Primary and Secondary Prevention of Dyslipidemia: Established Therapies and Emerging Paradigms
Sidney C. Smith, Jr. MD
Professor of Medicine
Director, Center for Cardiovascular Science and Medicine
University of North Carolina at Chapel Hill
Most MIs Arise From Smaller, Non flow-limiting Stenoses
68%
18%
14%
0
20
40
60
80
<50%
50%–70%
>70%
% Stenosis
Percent of MI Patients
Adapted from Falk et al. Circulation 1995; 92:657–671.
PCI
CABG
Effects of Statins on Coronary Disease: Primary & Secondary Prevention
Study LDL LDL Rx RRR ARR NNT
4S 188 122(-35%) 34%* 8.5% 12
CARE 139 98(-32%) 24%* 3.0% 34
LIPID 150 113(-25%) 23%* 3.4% 30
WSCPS 192 159(-26%) 29%* 2.2% 46
AFCAPS 150 113(-25%) 36%^ 1.8% 56
* = NFMI/CHD mort. ^ = NF/FMI, UAP
%
*
*
?
?
§
*Confidence interval (CI) not reported.
?95% CI, 14%-41%.
?95% CI, 16%-37%.
§95% CI, 12%-31%.
Hebert PR et al. JAMA. 1997;278:313-321.
Impact of Lowering LDL-C on CVD Events and Total Mortality
Nonfatal/ fatal CHD
CVD mortality
4S: Major CHD Event Reduction in a Subgroup of Patients With Diabetes
Py?r?l? K et al. Diabetes Care. 1997;20:614-620.
Proportion without major CHD event
Yr since randomization
- P=0.002
- P=0.0001
Diabetic, simvastatin
Diabetic, placebo
Nondiabetic, simvastatin
Nondiabetic, placebo
32%
55%
4S: Treatment Benefit in Subgroup With Impaired Fasting Glucose (FG 110-125mg/dL)
Haffner SM et al. Diabetes. 1998;(suppl 1):A54. Abstract.
Total mortality
Coronary mortality
Major coronary events
Revas- culari- zations
? in events (%)
P=0.005
P=0.001
P=0.010
Clinical Trial Findings: The Statins
Statins ? LDL-C by 25%-35%
Benefits at various LDL-C levels; evident soon after therapy
? in LDL-C required for ? in CHD morbidity/mortality
? in all-cause mortality in 2° prevention and in cardiovascular mortality in 1° prevention
Studies support treatment in various patient groups
women
elderly
diabetics
Lipid Lowering Therapy for the Prevention of Vascular Disease
When Should Lipid Lowering Therapy be started?
What should be the Treatment Goal? Findings of the HPS Study.
Should HDL – Cholesterol be a Target?
When to Start Cholesterol Lowering Therapy in Patients with Coronary Heart Disease
“ The cardiovascular specialist or attending physician should be responsible for starting some form of cholesterol lowering therapy in patients upon discharge from the hospital after acute coronary events……….The cardiovascular specialist thus should insure that appropriate therapy is initiated and maintained.”
AHA Science Advisory Circ. 1997;95: 1683
ACS: A Treatment Gap
Acute coronary
event
4S3
AFCAPS / TexCAPS/ WOSCOPS
CARE1 LIPID2
No history of CAD
Acute Coronary Syndromes
3 mo
t=0
6 mo
Randomization: CARE - 3–20 mo LIPID - 3–36 mo
Randomization: >6 mo
Stable CAD
Primary prevention
Secondary prevention
Duration of follow-up: 15.0 years; 26.1 years; 35.4 years.
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
Time of
High
Mortality
7
12
4
9
-27
-40
5
-16
-50
-40
-30
-20
-10
0
10
20
TC
LDL-C
HDL-C
TG
Placebo
Atorvastatin
80 mg
% ?
MIRACL: Change in Lipid Levels
Data from Schwartz GG et al. JAMA. 2001;285:1711-1718. Additional data courtesy of GG Schwartz.
unstable angina or non–Q-wave MI
3,086randomized
24–96 h
after admission
Followed 16 weeks
0
5
10
15
0
4
8
12
16
Time since randomization (wk)
Cumulative incidence (%)
RR = 0.84 (95% CI, 0.70-1.00) P = 0.048
Atorvastatin
Placebo
17.4
14.8
*Death (any cause), nonfatal MI, resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization. Schwartz GG et al. JAMA. 2001;285:1711-1718.
MIRACL: Time to First Ischemic Event*
MIRACL: Occurrence of Primary Combined End Point
Adapted from Schwartz GG et al. JAMA. 2001;285:1711-1718.
0.0
0.5
1.0
1.5
2.0
0
4
8
12
16
Time since randomization (wk)
RR = 0.50 (95% CI, 0.26-0.99)
P = 0.045
Atorvastatin
Placebo
1.6
0.8
MIRACL: Fatal or Nonfatal Stroke
Cumulative incidence (%)
Data from Schwartz GG et al. JAMA. 2001;285:1711-1718.
19,599 men and women < 80 yo discharged post AMI, 58 Swedish Hospitals, 1995-1998
5528 (28%) statin rx vs 14071 (72%) no statin rx, highest hospital rates of use 48%; lowest 12%
Stenestrand JAMA 2001;285;430-436
Early Statin Treatment and Survival in AMI
RR 0.75 (0.63-0.89)
P=0.001
25% Risk Reduction
PRISM: Event Rate Cur ves
Heeschen C et al. Circulation. 2002;105:1446-1452.
0 5 10 15 20 25 30
18
16
14
12
10
8
6
4
2
0
Follow-up (day)
Event rates (%)
Statins discontinued
No statins
Statins continued
Events = mortality, MI
Statin Trials and Goals of Cholesterol-Lowering Therapy
Grundy. Circulation. 1998;97:1436-1439.
The quantitative relation between the magnitude of cholesterol lowering and CHD reduction has not been precisely defined
3 models
a) Linear
b) Threshold
c) Curvilinear
25
20
15
10
5
0
50
70
90
110
130
150
170
190
210
TNT 80mg
TNT 10 mg
CARE-S
LIPID-S
4S-S
CARE-P
LIPID-P
TNT Entry
4S-P
CHD Event (%)
LDL-C (mg/dL)
Correlation Between CHD Events and LDL-C Levels
S=Statin treated; P=Placebo treated
AVERT 80mg:
LDL=77 mg/dL
13.4% Event Rate
I - Intervention is useful and effective
IIa -Weight of evidence/opinion is in favor of usefulness/efficacy
IIb - Usefulness/efficacy is less well established by evidence/opinion
III - Intervention is not useful/effective and may be harmful
Data from many large, RCTs
Data from fewer, smaller RCTS, careful analyses of nonrandomized studies, observational registries
Expert consensus
=
Level of evidence
Classification of Recommendations
ACC/AHA Practice Guidelines
LIPID LOWERING AT HOSPITAL DISCHARGE
Lipid-lowering agent and diet in patients
with LDL cholesterol &