Cardiovascular (CV) diseases remain the leading cause of morbidity and mortality in the world and in Slovenia. (1) They are most often caused by atherosclerosis. Several factors, of which hyperlipidemia is an important one, accelerate the process. (2) According to the latest European Guidelines on Cardiovascular Disease prevention in Clinical Practice, reducing LDL-cholesterol (LDL-C), in particular by statins, is essential for prevention of cardiovascular events. The risk of major cardiovascular events decreases further if the reduction of LDL-C is more significant. (3-5)

The efficacy of statin therapy is clearly evident and it has been employed in clinical practice for years, but even so the incidence of cardiovascular events remains high. (6-8) Unfortunately, adherence has been far from optimal with 80% of high-risk patients failing to achieve the recommended LDL-C levels. (2) Adherence decreases during the course of treatment, and according to reports, 77% of patients on statin therapy discontinue the treatment after two years. (4) Data from clinical trials show that physicians most often prescribe statin therapy at the low dose and very rarely titrate it up to the recommended dose. This is why patients are still at risk of cardiovascular disease development and progression despite the treatment. (4, 9)

Herein we describe the results of FROZEN, a non-interventional study aimed to assess the efficacy and safety of Krka’s rosuvastatin (Roswera^®; other brand names are used for the medication in different countries) in patients with hyperlipidaemia. (10)

The study was conducted from October, 2016 to the end of November, 2017 in family medicine clinics in Slovenia. A total of 1,627 patients with hyperlipidemia at moderate, high, or very high risk of a CV event were included. The monitoring period lasted for three months and included two scheduled visits. At visit 1, when a patient was enrolled in the study, the initial dose of rosuvastatin was determined in consideration of the patient’s baseline lipid levels and CV risk category. At visit 2, blood lipid levels, adverse reactions, and achievement of target LDL-C levels were assessed.

The successfulness of rosuvastatin therapy was assessed based on the frequency of patients who achieved target LDL-C levels, which were determined according to the ESC/EAS 2011 Guidelines valid at the time: (i) 2.99 mmol/L or lower for moderate-risk patients; (ii) 2.49 mmol/L or lower for high-risk patients; and (iii) 1.79 mmol/L or lower and/or ≥50% reduction for very high-risk patients.

Average patient age was 62.7±10.2 years, and 50% were men and 50% women. The study included 407 (25%) very high-risk, 780 (48%) high-risk, and 420 (26%) moderate-risk patients. No data on risk categories were available for 20 patients (1%). Before inclusion in the study, 24% of patients had not been treated for hyperlipidemia.

Roswera^® was prescribed at six different doses (5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg). At initiation, the overall mean dose of rosuvastatin was 17.8±9.1 mg. After three months, 1,543 patients (94.8%) continued therapy, 41 (2.5%) discontinued it, and no data were available for 43 (2.6%) patients. The overall mean dose used in maintenance therapy was 19.0±9.6 mg.

During the study, total cholesterol (TC), LDL-C, and triglycerides (TG) showed statistically significant reductions (p<0.0001). After three months, the mean absolute TC was reduced by 2.1±1.2 mmol/L and relative TC was reduced by 29.3±14.7%; the mean absolute LDL-C was reduced by 1.8±1.1 mmol/L and relative LDL-C was reduced by 37.2±22.7%; the mean absolute TG was reduced by 0.6±1.4 mmol/L and relative TG was reduced by 18.7±34.7%. There was no statistically significant change in HDL-cholesterol (Figure 1).

During the study, LDL-C was statistically significantly reduced (p<0.0001) regardless of the cardiovascular risk category. In moderate-risk patients it was reduced by 1.7±1.1 mmol/L or 35.1±22.7%, in high-risk patients by 1.9±1.1 mmol/L or 37.8±22.5%, and in very high-risk patients by 1.7±1.1 mmol/L or 38.1±23.4% (Table 1). In 685 patients (42.1%) Roswera^® therapy was assessed as very successful (target LDL-C levels were achieved) (Table 2).

Patients tolerated Roswera^® well and no adverse drug reactions (ADR) were recorded in 1,481 patients (91.0%). Adverse drug reactions were reported by 94 patients (5.8%), and no data were available for 52 patients (3.2%). In 86 patients (5.3%) ADRs were in causal association with the treatment and no causal association was recorded in the remaining 8 patients (0.5%). Myalgia was reported in 24 patients (1.5%) and was the most common ADRs. Other ADRs were less common (<1%). These results demonstrated the safety of rosuvastatin therapy.

Hyperlipidemia is a chronic CV disease that requires careful control and management. It is important that target LDL-C levels are achieved in the treatment and maintained in the long term. This is the only way to provide optimal protection.

This non-interventional study included Slovenian outpatients with hyperlipidemia, of which 76% had already been on cholesterol-lowering therapy and only 24% received into statin therapy for the first time. After the three-month course of treatment, TC, LDL-C, and TG were statistically significantly decreased (p<0.0001), demonstrating the efficacy of rosuvastatin therapy. After three months, 1,543 patients (94.8%) continued receiving Roswera^®.

Rosuvastatin was effective for all groups of patients, because the treatment was assessed as very successful or successful for most of them. If outcomes are analyzed by risk categories, it can be established that the treatment of moderate-risk patients was very successful for more patients (56.7%) than for high-risk and very high-risk patients (37.8% and 37.4% respectively). This means that patients at moderate risk achieved target LDL-C levels more easily than high-risk or very high-risk patients. Additionally, many other trials showed that achieving target levels poses a significant challenge for clinical practice. In certain trials, 80% of high-risk patients failed to achieve target levels. This indicates that despite therapy patients are still at risk of CV disease development and progression. (8, 9)

Data from certain clinical trials indicate that physicians tend to prescribe doses that are insufficient and only rarely titrate them up to the recommended doses, which was also shown by this study. (9)

The results also show that rosuvastatin therapy is safe and well-tolerated by patients. In the three-month course of the study, 91% of patients reported no adverse drug reactions. Adverse drug reactions associated with the medication were recorded in a mere 5.3% of patients. Safety results were comparable to the results of many large clinical trials. (9)

The primary long-term objective of hyperlipidemia treatment is to prevent CV events. This is why it is very important that patients with increased LDL-C levels achieve target levels recommended based on their CV risk categories and maintain them in the long term. Despite the very clear guidelines for the treatment of hyperlipidemias, patients in clinical practice are often left untreated or are inappropriately treated. Additionally, our study showed that therapy was often not sufficiently intensive for patients at high risk and very high risk of cardiovascular events, as they reached target LDL-C levels less often than patients at moderate risk. According to the results, we can conclude Roswera^® is a safe and effective medication for the treatment of hyperlipidemia in patients at moderate, high, and even very high risk of a cardiovascular event.