1. KMUK Kardiologijos klinika
Statinų saugumas
Dr. J. Plisienė
KMUK Kardiologijos klinika

2. Statinų saugumas
Saugumas
Efektyvumas

3. Dažniausi klausimai
Ar saugu skirti statinus, esant mažai
cholesterolio koncentracijai?
Ką daryti, jeigu atsiranda pašaliniai
reiškiniai?
Kada nutraukti statinų skyrimą?
Ar didelės statinų dozės saugios?
Kokia yra sąveika su kitais medikamentais?

4. Cholesterolio svarba Cholesterolis fiziologiškai svarbus
ląstelių membranai
Dalyvauja vitaminų sintezėje
Smegenų ląstelių, lytinių hormonų estrogenų
statybinė medžiaga

5. Mažos cholesterolio koncentracijos: Contra
Eksperimente didelės statinų dozės sukėlė encefalopatiją ir optinio disko atrofiją
Epidemiologiniuose tyrimuose pastebėtas ryšys mažos cholesterolio koncentracijos, intrakranijinių hemoragijų, savižudybių bei vėžio rizikos

6. Mažos cholesterolio koncentracijos: Pro
Sveikų naujagimių bendrojo cholest. koncentracija neviršija 1,8 mmol/l
Ateroskleroze nesergančių medžioklių genčių narių MTLC koncentracija 1,3-2,0 mmol/l
Šeimine hipolipoproteinemija sergančių aštuoniasdešimtmečių MTLC 0,5-1,0 mmol/l

7. PROVE IT- TIMI 22 studija
4162 pac. po persirgto ūmaus koronarinio sindromo
4 mėn. skirtas Atorvastatinas 80 mg arba Pravastatinas 40 mg
Atorvastatino grupėje pasiektas MTL-Ch<1,5 mmo/l (44% pac.), Simvastatino <2,4 mmol/l

8. PROVE IT- TIMI 22 studija MTL-Ch kiekis Saugumas Atorvast 80 mg
>80-100
2-2,6
>60-80
1,5 -2
>40-60
1,0-1,5
<40
<1,0 p
Mialgijos
Miozitas
KK>3X
KK>10X
Rabdomiolizė
ALT>3x
Hemoraginis insultas
Inkstų paž
Mirtis
K/v mirtis MI
Insultas
6,4
0,4
2,3
3,2
1,1
0,5
1,0
0,8
4,3
0,6
0,7
3,0
0,2
0,9
1,4
6,2
1,9
0,3
1,3
5,7
2,6
0,0
1,6
0,75
0,64
0,18
0,45
0,98
0,12
0,48
0,59
0,06
0,009
0,32

9. “Juo mažiau, juo geriau”
3.7 1
2.9
IŠL
rizika
2.2
1.7
1.3
The results of HPS and PROVE IT suggest that reducing LDL-C substantially below 100 mg/dL may provide additional benefit in high-risk patients. Neither of these trials indicated a lower threshold for LDL-C below which further LDL-C reduction did not provide further risk reduction.
1.0
TNT, IDEAL, PROVE-IT
1,1
1.8
2,6
3,4
4,1
4,9
LDL-C (mmol/l)
Grundy SM et al. Circulation 2004;110:227–239.

10. Dažniausi klausimai
Antrinei prevencijai, po persirgto MI
ar NKA - TAIP
Ar saugu skirti statinus, esant mažai
cholesterolio koncentracijai?
Ką daryti, jeigu atsiranda pašaliniai
reiškiniai?
Kada nutraukti statinų skyrimą?
Ar didelės statinų dozės saugios?
Kokia yra sąveika su kitais medikamentais?

11. Dažniausi klausimai
Ar saugu skirti statinus, esant mažai
cholesterolio koncentracijai?
Ką daryti, jeigu atsiranda pašaliniai
reiškiniai?
Kada nutraukti statinų skyrimą?
Ar didelės statinų dozės saugios?
Kokia yra sąveika su kitais medikamentais?

12. Statinų šalutiniai poveikiai
Bendrieji šalutiniai poveikiai
Galvos skausmas
Nuovargis
Virškinimo sutrikimai
Panašūs į gripą simptomai
Statin adverse events
Statins are very safe. 95% of patients can tolerate them; 5% cannot. Common side effects include headache, upset stomach, fatigue, flu-like symptoms, and myalgia (without changes in creatine kinase [CK]).
One or both liver transaminases may be elevated to >3 times the upper limit of normal on two consecutive occasions in 0.5% (with starting doses) to as high as 2.5% (with high doses) of patients in a dose-dependent manner. Whether statin-induced elevations in liver enzymes constitute true hepatotoxicity has not been determined. Cases of serious liver dysfunction or failure are exceedingly rare and not clearly related to statin therapy. Enzymes will frequently return to normal by reducing doses or even with continuation of therapy. If an elevation persists, discontinuation of therapy for a short period until levels return to normal is advised. Statin therapy may then be reinitiated.
Myopathy defined as muscle symptoms (muscle weakness, aches, or soreness) plus CK >10 times the upper limit of normal is seen in 2–4 patients per In 77,000 patient-years of use in the landmark clinical trials, 8 cases of myopathy were reported. Very rare cases of rhabdomyolysis, myoglobinuria, acute renal necrosis, and death have been reported. The incidence of myopathy appears related to the systemic blood concentration of the statin. Myopathy is most likely to occur with higher doses, in patients with renal impairment, when a statin is combined with a fibrate, when a drug interfering with the metabolism of the statin is given concurrently (e.g., macrolide antibiotics, certain antifungal medications, gemfibrozil, cyclosporine), and in elderly women. All patients started on statins should be instructed to report immediately muscle symptoms or brown urine and to have CK measured. If myopathy is present or strongly suspected, the statin should be discontinued immediately.

13. Statinų sukeliami pašaliniai reiškiniai
Miopatijos
Transaminazių koncentracijos padidėjimas
Proteinurija
Vaistų sąveika
Five main safety considerations arise with the use of statins: associated adverse events (eg, headache, nausea, myalgia); elevated transaminase levels; muscle toxicity; renal function; and drug interactions. Each of these topics will be covered in detail in this slide presentation.
One or both liver transaminases may be elevated to >3 times the upper limit of normal on two consecutive occasions in 0.5% (with starting doses) to as high as 2.5% (with high doses) of patients in a dose-dependent manner. Whether statin-induced elevations in liver enzymes constitute true hepatotoxicity has not been determined. Cases of serious liver dysfunction or failure are exceedingly rare and not clearly related to statin therapy. Enzymes will frequently return to normal by reducing doses or even with continuation of therapy. If an elevation persists, discontinuation of therapy for a short period until levels return to normal is advised. Statin therapy may then be reinitiated.
Myopathy defined as muscle symptoms (muscle weakness, aches, or soreness) plus CK >10 times the upper limit of normal is seen in 2–4 patients per In 77,000 patient-years of use in the landmark clinical trials, 8 cases of myopathy were reported. Very rare cases of rhabdomyolysis, myoglobinuria, acute renal necrosis, and death have been reported. The incidence of myopathy appears related to the systemic blood concentration of the statin. Myopathy is most likely to occur with higher doses, in patients with renal impairment, when a statin is combined with a fibrate, when a drug interfering with the metabolism of the statin is given concurrently (e.g., macrolide antibiotics, certain antifungal medications, gemfibrozil, cyclosporine), and in elderly women. All patients started on statins should be instructed to report immediately muscle symptoms or brown urine and to have CK measured. If myopathy is present or strongly suspected, the statin should be discontinued immediately.

14. Raumenų pažeidimo simptomai, gydant statinais
Miopatija – bendrinis terminas, nusakantis raumenų ligą (dažnis 0,2-0,4 proc.)
Mialgija – ilgai trunkantis raumenų skausmas ar silpnumas be KK padidėjimo
Miozitas – ilgai trunkantis raumenų skausmas ar silpnumas + KK padidėjimas
Rabdomiolizė – ilgai trunkantis raumenų skausmas ar silpnumas + KK padidėjimas 10 kartų, lydimas kreatinino padidėjimo
(tamsus šlapimas ir mioglobinas šlapime)
Pasternak RC et al. J Am Coll Cardiol. 2002;40: , Pasternak RC et al. Circulation. 2002;106:

15. Kreatinino k. padidėjimas
Miopatijų diagnostikos kriterijai
Raumenų simptomai
KK konc. padidėjimas
Kreatinino k. padidėjimas
Mialgija + -
Miozitas
Rabdomiolizė
+++
Raumenų simptomai – raumenų skausmai arba silpnumas
KK – kreatinkinazė

16. * 4S, WOSCOPS, CARE, LIPID, AFCAPS/TexCAPS*
Raumenų ir kepenų pažeidimas: statinų klinikinių tyrimų* metaanalizė (30 tūkst. pacientų)
Fermentas
Placebas
Statinas
p vertė
KK >10  ULN 40 50
0.29
ALT/AST >3  ULN
258
290
0.17
LaRosa et al conducted a meta-analysis of the 4S, WOSCOPS, CARE, LIPID, and AFCAPS/TexCAPS trials. These trials included over 30,000 participants. Forty patients in the placebo groups and 50 in the statin groups experienced asymptomatic elevations of CK (>10  ULN). This represents an odds ratio of 1.25, although this difference was not statistically significant.
There were 258 patients with elevated ALT/aspartate aminotransferase (AST) (>3  ULN) in the placebo groups compared with 290 in the statin groups. This corresponded to an odds ratio of 1.13 and again without any statistical significance.
LaRosa JC, He H, Vupputuri S. Effect of statins on risk of coronary disease. A meta-analysis of randomized controlled trials. JAMA. 1999;28:
* 4S, WOSCOPS, CARE, LIPID, AFCAPS/TexCAPS*

17. Raumenų pažeidimas Reported AE 2006 Safety Analysis PROVE-IT* IDEAL*
TNT*
Atorvastatin
10 mg
(n=7258)
80 mg
(n=4798)
Pravastatin
40 mg
(n=2063)
(n=2099)
Simvastatin
20 mg
(n=4449)
(n=4439)
(n=5006)
(n=4995)
Myalgia
2.9%
2.7% NR
1.1%
2.2%
4.7%
4.8%
Myopathy
0.02%†
0.25%†
0.14%†
Persistent CPK >10 x ULN
0.06%
Rhabdomyolysis
0.07%
0.05%
0.04%
A dose-dependent increase in the incidence of myopathy and rhabdomyolysis has been observed with some other statins (eg, simvastatin 80 mg, rosuvastatin ≥40 mg). As a result, there is a general perception that the risk of myopathy and rhabdomyolysis with all statins is dose-related. The 2006 safety meta-analysis, which included over 4500 patients receiving the 80-mg dose, did not show any evidence of a dose-dependent increase in myopathy and rhabdomyolysis with atorvastatin. No cases of rhabdomyolysis were observed across the 49 trials included in this analysis.1
Trials studying high-dose atorvastatin that were not included in the 2006 safety meta-analysis include PROVE IT, IDEAL, and TNT.
The incidences of persistent CPK elevations >10 x ULN and myopathy with the 80 mg dose of atorvastatin were low and similar across the trials.
No cases of rhabdomyolysis were reported in the PROVE-IT trial.2 Two cases of investigator-reported rhabdomyolysis were reported with atorvastatin 80 mg in the IDEAL trial and 5 cases of rhabdomyolysis were reported in the TNT trial (2 in the atorvastatin 80-mg group and 3 in the atorvastatin 10-mg group). All of the patients had at least one predisposing risk factor for myopathy and rhabdomyolysis and none was considered by the on-site investigator to be causally related to atorvastatin.3,4
NR, not reported
*Studies not included in 2006 safety meta-analysis
†Investigator-reported cases: did not meet criteria for definition of myopathy (persistent CPK elevations >10 x ULN with muscle symptoms)
1. Newman CB, et al. Am J Cardiol. 2006;97:61-67; 2. Cannon CP, et al. N Engl J Med. 2004;350: ; 3. LaRosa JC, et al. N Eng J Med. 2005;352: ; 4. Pedersen TR, et al. JAMA ;294: 17

18. Statinų miotoksinis ir hepatotoksinis poveikis
Statinas
Miozitas*
ALT/AST 
Atorvastatinas
<0.1%
0.7% gelta (n=1)
Fluvastatinas
Retas†
1.1% Mažai simptominis
Lovastatinas
0.06%
1.9% Besimptominis
Pravastatinas
1.2%
Besimptominis
Simvastatinas
0.05%
1.0%
Rosuvastatinas
0.1%
0.4% Gelta (n=2)
This slide shows the incidence of various adverse events associated with treatment with the available statins as presented in their package inserts. Myositis, defined as myalgias with a creatine kinase (CK) level >10 times upper limit of normal (ULN), is relatively rare, with an incidence of 0.1% or less. Elevations in liver aminotransferase levels are also uncommon, with incidence rates ranging from < 0.4% to 1.9%. Only a very few of these are associated with symptoms.
Atorvastatin calcium (Lipitor®) prescribing information. Pfizer Inc, New York, NY
Physician’s Desk Reference, 56th ed Thomson Healthcare, Montvale, NJ.
Rosuvastatin calcium (Crestor®) prescribing information. AstraZeneca Pharmaceuticals, Wilmington, Del
Atorvastatin calcium (Lipitor®) prescribing information. Pfizer Inc, New York, NY
Physician’s Desk Reference, 56th ed Thomson Healthcare, Montvale, NJ.
Rosuvastatin calcium (Crestor®) prescribing information. AstraZeneca Pharmaceuticals, Wilmington,
Del
*Mialgija ir CK >10  ULN.
†Nesiskiria nuo placebo

19. Gydymo taktika, nustačius KK koncentracijos padidėjimą be miopatijos simptomų
KK padidėjusius iki 5X, gydymą statinu galima tęsti, stebint KK koncentraciją
KK padidėjusius >5X, gydymą statinu nutraukti. KK sumažėjus pradėti gydymą kitu statinu arba mažesne naudoto statino doze
On initiating statin therapy, it is essential to obtain a baseline CK level and essential to monitor the level if a patient reports muscle symptoms. Minor CK elevations are not necessarily diagnostic in clinical practice because they are frequently seen in statin users as well as nonusers. Patients at high risk for a vascular event who report minor myalgias should be encouraged to continue treatment.
If serious myalgias or muscle weakness develops, however, statin treatment must be discontinued. Statins should also be discontinued if CK rises to >10  ULN and myalgias are reported, an indication of myositis. If patients who begin to develop muscle discomfort and/or weakness also begin to show progressive CK elevations, a reduction in dosage or temporary discontinuation of statin therapy is recommended. Then a decision whether or when to reinstitute statin therapy can be made.
Although it is rarely seen in patients on statin monotherapy, patients with complex medical problems and/or who are on polytherapy are more likely to present with myositis.
Pasternak RC, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:

20. Kitos miopatijos priežastys
Vaistai Prokainamidas, penicilinas, gliukokortikoidai, alkoholis, ampfetaminas, B2 adrenerginiai preparatai, androgenai
Infekcijos Gripas, bruceliozė, ŽIV
Kitos Sunkus fizinis darbas, hipotireozė, dehidratacija, elektrolitų sutrikimas
Neoplastiniai ir paraneoplastiniai procesai
For differential diagnosis, the physician should consider and rule out not only the statin, but also other causes of myopathy, including particular drugs the patient may be taking concomitantly, certain infectious diseases or agents, neoplasms, and paraneoplastic syndromes. Other possibilities include overexertion from work or exercise, myotonia, neural overactivity, undiagnosed hypothyroidism, dehydration, and electrolyte imbalances with decreased sodium, magnesium, calcium, or glucose levels.

21. Satinų sukeliamą miopatiją didina
Vyresnis amžius (ypač virš 80 m.), moterims amžiaus įtaka yra didesnė nei vyrams
Smulkus kūno sudėjimas
Sudėtinga gretutinė patologija (pvz. lėtinis inkstų nepakankamumas, ypač dėl cukrinio diabeto)
Politerapija
Perioperacinis periodas
Kai kurių vaistų vartojimas

22. Kepenų fermentų padidėjimas
Dažnis 0,5 – 2,5 proc., priklausomas nuo statino dozės
Ženklus kepenų pakenkimas yra nepaprastai retas
Sumažinus dozę ar nebeskiriant vaisto pokyčiai grįžtami
Statin adverse events
Statins are very safe. 95% of patients can tolerate them; 5% cannot. Common side effects include headache, upset stomach, fatigue, flu-like symptoms, and myalgia (without changes in creatine kinase [CK]).
One or both liver transaminases may be elevated to >3 times the upper limit of normal on two consecutive occasions in 0.5% (with starting doses) to as high as 2.5% (with high doses) of patients in a dose-dependent manner. Whether statin-induced elevations in liver enzymes constitute true hepatotoxicity has not been determined. Cases of serious liver dysfunction or failure are exceedingly rare and not clearly related to statin therapy. Enzymes will frequently return to normal by reducing doses or even with continuation of therapy. If an elevation persists, discontinuation of therapy for a short period until levels return to normal is advised. Statin therapy may then be reinitiated.
Myopathy defined as muscle symptoms (muscle weakness, aches, or soreness) plus CK >10 times the upper limit of normal is seen in 2–4 patients per In 77,000 patient-years of use in the landmark clinical trials, 8 cases of myopathy were reported. Very rare cases of rhabdomyolysis, myoglobinuria, acute renal necrosis, and death have been reported. The incidence of myopathy appears related to the systemic blood concentration of the statin. Myopathy is most likely to occur with higher doses, in patients with renal impairment, when a statin is combined with a fibrate, when a drug interfering with the metabolism of the statin is given concurrently (e.g., macrolide antibiotics, certain antifungal medications, gemfibrozil, cyclosporine), and in elderly women. All patients started on statins should be instructed to report immediately muscle symptoms or brown urine and to have CK measured. If myopathy is present or strongly suspected, the statin should be discontinued immediately.

23. Statinai ir CYP 450 fermentų sistema
Statinas
Kepenų
CYP450
fermentai
Statino arba jo
aktyvaus metabolito
Koncentracija kraujyje
Miopatijos
rizika
3A4
Following administration, the primary enzyme system responsible for the metabolism of statins is the CYP450 system, which includes more than 100 different CYP genes. The 2 isozymes predominantly responsible for the metabolism of statins are CYP3A4 and CYP2C9. Inhibitors of these enzymes can produce a decrease in the metabolism of statins, resulting in increased and prolonged blood concentrations of the statin or its active metabolites. This has the potential to increase the risk for muscle toxicity.
Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41:
2C9
Inhibitoriai ir
substratai
Williams D, Feely J. Clin Pharmacokinet. 2002;41:

24. Statinų ir P450 fermentų sąveika
Statinas
CYP3A4
CYP2C9
Atorvastatinas 
Fluvastatinas *
Lovastatinas
Pravastatinas
Rosuvastatinas
Simvastatinas
This chart identifies the CYP450 enzymes involved in the metabolism of various statins. The CYP3A family of enzymes is responsible for the metabolism of atorvastatin, lovastatin, and simvastatin. Fluvastatin is primarily metabolized by CYP2C9, as is rosuvastatin to a minor extent. Pravastatin, on the other hand, is not significantly metabolized by the CYP system; it is primarily eliminated unchanged by phase II reactions.
Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41:
Crestor® (rosuvastatin calcium) prescribing information. AstraZeneca Pharmaceuticals, Wilmington, Del.
*Minor.
Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41:

25. Gydymo taktika, padidėjus kepenų fermentams (ALT, AST)
ALT/AST> 3X, statinu negydyti, tyrimą kartoti po 1-2 mėn.
ALT/AST< 3X, gydymą statinu tęsti, stebint fermentų koncentraciją
ALT/AST> 3X, gydymą statinu nutraukti, sumažinti jo dozę arba keisti kitu, stebint fermentų koncentraciją
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:

26. Dažniausi klausimai
Ar saugu skirti statinus, esant mažai
cholesterolio koncentracijai?
Ką daryti, jeigu atsiranda pašaliniai
reiškiniai?
Kada nutraukti statinų skyrimą?
Ar didelės statinų dozės saugios?
Kokia yra sąveika su kitais medikamentais?

27. Klinikinėse studijose didėja skaičius pacientų, kuriems skiriama 80 mg Atorvastatino
1.388
167
3.910
1.780
4.925
4.681
1000
2000
3000
4000
5000
Pacientų skaičius
1996
2001
2004
Atorvastatin 10 mg
Atorvastatin 80 mg
In 2004, Newman, et al published a retrospective analysis of pooled data from 44 atorvastatin studies, including 16,495 patients, which examined the safety of atorvastatin 10, 20, 40, & 80 mg and placebo.1
In 2006, Newman, et al published a second retrospective analysis of pooled data from of 49 atorvastatin studies, including 14,236 patients, which examined the safety of atorvastatin 10mg, 80 mg and placebo.2
This figure shows the increase in patient-years of exposure to atorvastatin 80 mg in clinical trials since the first safety meta-analysis was completed in November 2001 and since the approval of the atorvastatin NDA in 1996.
Due to the wave of new trials examining the use of high-dose statins, patient exposure to the 80-mg dose in clinical trials has increased substantially over the past few years.
The second meta-analysis that was completed in 2004 represents over 4500 patient-years of exposure to the 80-mg dose of atorvastatin in clinical trials and provides a substantial amount of evidence on the safety and tolerability of this dose.2
>121 million patient-years of exposure to atorvastatin in the real world
Adapted from Newman CB, et al. Am J Cardiol. 2006;97:61-67.

28. Atorvastatino saugumas
No Dose-Response Relationshipfor Myalgia, Newman et al, 20031
Analysis did not include studies completed after Nov 1, 2001
Myalgia Rates Were Low and Not Dose Related, Newman et al, 20062
Analysis did not include studies completed after Sept 15, 2004
1,5
2,7
2,0
3,2
2,6 1 2 3 4 5 5 4
2,9
2,7
Patients Experiencing Myalgia (%)
Patients Experiencing Myalgia (%) 3 2
1,4
1,5
1,2 1
0,7
In 2004, Newman, et al published a retrospective analysis of pooled data from 44 atorvastatin studies, including 16,495 patients, which examined the safety of atorvastatin 10, 20, 40, & 80 mg and placebo.1
In 2006, Newman, et al published a second retrospective analysis of pooled data from of 49 atorvastatin studies, including 14,236 patients, which examined the safety of atorvastatin 10/ 80 mg and placebo.2
These retrospective analyses of the fixed-dose data grouping found that the incidence of myalgia did not increase across the atorvastatin dose range, and at each dose the proportion of patients experiencing the event was similar to that seen in the patients treated with placebo.  
Only 1 patient receiving atorvastatin in this group of 44 studies experienced persistent CPK elevations > 10 x ULN. The patient had no other AEs associated with the elevated enzymes.
Placebo n = 30/1949
10 mg n = 173/6343
20 mg n = 5/242
40 mg n = 30/186
80 mg n = 61/2,345
Placebo (n=2,180)
Atorvastatin 10 mg (n=7,258)
Atorvastatin 80 mg (n=4,798)
Atorvastatin
All Cause
Treatment Related
A retrospective analysis of pooled data from of 44 studies, 16,495 patients examining the safety of atorvastatin 10, 20, 40, & 80 mg and placebo
A retrospective analysis of pooled data from of 49 studies, 14,236 patients examining the safety of atorvastatin 10/ 80 mg and placebo
1. Adapted from Newman CB, et al. Am J Cardiol. 2003;92:
2. Adapted from Newman CB, et al. Am J Cardiol. 2006; 97:61-67.

29. Persistuojančio ALT/AST padidėjimo atvejai* (16,495 pac.)
Vidutiniškai 0,5% pacientų, gydytų atorvastatino atsirado persistuojantis ALT/AST padidėjimas**
Pacientai (%)
A retrospective analysis of 44 completed studies showed a low occurrence of persistent ALT/AST elevations. Persistent elevations were defined as > 3X ULN ALT/AST occurring on 2 consecutive occasions within 14 days. Of the patients treated with atorvastatin 10, 20, 40, and 80 mg, on average, 0.5% experienced persistent ALT/AST elevations. The incidence of persistent ALT/AST elevations ranged from 0.13% in the atorvastatin 10-mg group to 0.89% in the atorvastatin 80-mg group, which is consistent with product labeling.
The average value of ALT/AST for placebo was 0.28% (5/1789).
10 mg
20 mg
40 mg
80 mg
n =6093
n =2543
n =1983
n =3131
* Persistuojantis padidėjimas, kai 2 ALT/AST dydžiai > 3X ULN per 14 dienų
A retrospective analysis of pooled data from of 44 studies, 16,495 patients examining the safety of atorvastatin 10, 20, 40, & 80 mg and placebo.
Based on a patient population that experienced elevations of > 3 x ULN occurring on 2 consecutive occasions within 14 days
**Analysis did not include trials completed after Nov 1, 2001
Adapted from Newman CB, et al. Am J Cardiol. 2003;92:

30. Inkstų pažeidimas Albuminuria Hematuria % Pacientų skaičius
In the 2006 safety meta-analysis, the incidence of albuminuria and hematuria was slightly higher in the atorvastatin groups compared with placebo but there was no evidence of a dose-dependent increase in the incidence of these adverse events.
Only 2 cases of hematuria were considered to be treatment-related (one each in the atorvastatin 80-mg and placebo groups). The albuminuria adverse events were not considered to be treatment related.
The cases of albuminuria and hematuria were not associated with any serious renal adverse events or treatment discontinuations.1
Placebo (n=2180)
Atorvastatin 10 (n=7258)
Atorvastatin 80 (n=4798)
Placebo (n=2180)
Atorvastatin 10 (n=7258)
Atorvastatin 80 (n=4798)
A retrospective analysis of pooled data from of 49 studies, 14,236 patients examining the safety of atorvastatin 10/ 80 mg and placebo
Analysis did not include studies completed after Nov 1, 2001
Adapted from Newman C et al. Am J Cardiol. 2006;97:61-67.

31. Hematurija, vartojant statinus
Statinų sukeltos hematurijos dažnis
12% 12
10% 10 8% 8 7% 7%
Hematurijos dažnis — kraujas šlapime ≥1 (%) 6% 6
5% = PLACEBO 5% 5% 4% 4% 4% 4
A similar trend is seen with hematuria associated with rosuvastatin. This chart shows data from the same pooled analysis of rosuvastatin clinical trials, and demonstrates frequency of hematuria as measured by dipstick urinalysis.1
As you can see, rates of hematuria are generally higher with rosuvastatin, particularly at the higher doses, than with other statins or with placebo. It is important to note that with all doses of atorvastatin, the frequency of hematuria was below placebo.1
1. AstraZeneca FDA Advisory Committee Presentation. July 9, Available at: http// Accessed December 18, 2003. 3% 2% 2% 2
5 mg
n=653
10 mg
n=1202
20 mg
n=1460
40 mg n=2384
80 mg
n=804
10 mg
n=710
20 mg
n=667
40 mg
n=245
80 mg n=377
20 mg n=517
40 mg
n=356
80 mg n=337
20 mg n=191
40 mg
n=67
Rosuvastatinas
Atorvastatinas
Simvastatinas
Pravastatinas
Source: AstraZeneca FDA Advisory Committee Presentation. July 9, Available at: http// 3968s1.htm. Accessed December 18, 2003.

32. Proteinurija, vartojant statinus
12% 12 10 8
Proteinurijos dažnis- baltymas šlapime ≥2 (%) 6 4%
3% = PLACEBO 4% 4
This chart shows data from a pooled analysis of rosuvastatin clinical trials presented by AstraZeneca at last year’s FDA rosuvastatin Advisory Committee meeting, and demonstrates frequency of proteinuria as measured by dipstick urinalysis.1
As you can see, rosuvastatin demonstrated a dose-dependent trend toward increased rates of proteinuria. This same signal does not appear consistent across the dose ranges of other statins.1
It is also worth noting that there may be predisposing patient conditions or concomitant medications that may cause increased plasma concentrations of a drug. As such, a dose-dependent trend on rates of proteinuria may necessitate greater vigilance (even when administering lower doses).
1. AstraZeneca FDA Advisory Committee Presentation. July 9, Available at: http// Accessed December 18, 2003. 2% 2% 2% 2% 2% 2 1% 1%
0.4%
0.5%
0.6% 0%
5 mg
n=653
10 mg
n=1202
20 mg
n=1460
40 mg n=2384
80 mg
n=804
10 mg
n=710
20 mg
n=667
40 mg
n=245
80 mg n=377
20 mg n=517
40 mg
n=356
80 mg n=337
20 mg n=191
40 mg
n=67
Rosuvastatinas
Atorvastatinas
Simvastatinas
Pravastatinas
Source: AstraZeneca FDA Advisory Committee Presentation. July 9, Available at: http// 3968s1.htm. Accessed December 18, 2003.

33. Statinų sukelta proteinurija
Proteinuriją gali sukelti bet kuris statinas, sutrikdydamas baltymo reabsorbciją
Proteinurija nuo dozės priklausoma statinų klasės savybė
Su šlapimu išsiskiriantys proteinai yra mažos molekulinės masės
Statinų sukelta proteinurija nelemia inkstų funkcijos pablogėjimo
Statinai gerina inkstų kraujotaką ir didna glomerulų filtraciją
This topic will be expanded upon in the next slides.Rozuvastatino 80 mg doze sukele inkst7 nepakankamuma taciau derinyje su antibiotikais taciau 5-40 mg netgi sumazino kreatnino koncentracija

34. Dažniausi klausimai
Ar saugu skirti statinus, esant mažai
cholesterolio koncentracijai?
Ką daryti, jeigu atsiranda pašaliniai
reiškiniai?
Kada nutraukti statinų skyrimą?
Ar didelės statinų dozės saugios?
Kokia yra sąveika su kitais medikamentais?

35. Vaistai, atsargiai derintini su statinais
Fibratai
Nikotininė rūgštis
Ciklosporinai
Priešgrybeliniai azolo dariniai
Intrakonazolis ir ketokonazolis
Eritromicinai ir klaritromicinas

36. Vaistai, atsargiai derintini su statinais
ŽIV proteazių inhibitoriai
Nefazodonas (antidepresantas)
Verapamilis
Amiodaronas
Gausus greipfrutų sulčių vartojimas (daugiau nei 1,4 litro per dieną)
Piktnaudžiavimas alkoholiu (nepriklausomas miopatijų rizikos veiksnys)

37. Statinų sąveika su kitais medikamentais
Vaistas
Atorv
Fluv
Lov
Prav
Rosuv
Simv
Cyklosporinas + –
Digoxinas
Eritromcinas
Warfarinas
Cyclosporine has been shown to increase plasma concentrations of atorvastatin, lovastatin, pravastatin, simvastatin, and rosuvastatin. More importantly, an increased incidence of myopathy and rhabdomyolysis has been reported in transplant patients taking these agents concomitantly.
Macrolide antibiotics, such as erythromycin, are potent inhibitors of CYP3A4 and, therefore, have the potential to interact with statins metabolized by this pathway. Since fluvastatin, pravastatin, and rosuvastatin are metabolized by other routes, these agents are less likely to be influenced by this interaction.
Coadministration of simvastatin and digoxin has been reported to increase digoxin concentrations by 20%. Similarly, coadministration of atorvastatin increased digoxin levels by 15%. This means that digoxin concentrations should be monitored more frequently when these combinations are used.
Some statins (lovastatin, fluvastatin, simvastatin, and rosuvastatin) have been reported to interact with warfarin, with a few case reports of increased anticoagulant effects and bleeding. The coadministration of warfarin with any statin affects the international normalized ratio (INR). Increased and decreased prothrombin time responses have been reported in patients who are concurrently taking warfarin and statins. As with most medications, anticoagulant control should be carefully monitored when patients who receive oral anticoagulants begin taking statins.
Paoletti R, Corsini A, Bellosta S. Pharmacological interactions of statins. Atheroscler Suppl. 2002;3: Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41: Crestor® [package insert]. Wilmington, Delaware: AstraZeneca Pharmaceuticals; 2005.
Paoletti R, et al. Atheroscler Suppl. 2002;3:35-40;
Williams D, Feely J. Clin Pharmacokinet. 2002;41: ;
Crestor® [package insert]. Wilmington, Delaware: AstraZeneca Pharmaceuticals; 2005.

38. Kaip padidinti statinų ir fibratų derinio saugumą?
Gydyti vien tik statinais
Statino ir omega-3 riebiųjų rūgšių ar niacino derinys saugesnis, nei statinų ir fibratų derinys
Statinus ir fibratus derinyje skirti mažesnėmis dozėmis
Statiną ir fibratą skirti skirtingu paros laiku
Steps to minimize the risk of muscle toxicity with fibrate–statin combination therapy
The greatest issue with the use of a fibrate and statin in combination is the increased risk of causing myopathy and rhabdomyolysis. This risk is enhanced with high statin doses, in the presence of renal insufficiency, in older patients, and whenever drugs that may interfere with statin metabolism are given concurrently.
To minimize the muscle side effects when combining any of these drugs with a statin, the following suggestions are made.
Try to achieve LDL-C and non-HDL-C treatment goals with a statin alone.
If adding a triglyceride-lowering drug to the statin, give preference to fish oils or niacin, as the risk of myopathy appears low. If a fibrate is to be added, fenofibrate is preferred over gemfibrozil, since there may be a lower risk of myopathy.
Use the lowest effective dose of both the statin and fibrate to achieve treatment goals (e.g., starting dose of a statin with 63–126 mg of fenofibrate).
Dose the fibrate in the morning and the statin in the evening (note that this suggestion is based on theoretical considerations and not on any evidence that this recommendation will reduce the incidence of muscle toxicity).
Avoid (or cautiously use) statins in patients who have compromised renal function (as is often found in elderly patients) or hepatic function (including alcoholics).
Assure that no other drugs are or will be used concurrently that could interfere with the metabolism of the statin.
Obtain a baseline CK level and repeat it during the course of therapy if the patient reports muscle symptoms.
Teach the patient to recognize and report muscle weakness, tenderness, or pain and be prepared to evaluate patients who experience these symptoms.
Discontinue therapy if muscle symptoms are present and a CK is >10 times the upper limit of normal.

39. Kaip padidinti statinų ir fibratų derinio saugumą?
Neskirti derinio esant inkstų nepakankamumui
Įvertinti kitus skiriamus vaistus ir galimą tarpusavio sąveiką
Išmokinti pacientą pažinti raumeninius simptomus
Nutraukti gydymą, jei atsirado raumeniniai simptomai ar KK >10 kartų
Steps to minimize the risk of muscle toxicity with fibrate–statin combination therapy
The greatest issue with the use of a fibrate and statin in combination is the increased risk of causing myopathy and rhabdomyolysis. This risk is enhanced with high statin doses, in the presence of renal insufficiency, in older patients, and whenever drugs that may interfere with statin metabolism are given concurrently.
To minimize the muscle side effects when combining any of these drugs with a statin, the following suggestions are made.
Try to achieve LDL-C and non-HDL-C treatment goals with a statin alone.
If adding a triglyceride-lowering drug to the statin, give preference to fish oils or niacin, as the risk of myopathy appears low. If a fibrate is to be added, fenofibrate is preferred over gemfibrozil, since there may be a lower risk of myopathy.
Use the lowest effective dose of both the statin and fibrate to achieve treatment goals (e.g., starting dose of a statin with 63–126 mg of fenofibrate).
Dose the fibrate in the morning and the statin in the evening (note that this suggestion is based on theoretical considerations and not on any evidence that this recommendation will reduce the incidence of muscle toxicity).
Avoid (or cautiously use) statins in patients who have compromised renal function (as is often found in elderly patients) or hepatic function (including alcoholics).
Assure that no other drugs are or will be used concurrently that could interfere with the metabolism of the statin.
Obtain a baseline CK level and repeat it during the course of therapy if the patient reports muscle symptoms.
Teach the patient to recognize and report muscle weakness, tenderness, or pain and be prepared to evaluate patients who experience these symptoms.
Discontinue therapy if muscle symptoms are present and a CK is >10 times the upper limit of normal.

40. Gydymas statinais ir vėžiniai susirgimai (klinikinių tyrimų metaanalizė)
Vėžio lokalizacija
Statinas
(36,564)
Kontrolinė gr.
(36,570)
Skrandžio ir žarnyno
532 (1,5)
514 (1,4%)
Urogenitalinis
678 (1,9%)
695 (1,9%)
Kvėpavimo sistemos
411 (1,1%)
422 (1,2%)
Krūties
128 (0,4%)
124 (0,3%)
Kraujo
68 (0,5%)
76 (0,5%)
Melanoma
53 (0,4%)
62 (0,4%)
Kiti
70 (0,5%)
71 (0,6%)

41. Ką turi žinoti statinus vartojantis pacientas?
Ilgalaikio gydymo statinais svarbą, siekiant išvengti išeminių įvykių
Tikslines lipidų koncentracijas
Pašalinius statinų sukeliamus reiškinius
Statinų sąveiką su kitais medikamentais
Veiksnius, lemiančius statinų koncentracijos pokyčius

42. Išvados
Statinai gerai toleruojami ir sukelia nedaug pašalinių reiškinių
Dažniausiai pakitimai gryžtami, sumažinus statinų dozę
Didelės atorvastatino dozės saugios:
2 studijų metaanalizėse nebuvo nuo dozės priklausomų raumenų pažeidimo
Nebuvo rabdomiolizės atvejų
Nedidelis ALT/AST padidėjimas, priklausomai nuo dozės

43. Ačiū už dėmesį !