Download Lipid Disorders The Science and Art of Treatment in 2004

Lipid Disorders
The Science and Art of Treatment in 2004
Alan Jansujwicz, M.D.
DHMC Cardiology Update Symposium
2004
Session Outline
• Background
• Review of Data to Support Current Lipid
Treatment Paradigms
• Current Recommendations for Treatment
• Time for Questions (Hopefully)
Introduction
• CHD remains the no. 1 killer in the U.S.
– Eradicate CAD – life expectancy up to 84
– Eradicate Cancer – life expectancy up to 80
•
•
•
•
Dyslipidemia plays a major role in CHD
Safe and effective treatments available
Less than ½ of eligible patients treated
Many who are initially treated, stop Rx
Lipid Lowering Drugs and the Data
•
•
•
•
•
HMG Co-A Reductase Inhibitors
Niacin
Fibrates
Ezetimibe
Others
HMG Co-A Reductase Inhibitors
“Statins”
• Drugs structurally similar to HMG-CoA
– precursor of cholesterol
• Competitive inhibitors of HMG-CoA reductase
– last step in cholesterol synthesis
• Lower serum LDL concentrations by:
– Upregulating LDL receptor activity
– Reducing LDL entry into the circulation
• Most effective agents for lowering LDL
• Impressive body of evidence for CHD treatment
LDL Reduction by Individual Statins
5 mg 10 mg 20 mg 40 mg 80 mg
Atorvastatin
39% 43% 50% 60%
Fluvastatin
21% 24%
Lovastatin
21% 24% 30% 40%
Pravastatin
22% 32% 34%
Rosuvastatin 45% 52% 58% 69%
Simvastatin
22% 30% 35% 41% 47%
In general, doubling dose = additional 6% reduction in LDL
Source: Gau G, Mayo Clinic Cardiovascular Review
Chronic Statin Therapy
Initial Major Secondary Prevention Studies
• Scandinavian Simvastatin Survival Study (4S) – Lancet ‘94
– 4444 patients with remote MI or Angina
– Total Cholesterol 213-309 mg/dL
– Simvastatin 20/40 mg vs placebo for 5.4 years
• Cholesterol and Recurrent Events Trial (CARE) – NEJM ‘96
– 4159 patients with remote MI
– Total Cholesterol < 240 mg/dL, LDL 115-174 mg/dL
– Pravachol 40 mg vs placebo for 5 years
• Long-Term Intervention with Pravastatin (LIPID) – NEJM ‘98
– 9014 patients with remote MI or Angina
– Total Cholesterol 155 to 271 mg/dL
– Pravachol 40 mg vs placebo for 6.1 years
LDL in mg/dL
LDL Lowering in 4S, CARE, and LIPID
200
180
160
140
120
100
80
60
40
20
0
188
150
-35%
-25%
139 -29%
122
112
98
Baseline
Treatment
4S
CARE
LIPID
Risk Reduction in 4S, CARE, and LIPID
42
45
% Risk Reduction
40
35
37
30
30
27
25
20
22
24
20
15
9
10
5
0
4S
CARE
LIPID
20
Total Mortality
CHD Mortality
Revasc
LIPID Trial – Risk of CHD Death
Time Delay to Benefit…
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, N Engl J Med 1998;339:1349-1357
CARE Trial – CHD Events
Possible Lower Limit to Benefit…
Investigators postulated that there might be a “benefit floor”
Sacks, F. M. et al. N Engl J Med 1996;335:1001-1009
Chronic Statin Therapy
The Heart Protection Study
• 20K patients ages 40-80 years in the UK
• Inclusion criteria of
–
–
–
–
•
•
•
•
Known CAD
Known PVD
Diabetes
Males > 65 with HTN (also a high risk group, but only 1%)
No upper or lower limit of serum cholesterol
Assigned to simvastatin 40 mg vs placebo
Direct LDL measured from nonfasting samples
Followed for average of 5 years
HPS Collaborative Group. Lancet 2002;360: 7-22.
The Heart Protection Study
Lipid Levels
• Baseline Lipid Panel
–
–
–
–
Total Chol
dLDL
HDL
Trig
228 mg/dL
131 mg/dL (15% less than calculated LDL)
41 mg/dL
81 mg/dL
• Average dLDL levels during 5 years of follow-up
– Simvastatin
– Placebo
89 mg/dL
128 mg/dL
(85% avg compliance)
(17% avg crossover)
**Below previously suggested floor to benefit**
HPS Collaborative Group. Lancet 2002;360: 7-22.
The Heart Protection Study
Major Outcomes
16
Event Rate (%)
14
14.7
12.9
11.7
12
9.1
10
8
5.7 6.9
6
Simvastatin
Placebo
5.7
4.3
4
2
0
Total
Coronary
Mortality Mortality
RRR = 13%
Stroke
Revasc
RRR = 18% RRR = 25% RRR = 24%
All risk reductions statistically significant
The Heart Protection Study
Event Rate (%)
Safety Measures
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
0.42
0.31
Simvastatin
Placebo
0.11
0.06
Elev LFTs
(4x)
p = ns
Elev CK
(10x)
p = ns
0.05
0.01
Myopathy
(10x + sx)
p = ns
0.05 0.03
Rhabdo
(40x)
p = ns
Chronic Statin Therapy
Primary Prevention
• WOSCOPS – NEJM ’95
–
–
–
–
6595 men, age 45 to 64, with no documented CAD
Total cholesterol at least 252 mg/dL
Pravachol 40 mg vs placebo for 4.9 years
Primary Endpoint – Nonfatal MI or Death from CHD
• AFCAPS/TexCAPS – JAMA ’98
–
–
–
–
–
997 women (age 55-73) and 5608 men (age 45-73)
No documented CAD or PVD
Total cholesterol 180 to 264 mg/dL
Lovastatin 20/40 mg vs placebo for 5.2 years
Primary Endpoint – MI, USA, or Sudden Cardiac Death
Primary Prevention Trials
200
180
160
140
120
100
80
60
40
20
0
192
12
10.9
26%
150
142
10
25%
113
Baseline
Treatment
Event Rate (%)
LDL (mg/dL)
Lipid Lowering Results
7.9
8
6.8
5.5
Placebo
Drug
6
4
2
WOS
AFCAP
0
WOS
AFCAP
WOS – RRR 31%, due to reduction in nonfatal MI and CHD death
AFCAPS – RRR 37%, due to difference in nonfatal events
Acute Statin Therapy
• MIRACL – JAMA 2001
– 3086 patients undergoing noninvasive ACS treatment
– Total cholesterol less than 270 mg/dL; no lower limit
– Atorvastatin 80 mg vs placebo for 16 weeks
• PROVE-IT – NEJM 2004
– 4162 patients undergoing mostly invasive ACS treatment
– Total cholesterol less than 240 mg/dL (naïve), 200 mg/dL (Rx)
– Atorvastatin 80 mg vs Pravastatin 40 mg for 2 years
• A to Z – JAMA 2004
– 4497 patients with acute NSTEMI or STEMI (complicated trial)
– Total cholesterol less than 250 mg/dL; no lower limit
– Simva 40(1mo)/80 mg vs Placebo(4mo)/Simva 20 mg for 2 years
MIRACL Trial Results
17.5
124
120
17
100
16.5
72
80
60
40
BASE
PL
RX
Event Rate (%)
LDL (mg/dL)
140
17.4
135
16
15.5
14.5
20
14
0
13.5
Patients
14.8
15
Patients
RRR = 16% in Treatment Group at 16 weeks (p=0.048)
Higher baseline LDL not predictive of increased event rate
No significant association between % change in LDL and event rate
PL
RX
PROVE-IT and AtoZ Results
LDL (mg/dL)
100
30
112
106
25
95
81
80
62
60
40
20
66
BASE
MOD
INT
Event Rate (%)
120
26
22.4
20
16.7
14.4
MOD
INT
15
10
5
0
PROVEIT
0
PROVEIT
AtoZ
Similar Reductions in LDL achieved in both trials
RRR = 16% in PROVE-IT met significance
RRR = 11% in A to Z did not meet significance
Limitations in A to Z design likely responsible for lack of significant outcome
LDL Levels and CHD Risk
Lower is Better!
30
4S-PL
Event Rate (%)
25
20
4S-Rx
15
CARE-PL
AtoZ-PL LIPID-Rx
10
Secondary
Primary
ACS
LIPID-PL
AtoZ-Rx
PROV-Rx
CARE-Rx
HPS-Rx
PROV-PL
HPS-PL
5
AF-Rx
WOS-PL
AF-PL
WOS-Rx
0
50
100
150
LDL (mg/dL)
200
Niacin
• Cholesterol-lowering effect 1st reported in 1955
• Reduces LDL (5-25%) by decreasing peripheral
mobilization of FFAs from adipose tissue
• Most effective drug available clinically for raising
HDL (15-35%)
• Also effective for reducing triglycerides (25-50%)
• Reduces Lp(a) by 30%
• Converts small, dense LDL to large, buoyant LDL
Niacin
• Pitfalls with niacin therapy
–
–
–
–
–
Cutaneous flushing, pruritis, nausea, abd pain
Hepatotoxicity
Glucose intolerance
Increase risk of myositis if used with statin
Minimal hard endpoint outcome data
Niacin Outcome Data Trials
• Coronary Drug Project – JACC 1986
– 8,000+ men, post-MI, Rx with 1 of 5 drugs or placebo
– Patients treated for 6 years (some arms stopped early)
– Patients subsequently followed for 9+ years post-Rx
• HDL Atherosclerosis Treatment Study – NEJM 2001
–
–
–
–
–
160 patients with established CAD
Low HDL (31 mg/dL), “normal” LDL (125 mg/dL)
Four Rx regimens: Placebo, N+S, AV, N+S+AV
Followed for 3 years for clinical or angiographic events
All but 14 patients underwent an end of trial angiogram
Coronary Drug Project
Survival (%)
Long-Term Mortality Benefit of Niacin
100
90
80
70
60
50
40
30
20
10
Niacin
Placebo
P = 0.0012
0
2
4 6 8 10 12 14 16
Years of follow-up
Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255
source = www.lipidsonline.org
HDL-Atherosclerosis Treatment Study (HATS)
Niacin and Statin Outcome Trial
Composite Event Rate (%)
30
23.7
RRR = 89% p < 0.05
21.4
25
20
14.3
15
10
2.6
5
0
Placebo
S+N
AV
S+N+AV
LDL 116
LDL 75
LDL 112
LDL 79
HDL 34
HDL 40
HDL 33
HDL 36
Fibrates
•
•
•
•
•
•
•
Class of drugs which resemble short chain fatty acids
Increase oxidation of fatty acids in muscle and liver
Most effective class of drugs for lowering triglycerides
Increase size of LDL particles and enhance removal
May increase HDL-mediated reverse cholesterol transport
Reduce levels of plasminogen activator inhibitor type I
Currently available drugs in U.S.
– Gemfibrozil
– Fenofibrate (less risk of myopathy when used with a statin)
• ADRs: GI, ED, myopathy (CRF)
Major Fibrate Therapy Trials
• Helsinki Heart Study – NEJM 1987
–
–
–
–
Primary prevention trial
4,081 dyslipidemic (non-HDL > 200 mg/dL) men, age 40 to 55
Gemfibrozil 600 mg bid vs Placebo for 5 years
Primary endpoint – CHD death or nonfatal MI
• VA-HIT – NEJM 1999
–
–
–
–
–
Secondary prevention trial
2,531 men with documented CAD in the VA system
HDL < 40 mg/dL and LDL < 140 mg/dL
Gemfibrozil 600 mg bid vs Placebo for 5.1 years
Primary endpoint – CHD death or nonfatal MI
Major Fibrate Trials
Outcome Data
% CHD Death or MI
25
21.7
20
17.3
15
10
Treatment
Placebo
8
4.1
5
2.7
2.7
0
HHS
RRR = 34%
HHS-PostHoc
VA-HIT
RRR = 66%
RRR = 22%
* HHS-Post Hoc: Subgroup with TG > 200 mg/dL and HDL < 42 mg/dL
** All results met statistical significance
Ezetimibe
• 1st in new class of cholesterol absorption inhibitors
• Likely works by binding to and blocking the sterol
transporter on the intestinal brush border
• Results in increased LDL-R activity and LDL clearance
• Drug and its metabolites circulate enterohepatically with
little systemic penetration
• Potential toxicities essentially limited to liver
• Does not induce or inhibit cytochrome P450 system
• Single dosing option of 10 mg once daily
Lipid Lowering with Ezetimibe
60
50
51
% LDL Lowering
50
40
30
Zetia
Zetia+Atorv10
Atorv80
20
20
10
0
Zetia
Zetia+Atorv10
Atorv80
Ballantyne CM. Circulation 2003; 107: 2409-2415.
Lipid Risk Assessment
NCEP ATP III + Recent Update
• Obtain a fasting lipoprotein profile on all adults
aged 20 years or older (repeat every 5 years)
• Assess for CHD, CHD risk equivalents, and risk
factors for developing CHD
• Framingham Risk Assessment for intermediate
risk patients
• Assess for the metabolic syndrome
• Consider emerging risk factors (i.e. hs-CRP)
NCEP. JAMA 2001; 285(19): 2486-97.
Lipoprotein Profile Classification
• LDL Cholesterol
–
–
–
–
–
–
< 70
< 100
100-129
130-159
160-189
190+
Optimal in HRP
Optimal
Near Optimal
Borderline High
High
Very High
• HDL Cholesterol
– < 40
– 60+
Low
High
• Total Cholesterol
– < 200
Desirable
– 200-239 Borderline High
– 240+
High
• Triglycerides
–
–
–
–
< 150
150-199
200-499
500+
normal
Borderline High
High
Very High
CHD and CHD Risk Equivalents
• CHD
• CHD Risk Equivalents
–
–
–
–
–
Peripheral Vascular Disease
Abdominal Aortic Aneurysm
Symptomatic Carotid Arterial Disease
Diabetes
Framingham 10-year risk 20+%
Major Risk Factors
ATP III
•
•
•
•
Cigarette Smoking
Hypertension (140+/90+ or on meds)
Low HDL Cholesterol (< 40 mg/dL)
FH of Premature CAD
– Male 1st degree relative < 55
– Female 1st degree relative < 65
• Personal Age
– Male 45+
– Female 55+
Framingham Risk Assessment
For Intermediate Risk Patients
• Gender Specific
• Calculates risk based on
–
–
–
–
–
Age
Total Cholesterol (age stratified)
Current Smoking Status (age stratified)
HDL Cholesterol
Systolic Blood Pressure (Rx or no Rx)
• Overall point score allows for calculation of 10 year risk of
a CHD event
• Framingham Risk stratifies patients into
– CHD equivalent
– Moderately high risk
– Intermediate Risk
10-year risk > 20%
10-year risk 10-20%
10-year risk < 10%
The Metabolic Syndrome
Any 3 of the following
• Abdominal Obesity
– Men
– Women
• Triglycerides
• HDL
– Men
– Women
• Blood Pressure
• Fasting Glucose
(waist circumference)
> 40 inches
> 35 inches
150+ mg/dL
< 40 mg/dL
< 50 mg/dL
130+/85+ mm Hg
110+ mg/dL
Risk Stratification
Update to ATP III
• Very High Risk
–
–
–
–
CHD + multiple risk factors (diabetes)
CHD + poorly controlled risk factor (smoking)
CHD + metabolic syndrome
CHD + ACS
• High Risk
– CHD
– CHD Equivalents
• Moderately High Risk
– 2+ Risk Factors + Framingham Risk of 10-20%
• Intermediate Risk
– 2+ Risk Factors + Framingham Risk of < 10%
• Low Risk
– 0-1 Risk Factor
LDL Treatment Based on Risk Stratification
• Very High Risk Patient
– Optional LDL goal of < 70 mg/dL
– Standard LDL goal of < 100 mg/dL
– For LDL ≥ 100 mg/dL, initiate both lifestyle
changes and drug treatment
– For LDL < 100 mg/dL, lifestyle changes are
indicated, drug Rx is therapeutic option
LDL Treatment Based on Risk Stratification
• High Risk Patient (CHD / CHD Equivalent)
– LDL goal of < 100 mg/dL
– For LDL ≥ 100 mg/dL, initiate both lifestyle
changes and drug treatment
– For high TG / low HDL, consider adding niacin
or fibrate to statin
LDL Treatment Based on Risk Stratification
• Moderately High Risk Patients
–
–
–
–
2+ RFs and 10-year risk 10-20%
Optional LDL goal of < 100 mg/dL
Standard LDL goal of < 130 mg/dL
For LDL ≥ 130 mg/dL, initiate both lifestyle
changes and drug treatment
– For LDL 100 to 129 mg/dL, lifestyle changes
are indicated, drug Rx is therapeutic option
LDL Treatment Based on Risk Stratification
• Intermediate Risk Patients
–
–
–
–
2+ RFs and 10-year risk < 10%
LDL goal < 130 mg/dL
For LDL ≥ 130 mg/dL, initiate lifestyle changes
For LDL ≥ 160 mg/dL, initiate both lifestyle
changes and drug Rx
LDL Treatment Based on Risk Stratification
• Low Risk Patients
– 0 to 1 risk factor
– LDL goal < 160 mg/dL
– For LDL ≥ 160 mg/dL, initiate lifestyle
changes, drug Rx optional
– For LDL ≥ 190 mg/dL, initiate both lifestyle
changes and drug Rx
Secondary Goal – Non HDL Cholesterol
• Elevated triglycerides are an independent risk
factor for CHD (meta-analyses)
• Non HDL cholesterol captures risk of both LDL
and triglycerides
• Non HDL goals are set 30 mg/dL higher than LDL
goals
– High risk
– Int risk
– Low risk
non HDL goal < 130 mg/dL
non HDL goal < 160 mg/dL
non HDL goal < 190 mg/dL
hs-CRP
• Large body of evidence now supports CRP as in
independent predictor of CHD risk
• However, the data all comes from post hoc
analysis of lipid-lowering trials and observational
trials
• Probably most useful in identifying moderately
high risk patients who may be at greater risk than
predicted by traditional risk assessment
hs-CRP
• hs-CRP measurement is now a Class IIa
recommendation in two subgroups of
patients
– Moderately high risk Framingham patients (1020% risk)
– Patients with known CAD for risk assessment
of future events
Measuring and Using hs-CRP
• Measure twice, two weeks apart, in metabolically stable
patients
• Tertiles of risk
– Low risk
– Intermediate risk
– High risk
< 1 mg/dL
1-3 mg/dL
> 3 mg/dL
• High risk CRP results in moderately high risk patients and
in those with CHD should result in intensification of
treatment
• hs-CRP values > 10 mg/dL indicate an ongoing
inflammatory or infectious process and should not be used
When to Stop Treatment
• Statins and Ezetimibe
– Myopathy - Muscle aches with CK > 10x ULN
– Abnormal LFTs – 3x ULN
– Pregnancy and Breast Feeding
• Niacin
–
–
–
–
Abnormal LFTs (3x ULN) or chronic liver disease
Gout
Poorly controlled diabetes
Pregnancy
• Fibrates
– Chronic liver dysfunction or renal failure
– Abnormal LFTs or myopathy
– Pregnancy
Summary
• Recent clinical trials have confirmed the log-linear
relationship between CHD risk and LDL
cholesterol at lower levels
• This relationship means that risk reduction is
independent of initial cholesterol levels and is
dependent only on absolute reduction in levels
• This has led to more aggressive lipid lowering
benchmarks, especially in certain high risk groups
• Additionally, novel risk factors such as hs-CRP
have become available which allow us to further
stratify certain risk populations
• The charge remains to identify and effectively
treat our dyslipidemic patients over the long-term