The efficacy and safety of rosuvastatin in a wide population of patients with hyperlipidemia and the placement of additional strengths of 15 mg and 30 mg in clinical practice. The ROSU-PATH trial: international, randomized, open-label, prospective trial

M. Cevc, GA. Dan, I. Karadi, M. Lutai, Z. Reiner, E. Shlyakhto, M. Vrablik, B. Barbič-Žagar

Final results from the ROSU-PATH trial

Key words

Hyperlipidemia, additional strengths 15 mg and 30 mg, rosuvastatin, final results

ESC/EAS Guidelines – European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Guidelines

Abstract

Objectives: To establish the efficacy and safety of rosuvastatin in a wide population of patients with hyperlipidemia with an emphasis on the placement of additional strengths of 15 mg and 30 mg in clinical practice.

Design: Prospective, open-label, randomized, interventional clinical trial.

Setting: International, multicenter clinical trial conducted at 30 health care institutions in Croatia, the Czech Republic, Hungary, Romania, Russia, Slovenia and Ukraine.

Methods: The clinical trial included patients with primary hypercholesterolemia or mixed dyslipidemia not receiving a lipid-lowering therapy. The patients were randomized to either the standard (10 mg – 20 mg – 40 mg of rosuvastatin) or to the alternative titration arm (15 mg – 30 mg – 40 mg of rosuvastatin) and treated for 12 weeks. After the initial check-up, every patient had three more visits (at Weeks 4, 8 and 12) during which lipid levels were measured. When the defined LDL cholesterol (LDL-C) goal based on the 2011 ESC/EAS Guidelines for the management of dyslipidemias, valid at the time of the trial, was not met at each individual visit, the dose was increased according to the standard or alternative titration scheme.

Results: 494 patients were randomized in the trial and a total of 472 patients (239 in the standard and 233 patients in alternative titration arm) were included in the intention-to-treat statistical analysis. At the initial visit, there were no significant differences between both groups, except for the proportion of gender (57% vs. 47% of men in the standard and alternative titration arm, respectively; P < 0.05). The mean age of all the participants was 56.9 years ± 9.9 years. During the trial, the mean LDL-C was reduced from 4.38 ± 1.07 mmol/l at the baseline to 2.32 ± 0.69 mmol/l at the end of the trial (a relative reduction by 45.2% ± 18.8%, P < 0.0001), which resulted in 67% of patients achieving target LDL-C levels. The mean dose of rosuvastatin at the end of the trial was 22.4 mg (20.7 mg for the standard and 24.1 mg for the alternative titration arm).

Evaluating target LDL-C level attainment according to the three different cardiovascular (CV) risk groups revealed a success rate of 83.4%, 66.7% and 33.0% for moderate, high and veryhigh risk patients, respectively. Additionally, 22.7% of very-high risk patients achieved the secondary objective (≥ 50% of LDL-C reduction compared to the baseline value), resulting in 55.7% of the very-high risk patients in total achieving their treatment goals. The patients receiving treatment according to the alternative titration arm experienced a greater reduction of LDL-C after 4 weeks of therapy (–42.6% ± 17.3% vs. –37.5% ± 21.7%; P < 0.01) and at the end of the trial (–47.4% ± 15.9% vs. –43.0% ± 21.2%; P < 0.05). Greater reduction of LDL-C resulted in more patients achieving the target LDL-C levels in the alternative titration scheme (n = 154 vs. 131, 73% vs. 62%, respectively; P < 0.0001). Throughout the trial, 91 patients experienced adverse reactions; the majority of them were mild or moderate adverse reactions (12.6% and 5.5%, respectively). The comparison of adverse reactions between the standard and alternative titration arms showed no significant differences in the occurrence and severity of adverse reactions.

Conclusion: Therapy with rosuvastatin across the whole range of strengths was evaluated as effective and safe in a wide range of patients with hyperlipidemia. Evaluating the average difference value from the target LDL-C levels showed that moderate and high-risk patients achieved the targets, whereas the very highrisk patients failed – this suggests that the prescribed mean dose of rosuvastatin was too low and that higher doses should be used in patients requiring the most intensive lipid-lowering therapy. The ROSU-PATH trial is the first trial evaluating the use of rosuvastatin in strengths of 15 mg and 30 mg in clinical practice. In the alternative titration arm the reduction of LDL-C and target LDL-C attainment were superior to the standard titration arm, with no differences in the tolerability profile. The comparison of both titration arms suggests that the use of an alternative titration arm and thereby using 15 mg and 30 mg strengths in clinical practice would be beneficial for the LDL-C attainment rate. The additional strengths could enhance dose titration and thereby allow more patients to reach target lipid values.

Introduction

According to the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Guidelines for the management of dyslipidemias from 2011 – valid at the time of the trial, as well as in their newer editions from 2016 and 2019 – the primary target of dyslipidemia management therapy remains LDL cholesterol (LDL-C).^{1, 2, 3} Every 1.0 mmol/l reduction in LDL-C is associated with a corresponding 22% reduction in CVD mortality and morbidity.⁴ Furthermore, clinical studies have shown that a 1% reduction in LDL-C reduces the relative risk for major CHD events by approximately 1%.⁵ Guidelines strongly recommend modulating the intensity of preventive intervention according to the levels of total cardiovascular (CV) risk, meaning that LDL-C targets are lower when the total CV risk increases from moderate to high and very high.^{1, 2, 3}

Despite clear directions from the 2011 as well as 2016 ESC/EAS Guidelines for the management of dyslipidemias, statins are usually prescribed at a suboptimal dose and often not up-titrated to achieve the treatment goals in everyday care. In addition, long-term adherence is poor, with one third to one half of patients stopping statin treatment within a year. The outcome is evident – patients do not achieve the maximum treatment benefits. These patients remain at an increased CVD risk despite receiving treatment.^{6, 7, 8}

Traditionally, statins have been available in 10 mg, 20 mg, 40 mg and 80 mg strengths, with the exception of rosuvastatin, which in clinical practice is available in strengths from 5 mg to 40 mg.^{9, 10} Results from practice show that doctors usually do not opt for the highest doses and that the majority of patients are treated with one of the two lowest doses. Two new strengths (15 mg and 30 mg) of rosuvastatin were introduced to the market with an aim of facilitating optimal and effective hypolipidemic therapy. The wide range of rosuvastatin strengths enables treatment adjustment to the requirements of individual patients and ultimately increases the likelihood of reaching the target lipid levels.¹¹

Although the clinical efficacy of 15 mg and 30 mg is predictable from the linear extrapolation of the already approved rosuvastatin doses, the need for clinical evidence still existed. In order to investigate the efficacy and safety of the whole portfolio of rosuvastatin strengths, we carried out the international clinical trial ROSU-PATH (The efficacy and safety of ROSUvastatin dose titration in the treatment of PATients with Hyperlipidemia). The aim of this clinical trial was to establish the efficacy and safety of rosuvastatin in a wide population of patients with primary hypercholesterolemia and mixed dyslipidemia with an emphasis on the placement of additional strengths, 15 mg and 30 mg, in clinical practice.

Methods

Trial design

An international, randomized, multicenter, open-label, prospective, interventional clinical trial was conducted at 30 health care institutions in seven countries (Croatia, the Czech Republic, Hungary, Romania, Russia, Slovenia and Ukraine). Patients that met the inclusion criteria were randomized to either the standard (10 mg – 20 mg – 40 mg of rosuvastatin) or alternative titration arm (15 mg – 30 mg – 40 mg of rosuvastatin) and then treated for 12 weeks according to the treatment regimen (Figure 1). Each screened patient eligible for randomization was randomly assigned a patient randomization code and a central randomization method was implemented. The master randomization list was created using an online application available at http://www.randomization.com/. The medication administered orally to the patients was rosuvastatin (produced by Krka, d. d., Slovenia^* in strengths from 10 mg up to 40 mg. During the trial, patients took the investigational medical product once daily at any time during the day throughout the trial at the same time. The drug could be taken with or without food. Initial visit assessment (Week 0) was followed by three visits (at Weeks 4, 8 and 12) during which lipid levels and safety parameters were measured. If the target LDL-C level defined based on the 2011 ESC/EAS Guidelines for the management of dyslipidemias, valid at that time, was not met at each individual visit, the dose of rosuvastatin was titrated according to the standard or alternative titration scheme.

After the end of the trial, the patients who participated in the trial were able to continue the therapy at an adequate dose for them.

Figure 1. ROSU-PATH trial scheme diagram

Inclusion criteria

The trial included men and women between 18 and 75 years of age with primary hypercholesterolemia or mixed dyslipidemia, when the response to diet and other non-pharmacological measures had been insufficient to bring their LDL-C levels to the target values. Other requirements for inclusion were the written informed consent provided by the patients or the legally acceptable representative and the absence of a lipid-lowering therapy during at least 4 weeks prior to the initial visit. The details of the full exclusion criteria are provided in the Supplementary Appendix.

End points

The primary endpoint was to evaluate the efficacy of rosuvastatin in achieving the 2011 ESC/EAS Guidelines target LDL-C levels in patients with hyperlipidemia. The 2011 ESC/EAS Guidelines set the target LDL-C levels at < 1.8, < 2.5 or < 3.0 mmol/l, depending on risk category or a ≥ 50% reduction from baseline LDL-C when the target lipid level could not be reached for very highrisk patients. Secondary efficacy endpoints were as follows: investigate linear association between doses and the reduction of LDL-C, compare the differences between the group treated in accordance with the usual clinical practice (standard titration: 10 mg – 20 mg – 40 mg) and the group treated according to the alternative scheme (15 mg – 30 mg – 40 mg), evaluate the percentage change in HDL cholesterol (HDL-C), total cholesterol (TC) and triglycerides (TG), from baseline at all-time points (4, 8, 12 weeks), evaluate the percentage of patients achieving the 2011 ESC/EAS Guidelines LDL-C goal at all-time points (Weeks 4, 8, 12) and to evaluate adverse events.

Efficacy and safety analysis

At each visit, clinical and laboratory examinations were carried out. Clinical assessment included measurements of body weight and height, blood pressure and heart rate. Blood pressure was taken in the sitting position from the non-dominant upper arm using a cuff of an appropriate size.

Venous blood was used for laboratory examination. Before sampling, the patient had to remain fasting for 10–12 hours. TC, HDL-C and TG had been measured enzymatically, while Friedwald’s formula was used for LDL-C determination.¹

When calculating linear association between doses, we associated to each dosage scheme its dosage total (DT), which is the sum of doses at each visit (Table 1).

Table 1. Dosage scheme and their corresponding dosage totals

The therapeutic effect and total clinical efficacy of the treatment were evaluated at the last visit of the trial according to the protocol and the 2011 ESC/EAS Guidelines for the management of dyslipidemias.

Therapeutic effect:

Good: if target LDL-C levels for the different risk categories were reached;
Satisfactory: if LDL-C was reduced by at least 10% or more;
Unsatisfactory: if LDL-C was reduced by less than 10%.

Total clinical efficacy:

Excellent: if target LDL-C levels were reached without adverse reactions;
Very good: if target LDL-C levels were reached with mild adverse reactions;
Good: if LDL-C was reduced by at least 10% or more without adverse reactions;
Satisfactory: if target LDL-C levels were reached or LDL-C was reduced for at least 10% with moderate adverse reactions or if LDL-C was reduced by at least 10% or more with mild or moderate adverse reactions which did not necessitate withdrawal of the treatment;
Unsatisfactory: if LDL-C was reduced by less than 10% or the patient experienced adverse reactions that induced withdrawal of the treatment.

To assess the safety profile, an interview and physical examination were used at Visits 2, 3 and 4, during which patients were asked about any adverse symptoms. To calculate the severity of adverse reactions the following scale was used: mild – 1; moderate – 2; severe – 3. In this way the severity of an adverse reaction was viewed as a real-valued random variable. Definitions for the severity grades of adverse reactions are provided in the Supplementary Appendix.

Statistical analysis

All patients enrolled were analyzed according to their randomized group, regardless of treatment compliance or any other deviation from the protocol (intention-to-treat principle). The leading symptom parameters were considered to be ratio scale random variables (at each visit). For analysis of the variables, the following descriptive statistics were presented: the smallest and the largest values, the average (arithmetic mean), the (sample) standard deviation and the standard error of the mean. Due to the reasonably large sample, the asymptotic z-test was used to assess the difference between the means of two variables measured in the same population. Analogously, an asymptotic 95%-confidence interval for the difference between the means was used for interval estimation. Microsoft Office Excel 2013^© was used for the computational part of the analysis, and Microsoft Office Word 2013^© was used to compile the report.

Patient involvement

No patients were involved in setting the research questions or the outcome measures, nor were they involved in developing the plans for the design or implementation of the trial. No patients were asked to give their advice on interpretation or the writing of results. There are no plans to disseminate the results of the trial to trial participants.

Ethics approval and consent process

The trial and all of the amendments were reviewed by Independent national Ethics Committees (IEC) in all participating countries, appointed by a corresponding regulatory authority. Additionally, the study was also approved by the Local Ethics Committees where needed. The study was conducted in accordance with the ethical principles that are based on the Declaration of Helsinki.

Results

Trial population

In the ROSU-PATH trial, 507 patients from seven countries were screened: 494 patients who satisfied all inclusion criteria were included into the trial and 22 patients did not come to any of the control visits. Due to this fact, a total of 472 patients (239 in the standard and 233 patients in the alternative titration arm) were included in the intention-to-treat (ITT) statistical analysis. The flowchart of the patients is presented in Figure 2.

Figure 2. Flowchart of the patients in the ROSU-PATH clinical trial

At baseline, the study groups did not differ in demographic characteristics and baseline lipid values, except for the proportion of gender (57% vs. 47% of men in the standard and alternative titration arm, respectively; P < 0.05; Table 2).

The mean age of all participants was 56.9 years ± 9.9 years; there were more men than women included in the trial (52% vs. 48%), the mean body-mass index was 28.8 ± 4.9 and the mean systolic and diastolic blood pressures were 132.9 ± 15.3 mm Hg and 81.2 ± 9.2 mm Hg, respectively.

Table 2. Initial demographic and clinical characteristics of patients in standard and alternative titration arms (presented as mean (CI) or N (%)); * Definition can be found in the Supplementary Appendix.

LDL-C reduction and target LDL-C levels attainment

Among the patients that were included in the trial, the baseline mean LDL-C level was 4.38 ± 1.07 mmol/l. At the end of the trial, LDL-C decreased to 2.32 ± 0.69 mmol/l (a relative reduction by 45.2% ± 18.8%; P < 0.0001), resulting in 67% of patients achieving target LDL-C levels. Data are displayed in Table 4. The mean dose of rosuvastatin at the end of the trial was 22.4 mg.

Patients were distributed to three CV risk groups; 166, 78 and 255 patients to moderate, high and very-high CV risk group, respectively. An evaluation of target LDL-C level attainment in these CV risk groups revealed the success rate of 83.4%, 66.7% and 33.0%, respectively. Among very-high risk patients there were additional 22.7% of patients who failed to reach the target LDL-C level of < 1.8 mmol/l, but achieved the secondary objective (≥ 50% LDL-C reduction compared to the baseline value), resulting in 55.7% of very high-risk patients in total achieving their target goals. Among very high-risk patients the most common medical conditions were coronary heart disease, familial hypercholesterolemia, type 2 diabetes and myocardial infarction. The mean daily doses at the end of the trial were 18.7 mg, 21.8 mg and 25.3 mg of rosuvastatin for moderate, high and very high-risk patients, respectively. A sub analysis of the evaluation of the mean differences from the target LDL-C levels for different CV risk groups showed only the very high-risk patients failed to reach the target (distance from the target LDL-C level = 0.34 mmol/l; Table 3).

Table 3. Mean absolute differences from target LDL-C in a sub analysis of patients in different CV risk groups [mmol/l]

Linear association between doses and LDL-C reduction

The sample correlation of DT and the absolute LDL-C reduction between the baseline value and value at Week 12 is –0.195 (CI: –0.285, –0.097), while the sample correlation of DT and relative LDL-C reduction is –0.103 (CI: –0.198, –0.005). DT seems to be weakly, but statistically significantly, linearly correlated with LDL-C absolute reduction, and insignificantly linearly correlated with the relative difference of LDL-C between both visits. The absolute reduction of LDL-C in individual dose groups is presented in Figure 3. The rosuvastatin dose groups are presented here according to the final dose in the titration scheme.

Figure 3. Absolute LDL-C reduction in rosuvastatin dose groups

Standard vs. alternative titration scheme

There were no significant differences in the baseline levels of all lipids between standard and alternative titration arms (Table 2).

In the alternative titration arm, the reduction of LDL-C and target LDL-C levels attainment were superior to the standard titration arm at all-time points. The results of LDL-C reduction are presented in Table 4: 59% and 50% of the patients achieved target LDL-C levels after 4 weeks of treatment (Visit 2) in the alternative and standard titration arms, respectively (P < 0.05). Both achievements increased by the end of the trial (73% vs. 62% for the alternative and standard titration arm; P < 0.0001). The mean doses at the end of the trial were 20.7 mg and 24.1 mg for the standard and alternative titration arms, respectively. Furthermore, the comparison of both titration arms after Week 4 – when patients received 10 mg in the standard or 15 mg in the alternative titration arm – showed that the patients in the alternative titration arm experienced a greater reduction of LDL-C (–37.5% ± 21.7% vs. –42.6% ± 17.3%; P < 0.01; Table 4).

The changes of other lipids (TC, HDL-C and TG) were also greater at the end of the trial in the alternative titration arm vs. standard titration arm, but the difference was not statistically significant (Table 4).

Changes of other lipid levels (HDL-C, TC and TG) at all-time points

The changes of other plasma lipids and lipoproteins (TC, HDL-C and TG) at different time points are also presented in Table 4. Among all patients, the baseline mean TC, HDL-C and TG values were 6.53 ± 1.17 mmol/l, 1.36 ± 0.37 mmol/l and 1.90 ± 0.91 mmol/l, respectively. At the end of the trial, lipid changes were –32.8% ± 13.6%, +6.7% ± 23.4% and –17.5% ± 47.9% for TC, HDL-C and TG, respectively. All changes between the end of the trial and baseline were statistically significant (P < 0.0001 for all three lipid parameters).

Table 4. Changes of plasma lipids and lipoproteins (LDL-C, TC, HDL-C and TG) at all-time points

Comparison of the efficacy of rosuvastatin 15 mg with rosuvastatin 10 mg

In order to get a clearer picture of the efficacy of 15 mg of rosuvastatin in comparison to 10 mg strength, we additionally analyzed the patients who did not require titration. During the whole trial, 91 patients in the standard and 102 patients in the alternative titration arms did not need titrations to higher doses and were treated with the initial dose (10 mg or 15 mg, respectively). The comparison of these patients revealed that the patients treated with 15 mg experienced greater LDL-C reduction at all-time points of the trial (Figure 4) and thus more of these patients achieved target LDL-C levels compared to the patients on 10 mg (81% vs. 67%; P < 0.0001).

Figure 4. Comparison of LDL-C reduction for patients treated with 15 mg and 10 mg at all-time points

Tolerability and safety of the treatment

Altogether 113 patients (25.1% of all patients) experienced at least one adverse event (AE) during the trial. As assessed by the investigators, 91 of them (20.2%) were treatment-related and 22 (4.9%) were treatment-unrelated AEs. The majority of adverse reactions was mild or moderate (12.6% and 5.5%, n = 57 and 25, respectively) with only 1.8% of patients (n = 8) experiencing severe adverse reactions (for 1 patient (0.2%) we do not have the data regarding adverse reaction severity). These were headache, myalgia, abdominal pain, muscle spasm, insomnia, depression, muscular weakness, nausea, flatulence and dizziness. Out of the patients with severe adverse reaction, 2 patients were withdrawn from the trial and 1 was hospitalized, while in another the dose was decreased or symptomatic treatment was initiated. All together 28 patients (6.2%) were withdrawn from the trial and only 1 was hospitalized (mentioned above) due to the adverse reaction. There were neither cases of rhabdomyolysis nor the ones of alanine aminotransferase (ALT) increase of 3-times over the upper limit of normal (ULN). One patient experienced an increase of aspartate aminotransferase (AST) over 3x ULN, which resolved after discontinuation of the study drug. During the trial, no patients experienced any serious adverse event that would require reporting.

The comparison of adverse reactions between the standard and alternative titration arms showed no significant differences in the occurrence and severity of adverse reactions. There were 45 out of 226 patients in the standard and 46 out of 225 in the alternative titration arms, respectively, who experienced an adverse reaction other than asymptomatic safety parameters elevations: 82 adverse reactions with an average severity of 1.43 occurred in the standard, while in the alternative titration arm 97 adverse reactions with an average severity 1.57 were recorded. The data did not exhibit a statistically significant difference between both titration arms.

Therapeutic effect and total clinical efficacy of the treatment

At the end of the trial, 67.5% of the patients achieved a good therapeutic effect, while in 28.5% and 4.0% of the patients the results were satisfactory and unsatisfactory, respectively. Moreover, the total clinical efficacy of the treatment was evaluated as excellent, very good or good in 56.0%, 10.0% and 21.0% of patients, respectively. In 6.9%, it was evaluated as satisfactory and in 6.2% of the patients as unsatisfactory. Patients with no data were excluded from the calculation of the therapeutic effect and the treatment’s total clinical efficacy.

Discussion

Key findings

The main objective of the ROSU-PATH trial was to evaluate the efficacy and safety of rosuvastatin in a wide population of patients with primary hypercholesterolemia or mixed dyslipidemia with an emphasis on the placement of additional strengths of 15 mg and 30 mg in clinical practice. To this end, a comparison between the standard titration arm with the usual dose escalation and the alternative titration arm using the additional rosuvastatin doses of 15 and 30 mg, respectively, was made.

The effect of rosuvastatin on LDL-C reduction is well known from previous clinical trials conducted in various patients’ groups.¹² On the other hand, the data on the achievement of target LDL-C levels differ between trials and depend on the LDL-C set target levels, baseline levels of LDL-C and, of course, the dose of rosuvastatin.^13,14 In the ROSU-PATH trial, LDL-C was significantly decreased at the end of the trial (45.2% ± 18.8%; mean dose 22.4 mg), which led to the 2011 ESC/EAS Guidelines LDL-C target attainment in 67% of all patients. While the patients in the moderate and high-risk groups achieved their targets, the very high-risk patients (most frequently with established CHD, familial hypercholesterolemia and/or type 2 diabetes) failed. Not reaching the target LDL-C level in this group of patients suggests that the prescribed mean dose of rosuvastatin (25.3 mg) was too low. This was also demonstrated in the EUROASPIRE IV survey and the latest EUROASPIRE V since only 21% and 29% of treated patients, respectively, succeed to reach LDL-C < 1.8 mmol/l.^7,8 Nevertheless, in 33% of very high-risk patients included in the ROSU-PATH trial the primary treatment goal of LDL-C < 1.8 mmol/l from the 2011 ESC/EAS Guidelines could have been reached. Additionally, 22.7% of the very high-risk group reached the achieved secondary objective of LDL-C reduction below 50% of the baseline values.

The dose-dependent LDL-C reduction of rosuvastatin had already been proven.^10,15 Interestingly, it was shown for the first time that an initial dose of 15 mg of rosuvastatin leads to a greater decrease of LDL-C than the 20 mg dose used as a second titration step. This provides new evidence on the benefit of using the alternative dose of 15 mg of rosuvastatin as an initial step in the treatment of dyslipidemia.

Moreover, the comparison of both titration arms showed that the reduction of LDL-C at the end of the trial was significantly greater in the alternative titration arm, which included both additional strengths, 15 mg and 30 mg of rosuvastatin. The patients enrolled in the alternative titration arm of the study achieved target LDL-C levels earlier and more often when compared to the standard titration arm at all follow-up visits. Already after 4 weeks of the trial, before the first possible titration, patients in the alternative titration arm experienced significantly greater LDL-C reduction compared to the patients in the standard titration arm (42.6% vs. 37.5%, respectively).

Some patients did not need titrations and were treated with the initial dose of rosuvastatin (10 mg or 15 mg daily) during the whole trial. The comparison of these patients revealed that significantly more patients on rosuvastatin 15 mg achieved target lipid levels compared to the patients on rosuvastatin 10 mg (81% vs. 67%).

The evaluation of safety parameters showed that the treatment with rosuvastatin was well tolerated since 74.9% of patients did not experience any adverse events during the course of the trial. Out of the patients who experienced adverse reactions the majority had mild to moderate adverse reactions, with only 1.8% of all patients experiencing severe adverse reactions. The occurrence of high liver enzymes and other side effects was comparable and even lower than the results from other clinical trials.¹⁶

Also, the safety of the standard vs. alternative titration arm and rosuvastatin 10 mg vs. rosuvastatin 15 mg were compared. Both results of safety showed that there were no significant differences regarding the occurrence and severity of adverse reactions between titration arms and between both doses, suggesting that rosuvastatin has a good tolerability profile in its entire portfolio of strengths.

Taking into consideration the efficacy and safety of rosuvastatin, total clinical efficacy was evaluated as excellent, very good or good in 87% of patients. Thus, 56% of participants achieved target LDL-C levels without any adverse reactions, another 10% achieved target LDL-C levels experiencing mild adverse reactions, and 21% showed at least 10% LDL-C reduction without adverse reactions.

Strengths and limitations

This was the first study comparing the safety and efficacy of two novel doses of rosuvastatin, e.g. 15 mg and 30 mg in a broad spectrum of patients with dyslipidemia. The study was performed as an international, multicenter clinical trial; nevertheless, the study population as well as study procedures do, in fact, reflect real clinical practice. The results do apply to the real-world situation and can be used for clinical guidance. The most important limitation of the study is its openlabel design. However, as we compared two similar treatments (both groups were treated with rosuvastatin, but according to a different titration scheme), we believe the open-label design did not have a significant impact on the results. Another limitation of the study is protocol violation, as some patients were not titrated according to the specified titration scheme. Nevertheless, the number of participants who did not have their medication up-titrated, despite not achieving the target values, was comparable in both study arms.

Conclusions and implications of findings

Therapy with rosuvastatin in the whole spectrum of doses was demonstrated as effective and safe in a wide range of patients with hyperlipidemia offering the achievement of target LDL-C values, especially for patients at moderate and high CV risk. In very high-risk patients, the target level of LDL-C group was achieved in one third of the patients.

The ROSU-PATH trial provides the first evidence to support the use of an alternative titration scheme (which includes additional strengths of 15 and 30 mg) in clinical practice. Throughout the whole trial the reduction of LDL-C and target LDL-C attainment were in favor of patients treated according to the alternative compared to the standard titration arm. Furthermore, the data suggest there are no differences regarding the occurrence and severity of adverse reactions between both titration arms. Additional doses of rosuvastatin, 15 mg and 30 mg, could potentially be a solution to the issue in clinical practice where the majority of patients do not achieve the maximum treatment benefits due to the lack of up-titration.

Acknowledgment: We gratefully acknowledge the investigators: Dean Köveš, Polonca Vobovnik Grobelnik, Peter Strouhal, Martina Hrovat, Tatjana Jezerc Križanič, Jarmila Trček Breznikar, Marija Jenko Burgar, Nuša Potočnik, Vladimir Soška, Igor Karen, Pavel Kraml, Boris Starčević, Hrvoje Vražić, Jasmina Ćatić, Jožica Šikić Vagić, Edvard Galić, Jarai Zoltan, Müller Gabor, Böröcz Zoltan, Zdrenghea Dumitru, Caloioan Bogdan, Pop Mandru Daniel, Petrescu Virgil, Antonescu Sorin Alexandru, Antonescu Irina, Valentyn Shumakov, Marina Dolzhenko, Ageev Fail Taipovich, Kobalava Zhanna Davidovna, Drapkina Oksana Mihailovna, Grinstein Yury Isaevich, Kuharchuk Valeriy Vladimirovich, Susekov Andrey Vladimirovich. We would additionally like to thank all trial coordinators, the patients who participated in this trial and Urban Brumen in his assistance in the preparation of this manuscript.

Funding: The trial was financially supported by Krka, d. d, Novo mesto, Slovenia.

Transparency: Authors affirm that the manuscript is an honest, accurate, and transparent account of the trial being reported; that no important aspects of the trial have been omitted; and that any discrepancies from the trial as planned have been explained.

Data sharing: we agree to share data upon reasonable request.

Supplementary appendix

Inclusion criteria

Patients of both genders with primary hypercholesterolemia or mixed dyslipidemia (type IIb), when the response to diet and other non-pharmacological measures had been inadequate.
Age 18 years to 75 years.
Written informed consent provided by patients or the legally acceptable representative.
Absence of hypolipidemic therapy during at least 4 weeks prior to the 1^st visit.

Pre-admission exclusion criteria

Serum TG values exceeding 4.5 mmol/l: the aim is to exclude patients with predominant hypertriglyceridemia or with severe combined hyperlipidemia because of their influence on the evaluation of results.
TC values exceeding 10 mmol/l: this criterion will be used to exclude from the study patients with severe hypercholesterolemia, including homozygote familial hypercholesterolemia.
Secondary hyperlipidemia due to hypothyroidism, nephrotic syndrome, type I diabetes mellitus, obstructive gallbladder, biliary disease, pancreatitis, immunologic abnormalities, or drug induced secondary hyperlipidemia.
Hypersensitivity to rosuvastatin or to any of the excipients.
Active liver disease, including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN).
Severe renal impairment (creatinine clearance < 30 ml/min or 0.5 ml/s).
Statin-induced myopathy (an abnormal condition of skeletal muscle characterized by muscle weakness, wasting, and histologic changes within muscle tissue) that can present as myalgia (muscle aches or weakness without creatinine kinase (CK) elevation) or rhabdomyolysis (muscle symptoms with marked CK elevation more than 5 times over the upper limits of normal).
Treatment with the following drug: cyclosporine, other lipid-lowering medicines (statins, fibrates, nicotinic acid, bile acid exchangers, probucol, ezetimibe).
Pregnancy and lactation and childbearing potential in women not using appropriate contraceptive measures.
Pathological clinical states that could affect patient’s compliance, or have any impact on patient’s survival rate (malignant diseases, alcohol abuse, medicine addiction, psychiatric diseases).
Acute disease state (infections, acute exacerbation of chronic diseases, trauma, surgical intervention) within the period of the past two months.
Severe, unstable heart failure.
Participation in another clinical trial within thirty days prior to enrolment.
Patients who are not able out of any reason to fulfill the requirements of the protocol.

Habits

Smoking

Smokers: regular smoker (> 3 cigarettes per week, or who quit smoking less than 3 months ago) or occasional smoker (3 cigarettes or less/week)
Ex-smoker: did not smoke for more than 3 months

Alcohol consumption
Consumption of alcohol up to 3 glasses of wine/beer per day or up to 20 drinks per week.

Adverse events

Adverse event: any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product, whether or not considered related to the investigational medicinal product

Adverse reaction of an investigational medicinal product: all untoward and unintended responses to an investigational medicinal product related to any dose administered. All adverse events judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to a medicinal product qualify as adverse reactions. The expression reasonable causal relationship means to convey in general that there is evidence or argument to suggest a causal relationship.

Severity grades of the adverse event:

Mild – An adverse event that does not disturb the patient; the patient is aware of it but can tolerate it.
Moderate – An adverse event that disturbs the patient and interferes to some degree with the patient’s normal daily activities.
Severe – An adverse event that is very disturbing and interferes with the patient’s work and daily activities; the patient wishes to stop the treatment.

Serious adverse event or serious adverse reaction: any untoward medical occurrence or effect that at any dose:

results in death,
is life-threatening,
requires hospitalisation or prolongation of existing inpatients´ hospitalisation,
results in persistent or significant disability or incapacity,
is a congenital anomaly or birth defect.

References

ESC/EAS Guidelines for the management of dyslipidemias (version 2011). Eur Heart J 2011; 32: 1769–818.
2016 European Guidelines on cardiovascular disease prevention in clinical practice. EHJ 2016; 37 (29): 2315-81.
Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis 2020; 292: 160-62.
Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376: 1670-82.
Grundy SM, Cleeman JI, Bairey Merz CN et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227-39.
Wood DA, Kotseva K, Connolly S et al. Nurse-coordinated multidisciplinary, family-based cardiovascular disease prevention programme (EUROACTION) for patients with coronary heart disease and asymptomatic individuals at high risk of cardiovascular disease: a paired, cluster-randomised controlled trial. Lancet 2008; 371: 1999–2012.
Kotseva K., Wood D, De Backer D, et al. EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur J Prev Cardiol 2016; 23(6): 636-48.
De Backer G, Jankowski P, Kotseva K. Management of dyslipidaemia in patients with coronary heart disease: Results from the ESC-EORP EUROASPIRE V survey in 27 countries. Atherosclerosis 2019; 285: 135-46.
Kendrach MG, Kelly-Freeman M. Approximate equivalent rosuvastatin doses for temporary statin interchange programs. Ann Pharmacother 2004; 38: 1286-92.
Jones PH, Davidson MH, Stein EA et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin and pravastatin across doses. Am J Cardiol 2003; 92: 152-60.
Brus S. Clinical evidence of the efficacy of Krka’s rosuvastatin in the treatment of hyperlipidemia with focus on additional doses. Krka Med Farm 2014; 26 (38): 62-71.
Luvai A, Mbagaya W, Hall AS et al. Rosuvastatin: a review of the pharmacology and clinical effectiveness in cardiovascular disease. Clin Med Insights Cardiol 2012; 6: 17-33.
Palmer MK, Nicholls SJ, Lundman P et al. Achievement of LDL-C goasl depends on baseline LDl-C and choice and dose of statin: An analysis from the VOYAGER database. Eur J Prev Cardiol 2013; 20(6): 1080-7.
Karlson BW, Toth PP, Palmer MK et al. Achievement of combined goals of low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol with three different statins: Results from VOYAGER. IJC Metabolic & Endocrine 2014; 5: 61–6.
Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Brit Med J 2003; 326: 1423-30.
Ridker PM, Danielson E, Fonesca FAH et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 (21): 2195-207.

* The product is marketed under different brand names in different countries: Roswera, Roxera, Sorvasta, Rosuvador.

Author

M. Cevc
University Medical Centre of Ljubljana, Department of Vascular Diseases, Ljubljana, Slovenia

GA. Dan
Colentina University Hospital, University of Medicine “C. Davilla”, Bucharest, Romania

I. Karadi
Semmelweis University, 3rd Department of Internal Medicine, Budapest, Hungary

M. Lutai
“M.D. Strazhesko Institute of Cardiology”, Academy of Medical Sciences of Ukraine, Department of atherosclerosis and CHD NSC, Kyiv, Ukraine

Z. Reiner
University Hospital Centre Zagreb, Department of Internal medicine and Division for Metabolic Diseases, Zagreb, Croatia

E. Shlyakhto
Almazov Federal Heart Centre, Heart Blood Endocrinology Centre, Saint Petersburg, Russian Federation

M. Vrablik
Charles University of Prague, 3rd Department of Internal Medicine, 1st Faculty of Medicine, Prague, Czech Republic

B. Barbič-Žagar
Krka, d. d., Novo mesto, Slovenia

Correspondence to: Michal Vrablik (vrablikm@seznam.cz)

Krka’s medicines are marketed in different countries under different brand names.

Some products may not be available in all countries due to still valid patent protection.

For complete information on the products please refer to the Summary of Product Characteristics. You can obtain it from Krka’s medical representatives.

We have compiled a collection of scientific papers in which we present the rich experience obtained from the clinical studies with Krka’s medicines.

Published: May, 2021