe plus simvastatin led to a reduction in cardiovascular events compared with conventional lipid-lowering treatment (simvastatin monotherapy) in patients with ACS.¹⁰ Unfortunately, HF was not considered an event in IMPROVE-IT. The present study is the first to examine the effects of ezetimibe on HF events. Our study was a subanalysis, and various confounding factors may have affected the results; however, even after performing multivariable analysis using multiple models, we found that the addition of ezetimibe led to a reduction in HF events. When all participants in the present study were divided into quartiles of the percentage reduction in LDL-C levels from baseline to follow-up, there was no difference in the incidence of HF events according to the reduction in LDL-C levels. Furthermore, even when the percentage reduction in LDL-C was added to the multivariable analysis, the use of ezetimibe remained a determining factor for reducing the occurrence of HF events.

The suppression of HF events by intensive therapy with ezetimibe cannot be explained solely by the LDL-C-lowering effect of ezetimibe. Inflammation, oxidative stress, and myocardial fibrosis play a role in the development of HF.^13,14 Previous clinical and basic research have proposed mechanisms to explain the reduction in HF hospitalizations with intensive statin therapy.^15–17 It has been reported that statin therapy reduces the risk of developing HF not only by preventing ischemic events, but also through unrecognized pleiotropic mechanisms that are not linked to reductions in LDL-C levels, such as anti-inflammatory effects.^8,9 Kato et al. reported that ezetimibe had cardiovascular protective effects in animal models, including lowering superoxide production in the thoracic aorta, reducing oxidative stress, preserving cardiomyocyte ultrastructure, and reducing interstitial fibrosis in the left ventricular myocardium.¹⁸ Moreover, some studies have reported anti-inflammatory effects of ezetimibe.^19–23 A recent meta-analysis examining the effects of lipid-lowering therapies on CRP reported that ezetimibe significantly reduced CRP levels.¹¹ Notably, in the present study, hs-CRP levels at the 12-month follow-up tended to be lower in the pitavastatin+ezetimibe than pitavastatin monotherapy group. These findings may indirectly support the clinical benefit of ezetimibe in reducing HF events in patients with ACS. The anti-inflammatory effects of statins and ezetimibe may underlie the effectiveness of these agents in suppressing HF events. Both statins and ezetimibe may suppress HF events via a mechanism that is independent of their ability to lower LDL-C levels. In addition to lowering LDL-C levels and suppressing cardiovascular disease events, the use of ezetimibe in patients with ACS may be expected to suppress HF events.

This study has some limitations. First, the study was retrospective and based on a subgroup analysis of a prospective study. Second, the study consisted entirely of Japanese patients with ACS, which may affect the generalizability of our findings. Third, in the original HIJ-PROPER trial, the doses of pitavastatin differed between the intensive lipid-lowering and conventional lipid-lowering arms. Although both univariate and multivariable analysis indicated that the dose of pitavastatin did not affect the results, we cannot entirely exclude an effect of statin dose on the results. Fourth, we did not have medication records for the post-ACS treatment phase. Fifth, no echocardiogram data were available. Therefore, we are not sure of the etiology of HF. Sixth, the peak creatine kinase-myocardial band levels were unknown, so we could not determine infarct size. Seventh, we have no data on frailty and sarcopenia. These factors may have influenced the results. Therefore, further studies with larger and more ethnically diverse patient populations are required to confirm our findings.

In conclusion, intensive lipid-lowering therapy with pitavastatin and ezetimibe is associated with a lower incidence of hospitalization for HF in patients with ACS.

Acknowledgments

The authors thank the HIJ-PROPER participants, investigators, and the administrative staff of the original parent study for their contributions. The authors also thank Editage (www.editage.com) for English language editing and publication support.

Sources of Funding

No additional financial support was provided for this subanalysis.

Disclosures

H.A. and H. Otsuki are affiliated with the Clinical Research Division for Cardiovascular Catheter Intervention and are financially supported by donations from Abbott, Boston Scientific, Medtronic, and Terumo. N.H. is a member of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

Author Contributions

H. Ogawa, J.Y., and N.H. conceptualized and designed the original study. M.Y., A.H., H.A., and E.K.-W. analyzed and interpreted the data. M.Y., A.H., and H.A. drafted and wrote the manuscript. E.K.-W., J.Y., H. Otsuki, E.S., H. Ogawa, and N.H. reviewed the manuscript. All authors, had full access to all data (including statistical reports and tables) in the study and take responsibility for the integrity of the data and accuracy of the analysis.

IRB Information

This study was approved by the Institutional Review Board of the Tokyo Women’s Medical University (Reference no. 1741). The original trial is registered with the UMIN Clinical Trials Registry (ID: UMIN000002742).

Data Availability

Patient characteristics data and the results of this study will be shared for 2 years after publication. The data that support the findings of this study are available from the corresponding author according to the ethics committee rules for this study upon reasonable request. For any purpose, the data will be shared as Excel files via email.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0536

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