CC Cardiol Croat Cardiologia Croatica Cardiol. Croat. 1848-543X 1848-5448 Croatian Cardiac Society CC_12(4)_161-165 10.15836/ccar2017.161 Professional Article Evidence-based therapy with Krka’s rosuvastatin in primary and secondary prevention of cardiovascular disease http://orcid.org/0000-0001-5085-9823JarhDarja Milovanovičhttp://orcid.org/0000-0002-4035-7691GrošeljMatejahttp://orcid.org/0000-0002-1173-7361Barbič-ŽagarBreda Krka, d. d., Novo mesto, Slovenia Address for correspondence: Breda Barbič-Žagar, Krka d. d., Dunajska 65, SLO-1000 Ljubljana, Slovenia 
Phone: +386-1-4751-339 / E-mail: breda.zagar@krka.biz 042017 12 4 161 165 0504201720042017 2017 Summary

Cardiovascular disease is the leading cause of death worldwide. Among the risk factors, hyperlipidemia has been associated with the highest population attributable risk for cardiovascular disease. Despite many proven therapies and decades of their use, cardiovascular event rates remain high. International guidelines have identified the problem of statins being prescribed at the lowest dose and often not up-titrated to attain the goal of treatment. The fact that a majority of patients are treated with the initial low doses of statins and that doctors rarely reach for the higher doses indicates a need for intermediate doses. In order to bridge this gap, Krka produces a wide range of rosuvastatin strengths, including the intermediate strengths of 15 and 30 mg. This additional strengths enables treatment to be adjusted to the requirements of individual patients and increase the percentage of patients reaching target lipid levels.

 Keywords: rosuvastatincardiovascular diseaseLDL cholesterolefficacysafetyadditional strengths

Cardiovascular disease (CVD) is the leading cause of death worldwide. More than 17 million people die from CVD each year. Among the risk factors, hyperlipidemia is associated with the highest population attributable risk for CVD. (1) Despite many proven therapies and decades of their use, cardiovascular event rates remain high. (2, 3) As evidenced by the recently published EUROASPIRE IV survey, more than 80% of high- or very-high-risk patients do not attain the target levels of plasma lipids and thus do not get the maximum benefit of statin therapy. (4)

As recognised by international guidelines, statins are usually prescribed at the lowest dose and often not up-titrated to attain the therapeutic goal. (1) In addition, treatment adherence over the long term is poor, with up to a third of patients or more stopping their statin treatment within a year. As a consequence, these patients are not getting the maximum benefit of this preventive strategy. (5) They remain at an increased risk for the development and/or progression of CVD despite receiving treatment.

Statins are normally available in 10 mg, 20 mg, 40 mg and 80 mg strengths, with the exception of rosuvastatin, which is available in strengths from 5 mg to 40 mg. (6, 7) Data from clinical practice show that usually physicians do not reach for the highest doses and that a majority of patients are treated with one of the two lowest doses. This indicates the need for intermediate doses.

Two new strengths (15 mg and 30 mg) of Krka’s rosuvastatin (RosweraÆ) have been introduced on the market with the aim to facilitate 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 level. (8)

Although the clinical efficacy of the 15 mg and 30 mg strengths is predictable from the linear extrapolation of data on already approved rosuvastatin doses, clinical evidence was required as supporting evidence.

The efficacy and safety of ROSUvastatin dose titration in the treatment of PATients with Hyperlipidemia (the ROSU-PATH clinical study)

The international, randomised, multicentre, open-label, prospective clinical study ROSU-PATH (The efficacy and safety of ROSUvastatin dose titration in the treatment of PATients with Hyperlipidemia) was performed to establish the efficacy and safety of the additional doses of 15 mg and 30 mg of rosuvastatin in patients with primary hypercholesterolemia or mixed dyslipidemia and to determine the percentage of patients reaching the target LDL-cholesterol (LDL-C) levels as defined by the 2011 ESC/EAS guidelines current at the time of the study.

In this international, randomised, multicentre, open-label, prospective clinical study conducted at 30 healthcare institutions in Croatia, the Czech Republic, Hungary, Romania, Russia, Slovenia and Ukraine, 494 patients (aged 56.9 ± 9.9 years) were randomised to either the standard (10 mg – 20 mg – 40 mg of rosuvastatin) or the alternative titration arm (15 mg – 30 mg – 40 mg of rosuvastatin).

Baseline assessment was followed by three visits (at weeks 4, 8 and 12) where lipid levels and safety parameters were measured. At each visit the dose of rosuvastatin was titrated according to the standard or alternative titration scheme to achieve target LDL-C levels (Figure 1).

ROSU-PATH (The efficacy and safety of ROSUvastatin dose titration in the treatment of PATients with Hyperlipidemia) dosage diagram.

 Comparison of the efficacy and safety of rosuvastatin 15 mg vs 10 mg

At baseline, there were no significant differences between the groups, except that there were more men in the alternative than in the standard titration arm (57% vs 47%; P < 0.05).

At week 4, patients in the alternative titration arm showed a significantly greater LDL-C reduction compared to patients in the standard titration arm (Table 1). (9)

LDL-cholesterol (LDL-C) values at baseline and at week 4.
LDL-C value Standard titration arm Alternative titration arm
Baseline (mmol/l) 4.33 ± 1.11 4.44 ± 1.02
Week 4 (mmol/l) 2.64 ± 0.93 2.52 ± 0.80
Baseline–week 4 (mmol/l)(absolute change) –1.69 ± 0.99 –1.95 ± 0.98
P < 0.005
Baseline–week 4 (mmol/l)(relative change) –37.5% ± 21.7% –42.6% ± 17.3%
P < 0.01

Significantly more patients on rosuvastatin 15 mg reached target lipid levels compared to patients on rosuvastatin 10 mg (81% vs 67%; P < 0.0001) (Figure 2), while the tolerance and safety profiles were comparable in both arms. (9)

Percentage of patients with LDL-cholesterol reaching target levels after 10 mg and 15 mg doses at the end of the study.

 Target LDL-C level attainment rate in patients at different CV risk levels

An intention-to-treat analysis included 469 patients; 166, 78 and 225 patients at moderate, high and very high CV risk, respectively. Evaluation of the target LDL-C level attainment in these CV risk groups revealed success rates of 83.4%, 66.7% and 33.0%, respectively. Among very-high-risk patients, there were 22.7% of patients who failed to reach the target LDL-C level of < 1.8 mmol/l, but had a ≥ 50% LDL-C reduction compared to baseline, resulting in 55.7% of very-high-risk patients reaching the LDL-C goal. The mean daily doses were 18.7 mg, 21.8 mg and 25.3 mg for moderate-, high- and very-high-risk patients, respectively (Figure 3). 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 (Table 2). (10)

Evaluation of LDL-cholesterol goal attainment by cardiovascular risk group.

 Mean absolute differences from target LDL-cholesterol in different cardiovascular risk groups [mmol/l].
Group Baseline Week 4 Week 8 Week 12 Significance (Baseline : week 12)
Moderate risk(target LDL-C< 3.0 mmol/l) 1.64 –0.35 –0.53 –0.50 P < 0.0001
High risk (target LDL-C< 2.5 mmol/l) 2.05 0.27 0.18 –0.11 P < 0.0001
Very high risk(target LDL-C< 1.8 mmol/l) 2.33 0.66 0.30 0.34 P < 0.0001
Conclusions and implications of the findings

The clinical study ROSU-PATH was the first clinical evaluation of the use of the rosuvastatin 15 mg strength in clinical practice. Therapy with any of the investigated strengths of rosuvastatin was evaluated as effective and safe in a wide range of patients with hyperlipidemia. Significantly more patients in the alternative arm, on rosuvastatin 15 mg, reached target lipid levels compared to patients on rosuvastatin 10 mg. Moreover, significantly fewer dose titrations were needed in the alternative dosing arm. We can conclude that the 15 mg dose of rosuvastatin is an effective and safe initial dose of rosuvastatin, bringing more patients to target LDL-C level. (9)

Evaluation of mean differences from target LDL-C levels showed that moderate- and high-risk patients reached their targets, while the very-high-risk patients failed, suggesting that the mean dose of rosuvastatin in this group (25.3 mg) was too low. (10) The additional strengths of rosuvastatin of 15 mg and 30 mg might be a welcome alternative for patients not getting the greatest possible benefit from statin treatment due to not being treated with the optimal dose.

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