The 4th Annual Central California Cardiometabolic Risk
Symposium – 2012 Treatment of the High Risk Patient
With Low HDL-c
National Cholesterol Education Program
Adult Treatment Panel III Guidelines
(NCEP-ATPIII)
Grundy S.M. et al Circulation.2004;110:227-239
A.) High Risk:
1.) CHD-Hx of MI, unstable angina, stable angina, CAD procedures
(PTCA/CABG) or evidence of clinically significant myocondial Ischomia
2.) CHD risk equivalent-PAD,AAA, carotid disease (TIA,CVA or>50% obstruction
of carotid artery),DM, 2 or more risk factors with 10 year risk for hard CHD>
20%
B.) Very High Risk:
1.) CVD plus A.) multiple major risk factors (especially DM)
B.) several and poorly controlled risk factors especiall
continued cigarette smoking
C.) multiple risk factors of metabolic syndrome especially
high triglycerides ≥ 200mg/dl plus non-HDL ≥ 130mg/dl
with low HDL(<40mg/dl)
D.) Acute coronary Syndromes
NCEP ATP III
• Recommendations for modification to
footnote the ATPIII treatment algorithm for
LDL-C
– Table 3 page 237
– If a high-risk person has high triglycerides or low
HDL-C, consideration can be given to combining a
Fibrate or Nicotinic Acid with an LDL-lowering
drug
Grundy S.M et al
Circulation 2004:110.
Extent to which Accepted Serum Lipid Goals are Achieved in a
Contemporary General Medical Population with Coronary Heart
Disease Risk Equivalents
• 44,052 electronic medical records from a large
primary care practice affiliated with an academic
tertiary care hospital
• 1,512 high risk patients (877 with CHD risk
equivalents, 635 with CHD) with complete lipid
profiles in the preceding yea
• Following lipid values were considered optimal (at
goal): LDL-C < 100mg/dl; HDL-C ≥ 40mg/dl in men, ≥
50mg/dl in women, non-HDL <130 mg/dl in patients
with triglycerides > 200mg/dl
Alsheikh-Ali A.A, Lin Jen-Liang,Abourjaily P et al.
Am. J. Cardiol.2006;98:1231-1233
Alsheikh-Ali A.A, Lin Jen-Liang,Abourjaily P et al.
Am. J. Cardiol.2006;98:1231-1233
Alsheikh-Ali A.A, Lin Jen-Liang,Abourjaily P et al.
Am. J. Cardiol.2006;98:1231-1233
Low HDL
Triglycerides ≥ 200mg/dl
Nichols GA, Vupputuri S, and Rosales AG.
Am. J. Cardiol. 2011;108:1124-1128
1. An observational study of 30,067 members in Kaiser
Permanente Northwest and Kaiser Permanente Georgia
with Type 2 DM and had 2 HDL-C measurements, 1 before
2004 and a 2nd HDL-C measurement 6 to 24 months after
registry entry, during 2001 to 2006.
2. Patients were followed up to ≤ 8 years from date of the
2nd HDL-C measurement until they died, left the health
plan for other reasons or until 12/31/2009.
3. Outcome was hospitalization with a primary discharge
diagnosis of CAD, hemorrhagic stroke, ischemic stroke or
other acute but ill-defined cerebrovascular disorder.
Nichols GA, et al. Am. J. Cardiol. 2011;108:1124-1128
Model
Fully Adjusted
HR (95% CI)
p Value
Baseline HDL-C per 5mg/dl
0.94 (0.92-0.96)
<0.0001
HDL-C change per 5mg/dl
0.96 (0.94-0.99)
0.003
0.94 (0.92-0.96)
<0.0001
-Continuous change models
-Categorical change models
Baseline HDL-C per 5mg/dl
HDL-C remained ± 6.4 mg/dl
1.00
HDL-C decreased < 6.5 mg/dl
1.11 (1.00-1.24)
0.047
HDL-C increased ≥ 6.5 mg/dl
0.92 (0.84-1.01)
0.077
Nichols GA, et al. Am. J. Cardiol. 2011;108:1124-1128
1.
2.
3.
4.
5.
After multivariate adjustment each 5mg/dl HDL-C baseline and
follow-up increase were associated with 6%, 4% respective
decreases in CVD hospitalization risk. (p<0.0001; p<0.003
respectively).
In categorical analysis ≥6.5mg/dl HDL-C decrease was associated
with a 11% increased CVD risk (p=0.47) relative to those with
stable HDL-C.
In categorical analysis a ≥6.5mg/dl HDL-C increase was associated
with a 8% decreased CVD risk (p=0.077) relative to those with
stable HDL-C.
Our results add to the growing body of evidence tht increasing the
HDL-C levels might be an important strategy for CVD risk
reduction.
The prevention of HDL-C decreases could be equally important.
Nichols GA, et al. Am. J. Cardiol. 2011;108:1124-1128
Low HDL Cholesterol and Type 2 Diabetes
<40mg/dl for men and <50mg/dl for women *P<0.01 for
comparison between sexes
Diabetes Care 30:479-484, 2007
Richard W. Grant, MD, MPH
James B. Meigs, MD, MPH
Usefulness of Serum High-Density Lipoprotein
Cholesterol Level as an Independent Predictor of OneYear Mortality After Percutaneous Coronary
Interventions
P=.001 for trend
Men
Ghazzal Z.B, Dhawan S.S, Sheikh A. et al
Am. J. Cardiol.2009;103:902-906
*P=.04 compared to
< 33
Women
*P=.04 compared to < 38
Ghazzal Z.B, Dhawan S.S, Sheikh A. et al
Am. J. Cardiol.2009;103:902-906
Variables
Hazard Ratio
95% CI
P Value
Emergency PCI
2.6
1.56-4.38
.0002
EF < 30%
2.5
1.5-4.2
.001
HDL-C < 35 mg/dl
1.9
1.36-2.8
.003
Age(10 year
increments)
1.7
1.42-1.98
< .0001
First time PCI
1.6
1.09-1.59
.02
Diabetes
1.4
1.01-1.93
.05
Ghazzal Z.B, Dhawan S.S, Sheikh A. et al
Am. J. Cardiol.2009;103:902-906
Analysis of 4 prospective American Studies:
-Framingham Heart Study
-Lipid Research Clinics Prevalence Mortality Follow up Study
-Coronary Primary Prevention Trial
-Multiple Risk Factor Intervention Trial
Showed:
For every 1mg/dl↑in HDL
Risk of significant CHD ↓2% men
↓ 3% women
Gordon DJ,Probstfield JL, Garrison RJ etal Circulation 1989:79:8-15
Roswitha M. Wolfram MD, H. Bryan
Brewer, MD, Zhenyi Xue, MS, Lowell F. Satten, MD,
Augusto D. Pichard, MD Kenneth M. Kent, MD, PHD, and Ron Waksman,
MD.
Am. J. Cadriol 2006;98:711-717
1.) 1,032 consecutive patients who underwent
angioplasty with drug eluting stent implantation for
acute coronary syndrome
2.) 550 patients with low HDL cholesterol(HDL-C): < 40
mg/dl in men and < 45 mg/dl in women were
compared to 482 patients with high HDL-C: > 40
mg/dl in men and > 45 mg/dl in women
3.) Patients were contacted at 30 days, 1 year
Wolfram et al Am. J. Cardiol 2006;98:711-717
Wolfram et al Am. J. Cardiol 2006;98:711-717
Wolfram et al Am. J. Cardiol 2006;98:711-717
Wolfram et al Am. J. Cardiol 2006;98:711-717
Wolfram et al Am. J. Cardiol 2006;98:711-717
Multivariate Regression Analysis by the Cox
proportional hazard model
Key independent predictions:
TLR/MACE at 1 year follow-up
Wolfram et al Am. J. Cardiol 2006;98:711-717
“ In conclusion, regardless of baseline
low-density lipoprotein cholesterol
levels and Statin therapy, additional
strategies to increase HDL
cholesterol should be evaluated in
patients with acute coronary
syndrome.”
Wolfram et al Am. J. Cardiol 2006;98:711-717
Rahilly-Tierney C, Bowman TS,
Djoussé L, Sesso HD, and Gaziano JM.
Am. J. Cardiol. 2008;102:1663-1667.
1. 15,120 of 22,071 apparently healthy physicians
returned blood samples from 8/82 to 8/83. Of these
9,436 returned a second blood sample between
12/95 and 1/98.
2. 4,501 male physicians with 2 blood samples collected
approximately 14 years apart were evaluated.
3. Follow up started on the date of receipt of each
subjects final blood sample.
4. Mean follow up 7.9 years during which 123incident
cases of CHD occurred including 103 confirmed MI’s
and 29 cardiac deaths.
Rahilly-Tierney C, et al. Am. J. Cardiol. 2008;102:1663-1667.
Change in HDL-C
(mg/dl)
n
Incident CHD
≤ -2.5
1,633
53 (3.3%)
Reference
Reference
Reference
-2.5 to +2.5
937
23 (2.5%)
0.74
0.66
0.70
+2.5 to +12.5
1,339
34 (2.5%)
0.76
0.56
0.64
≥12.5
592
13 (2.2%)
0.61
0.43
0.52
0.08
0.003
0.03
p Value for trend
Age Adjusted Model 1 * Model 2 †
*Adjusted for age, initial HDL-C, DM, HTN, hx of cholesterol modification, and non-HDL-C
†Adjusted for above plus BMI, smoking, alcohol consumption, and exercise.
Rahilly-Tierney C, et al. Am. J. Cardiol. 2008;102:1663-1667.
1. In conclusion, our findings were consistent
with an inverse graded relation between 14
year increase in HDL cholesterol and risk of
subsequent CHD.
2. Larger HDL-C increases of ≥12.5mg/dl were
associated with a 57% lower risk of CHD.
Rahilly-Tierney C, et al. Am. J. Cardiol. 2008;102:1663-1667.
Prevalence of low HDL (≤ 40mg/dl in men, ≤ 50mg/dl in
women) across LDL-C Levels
1,512 High Risk patients:635 CHD, 877 CHD RE
Kuvin J.T. et al. Am. J. Cardiol 2007;100:1499-1501
Evaluating the Incremental Benefits of Raising HighDensity Lipoprotein Cholesterol Levels During Lipid
Therapy after Adjustment for the Reductions in Other
Blood Lipid Levels
Methods:
1.) 454 patients from the Framingham off-spring study who
started lipid therapy between visits 2 and 6. 96% of patients
were taking 1 drug only: Statins(72%), Fibrates(17%),
Resins(4%), Niacin(7%) and 4% were taking more than one
drug.
2.) Using cox proportional-hazarch regression the risk of a CV
event associated with changes in blood lipid levels among
individuals who started lipid therapy was evaluated
Grover S.A., Kaovache M, Joseph L et al.
Arch Intern. Med. 2009;169(19):1775-80
1.) The change in HDL-C level was a strong independent risk
factor for CV events (hazard ratio,.79 per 5mg/dl increase, 95
CI .67-.93) after adjustment for other lipid changes associated
with treatment
2.) A 1% increase in HDL-C level was associated with a 2%
reduction in CV risk
3.) An important interaction was observed: the lower the
pretreatment LDL-C level, the greater the impact of raising
the HDL-C
Grover S.A., Kaovache M, Joseph L et al.
Arch Intern. Med. 2009;169(19):1775-80
Grover S.A., Kaovache M, Joseph L et al.
Arch Intern. Med. 2009;169(19):1775-80
Cholesterol Treatment Trialists’ (CTT)
Collaboration. Lancet. 2010;376:1670-1681
1. 5 trials more versus less statin: PROVE IT, A
to Z, TNT, IDEAL, SEARCH
2. 21 trials statin versus control: 4S, WOSCOPS,
CARE, POST-CABG, AFCAPS/TexCAPS, LIPID,
GISSI-P, LIPS, HPS, PROSPER, ALLHAT-LLT,
ASCOT-LLA, ALERT, CARDS, ALLIANCE, 4D,
ASPEN, MEGA, JUPITER, GISSI-HF, AURORA.
Cholesterol Treatment Trialists’ (CTT) Collaberation. Lancet. 2010;376:1670-1681
HDL-C
HDL-C
HDL-C
≤38.6mg/dl
38.7-50.2mg/dl
>50.2mg/dl
Cholesterol Treatment Trialists’ (CTT) Collaberation. Lancet. 2010;376:1670-1681
1682
1378
951
821
2907
2341
1545
1315
4287
3370
1878
1662
HDL-C mg/dl
HDL-C mg/dl
HDL-C mg/dl
≤38.6
38.7-50.2
>50.2
Cholesterol Treatment Trialists’ (CTT) Collaberation. Lancet. 2010;376:1670-1681
p= 0.5
p-trend= 0.7
HDL-C mg/dl
≤38.6
38.7-50.2
>50.2
≤38.6
38.7-50.2
Cholesterol Treatment Trialists’ (CTT) Collaberation. Lancet. 2010;376:1670-1681
>50.2
Duggal JK, Singh M, Attri N, et al.
Journal of Cardiovascular
Pharmacology and Therapeutics.
2010;15(2):158-166
:
1. Computerized literature search using EMBASE,
CINAHL, PubMed and Cochrane database using
keywords niacin, nicotinic acid, CV diseases, and
atherosclerosis
2. Inclusion Criteria: All studies had to meet:
A. Randomized clinical trials
B. Include patients with hx of MI or evidence of CAD, with a
minimum 12 month follow-up
C. Niacin was one of the pharmacological agents to study
the CV benefit from anti-lipid therapy
D. Report at least 1 of the CV outcomes: all-cause mortality,
non-fatal MI, coronary artery revascularization,
stroke/TIA
Duggal JK, et al. J. Cardiovasc. Pharmacol. Ther. 2010;15(2):158-166
1.
2.
3.
4.
5.
6.
7.
8.
CDP JAMA 1975;231(4):360-381
CLAS-1 JAMA 1987;257(23):3233-3240
CLAS-2 JAMA 1990;264(23):3013-3017
Stockholm Study Acta Med
Scand.:1988;223(5):405-418
FATS NEJM 1990;323(19):1289-1298
HATS NEJM 2001;345(22):1583-1592
ARBITER 2 Circulation 2004;110(23):3512-3517
AFREGS Ann Intern Med. 2005;142(2):95-104
Duggal JK, et al. J. Cardiovasc. Pharmacol. Ther. 2010;15(2):158-166
Model
Fixed
Study
Name
Statistics for each study
Events/Total
Risk
Ratio
Lower
limit
Upper
limit
pValue
Group
A
Group
B
FATS
0.197
0.046
0.844
0.029
2/48
11/52
AFREGS
0.338
0.114
0.998
0.050
4/71
12/72
ARBITER
2
0.230
0.026
2.014
0.184
1/87
4/80
HATS
0.167
0.021
1.319
0.090
1/38
6/38
CLAS 1
2.00
0.184
21.683
0.569
2/94
1/94
0.307
0.150
0.628
0.001
Duggal JK, et al. J. Cardiovasc. Pharmacol. Ther. 2010;15(2):158-166
Model
Fixed
Study
Name
Statistics for each study
Events/Total
Risk
Ratio
Lower
limit
Upper
limit
pValue
Group
A
Group
B
Stockhol
m study
0.692
0.456
1.032
0.071
35/279
50/27
6
Coronary
Drug
Project
0.736
0.604
0.896
0.002
114/
1119
386/
2789
ARBITER
2
0.920
0.133
6.375
0.932
2/87
2/80
HATS
0.250
0.029
2.135
0.205
1/38
4/38
CLAS 1
0.250
0.028
2.195
0.211
1/94
4/94
0.719
0.603
0.856
0.000
Duggal JK, et al. J. Cardiovasc. Pharmacol. Ther. 2010;15(2):158-166
Model
Fixed
Study
Name
Statistics for each study
Events/Total
Risk
Ratio
Lower
limit
Upper
limit
pValue
Group
A
Group
B
Stockhol
m study
1.187
0.367
3.844
0.775
6/279
5/276
Coronary
Drug
Project
0.761
0.612
0.984
0.015
95/
1119
311/
2789
AFREGS
0.203
0.010
4.150
0.300
0/71
2/72
ARBITER
2
0.307
0.013
7.425
0.467
0/87
1/80
HATS
0.200
0.010
4.032
0.294
0/38
2/38
0.759
0.613
0.940
0.012
Duggal JK, et al. J. Cardiovasc. Pharmacol. Ther. 2010;15(2):158-166
Model
Fixed
Study
Name
Statistics for each study
Events/Total
Risk
Ratio
Lower
limit
Upper
limit
pValue
Group
A
Group
B
Stockhol
m study
0.712
0.524
0.969
0.031
54/279
75/27
6
Coronary
Drug
Project
0.937
0.821
1.059
0.334
238/
1119
633/
2789
AFREGS
3.042
0.126
73.436
0.493
1/71
0/72
ARBITER
2
0.460
0.043
4.974
0.522
1/87
2/80
HATS
0.333
0.014
7.933
0.497
0/38
1/38
CLAS 1
0.333
0.014
8.080
0.499
0/94
1/94
0.895
0.794
1.010
0.073
Duggal JK, et al. J. Cardiovasc. Pharmacol. Ther. 2010;15(2):158-166
• “In meta-analysis of seven trials of secondary
prevention, niacin was associated with a
significant reduction in cardiovascular events
and possible small but non-significant
decreases in coronary and cardiovascular
mortality”
Duggal JK, et al. J. Cardiovasc. Pharmacol. Ther. 2010;15(2):158-166
Bruckert E, Labreuche J, Amarenco P.
Atherosclerosis. 2010;210:353-361
1. PubMed literature search using terms niacin,
nicotinic acid, niaspan, and acipimox. Trials
published between 1/1966 and 11/2009.
2. Studies selected subjects aged 18 years or
older, randomized controlled design, data
available about clinical events and/or
atherosclerosis outcome (coronary, carotid,
or femoral arteries) in each group.
3. 14 reports included.
Bruckert E, et al. Atherosclerosis. 2010;210:353-361
Study
Treatment
n/N
Control
n/N
Peto OR 95% CI
Guyton JR et
al
0/676
1/272
0.03 (0.00, 2.331)
AFREGS
0/71
2/72
0.14 (0.01, 2.18)
ARBITER 2
0/87
1/80
0.12 (0.00, 6.27)
HATS
0/38
2/38
0.13 (0.01, 2.15)
STOCKHOLM
6/279
5/276
1.19 (0.36, 3.92)
CDP
95/1119
311/2789
0.75 (0.60, 0.94)
TOTAL
0.74 (0.59, 0.92)
Test for heterogeneity: P=0.27, P=21.9%
Test for overall effect: P=0.007
Subtotal excluding CDP
0.51 (0.20, 1.35)
Bruckert E, et al. Atherosclerosis. 2010;210:353-361
Study
Treatmen
t n/N
Control
n/N
Peto OR 95% CI
ARBITER 6
HALTS
2/187
9/176
0.25 (0.09, 0.84)
Guyton JR et
al
1/676
2/272
0.16 (0.01, 1.90)
AFREGS
1/71
2/72
0.52 (0.05, 5.04)
ARBITER 2
3/87
7/80
0.39 (0.11, 1.40)
HATS
1/38
12/38
0.12 (0.04, 0.44)
UCSF SCOR
0/48
1/49
0.14 (0.00, 6.96)
FATS
2/48
10/52
0.24 (0.07, 0.81)
STOCKHOLM
73/279
104/276
0.59 (0.41, 0.84)
CLAS
17/94
21/94
0.77 (0.38, 1.56)
CDP
914/1119
2333/2789
0.87 (0.72, 1.05)
TOTAL
0.73 (0.63, 0.85)
Test for heterogeneity: P=0.009, P=59.2%
Test for overall effect: P<0.0001
Subtotal excluding CDP
0.49 (0.37, 0.65)
Bruckert E, et al. Atherosclerosis. 2010;210:353-361
Study
Treatment
n/N
Control n/N
RR (fixed) 95% CI
AFREGS
33/66
26/62
1.19 (0.82, 1.74)
UCSF
SCOR
13/40
4/32
2.60 (0.94, 7.21)
FATS
14/36
5/46
3.58 (1.42, 9.01)
CLAS
13/80
2/82
6.66 (1.55, 28.59)
TOTAL
Test for heterogeneity: P=0.01, P=72.7%
Test for overall effect: P<0.0001
Bruckert E, et al. Atherosclerosis. 2010;210:353-361
1.92 (1.39, 2.67)
Study
N
Treatment
Mean (SD)
N
Control
Mean (SD)
WMD (fixed)
95% CI
ARBITER 6
HALTS
97
-12(36)
111
-1(31)
-12 (-21, -2)
Thoenes
M et al
30
-5(11)
15
9(12)
-14 (-21, -7)
ARBITER 2
78
14(104)
71
44(100)
-30 (-63, 3)
CLAS
39
-12(20)
39
12(20)
-25 (-34, -16)
TOTAL
Test for heterogeneity: P=0.13, P=47.4%
Test for overall effect: P<0.0001
Bruckert E, et al. Atherosclerosis. 2010;210:353-361
-17 (-22, -12)
1. Although the studies were conducted before
statin therapy became standard care and mostly
in secondary prevention with various doses of
Nicotinic acid 1-3 gram/day, this meta-analysis
found positive effects of Niacin alone or in
combination on all cardiovascular events and on
atherosclerosis evolution.
2. A therapeutic strategy including Nicotinic acid
treatment decreased major coronary events by
25% (p<0.0001) stroke by 26% (p=0.007) and all
cardiovascular events by 27% (p<0,0001)
Bruckert E, et al. Atherosclerosis. 2010;210:353-361
ER Niacin 1500 mg or 2000mg + Simvastatin
20/40/80mg ± Ezetimibe 10mg
Simvastatin 40mg + ER Niacin
500mg/1000mg/1500mg/2000mg
ER Niacin increased Weekly
1-2 Month
Run In
Mean Follow-up 3 years
Simvastatin 20/40/80mg ± Ezetimibe 10mg LDL-C
maintained 40-80mg/dl
• Can a short period of exposure to ER
Niacin have an effect on endothelial
function in patients with CAD with low
HDL-C on Statin therapy?
* P=0.001
*
LDL-C <100mg/dl + HDL-C
≤36mg/dl (ER Niacin) or
>36mg/dl (Control)
HDL-C (mg/dl)
30.5
40.5
42.3
39.8
LDL-C (mg/dl)
70.3
64.1
73.2
72.2
Kuvin JT, et al. Am. Heart J. 2002;144:165-172
R=0.7
P<0.02
Kuvin JT, et al. Am. Heart J. 2002;144:165-172
Hamilon SJ, Chew G, Davis T, Watts G. Diabetes
& Vascular Disease Research. 2010;7(4):296-299
1. 15 Type II DM age 40-79 on stable statin therapy ≥ 6
weeks
2. LDL-C ≤ 96 mg/dl
3. Endothelial dysfunction: Brachial artery flow-mediated
dilation <6%
4. Single blind to either additional therapy (N=7) with niacin
(Nicotinic acid prolonged release) or no additional
treatment (no niacin) (N=8)
5. Use of other lipid-regulating therapies, HgA1c >9.0%, BP
>150/90 mmHg or gout were excluded.
6. No significant difference between Niacin tx or no
additional tx: ARB (40%), ACE (33%), calcium blocker
(20%), oral hypoglycemic (66%)
Hamilton SJ, Chew G, Davis T, et al. Diabetes & Vascular Disease Research. 2010;7(4):296-299
1. Niacin titrated over 8 weeks to a maximum
dose of 1500mg/day. Dose was maintained
for 12 additional weeks.
2. Forearm vasodilatory function and arterial
compliance at baseline and study end.
3. Aspirin 100 mg/day started in aspirin-naïve
subjects at least 3 weeks prior to baseline
vascular measures.
Hamilton SJ, Chew G, Davis T, et al. Diabetes & Vascular Disease Research. 2010;7(4):296-299
Effect of niacin compared with no additional
treatment on serum lipid and apolipoprotein
concentrations, glycemic control, and plasma urate in
the statin-treated type II Diabetic subjects
No Niacin
Niacin
p value
Pre-Tx
On-Tx
Pre-Tx
On-Tx
Cholesterol mg/dl
154.6
150.8
146.9
143.1
0.69
Triglyceride mg/dl
132.8
115.1
132.8
88.6
0.04
HDL-C mg/dl
42.9
39.4
41.4
43.3
0.24
Non-HDL-C mg/dl
110
111
104
101
0.41
LDL-C mg/dl
85.1
85.1
77.3
77.3
0.73
Apo A1 mg/dl
147
146
56.4
60.3
0.36
Apo B mg/dl
93
86
79
72
0.77
Glucose mmol/l
7.0
6.6
7.3
7.5
0.26
HgA1c %
7.0
7.1
7.8
8.0
0.52
0.37
0.39
0.37
0.33
0.83
Urate mmol/l
Hamilton SJ, Chew G, Davis T, et al. Diabetes & Vascular Disease Research. 2010;7(4):296-299
p=0.001
p=0.01
Hamilton SJ, Chew G, Davis T, et al. Diabetes & Vascular Disease Research. 2010;7(4):296-299
• MEMORY: Prior Niacin Exposure Makes a
Difference
– Coronary Drug Project Mean Follow-up 15 years
• Nearly 9 years after termination of trial
*
AIM-High
(previous use of Niacin or Niaspan)
• Placebo + Statin- 19.9%
• ER Niacin + Statin- 18.9%
Canner PL, et al. J. Am. Coll. Cardiol. 1986;8:1245-1255
• Short term ER niacin significantly impacts HDL-C, Tg, Inflammatory
markers, LDL, HDL particle concentration
–
–
–
–
Stable CAD patients
100% on Statin
ER Niacin 500mg for 2 weeks then 1,000mg for 10 weeks
Placebo control
*
*
**
**
*
***
Kuvin JT. Am. J. Cardiol. 2006;98:743-745
**
• 6 month, prospective, observational
• 100% on Statin
• Prolonged release Niacin
– week 1: 375mg, week 2: 500mg, week 3: 750mg, weeks 4-7: 1000mg,
Maximum dose: 2000mg
– CAD: MI or CVA; CABG or PTCA/STENT
– Type II DM
– 10 years Procam Risk of MI >20%
Baseline mg/dl
34.8
283
101
Birjmohun RS, et al. Curr. Med. Res. Opin. 2007;23(7):1707-13
182
Very Low Dose Niacin Does Make a Difference on HDL-C
– Blinded- 3 months
– Stable statin tx
*
Mean Changes in Cholesterol Parameters
Wink J, et al. Am. Heart J. 2002;143:514-8
Niacin Group
Placebo Group
p Value
HDL mg/dl
2.1
-0.56
0.025
Total Cholesterol mg/dl
0.31
-11.0
0.10
LDL mg/dl
-3.13
-7.98
0.45
Triglyceride mg/dl
-5.93
-12.1
0.71
• Gordon DJ, et al. Circulation. 1989;79:8-15
– For each 1mg/dl ↑ HDL-C, CHD risk ↓ 2% men and ↓ 3% women.
– However: Aim-High (P+Statin) only 14.8% women,
Aim-High (ER Niacin+Statin) only 14.7% women
Aim-High HDL-C (mg/dl) (mean)
Baseline
Year 3
∆HDL-C
Difference
P + Statin
35.3
39.1
3.8
5.5
ER Niacin + Statin
34.8
44.1
9.3
3% x 0.148 x 5.5 =
2.44%
2% x 0.852 x 5.5 =
9.37%
11.81%
Aim-High- Thus, a 5.5 mg/dl HDL-C difference would
predict a 11.81% difference in events.
• Cholesterol Treatment Trialists’ (CTT) Collaboration.
Lancet. 2010;367:1670-1681
– 24,323 Events, 169,138 Participants
– “overall, the weighted average reduction in major vascular events
was 21% (95% CI 19-23; p<0.0001) per 1.0 mmol/l reduction in LDL
cholesterol”
Aim-High LDL-C (mg/dl) (mean)
Baseline
Year 3
∆LDL-C
Difference
P + Statin
75.8
68.3
7.5
3.5
ER Niacin + Statin
76.2
65.2
11.0
1mmol/l=
38.66mg/dl
21%/38.66=
0.543% per mg/dl LDL-C
Aim-High- Thus, a 3.5mg/dl LDL-C difference would predict
1.9% difference in events.
:
• Event driven trial, 800 1o events, mean follow up 4.6 years.
• 85% power to detect 25% reduction in the revised 5
component 1o end point.
Aim-High
Predicted CV Event Rate Reduction: From LDL-C, HDL-C
Results
A.
B.
5.5 mg/dl HDL-C difference- 11.8%
3.5 mg/dl LDL-C difference- 1.9%
Estimated total HDL-C, LDL-C
Difference in event rate reduction= 13.7%
 The Predicted CV Event Rate Reduction (13.7%) is only 54% of
the original event rate reduction (25%) which was used in the
power calculation.
 Thus, the Aim-High Trial was inadequately powered to test the
hypothesis whether ER Niacin added to Simvastatin in patients
with CVD to raise low levels of HDL-C is superior to Simvastatin
alone in reducing residual risk.
Clinical and Economic Impact of Combining Comprehensive
Lipid Profiling With a Heart Disease Treatment Protocol
• McAna et. al. Presented at the
International Society for
Pharmacoeconomics and Outcomes
Research (ISPOR) 15th Annual
International Meeting, May 15-19, 2010
(poster number PCV19) Atlanta, GA, USA
• e-publication available August 2011
69
Study Design
• A large Provider Health Plan (100K lives)
utilizes the VAP test in its chronic care
management programs for patients with
IHD or CHF. In cooperation with primary
care physicians and their clinics, this
group integrates results from the VAP
test with an aggressive treatment
protocol using combination statin and
niacin medication therapy, individually
targeted for the specific dyslipidemias
found.
70
Study Design cont.
• n=1,767 pts (cases) received VAP testing
compared to n=289 pts (controls)
receiving usual care with routine
cholesterol results
• Cases and controls were compared on:
– demographics
– costs
– utilization
– LDL level.
71
Study Design cont.
• Usual Care: (controls) – Standard Lipid
Panel
– Target LDL <70mg/dL
• Cases: VAP Analysis
– Target LDL <70mg/dL
– If LDL Phenotype A/B or B add Niaspan ER or
FDC Advicor
– If HDL2 <15mg/dL add Niaspan ER or FDC
Advicor
72
Utilization and Cost Comparisons
73
Conclusions
• Overall, claims costs were lower in the
second year of the study for the cases
• Prescription drug usage results suggest a
more targeted and aggressive therapeutic
approach being used for the cases
compared to the controls.
– Niacin was the predominate second agent
74
Conclusions cont.
• In year two of the study, the average
claims costs for controls were
approximately $2500 higher for controls
than cases. The cost of the
comprehensive lipid profile was only
about $15 higher per test than the
standard profile.
• $4.5 million dollars in total cost savings,
after 2 years, using the VAP along with
aggressive combination
75 therapy
1.) TIME!!!
You can’t do the patient justice with a 10 minute office visit
to initiate ER Niacin. Schedule the patient for a 20-30 minute
visit.
2.) First explain to the patient how important this therapy is for
their care. I give a copy of the ER Niacin PI to the patient. If
they have had an MI you are trying to prevent a recurrent MI;
if they have Coronary Atherosclerosis you are trying to
promote regression and reduce progression.
3.) Tell the patient they will probably have flushing and this can
be mitigated
4.) Also tell patients that ER Niacin can increase uric acid,
glucose, and can precipitate GI bleeding and this also can be
mitigated
The “________________________ Tw o” Protocol
to LIMIT or ELIMINATE the side effects
of Niaspan ER
Main Side Effects of Niaspan and Statins:
1) Flushing
2) Gastrointestinal side effects
3) Skin reactions (i.e., pins and needles)
4) Liver function test abnormalities
5) Muscle side effects
6) Worsen diabetic control
7) Gout
Take immediately FOLLOWING dinner:
(Statin)
_________________
_______mg
+ AND +
Niaspan 500 à 1000 à 1500 à 2000mg
81(1 tablet) à 325mg (4 tablets)
YELLOW COATED
Bayer Aspirin
One Hour Prior
to Dinnertime
AM
Breakfast
Noon
Lunch
PM
Dinner
…Then take the
Statin&Niaspan
immediately following dinner
For Emergency Use if with side effects following Niaspan and Statin use:
Chew a White UnCoated 325mg Aspirin, swish it around mouth for 1-2 minutes, letting the mucous
membranes of mouth absorb it for relief. (KEEP THESE BY THE BEDSIDE!)
Next Day: Increase your dose of Yellow Coated Bayer Aspirin by 1 tablet
1.) Patients take the ER Niacin 500mg at the end of dinner with their Statin
**2.) Most important- 1 hour prior to dinner take 81mg→325mg Bayer,
yellow coated aspirin. Keep long term aspirin < 200mg/ day in patients on
long term Plavix.
**3.) Explain to patients if they have significant break-through flushing they
can take 325mg, white, uncoated, aspirin/ chew it and swirl around in
mouth then swallow. The skin and flushing side effects should resolve in
10 minutes. The next day increase the yellow coated Bayer aspirin by 81
mg.
4.) Obtain blood work (comprehensive metabolic panel, CPK, uric acid, lipid
panel) in 6 weeks with an appointment for 8 weeks (earlier if you get your
blood work back sooner). Then if no problems increase ER Niacin to 1,000
mg/day
5.) We like a minimum of 1,000mg ER Niacin/day (Arbiter 2,3). Increase to a
maximum 2,000 mg ER Niacin/day if necessary to get HDL-C > 50mg/dl
10/31/09
12/23/09
TC/LDL
260/185
137/61
HDL/2/3
23.8
31/7/24
Tg/VLDL
256
118/21
Apo B
-
83
ALT/AST/CPK
24/23/30
20/23/54
Bun/creat
27/1.1
27/1.3
eGFR
51
42
Glucose
106
116
Luric Acid
-
7.7
Lipiton
Start 40mg
Niaspan ER
Start 40mg
6/29/04
8/19/04
10/19/04
3/29/05
6/30/05
Tc/LDL
534
111/57
120/57
97/39
124/51
HDL/2/3
33
35
28
39
60
Tg/vLDL
948
94
173
94
65
Lp(a)
113.8
132.6
93.7
78.6
ALT/AST/CPK
13/11/62
19/14/47
24/16/45
25/27/59
21/21/168
BUN/Creat
19/1.2
23/1.4
16/1.2
17/1.2
21/1.2
103
95
97
88
91
4.0
6.0
13.2
eGFR
Glucose
Luric Acid
Crestor
Start 10mg
10mg
10mg
10mg
10mg
Tricor
Start 160mg
160mg
160mg
160mg
160mg
Start 500mg
1,000mg
1,500mg
1,500mg
Niaspan ER
7/13/09
8/5/09
8/12/09
9/16/09
12/2/09
Tc/LDL
214/168
108/45
106/39
130/43
HDL/2/3
16
36/7/30
40/9/31
60/14/46
Tg/vLDL
149
111/17
110/17
60/13
57
54
52
30/23/46
17/17/47
17/16/
Bun/creat
20/1.0
22/1.2
eGFR
>60
52
57
Glucose
97
77
99
8.0
6.3
Apo B 100
ALT/AST/CPK
44/26
Luric acid
Crestor
Start 10mg
10mg
10mg
10mg
10mg
Fish oil
4gm/day
4gm
4gm
4gm
4gm
Start500mg
500mg
1000mg
1000mg
Niaspan ER
8/8/08
11/18/08
6/23/09
8/25/09
Tc/LDL
213/157
208/117
206/113
133/55
HDL/2/3
38
43/8/35
46/10/36
50/12/38
Tg/vLDL
92
141/24
162/26
82/15
112
108
63
Apo B 100
ALT/AST/CPK
51/38/458
40/29/271
44/32/289
38/31/341
Bun/creat
14/.8
18/.8
13/.9
16/.9
103/5.7
102
123/5.6
104
6.1
7.3
5.8
eGFR
Glucose/HgAic
Luric Acid
ER Niacin
Start 500mg
1000mg
500mg
500mg
Welchol
Start 3 Bid
3 Bid
3 Bid
2 Bid
Start
200mg
200mg
Fish Oil
CONT
CONT
Crestor
Start 10mg
10mg
CoQ10 200
1.) After LDL, Non HDL goals achieved
2.) Treat low HDL in HIGH RISK PATEINTS!!!
3.) No prescription medication increases HDL more than Niaspan
ER© or Niacor©
4.) It is crucial that you spend time with your patient (> 20
minutes) when you start the patient on ER Niacin. The patient
needs to understand the importance of the medication and
how to mitigate any potential side effects. Make sure to give
the patient a copy of the protocol.
5.) Monitor your patient with blood work every 4 to 6 months
when on combination therapy (Statin± Niacin ± Fibrate)
6.) Celebrate the reduction in cardiovascular morbidity and
mortality