Non-Interventional Study of Efficacy and Safety of Rosuvastatin Therapy and Introduction of Additional Doses to Clinical Practice in Patients with Hyperlipidemia

    Authors

    Abstract

    Cardiovascular (CV) diseases remain the leading cause of morbidity and mortality in the world and in Slovenia. According to the recommendations of the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice, reducing LDL-cholesterol levels, especially with statins, is essential for prevention of CV events. A number of clinical studies and years of experience demonstrate the efficacy of statin therapy. Nevertheless, they are still rarely used in clinical practice or are used at insufficient doses. The clinical efficacy of all doses of Krka’s rosuvastatin (Roswera®) was monitored in FROZEN, a three-month non-interventional study. The results showed that patients at high or very high risk of a cardiovascular event were undertreated and were less likely to reach target LDL-C levels than moderate-risk patients. Treatment was evaluated as safe and effective during the follow-up period in patients at a moderate, high, and very high CV risk.

    Keywords

    rosuvastatin, hyperlipidemia, low-density lipoprotein cholesterol, efficacy, safety

    DOI

    https://doi.org/10.15836/ccar2020.75

    Full Text

    ## Introduction 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) ## Patients and Methods 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. ## Results 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® therapy was assessed as very successful (target LDL-C levels were achieved) (**Table 2**). ### TABLE 1: LDL-C reduction with respect to a cardiovascular risk category. LDL-C – low-density lipoprotein cholesterol. | | **Visit 1** | **Visit 2** | **Absolute difference** | **Relative difference** | **P** | | --- | --- | --- | --- | --- | --- | | **LDL-C** | mmol/l | mmol/l | mmol/l | % | | | **Moderate risk** | 4.6±0.1 | 2.9±0.8 | –1.7±1.1 | –35.1±22.7 | p® 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 (®. 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) ## Conclusions 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.

    Literature

    1. World Heart Organization. Fact sheets. Cardiovascular diseases (CVD). [cited 2019 September 3]. https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
    2. Lansberg P, Lee A, Lee ZV, Subramaniam K, Setia S. Nonadherence to statins: individualized intervention strategies outside the pill box. Vasc Health Risk Manag. 2018 May 24;14:91–102. https://doi.org/10.2147/VHRM.S158641
    3. Hanžel J, Šabovič M. Novosti v zdravljenju hiperholesterolemije in arterijske hipertenzije. Farm Vestn. 2020 January 15;2016(67):134–40. http://www.sfd.si/uploads/datoteke/abovi.pdf
    4. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016 August 1;37(29):2315–81. https://doi.org/10.1093/eurheartj/ehw106
    5. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 January 1;41(1):111–88. https://doi.org/10.1093/eurheartj/ehz455
    6. Zoungas S, Curtis AJ, McNeil JJ, Tonkin AM. Treatment of dyslipidemia and cardiovascular outcomes: the journey so far--is this the end for statins? Clin Pharmacol Ther. 2014 August;96(2):192–205. https://doi.org/10.1038/clpt.2014.86
    7. Mendis S, Puska P, Norrving B. Global atlas on cardiovascular disease prevention and control. [internet] Published by the World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization. Geneva 2011. [cited September 3]. https://apps.who.int/iris/handle/10665/44701
    8. Vonbank A, Agewall S, Kjeldsen KP, Lewis BS, Torp-Pedersen C, Ceconi C, et al. Comprehensive efforts to increase adherence to statin therapy. Eur Heart J. 2017 August 21;38(32):2473–9. https://doi.org/10.1093/eurheartj/ehw628
    9. Milovanovič Jarh D, Grošelj M, Barbič-Žagar B. Evidence-based therapy with Krka’s rosuvastatin in primary and secondary prevention of cardiovascular disease. Cardiol Croat. 2017;12(4):161–5. https://doi.org/10.15836/ccar2017.161
    10. Zaključno poročilo. Neintervencijsko spremljanje učinkovitosti in varnosti zdravljenja z rosuvastatinom (Sorvasta®) in uvajanje dodatnih jakosti v klinično prakso pri bolnikih s hiperlipidemijo – FROZEN. Podatki iz dokumentacije. Krka, d. d., Novo mesto, Slovenija, 2019.
    Cardiologia Croatica
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    Non-Interventional Study of Efficacy and Safety of Rosuvastatin Therapy and Introduction of Additional Doses to Clinical Practice in Patients with Hyperlipidemia

    Professional Article
    Issue3-4
    Published
    Pages75-79
    PDF via DOIhttps://doi.org/10.15836/ccar2020.75
    rosuvastatin
    hyperlipidemia
    low-density lipoprotein cholesterol
    efficacy
    safety

    Authors

    Borut Jug*ORCIDUniverzitetni klinični center Ljubljana, Ljubljana, Slovenija
    Breda Barbič-ŽagarORCIDKrka, d. d., Novo mesto, Slovenija
    Mateja GrošeljORCIDKrka, d. d., Novo mesto, Slovenija
    Darja Milovanović JarhORCIDKrka, d. d., Novo mesto, Slovenija
    Tjaša LipuščekORCIDKrka, d. d., Novo mesto, Slovenija

    *Correspondence email: borut.jug@kclj.si

    Abstract

    Cardiovascular (CV) diseases remain the leading cause of morbidity and mortality in the world and in Slovenia. According to the recommendations of the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice, reducing LDL-cholesterol levels, especially with statins, is essential for prevention of CV events. A number of clinical studies and years of experience demonstrate the efficacy of statin therapy. Nevertheless, they are still rarely used in clinical practice or are used at insufficient doses. The clinical efficacy of all doses of Krka’s rosuvastatin (Roswera®) was monitored in FROZEN, a three-month non-interventional study. The results showed that patients at high or very high risk of a cardiovascular event were undertreated and were less likely to reach target LDL-C levels than moderate-risk patients. Treatment was evaluated as safe and effective during the follow-up period in patients at a moderate, high, and very high CV risk.

    Full Text

    Introduction

    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)

    Patients and Methods

    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.

    Results

    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).

    FIGURE 1. Graphic presentation of mean blood lipid levels at visit 1 and visit 2. TC – total cholesterol; LDL-C – low-density lipoprotein cholesterol; HDL-C – high-density lipoprotein cholesterol; TG – triglycerides

    During the study, LDL-C was statistically significantly reduced (p® therapy was assessed as very successful (target LDL-C levels were achieved) (Table 2).

    TABLE 1: LDL-C reduction with respect to a cardiovascular risk category. LDL-C – low-density lipoprotein cholesterol.

    LDL-C
    Visit 1
    mmol/l
    Visit 2
    mmol/l
    Absolute difference
    mmol/l
    Relative difference
    %
    Moderate risk
    Visit 1
    4.6±0.1
    Visit 2
    2.9±0.8
    Absolute difference
    –1.7±1.1
    Relative difference
    –35.1±22.7
    P
    p<0.0001
    High risk
    Visit 1
    4.6±1.1
    Visit 2
    2.8±0.9
    Absolute difference
    –1.9±1.1
    Relative difference
    –37.8±22.5
    P
    p<0.0001
    Very high risk
    Visit 1
    4.1±1.2
    Visit 2
    2.4±0.8
    Absolute difference
    –1.7±1.1
    Relative difference
    –38.1±23.4
    P
    p<0.0001

    TABLE 2: Successfulness of therapy with respect to cardiovascular risk categories.

    Very successful
    Moderate risk
    238 (56.7%)
    High risk
    295 (37.8%)
    Very high risk
    152 (37.4%)
    Successful
    Moderate risk
    130 (30.9%)
    High risk
    371 (47.5%)
    Very high risk
    206 (50.6%)
    Unsuccessful
    Moderate risk
    29 (6.9%)
    High risk
    54 (6.9%)
    Very high risk
    27 (6.6%)
    No data
    Moderate risk
    23 (5.5%)
    High risk
    61 (7.8%)
    Very high risk
    22 (5.4%)

    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.

    Discussion

    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®.

    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)

    Conclusions

    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.

    Literature

    1. 1.
      World Heart Organization. Fact sheets. Cardiovascular diseases (CVD). [cited 2019 September 3].Link
    2. 2.
      Lansberg P, Lee A, Lee ZV, Subramaniam K, Setia S. Nonadherence to statins: individualized intervention strategies outside the pill box. Vasc Health Risk Manag. 2018 May 24;14:91–102.DOI
    3. 3.
      Hanžel J, Šabovič M. Novosti v zdravljenju hiperholesterolemije in arterijske hipertenzije. Farm Vestn. 2020 January 15;2016(67):134–40.Link
    4. 4.
      Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016 August 1;37(29):2315–81.DOI
    5. 5.
      Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 January 1;41(1):111–88.DOI
    6. 6.
      Zoungas S, Curtis AJ, McNeil JJ, Tonkin AM. Treatment of dyslipidemia and cardiovascular outcomes: the journey so far--is this the end for statins? Clin Pharmacol Ther. 2014 August;96(2):192–205.DOI
    7. 7.
      Mendis S, Puska P, Norrving B. Global atlas on cardiovascular disease prevention and control. [internet] Published by the World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization. Geneva 2011. [cited September 3].Link
    8. 8.
      Vonbank A, Agewall S, Kjeldsen KP, Lewis BS, Torp-Pedersen C, Ceconi C, et al. Comprehensive efforts to increase adherence to statin therapy. Eur Heart J. 2017 August 21;38(32):2473–9.DOI
    9. 9.
      Milovanovič Jarh D, Grošelj M, Barbič-Žagar B. Evidence-based therapy with Krka’s rosuvastatin in primary and secondary prevention of cardiovascular disease. Cardiol Croat. 2017;12(4):161–5.DOI
    10. 10.
      Zaključno poročilo. Neintervencijsko spremljanje učinkovitosti in varnosti zdravljenja z rosuvastatinom (Sorvasta®) in uvajanje dodatnih jakosti v klinično prakso pri bolnikih s hiperlipidemijo – FROZEN. Podatki iz dokumentacije. Krka, d. d., Novo mesto, Slovenija, 2019.