Martsevich lipid-lovering therapy 2015 Vienna

1. The lipid-lowering therapy in
patients with high risk of
cardiovascular complications and
with liver diseases
Professor Sergey MARTSEVICH
National Research Center for Preventive Medicine
Moscow, Russia
Vienna, April 22, 2015

2. Disclosures
• Research Support – PRO.MED.CS Praha a.s.
• Speaker Honoraria - PRO.MED.CS Praha a.s.

3. Background
• Cardiovascular diseases (CVD) remain the main cause
of mortality in all developed countries.
• Hyperlipidaemia is one of the most significant CVD
risk factors; its correction plays important role in
reduction of CVD morbidity and mortality.
• According to recent Clinical Guidelines, target
cholesterol (CH) levels become more and more low.
• To achieve target CH levels, intensive hypolipidemic
therapy (preferably statins) is usually required.

5. Recommendations for treatment targets
for LDL-C, ESC 2011
In patients at VERY HIGH CV risk LDL-C
goal is < 1.8 mmol/l
In patients at HIGH CV risk LDL-C goal is
< 2.5 mmol/l

6. How to achieve this goal?
Recommendations for the pharmacological treatment of
hypercholesterolaemia. ESC, 2011
Prescribe statin up to the highest
recommended dose or highest
tolerable dose to reach the
target level.

7. Hypolipidemic therapy – evidence and
reality
• Statins are the mainstay of the modern lipid-
lowering therapy since they are the only group
of drugs which have evident efficacy in reducing
the risk of CV morbidity and mortality in
different cardiovascular diseases.
• However, only a minor part of patients who
really need statins receive them in real clinical
practice.

9. Medications Percent of administration
Antiplatalets 5,7%
Statins 0,7%
Diuretics 9,9%
ACE-inhibitors 26,8%
Beta-blockers 10,2%
Angiotensin receptror blockers 1,8%
Calcium antagonists 7,6%
Oral anticoagulants (n=252 AF) 2,3%
Medical therapy prior to stroke (n=960). LIS-2
Registry data (Liubertsy, Moscow Region)
86% of patients already had AH, 21% - DM, у 26% -AF, 21% - had previous stroke, 13%
- previous MI.

10. The other part of the problem:
Even in those patients who receive statins, target LDL-CH levels
are rarely achieved
Why statin dose was not increased ?
31
87
% of target CH-LDL levels
Yes
No
• Statin safety data
0
20
40
60
80
100
120
140
160
180
No
Yes
Only in ¼ of high CV-risk
patients target CH-LDL levels
were achieved
“PROFILE” OUTPATIENT REGISRTRY data, Moscow, 2014

11. The situation with statin administration is
much more complicated in patients with
concomitant diseases
• What do we know about statin administration in
CVD patients with concomitant
– liver diseases
– renal diseases
– muscle diseases
– In elderly patients
– …….

12. The situation with statin administration is
much more complicated in patients with
concomitant diseases
• What do we know about statin administration in
CVD patients with concomitant
– liver diseases
– renal diseases
– muscle diseases
– In elderly patients
– …….

13. • Statins and the liver
– Although liver toxicity has been a concern since
their initial introduction, several clinical studies
has shown that statins are generally safe to use
for prevention of coronary disease and death,
even in the setting of chronic liver disease…

14. Statins and liver
toxicity
• However, statin treatment is associated with some hepatic
adverse effects, the most common of which is an
asymptomatic and usually transient elevation of serum
aminotransferase levels that often occurs in the first 12
weeks of therapy.
• This effect is dose-dependent.
• This finding is generally not correlated with
histopathological changes and is not an indicator of liver
injury.
• Clinically important statin-related hepatotoxicity is an
extremely rare adverse effect.

15. Statins and liver toxicity

16. It should be pointed out that most
of randomised trials excluded
patients with transaminase levels
more than 1-2 times the upper
limit of normal, so the safety of
statins in these people has not
been systemically assessed.

17. Monitoring liver and muscle enzymes,
ESC Guidelines, 2011
Current Clinical
Guidelines propose for
the physician a strict
algorithm for
management of
abnormal liver
enzymes before and
during statin
treatment…
In some situations, which
are not rare, physician has
to stop statin therapy or
to reduce the dose despite
high CV risk….

18. Furthermore,
• Official documents contain some restrictions
on the use of statins in patients with liver
diseases…

19. CONTRAINDICATIONS TO STATINS
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020702s057lbl.pdf

20. CONTRAINDICATIONS TO ATORVASTATIN
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020702s057lbl.pdf
Patients who have persistent AST>3 ULN increase, reduction
of dose or withdrawal of atorvastatin is recommended.
Atorvastatin should be used with caution in patients who
consume substantial quantities of alcohol and/or have a
history of liver disease.
Active liver disease or unexplained persistent elevations of
serum transaminases.

21. • Despite the fact that these adverse effects are reversed
after treatment withdrawal, many patients with an
indication for statins refuse therapy because of concerns
about muscle or liver toxicity.
• This may represent a significant barrier to maximizing
cardiovascular risk reduction for many patients with
dislipidemia.
What are the consequences….

22. Moreover,
• A substantial part of physicians are afraid of
prescribing statins to such patients, even in
case of high CV risk….

23. Results of a survey of 70 general practitioners in
Moscow (April, 2015).
• 1. Do you usually prescribe statins
to CVD patients with concomitant
liver diseases (n=70) ?
• 2. In what conditions do
you feel possible to
prescribe statins to CVD
patients with
concomitant liver
diseases (n=46)?
– Normal serum transaminases
– 14 (30,4%)
– Serum transaminases lelel is
< 3 UNL – 14 (30,4%)
– Concomitant administration
of hepatoprotectors – 13
(28,3%)
– Normal serum transaminases
+ hepatoprotectotor
administration – 5 (10,9%)
7,1%
22,9%
70%
0
10
20
30
40
50
60
always
never
only under
certain
conditions

24. All these approaches have low level of evidence (Class IIb, C)
How the problem could be
solved ?

25. Treating statin intolerant patients
• Combination therapy is the most reasonable
approach, since it permits to reduce statin dose and
ideally to diminish statin side-effects…
• Different hypolipedemic drugs can be combined
with statins, however, many of them are not safe
when combined with statins or not sufficiently
effective….

26. Ursodeoxycolic acid has lipid-
lowering effect

27. Effect of ursodeoxycholic acid combined with
statins in hypercholesterolemia treatment: a
prospective clinical trial
• Gabezas Gelabert R. Rev Clin Esp 2004; 204:632-635.
• Random prospective clinical trial in 48 patients with primary family
hypercholesterolemia nonrespondent to simvastetin or atorvastatin
treatment.
• Simvastatin 20 mg/day + UDCA 300 mg/day yielded significantly greater
reduction of LDL-CH than simvastatin 40 mg/day.
• Addition of atorvastatin 20 mg/day to UDCA 300 mg/day was more effective
than atorvastatin 40 mg in LDL-CH reduction.
•The results of this study show that combination therapy with
low doses of statins and UDCA is effective in patients initially
nonrespondent to low doses of statins.

28. Assessment of influence of ursodeoxyholic
acid on the efficacy and safety of statin
administration in patients with liver diseases
“RACURS”
National Society for evidence-based pharmacotherapy
Russia

29. Study background:
 Statins are the background of modern hypolipidemic therapy and are
indicated to the majority of patients with high CV risk.
 Long-term statin therapy is generally safe and well-tolerated. The most
significant statin side-effects are myopathy and liver enzymes elevation.
 Liver toxicity has been a concern since initial statin introduction, however,
several clinical trials have shown that these drugs are safe for the
prevention of CAD and death, even in patients with chronic liver disease.
 Despite these facts, some official restrictions do exist concerning safety of
long-term statin administration in patients with some functional liver
disturbances.
 Ursodeoxycholic acid (UDCA) can potentially enhance the efficacy of statins
and reduce their influence on hepatic transaminases. However, no studies
have addressed this problem.

30. • To assess efficacy and safety of combined
administration of statins and UDCA in patients
with hуperlipidemia and high CV risk, who have
concomitant liver diseases.
Study aim:

31. Moscow
(4 outpatient clinics)
Rostov-on-Don
(2 outpatient clinics)
Novosibirsk
(2 outpatient clinics)
Yekaterinburg
(2 outpatient clinics)
Vladivostok
(2 outpatient clinics )
262 patients
in Russia
Patients inclusion

32. RACURS – observational registry-based
study
• Every physician who took part in the study,
included all consecutive patients who fulfilled
inclusion criteria and recommended to add UCDA to
statin therapy . All prescriptions were made in
accordance with official recommendations for the
use of study drugs.
• A special questionnaire was designed to assess
actual compliance to the study drugs.

33. Ethical problems
• The study protocol was approved by Local
Ethical Committee of the National Research
Center for Preventive Medicine.
• All the patients gave written informed
consent to participate in the study.

34. INCLISION CRITERIA
• Men and women > 18 years;
• Confirmed cardiovascular or cerebrovascular
diseases of atherosclerotic origin or/and
diabetes mellitus;
• Confirmed diagnosis of liver disease and/or
laboratory abnormalities, typical for liver
diseases.

35. Exclusion criteria
• Official contraindications to prescribe any of
the study drugs (statins, UDCA);
• Acute liver diseases;
• Decompensated liver cirrhosis;
• Unstable coronary artery disease,
decompensated chronic heart failure;
• Chronic renal failure;
• Patient’s refusal to participate in the study.

36. Patients who fulfill
inclusion criteria
Received
statins
Did not
receive statins
M0-1
M0
M1
M3 M6
Study design:
Follow-up 6 months
UDCA recommended
Administration
of statins

37. • Clinical evaluation – all visits.
• Blood pressure, heart rate - all visits.
• Laboratory data - serum transaminases, CK,
bilirubin, glucose, lipids - all visits.
• Special questionnaire (adherence
assessment) - all visits.
METHODS

38. Efficacy and safety assessment:
• Efficacy was assessed by reducing of CH-LDL
levels and by reaching target CH-LDL levels.
• Safety was assessed by clinical status, serum
transaminase and CK level dynamics, serum
bilirubin level dynamics.

39. Patients’ characteristics (n=262)
• Included 127 men and 135 women
Data
Age (years) 59,9 ± 8,7 31 - 86
BMI(kg/m2) 29,3 ± 4,8 18,7 - 49,7
Obesity 36,1% of patients with BMI > 30 kg/m2
Arterial hypertension 60,4%
Smoking status Do not smoke – 192 (75%), smoke – 61 (24%),
no data –2 (1%)
Allergy 7,5%

40. Cardiovascular diseases and/or DM
Condition N m/w %
Prior angioplasty 47 37/10 18,4
Prior myocardial infarction 73 50/23 28,6
Positive exercise test 88 58/33 34,5
Positive CA/scintigraphy 77 55/22 30,1
Peripheral atherosclerosis 111 53/58 43,5
Diabetes mellitus 112 68/44 43,9
Prior stroke or TIA 23 10/13 9,0

41. Liver diseases
Condition N m/f %
Non-alcoholic fatty liver
disease
156 79/77 61,2
Сholelithiasis uncompicated 76 30/46 29,8
Postcholecystectomical
syndrome
30 11/19 11,8
Chronic viral hepatitis 18 17/1 7,1
Biliary dyskinesia 84 42/42 32,9
Gilbert's Syndrome 3 1/2 1,2

42. Statin administration prior to study
inclusion
184; 70%
78; 30%
received statins did not receive statins

43. Serum lipids in patients who received and who
did not receive statins prior to the study
Plasma lipids Received statins Did not receive
statins
Р
Total CH 5,89 ± 1,21 6,23 ±1,02 0,006
LDL CH 3,80 ± 1,15 4,05 ± 1,14 0,030
HDL CH 1,16 ± 0,26 1,14 ± 0,35 n.s.
TG 1,89 ±0,73 2,13 ± 1,27 0,015

44. Study results

45. Serum lipid dynamics – all patients (n=262)
5,9
4,9 4,3
6,2
5,1
0
2
4
6
8
baseline 1 month 3 months 6 months
with statin without statin
3,8
2,9
2,3
4,1
3,2
0
1
2
3
4
5
baseline 1 month 3 months 6 months
Total cholesterol, mmol/l
LDL-CH, mmol/l
***
***

46. Laboratory data before study initiation and at
the end of study – all patients (n=262)
0
40
80
120
baseline after 6 months
U/l mkmol/l

47. Real compliance to UDCA
• The main reason for noncompliance – high cost of UDCA
At the end of the study 62 patients (23%) din not take UDCA
219
204
179
43
19 19
32
43
0
50
100
150
200
250
1 month 3 months 6 months
administered not administered withdrawals no data

48. Analysis of adherence to UDCA during the study
All patients
(n=262)
Included into
analysis (n=241)
MAIN GROUP (ADHERENT)
Patients who received UDCA
(n=179)
CONTROL GROUP (NON-ADHERENT)
UDCA was not administered/patient’s refusal/
low adherence
(n=62)
Excluded due
the lack of
adherence
data(n=21)

49. STUDY RESULTS ANALYSIS
ALL PATIENTS
(n=262)
INCLUDED INTO
ANALYSIS
(n=241)
MAIN GROUP
TOOK UDCA
(n=179)
CONTROL GROUP
UDCA not administered/patient’s refusal/ low
adherence
(n=52)
EXCLUDED DUE
TO THE LACK OF
ADHERENCE
DATA (n=21)
PROPENSITY SCORE MATCHING
MAIN GROUP
after propensity score matching
(n=52)

50. Patients who took UDCA
(n=52)
Patients who did not take
UDCA (n=52) p<0,05
Age 61,6 (6) 60,8 ± 7,7 NS
Waist sirc. 98(12) 97(10) NS
BMI 28,2 (5,3) 28,9 (5,1) NS
ALT 23 (28,9) 26 (18) NS
AST 25,9 (19,2) 26 (11) NS
CH total 6 (1,5) 6,3 (1,6) NS
LDL-CH 3,9 (1,48) 4,1 (1,8) NS
TG 1,9 (0,5) 1,9 (1,09) NS
CK 106 (71) 135 (52) NS
Bilirubin 12,7 (9,6) 12 (5,3) NS
Propensity score – matching: patients who took and who did not
take UDCA. Initial data.

51. Patients who took UDCA
(n=52)
Patients, who did not take
UDCA (n=52) p<0,05
ALT 20 (11,1) 24 (10,5) NS
AST 22 (10) 24 (7) NS
CH total 4,0 (0,85) 4,52 (0,68) p<0,05
LDL-CH 1,92 (0,73) 2,6 (0,7) p<0,05
TG 1,2 (0,56) 1,3(0,64) NS
CK 105 (72) 126 (50) NS
Bilirubin 12,2 (7,2) 10,9 (6,5) NS
Comparison of two groups (adherent and not adherent to
UDCA) after propensity score matching at the end of the
study

52. Patients who took UDCA
(n=52)
Patients, who did not take
UDCA (n=52) p<0,05
ALT 20 (11,1) 24 (10,5) NS
AST 22 (10) 24 (7) NS
CH total 4,0 (0,85) 4,52 (0,68) p<0,05
LDL-CH 1,92 (0,73) 2,6 (0,7) p<0,05
TG 1,2 (0,56) 1,3(0,64) NS
CK 105 (72) 126 (50) NS
Bilirubin 12,2 (7,2) 10,9 (6,5) NS
Comparison of two groups (adherent and not adherent to
UDCA) after propensity score matching at the end of the
study

53. Achievement of target CH-LDL levels (<1,8 mmol/l) at
the end of study in the two groups of patients
35%
100%
0
10
20
30
40
50
60
with UDCA without UDCA
1,8 or more <1,8 mmol/l
n = 52 Χ2 = 21,77; р<0,01
65%

54. Conclusions (1)
• 1. RACURS study, performed in terms of specially
designed registry, demonstrated possibility and
safety of combined administration of statins and
UDCA in patients with high cardiovascular risk and
concomitant liver diseases.
• 2. High adherence to UDCA was revealed.
• 3. Decrease in lipids levels (total CH and CH-LDL) by
the end of 6-months therapy can be explained by
ability of UDCA to potentiate statins hypolipidemic
activity or by its own hypolipidemic action.

55. Conclusions (2)
• 4. The lack of increase of serum transaminases and
bilirubin at the end of 6-months treatment period
may be the consequence of hepatoprotective
activity of UDCA.
• 5. Combined administration of statins and UDCA is a
promising approach to treat hyperlipidemia in
statin intolerant patients which should be checked
in a special controlled study.

56. Thank you for your attention !