Assessing the effect of high-dose rosuvastatin in elderly patients over 75 with acute coronary syndrome

Abstract

Backgrounds and objective

Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, are pivotal in managing hypercholesterolemia and reducing cardiovascular risk. While rosuvastatin demonstrates superior efficacy and tolerability compared to other statins, its safety profile in elderly patients older than 75 years old with acute coronary syndrome (ACS) remains underexplored. So, the objective of this study is to evaluate the frequency of adverse reactions and investigate the efficacy of high-dose rosuvastatin on lipid profiles in elderly patients aged over 75 with ACS.

Methods

In this observational study, 110 consecutive elderly ACS patients attending Modarres Hospital in Tehran, Iran, in 2019 were enrolled. The effects of high-dose rosuvastatin were assessed in elderly patients older than 75 years old by comparison of the adverse effects, lipid profile, cardiac function, and other biomarkers at the baseline and after 6 weeks of rosuvastatin therapy with a dose of 40 mg.

Results

Following 6 weeks of treatment, there was a significant reduction in total cholesterol (136.2 ± 24.3 to 115.5 ± 24.0, p = 0.001) and LDL levels (72.6 ± 17.5 to 50.9 ± 18.9, p = 0.001), accompanied by a notable increase in HDL levels (38.3 ± 7.1 to 47.2 ± 7.4, p = 0.001). Cardiac function, as measured by ejection fraction (EF), significantly improved from 43.4 ± 8.8 to 48.5 ± 8.5 (p = 0.001). Adverse effects such as cramps (N = 12, p = 0.001), weakness (N = 28, p = 0.001), and anorexia (N = 12, p = 0.001) were reported but did not warrant discontinuation of therapy. Notably, no cases of jaundice were observed. Two deaths occurred due to major adverse cardiac events (MACE) during the study period, unrelated to stroke or recurrent myocardial infarction.

Conclusion

Totally, high-dose rosuvastatin therapy effectively improved lipid profiles, cardiac function, and liver enzyme levels in elderly ACS patients, with manageable adverse effects. These findings underscore the importance of rosuvastatin in optimizing cardiovascular health in this vulnerable population.

Introduction

Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, which were first assessed for their effectiveness in human samples in 1978 [1]. These drugs serve as the primary pharmacological choice for treating hypercholesterolemia and related cardiac issues and have been associated with a significant reduction of mortality risk [2,3,4]. Statins, operating by inhibiting the synthesis of cholesterol, can reduce low-density lipoprotein cholesterol (LDL-C) levels by 30–40% [5]. Moreover, statins can lead to a reduction in the systemic prevalence of vascular atherosclerosis and ultimately result in a decreased risk of cardiovascular diseases [2]. Furthermore, the use of statins is associated with a 29% reduction in the relative risk of mortality due to myocardial infarction (MI) [6]. Generally, there are two types of statins. First, hydrophilic statins include rosuvastatin and pravastatin. Secondly, lipophilic statins include simvastatin, lovastatin, and atorvastatin [7]. The lipophilic statins can passively enter the cells of tissues outside the liver, potentially causing adverse effects like muscle toxicity.

In contrast, hydrophilic statins exhibit greater selectivity for the liver, relying on an active transport mechanism for entry, and are therefore excluded by tissues beyond the liver. Nevertheless, the optimal balance between the intended and unintended consequences of both lipophilic and hydrophilic statins is yet to be determined [7]. However, in this study, rosuvastatin (a hydrophilic statin) is under investigation for its efficacy and safety in elderly patients with acute coronary syndrome (ACS).

There are some reasons that rosuvastatin is preferred in vulnerable patients. First, rosuvastatin, owing to its unique interference with the enzyme HMG-CoA reductase, is capable of reducing LDL-C levels by over 40%, making them the first choice for patients at high risk [5, 8, 9]. A greater reduction of LDL level and a higher percentage of reaching the target level is observed in patients treated with rosuvastatin compared to atorvastatin [10]. Secondly, among statins, rosuvastatin is a member of the group used in patients who do not tolerate other drugs in this class. An observational study indicated that 89% of patients who exhibited intolerance to simvastatin and atorvastatin showed good tolerance to daily or intermittent rosuvastatin regimens [11]. Muscle-related symptoms are an example of the side effects. Myopathy, as a common side effect of statins (involving below 5% of statin users), is tolerated better in hydrophilic statin (including rosuvastatin) than lipophilic statins (including simvastatin, lovastatin, atorvastatin, and Fluvastatin). As a result, rosuvastatin is considered an alternative treatment for individuals experiencing muscular symptoms with other statins [11,12,13,14].

However, it is important to note that rosuvastatin is not without potential side effects. Although with lower incidence compared to other statins, some patients using rosuvastatin have reported musculoskeletal complaints, including myalgia, muscle stiffness, and weakness, irrespective of muscle enzyme elevations. Furthermore, this drug may adversely affect not only the musculoskeletal system but also other organs. These potential adverse effects encompass liver toxicity, characterized by elevations in liver enzymes, as well as renal toxicity, marked by higher serum creatinine levels, proteinuria, and hematuria. Gastrointestinal adverse effects, such as diarrhea or constipation, nausea, abdominal pain or discomfort, and dyspepsia, have also been documented [15]. Also, the occurrence of pancreatitis is reported to be associated with the use of rosuvastatin [16]. Patients may experience central nervous system-related symptoms, including headaches, dizziness, and paresthesia [15]. Moreover, some studies have indicated a potential association between the use of rosuvastatin and the incidence of new-onset diabetes mellitus [17, 18].

Although the efficacy and safety of high-intensity statin therapy were assessed in some RCTs, the age of the patients included ranged below 75 [19]. In this study, we aimed to evaluate the frequency of adverse reactions and investigate the efficacy of high-dose rosuvastatin on the lipid profile (HDL-c, LDL-c, total cholesterol, triglyceride) in elderly patients aged over 75 with ACS.

Methods and materials

Study design

This observational study involved the examination of 110 patients with ACS at the Modarres Heart Hospital in Tehran, Iran. The patients were assessed upon admission and again 6 weeks later.

The inclusion criteria included patients aged 75 years or older who presented with chest pain or discomfort lasting at least 15 min, occurring at rest or with minimal physical activity, within 24 h before admission. The exclusion criteria included patients with serum cholesterol levels above 270 dl/mg, those who had developed Q waves due to acute MI within the past 4 weeks, those with a history of coronary artery bypass surgery within 3 months or coronary percutaneous intervention (PCI) within the last 6 months, patients with left bundle branch block or ventricular-paced rhythm, those with severe heart failure, and individuals taking lipid-lowering medications other than niacin (at a dose of 500 mg) and vitamin E, or drugs that could cause rhabdomyolysis in conjunction with statins, severe anemia, dialysis-dependent renal failure, poor hepatic function (ALT levels exceeding twice the upper limit of the normal range), insulin-dependent diabetes, and pregnancy.

The patients who were included in the study received a daily dosage of 40 mg of rosuvastatin within 24 to 96 h after admission. The collection of data was performed at the beginning of admission and then repeated 6 weeks later.

Data collection

Data was collected using various methods, including patient interviews, medical examinations, and laboratory tests. Baseline information on patients included demographics (sex, age, height, weight, education), BMI, angiography results, ejection fraction, comorbidities (thyroid, liver, kidney diseases), and medications. Also, two series of events in patients were investigated throughout these 6 weeks. First, Major events include mortality rates, non-lethal acute MIs, cardiac arrests with resuscitation, and re-admission due to symptomatic cardiac incidents. Secondly, other events include non-life-threatening strokes, new or exacerbated heart failure, worsening angina pectoris demanding hospitalization without evidence of ischemia, revascularization procedures through coronary artery surgery or percutaneous intervention, and alterations in lipid profiles.

Laboratory tests were conducted at the beginning of hospitalization and 6 weeks later, measuring levels of creatinine, FBS, HbA1c, creatinine kinase (CK), LDL-c, HDL, total cholesterol, and triglycerides.

Musculoskeletal symptoms (myalgia, tenderness, pain, stiffness, cramps, weakness, and fatigue) were assessed at the beginning and after 6 weeks. Additionally, hepatotoxic symptoms (severe weakness, loss of appetite, abdominal pain, jaundice, or scleral icterus) were evaluated at these time points. Symptoms reported by patients were gathered using questionnaires administered both by the patients themselves and by an independent individual not affiliated with the study.

Ejection fraction was calculated at the beginning of hospitalization using echocardiography.

Data analysis

Data was analyzed using SPSS software version 26. Quantitative variables were investigated as means and standard deviations, while qualitative variables were presented as absolute and relative frequencies.

Our data was compared before and after using rosuvastatin. So, the Paired t-test and Wilcoxon Signed-Rank Test were used to assess the difference between normal and non-normal continuous data before and after using rosuvastatin in patients. Also, the nominal data, which were reported as percentages, were analyzed using McNemar’s test to assess if there is a significant difference between before and after using rosuvastatin. A p-value of less than 0.05 was considered to be significant for all of the analyses.

Ethical considerations

Ethical approval

for the study was obtained from the Ethics Committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.RETECH.REC.1397.63).

Patient data and privacy were strictly maintained. Informed consent was obtained from all patients, providing them with the opportunity to exit the study at any point voluntarily.

No cost was applied to the participants.

Result

In this study, 110 individuals who were under treatment with a dose of 40 milligrams of the drug rosuvastatin were examined. According to Table 1, which indicates the distribution of background variables, 53.6% of the patients were between 75 and 80 years old, and the other patients were older than 80. Also, 72.7% were male, and 64.5% had education levels lower than a diploma. Besides, 14.5% of patients had a past medical history of DM, and 20.9% had HTN when they enrolled in our study.

Table 1 Baseline characteristics of included patients

Primary outcome

After 6 weeks of using high-dose rosuvastatin, the levels of total cholesterol and LDL were significantly decreased (P value = 0.001). Prior to the treatment, the levels of total cholesterol and LDL stood at 136.2 ± 24.3 and 72.6 ± 17.5, respectively. Post-treatment, these levels decreased to 115.5 ± 24.0 and 50.9 ± 18.9. Also, the level of HDL was 38.3 ± 7.1 before treatment and remarkably increased to 47.2 ± 7.4 after treatment (P value = 0.001). Besides, the EF of patients was significantly increased from 43.4 ± 8.8 to 48.5 ± 8.5 after using high-dose rosuvastatin (Table 2).

Table 2 The difference in biomarkers before and after high-intensity statin therapy

The incidence of adverse effects of the high-dose rosuvastatin was also evaluated. Our results revealed that the patients who used high-dose rosuvastatin for 6 weeks had a high probability of having cramps (N = 12, P value = 0.001), weakness (N = 28, P value = 0.001), and anorexia (N = 12, P value = 0.001). However, the severity of these adverse effects was not enough to lead to discontinuation of the drug. However, the incidence of myalgia (N = 2, P value = 0.160) and abdominal pain (N = 2, P value = 0.160) was not significantly high after using rosuvastatin (Table 3). Also, jaundice was not seen after using high-dose rosuvastatin.

Table 3 The incidence of adverse effects of high-intensity statin therapy after treatment

Also, during the 6 weeks of using high-dose rosuvastatin, two patients died because of major adverse cardiovascular events (MACE) among the included patients. It has to be mentioned that these deaths were not due to stroke, recurrent MI, or fatal MI (Table 4).

Table 4 The incidence of major adverse cardiovascular events after treatment with high-dose statins

Secondary outcome

The levels of CK, AST, and ALT decreased significantly after using high doses of rosuvastatin. The levels of CK, AST, and ALT were 110.5 ± 60.5, 28.2 ± 10.7, and 26.4 ± 14.7 before treatment, respectively, and 80.5 ± 40.3, 21.8 ± 9.8 and 21.3 ± 12.5 after treatment. Also, the FBS of patients was 122.8 ± 37.9 before statin therapy and decreased to 114.0 ± 37.8 after using a high dose of rosuvastatin. However, the levels of HbA1C were significantly increased in these patients. Moreover, the levels of creatinine were reduced remarkably (P value = 0.001) (Table 2).

Discussion

In this study, 110 patients aged 75 and older with ACS were admitted to the Modarres Heart Hospital and initially treated with a daily full dose of 40 mg rosuvastatin. Six weeks later, the patients were reassessed using a questionnaire. All laboratory parameters examined, including hemoglobin, AST, CK, fasting blood sugar, A1C, total cholesterol, HDL cholesterol, LDL cholesterol, ALT, creatinine, and fractional shortening, showed significant differences between the pre- and post-treatment phases. Significant differences were found in cramps, weakness, and decreased appetite between pre- and post-intervention. However, no significant differences were found in myalgia and abdominal pain.

Our results showed that the lipid profile significantly improved after using high-dose rosuvastatin. Besides, Anna Lis et al. [20] conducted a study on 1413 patients with a very high cardiovascular risk. The prescription was atorvastatin ≥ 40 mg or rosuvastatin ≥ 20 mg, and the main desired outcome was defined as LDL-C < 55 mg%. After a 12-month lipid profile follow-up in 652 individuals, the therapeutic goal was achieved in 255 patients. Also, a study by Patrica Wambua et al. [21] was conducted to survey lipid management in post-MI patients. The individuals were on 40 mg or 80 mg of atorvastatin or 20 mg or 40 mg of rosuvastatin, a median follow-up time of five months was done. Out of 39 patients, only six achieved the LDL-C goal of < 1.4 mmo/L, while only 16 achieved a greater than 50% reduction from their baseline LDL-C level, with three (8.6%) patients having an increased LDL-C level from baseline.

Moreover, A study by R. Luo et al. [22] was conducted to compare the beneficial effects of high-dose rosuvastatin (20 mg/d) and conventional-statin therapy(10 mg/d). Similar to our results, the decrease of LDL-C, increase of HDL, and improve of left ventricular ejection fraction was significant (P < 0.05).

In this study, it was reported that the levels of CK, AST, and ALT were reduced after high-dose rosuvastatin therapy. It has to be mentioned that acute MI leads to increased CK, AST, and ALT [23, 24]. So, the reduction in the levels of these biomarkers can be usual after ACS, and besides, it showed that the high-intensity statin therapy had no adverse effect on liver function, resulting in an increase in these biomarkers. Also, a review article mentioned that the incidence of AST and ALT levels elevation was below 5% in patients receiving conventional or high-dose rosuvastatin [25]. The rate of liver failure was assessed in the CORONA study, which evaluated elderly patients with systolic heart failure treated with a conventional dose of rosuvastatin, and there was no significant difference between the treatment group and placebo [26].

In contrast to the decrease in FBS level in our study, we found that the HbA1c level was increased. Although this finding may not lead to a definite diagnosis of diabetes, this is similar to the findings of Zhao and his colleagues [27]. They investigated the effects of different statins on the development of diabetes. In their study, four statins, atorvastatin, pravastatin, rosuvastatin, and pitavastatin, were assessed. All statins were found to cause damage to pancreatic beta cells to varying degrees and increase insulin resistance in skeletal muscle cells.

Investigations have shown that elevated levels of high-sensitivity C-reactive protein (hs-CRP) can lead to cardiovascular events in individuals. In a study done by Sattar et al. [17], healthy males and females with LDL levels below 130 and hs-CRP levels above 2 were treated with rosuvastatin 20, and some patients were given a placebo. In the follow-up, 50% of the patients treated with rosuvastatin experienced a reduction in LDL, and 37% experienced a reduction in hs-CRP. The primary goal of that study was to assess the reduction in heart attack, stroke, revascularization, and hospitalization due to unstable angina, and it was shown that all these factors were significantly reduced in patients treated with rosuvastatin compared to the control group. Additionally, no significant difference in the incidence of myopathy and cancer was observed in patients treated with rosuvastatin compared to the control group, but the incidence of diabetes in these patients was higher, which is not consistent with the findings of our study.

The findings of muscular symptoms in our study, including cramps and weakness, resemble previous studies [28]. Side effects have been associated with all commonly used statins and are dose-dependent [29]. However, we reported that these muscular symptoms did not lead to discontinuation of drug usage. This is aligned with the previous findings, which reported better tolerance of rosuvastatin compared to other statins and a possible alternative for patients complaining of other statin-induced muscle symptoms [30].

In a study conducted by Cham and colleagues [31], 354 patients with statin-related muscular symptoms were examined. The type of statin, its dosage, the nature of muscular problems, the onset of symptoms, improvement, recurrence, and the quality of life of the individuals under study were assessed. Among individuals treated with atorvastatin, 61% experienced muscular pain, compared to those treated with lovastatin. The onset of muscular symptoms varied after the initiation of different statins but averaged 14 weeks. Some muscular symptoms occurred after a prolonged period, significantly impacting the quality of life. Furthermore, it was concluded that there is a relationship between drug dosage and muscular symptoms.

In another study by Meek et al. [11], some patients who did not tolerate other statins were treated with rosuvastatin 5 daily or intermittently. 289 patients experienced simvastatin-related adverse effects, and 63% experienced atorvastatin-related adverse effects. 89% of the patients tolerated rosuvastatin well, and treatment with rosuvastatin was discontinued for 11% of the patients due to adverse effects during the study period. The use of rosuvastatin reduced total cholesterol by 31%, triglycerides by 15%, and LDL by 43%. Weekly rosuvastatin reduced total cholesterol by 26% and LDL by 32%. Daily rosuvastatin reduced total cholesterol by 17% and LDL by 23%, but had no effect on triglycerides. No myositis or rhabdomyolysis was observed in these patients, and the levels of alanine aminotransferase and CK remained within normal limits. The study has shown that 5 mg of rosuvastatin daily or weekly can be safe and effective in patients who have intolerance to other statins, confirming the findings of our study.

Our study reported that there was no acute MI, recurrent MI, or stroke after using high-dose rosuvastatin. Also, two deaths were reported within 6 weeks of receiving 40 mg of rosuvastatin, which was not related to the administration of the rosuvastatin. One of the deaths was due to cancer, and the other one was after an orthopedic surgery. In the study by Schwartz and colleagues [32], which involved 3086 patients, the effects of atorvastatin on early ischemic events in patients with ACS were investigated. These patients were randomly assigned to receive either placebo or atorvastatin 80 mg for 16 weeks within 24 to 96 h of hospital admission. The assessments included the occurrence of events such as death, non-fatal acute MI, cardiac arrest with resuscitation, and recurrent symptomatic ischemic myocardial rehospitalization, and overall, these events occurred in 228 patients (14.8%) in the atorvastatin group compared to 269 patients (17.4%) in the placebo group, with no significant difference in the rates of death, non-fatal acute MI, or cardiac arrest with resuscitation. However, the incidence of recurrent symptomatic ischemic events requiring rehospitalization was lower in the atorvastatin-treated group. Additionally, there were no differences between the two groups in terms of coronary revascularization, worsening heart failure, and worsening angina, but the level of C-reactive protein was lower in individuals treated with atorvastatin. However, the levels of abnormal liver enzymes were higher in individuals treated with atorvastatin. It is worth noting that in our study, differences were observed in some cases, considering the differences in power and sampling method.

In a meta-analysis study done by Yu et al. [19], 16 RCTs, including 26,497 patients, were assessed, and the outcome of high-intensity statin therapy was compared to standard statin regimens in patients with ACS. The findings from this research indicate that high-intensity statin treatment could potentially lower the occurrence of MACE in ACS when compared to standard statin therapy. However, the prediction interval implies that this effect may not be universally applicable to all patients. Moreover, instances of severe adverse events linked to the administration of high-intensity statins were infrequent. The mean age of patients in the included studies ranged between 56.5 and 75.2 years. However, only one study had a mean age of 75, and the mean age of other included studies was about 60 years old. It shows that the efficacy and safety of high-dose statin therapy was mainly assessed in patients below 75. In our study, our results showed that high-dose statin therapy is efficient in reducing lipid profiles, and the major adverse effects were not significant. However, more investigations are needed to confirm our results.

There were no specific limitations in the planning and implementation of this interventional study. However, due to the selection of samples from a referral medical center, the generalizability of the results decreases. Additionally, some patients were not willing to cooperate with the research and withdrew from the study.

It is recommended that further studies be conducted with a larger sample size to confirm the findings of this study. Additionally, further investigations into methods for reducing the side effects of statin therapy in the elderly should be considered for future studies. Furthermore, it is suggested that necessary interventions be planned based on existing risk factors to reduce the side effects of various therapeutic drug methods in cardiac patients.

Conclusion

In sum, the results obtained from this study suggest that rosuvastatin is an effective and low-risk drug for older people and is recommended for improving the lipid profile of older adults older than 75. Moreover, no significant cardiovascular event or major complication was observed in this study after receiving rosuvastatin. Though these findings are promising, it is recommended that this drug be investigated further in large-scale randomized controlled trials, and its effects should be compared with other statins in future studies. Until such evidence is available, clinicians may exercise caution and consider individual patient factors when prescribing high-dose rosuvastatin to elderly patients.