Transcript Reducing CHD in high risk patients

LDL-Cholesterol – Lower is Better
Reducing CHD in high risk patients
04/16 CARD-1063303-0004
Date of preparation May 2014
Contents
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Contents Slide
Presentation summary
Title slide: LDL-Cholesterol – Lower is Better: Reducing CHD in high risk patients
OPTIONAL SLIDE #1: Cardiovascular disease and cholesterol: Key facts
Identifying ‘higher risk’ patients
Why treat high risk patients?
The impact of lowering LDL-C: Lower is better – however you achieve it
Beneficial CV risk reduction with lowering LDL-C – however you achieve it
OPTIONAL SLIDE #2: What does NICE advise for high risk patients?
What are your options?
Title slide: Treatment options: What the trials say
OPTIONAL SLIDE #3: Trial overview
Lowering LDL-C: Treatment options
ALTERNATIVE VERSION TO SLIDE #12: Lowering LDL-C: Treatment options
Treating high risk patients: What are your choices?
NICE recommendations for treatment with ezetimibe
OPTIONAL SLIDE #4: Safety data for ezetimibe
What NICE says... Patients with Type 2 diabetes
What NICE says... Patients with Familial Hypercholesterolaemia
In summary: Treating higher risk patients
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OPTIONAL SLIDE #5 Additional Slides
Date of preparation May 2014
Presentation summary
1.
Cholesterol and CVD, leading cause of death and high cost
2.
Reducing LDL-C levels significantly reduces the risk of CHD
3.
Treatment strategies for the cohort of high risk patients
4.
Review evidence, clinical trials, clinical practice and NICE Guidance to
manage this difficult group of patients
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Cardiovascular disease and cholesterol: Key facts
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CVD is the leading cause of death in England and
Wales1
The annual cost of managing CVD exceeds
£30 billion2
Over 80% of premature CVD is avoidable2,3
Reducing CVD risk by 1% over 10 years would
prevent 25,000 new cases of CVD4
Reducing total cholesterol levels by 5% would save
the NHS £80 million per annum4
LDL-C is a key modifiable CVD risk factor1
NICE targets for secondary prevention of CVD (high
risk patients): TC < 4 mmol/L or LDL-C < 2 mmol/L1
More than 50% of patients will not achieve their
target lipid levels on statin therapy alone1
1. NICE Clinical Guideline 67. May 2008. Reissued March 2010, 2. British Heart Foundation. Modelling the UK burden of cardiovascular disease to 2020. September 2008.
Available at: http://www.bhf.org.uk/plugins/PublicationsSearchResults/DownloadFile.aspx?docid=ad18e5a0-7da6-4c7c-8142-f68f27cde451 [Accessed on 21 January 2014], 3. WHO. Cardiovascular
diseases. Available at: http://www.euro.who.int/en/what-we-do/health-topics/noncommunicable-diseases/cardiovascular-diseases/facts-and-figures [Accessed on 21 January 2014], 4. Barton P
et al. BMJ 2011 Jul 28; 343:d4044.
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Identifying ‘higher risk’ patients
Who are the higher risk patients?
• There is a population of patients
who are difficult to treat and at
increased risk of CVD:
– Patients with Type 2 diabetes and
established CVD who need to
achieve a total cholesterol or an
LDL-C of < 4mmol/L and <
2mmol/L, respectively2,3
– Those with familial
hypercholesterolaemia requiring
> 50% reduction in LDL-C4
1. Trusler D. BMJ 2011; 343: d4350, 2. NICE Clinical Guideline 67. May 2008. Reissued March 2010, Reproduced with permission 3. NICE Clinical Guideline 87. May 2009.
Reproduced with permission 4. NICE Clinical Guideline 71 August 2008. Reproduced with permission.
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Why treat high risk patients?
• Patients with T2DM die from complications of their disease
• > 70% of patients with T2DM die from cardiovascular causes1
• Patients at high risk of cardiovascular disease have the most to gain from risk
factor modification2
• Intensive LDL-C reduction results in significant reductions in cardiovascular
morbidity and mortality3
• A 1 mmol/L reduction in LDL-C results in a 22% reduction in the risk of major
vascular events4
• The opportunity to improve cardiovascular outcomes by treating atherogenic
dyslipidaemia in diabetes (or diabetic patients) should not be missed3
1. Laakso M. Diabetes Care 2010; 33(2): 442–449, 2. SIGN97. Feb 2007 Available at: http://www.sign.ac.uk/pdf/sign97.pdf [Accessed on 22 January 2014], 3. Nesto RW. Clinical Diabetes
2008; 26(1): 8–13, 4. Cholesterol Treatment Trialists’ (CTT) Collaboration. The Lancet 2010; 376(9753): 1670–1681.
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The impact of lowering LDL-C: Lower is better – however
you achieve it
• For every 1 mmol/L reduction in LDL-C there is a
22% reduction in the risk of major vascular events
at 1 year1
• There is a proportional relationship between
lowering LDL-C and reducing 5-year
non-fatal MI and CHD death risk – irrespective
of how LDL-C is lowered2
1. Cholesterol Treatment Trialists’ (CTT) Collaboration. The Lancet 2010; 376(9753): 1670–1681, 2. Robinson JG et al. J Am Coll Cardiol 2005; 46(10): 1855–1862.
1 mmol/L
22%
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Beneficial CV risk reduction with lowering LDL-C –
however you achieve it
Nonfatal myocardial infarction and CHD death
Estimated relative risk reduction (%)
Meta-analysis of data from 19 trials with 81,859 participants1
100
80
Oslo
POSCH
HPS
MRC
4S
ALERT
Los Angeles
WOSCOPS
PROSPER
Upjohn
CARE
ASCOT-LLA
LRC
LIPID
CARDS
NHLBI
AF/TexCAPS
60
The London and Sydney trials are
not shown, but were included in
the analysis
40
20
0
Relative risk reduction
95% probability interval
Slope=1
-20
15
20
25
30
35
40
LDL-C reduction (%)
Adapted from Robinson JG et al. J Am Coll Cardiol 2005;46(10):1855–1862
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Data from 5 diet, 3 bile acid sequestrant and 10 statin trials
Data from 1 surgery trial
1. Robinson JG et al. J Am Coll Cardiol 2005; 46(10): 1855–1862.
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What does NICE advise for high risk
patients?
• What guidance is available for lowering cholesterol?
– Diabetes NICE CG871, FH NICE CG712, Lipids NICE CG673
NICE
Recommended
Levels:
LDL-C: 2.0 mmol/L
or
TC: 4.0 mmol/L
• Which of these guidelines relate to high risk patients?
– Diabetes NICE CG87
• Initiate simvastatin 40 mg, increasing to 80 mg* unless
TC < 4mmol/L or LDL-C < 2mmol/L
• Consider intensifying therapy with statin or ezetimibe if existing or new CVD
or increased albumin excretion rate
– FH NICE CG71
• High intensity statin to achieve a recommended LDL-C reduction of 50% from baseline.
Ezetimibe co-administered with a statin (if) target lipid levels are not controlled
after dose titration of initial statin, or because titration is limited by intolerance
to initial statin
*MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in
patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment
goals on lower doses, when the benefits are expected to outweigh the potential risks.”4
Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated
1. NICE Clinical Guideline 87. May 2009. Reproduced with permission. 2. NICE Clinical Guideline 71. August 2008 Reproduced with permission. 3. NICE Clinical Guideline 67. May 2008. Reissued March 2010.
Reproduced with permission. 4. MHRA. Drug Safety Update. May 2010. Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2014].
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What are your options?
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Lifestyle
Statin
Fibrate
Resin, fish oil, nicotinic acid*
Cholesterol absorption inhibitor
*No longer available as a modified release medicine in the EU. Instant release available as a
supplement in health shops.
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Treatment options
What the trials say
04/16 CARD-1063303-0004
Date of preparation May 2014
LDL-C lowering efficacy of lipid lowering therapies
Therapy
Rosuvastatin
5 mg
38-45%
10 mg
in LDL-C.1,2
43-52%
Atorvastatin
37%
Simvastatin
27-30%
Pravastatin
20 %
Statin +
ezetimibe
Statin + Anion
exchange resin
20 mg
in LDL-C.1,2,3
in LDL-C.1,3
in LDL-C.1,3,4
in LDL-C.1,3
46%
in LDL-C
eze 10 + simva 10 mg
vs.
35%
in LDL-C
simva 20 mg.9
48-55%
43%
40 mg
in LDL-C.1,2,3
in LDL-C.1,3
80 mg
53-63%
in LDL-C.1,2,3
48-49%
in LDL-C.1,3
51-55%
in LDL-C.1,3
42-47%
in LDL-C.1,3,4
32-38%
in LDL-C.1,3,4
37-41%
in LDL-C.1,3,4
23-24 %
in LDL-C.1,3,5
29-34%
in LDL-C.1,3,6
31%
in LDL-C
eze 10 + atorva 20 mg
vs.
11%
in LDL-C
atorva 40 mg.7
27%
in LDL-C
eze 10 + atorva 40 mg
vs.
11%
in LDL-C
atorva 80 mg.8
51%
in LDL-C
eze 10 + simva 20 mg
vs.
42%
in LDL-C
simva 40 mg.9
55%
in LDL-C
eze 10 + simva 40 mg
vs.
46%
in LDL-C
simva 80 mg*.9
61%
in LDL-C
eze 10 + simva 80 mg*
vs.
46%
in LDL-C
simva 80 mg*.9
42% in LDL-C colesevelam 42% in LDL-C colesevelam
3.8 mg + simva 10 mg
2.3 mg + simva 20 mg
vs.
vs.
26% in LDL-C simva 10 mg 34% in LDL-C simva 20 mg
vs.
vs.
16%
in LDL-C colesevelam 8%
in LDL-C colesevelam
3.8 mg.10
2.3 g.10
All reductions are from baseline as specified in the relevant studies.
*MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in patients with severe
hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are
expected to outweigh the potential risks.”4
1. Law MR et al. BMJ 2003; 326(7404); 1423–1427, 2. Crestor Summary of Product Characteristics, 3. Jones PH et al. Am J Cardiol 2003; 93: 152–160, 4. Zocor Summary of Product Characteristics,
5. Lipostat Summary of Product Characteristics, 6. Shepherd J et al. The Lancet 2002; 360(9346): 1623–1630, 7. Conard SE et al. Am J Cardiol 2008; 102: 1489–1494, 8. Leiter LA et al. Am J Cardiol
2008; 102(11): 1495–1501, 9. Goldberg AC et al. Mayo Clin Proc. 2004; 79: 620–629, 10.Knapp HH et al. Am J Med 2001; 110(5): 352–360.
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Lowering LDL-C: Treatment options
Treatment option
% LDL-C reduction from
treated baseline
Doubling statin
6%1,2
Switching statin
8%1
Adding ezetimibe
23.2%1
1. NICE Technology Appraisal Guidance 132, November 2007, 2. Knopp RH. N Engl J Med 1999; 341: 498–511.
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Lowering LDL-C: Treatment options
5
% LDL-C reduction from baseline
Treated baseline
Treatment option
0
-5
% LDL-C reduction from
treated baseline
Doubling statin
6%1,2
Switching statin
8%1
Adding ezetimibe
23.2%1
-10
-15
-20
Graphical version of
previous slide
-25
1. NICE Technology Appraisal Guidance 132, November 2007, 2. Knopp RH. N Engl J Med 1999; 341: 498–511.
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Treating high-risk patients: What are your choices?
Risk factors
NICE-recommended treatment
Type 2 diabetes (T2DM) 1,2
Initiate patient on simvastatin 40 mg
T2DM, 1–3 months after initiation, if on assessment LDL-C
> 2 mmol/L or total cholesterol > 4 mmol/L, or other CVD risk
factors develop2
Intensify statin therapy to simvastatin
80 mg*
T2DM: If there is existing CVD, increased albumin excretion or
inadequate lipid level control 2
Intensify statin therapy; or consider
statin + ezetimibe
Secondary prevention of
CVD1
Initiate simvastatin 40 mg (or a lower dose if
potential drug interactions or 40 mg is
contraindicated)
Secondary prevention CVD if lipid levels are LDL-C > 2 mmol/L
or total cholesterol > 4 mmol/L1
Intensify statin therapy to simvastatin 80
mg* (or switch to drug of similar efficacy) if
lipid targets not met
Acute Coronary Syndrome (ACS)1
Treat with higher intensity statin
Combined statin + ezetimibe
Familial Hypercholesterolaemia3
Ezetimibe monotherapy if patient cannot
tolerate statins
*MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in
patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment
goals on lower doses, when the benefits are expected to outweigh the potential risks.”4
Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated
1. NICE Clinical Guideline 67. May 2008. Reissued March 2010, 2. NICE Clinical Guideline 87. May 2009 , 3. NICE Clinical Guideline 71. August 2008, 4.MHRA. Drug Safety Update. May 2010.
Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2013].
04/16 CARD-1063303-0004
Date of preparation: May 2014
NICE recommendations for treatment with ezetimibe1
• Ezetimibe is recommended, as an option, in combination with a statin, when:
– Serum total or LDL-C concentration is not appropriately controlled
• either after appropriate dose titration of initial statin or
• because dose titration is limited by intolerance to the initial statin therapy
– You are considering switching from the initial statin therapy
• Ezetimibe monotherapy is recommended, as an option, in adults with primary
hypercholesterolaemia
– who are intolerant to statins, or who are contraindicated for statin therapy
“The Committee agreed that there is sufficient evidence to link reductions in LDL
cholesterol concentrations induced by treatment with ezetimibe with future
reductions in cardiovascular events.”* 1
*Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated
1. NICE Technology Appraisal Guidance 132. November 2007. Reproduced with permission.
04/16 CARD-1063303-0004
Date of preparation: May 2014
Safety data for ezetimibe1
AEs in clinical studies of
up to 112 weeks duration
Ezetimibe coEzetimibe monotherapy
administered with a statin
(n=2,396) vs. placebo (n=1,159) (n=11,308) vs. statin
alone (n=9,361)
Common
(≥ 1/100 to < 1/10)
Abdominal pain, diarrhoea,
flatulence, fatigue
ALT and/or AST increased,
headache, myalgia
Uncommon
(≥ 1/1,000 to < 1/100)
ALT and/or AST increased, blood
CPK increased, GGT increased,
liver function test abnormal,
cough, dyspepsia, gastrooesophageal reflux disease,
nausea, arthralgia, muscle
spasms, neck pain, decreased
appetite, hot flush,
hypertension, chest pain, pain
Paraesthesia, dry mouth,
gastritis, pruritus, rash,
urticaria, back pain,
muscular weakness, pain
in extremity, asthenia,
oedema peripheral
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; GGT, gamma-glutamyltransferase
Importantly, evidence from 13 randomised, blinded clinical trials in which ezetimibe and simvastatin were administered in combination
either as separate or combined tablets (n=4,558) suggests that ezetimibe does not enhance nor aggravate the known muscle effects of
simvastatin when compared to simvastatin monotherapy (n=2,563).2
1. Ezetrol 10 mg Tablets Summary of Product Characteristics, 2. Davidson MH et al. Am J Cardiol 2006; 97(2): 223–228.
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What NICE says… Patients with Type 2 Diabetes
“Consider intensifying cholesterol-lowering therapy
(with a more effective statin or ezetimibe in line with
NICE guidance) if there is existing or newly
diagnosed cardiovascular disease, or if there is an
increased albumin excretion rate, to achieve a total
cholesterol level below 4.0 mmol/litre (and HDL
cholesterol not exceeding 1.4 mmol/litre) or an LDL
cholesterol level below 2.0 mmol/litre.”
National Institute for Health and Care Excellence. Type 2 Diabetes. Clinical Guideline 87 July 2011. London:NICE. Available from http://guidance.nice.org.uk/CG87. Reproduced with permission
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What NICE says…Patients with Familial
Hypercholesterolaemia
“Ezetimibe, co-administered with initial statin therapy, is recommended
as an option for the treatment of adults with heterozygous-familial
hypercholesterolaemia who have been initiated on statin therapy when:
• Serum total or LDL-C concentration is not appropriately controlled
either after appropriate dose titration of initial statin therapy
or because dose titration is limited by intolerance to the initial
statin therapy;
and
• Consideration is being given to changing from initial statin therapy to
an alternative statin.”
National Institute for Health and Care Excellence. FH. Clinical Guideline 71 August 2008. London: NICE. Available from http://guidance.nice.org.uk/CG71. Reproduced with permission
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In summary: Treating higher risk patients
• In secondary prevention patients NICE recommends to consider increasing the
statin to simvastatin 80mg, or a drug of similar efficacy and acquisition cost, if TC
<4mmol/L or LDL-C<2mmol/L is not attained1
• The evidence indicates that a greater reduction in baseline LDL-C can be
achieved by adding ezetimibe to a statin, than by increasing the statin dose,2 or
by switching from simvastatin to atorvastatin3
• In patients with CVD, NICE recommends intensified treatment for
hypercholesterolaemia.1 In these patients, ezetimibe added to a statin can help
more patients achieve NICE-recommended lipid management levels
• Reduction in LDL-C, irrespective of how it is achieved, reduces the risk of
CVD.4 NICE have accepted there is sufficient evidence to link LDL-C reduction via
ezetimibe use with a reduction in future CV events*5
*Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated
1. NICE Clinical Guideline 67. May 2008. Reissued March 2010. Reproduced with permission. 2. Conard SE et al. Am J Cardiol 2008; 102(11): 1489–1494, 3. McCormack T et al. Int J Clin Prac 2010; 64(8):
1052–1061, 4. Robinson JG, et al. J Am Coll Cardiol 2005; 46(10): 1855–1862, 5. NICE Technology Appraisal Guidance 132, November 2007. Reproduced with permission.
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Additional Slides
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Leiter LA et al.
Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with
up-titration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high
risk of coronary heart disease. Am J Cardiol 2008; 102 (11): 1495–1501.
04/16 CARD-1063303-0004
Date of preparation May 2014
Efficacy of adding ezetimibe to atorvastatin 40mg vs.
up-titrating to atorvastatin 80mg
•
•
•
•
•
Randomised, multi-centre, double-blind study
Criteria – hypercholesterolaemia and high risk of CHD
LDL-C ≥1.8mmol/L and ≤4.1mmol/L
Run-in – atorvastatin 40mg for at least 4 weeks
Treatment – up-titration to atorvastatin 80mg or addition of ezetimibe
10mg to atorvastatin 40mg for 6 weeks
Leiter LA et al. Efficacy and Safety of Ezetimibe Added on to Atorvastatin (40mg) Compared with Uptitration of Atorvastatin (to 80mg) in Hypercholesterolemic Patients at High Risk of Coronary
Heart Disease Am J Cardiol 2008; 102: 1495–1501.
04/16 CARD-1063303-0004
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Efficacy of adding ezetimibe to atorvastatin 40mg vs.
up-titrating to atorvastatin 80mg
Baseline
% change in LDL-C from treated baseline at week 6
0
Atorvastatin 80mg (n=279)
-5
Atorvastatin/ezetimibe 40/10mg (n=277)
-10
Baseline LDL-C 2.3mmol/L
p<0.001 for treatment difference between arms
-11%
-15
-20
-25
-27%
-30
Leiter LA et al. Am J Cardiol 2008; 102: 1495–1501.
Note: A beneficial effect of EZETROL on
cardiovascular morbidity and mortality has not yet
been demonstrated
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Tolerability of adding ezetimibe to atorvastatin 40mg vs.
up-titrating to atorvastatin 80mg
• Tolerability profiles of both treatments generally similar and consistent with
previous studies of similar duration
• Serious adverse event incidence low
– None considered drug-related
• No myopathy or rhabdomyolysis
• No significant differences in pre-specified AEs between groups
Leiter LA et al. Am J Cardiol 2008; 102: 1495–1501.
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Jones PH et al.
STELLAR Study Group. Comparison of the efficacy and safety of
rosuvastatin versus atorvastatin, simvastatin and pravastatin across doses.
Am J cardiol 2003; 93: 152–160.
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Comparison of the efficacy and safety of rosuvastatin vs.
atorvastatin, simvastatin and pravastatin across doses
(STELLAR trial)1
• Randomised, multi-centre, parallel group, open-label (n = 2431)
• Patient criteria – hypercholesterolaemia i.e. LDL-C between  4.10 and < 6.42
mmol/l ( 160 and < 250 mg/dl)
• Treatment duration – 6 weeks
• Randomised treatments:
–
–
–
–
rosuvastatin 10, 20, 40 or 80 mg*
atorvastatin 10, 20, 40 or 80 mg
simvastatin 10, 20, 40 or 80 mg†
pravastatin 10, 20, or 40 mg
* Rosuvastatin 80 mg is not licensed
† MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in
patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment
goals on lower doses, when the benefits are expected to outweigh the potential risks.”2
1. Jones PH et al. Am J Cardiol 2003; 93: 152–160, 2. MHRA. Drug Safety Update. May 2010.
Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2014].
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Pooled-dose analyses: rosuvastatin reduced mean LDL-C
at 6 weeks more than atorvastatin, simvastatin and
pravastatin
Baseline
Increased mean % reductions in LDL-C from baseline at
Week 6 with rosuvastatin vs. comparator statins
0
Reduction compared with atorvastatin 10–80 mg
-5
-10
Reduction compared with simvastatin 10 to 80 mg
Reduction compared with pravastatin 10 to 40 mg
-8.2%
p <0.001 (for all 3 comparisons)
-15
-20
-12 to -18%
-25
-26%
-30
Adapted from Jones PH et al. Am J Cardiol 2003; 93: 152–160
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Safety: rosuvastatin vs. atorvastatin, simvastatin and
pravastatin
• Drug tolerability was similar across treatments
• Percentage of patients reporting AEs ranged from 40 – 56% across treatments;
most mild to moderate in intensity and dose-related
• Most common AEs: pain (6%), pharyngitis (5%), myalgia (4%), headache (4%)
• 29 serious adverse events reported
• 2 patients died (1 received simvastatin 10 mg, 1 atorvastatin 40 mg); both
deaths due to CV disease – unrelated to treatment
Jones PH et al. Am J Cardiol 2003; 93: 152–160
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