Beyond Statins: What Therapies
Really Work?
Peter A. McCullough, MD, MPH, FACC, FACP, FAHA, FCCP
Consultant Cardiologist, Chief Academic and Scientific Officer
St. John Providence Health System, Providence Park Heart Institute, Novi, MI
USA, e-mail: peteramccullough@gmail.com
Rapidly Changing Epidemiology
of Acute Myocardial Infarction
Reductions in All Forms of
Acute Myocardial Infarction
Use of Preventive Therapies
Optimal CV Risk Reduction
Lifestyle
Intervention
Lipid
Modification
Adiposity control
Fitness
Nutrition
Optimal
CV Risk
Reduction
Glucose
Lowering
Smoking cessation
BP
Lowering
Thrombotic
Management
Residual Risk in the TNT Study: Impact of
Glucometabolic Characteristics on Risk of
Major Cardiovascular Events Among All
Patients
Patients with Major
Cardiovascular Event (%)
16
Characteristic Absent
Characteristic Present
12
HR = 1.33
HR = 1.30
HR = 1.24
HR = 1.18
HR = 1.48
8
4
0
Low
High-Density
Lipoprotein
Fasting
Glucose
100 mg/dL
Body-Mass
Index
28 kg/m2
TNT = Treating to New Targets study
Reprinted from Deedwania P, et al. Lancet. 2006;
368:919–928, with permission from Elsevier.
Triglycerides Hypertension
250 mg/dL
Intensity of Medical Therapy
and Outcomes
Cumulative Probability of
Cardiovascular Events (%)
35
P=0.001
Poor Rx
(n=75)
30
25
20
Moderate Rx
(n=123)
15
10
5
Maximal Rx
(n=90)
0
0
6
12
18
24
30
Months
Rx, treatment.
Sdringola S, et al. J Am Coll Cardiol. 2003;41:263-272.
36
42
48
54
60
Optimal Medical Therapy for Atherosclerosis
 Reduction in LDL-C
 Reduction in non-HDL-C
 Blood pressure control without hypotension
– RAS blockers
– Others
 Reduction in platelet aggregation
– ASA
– Thienopyridine
 Glycemic control without hypoglycemia
 Smoking cessation/avoidance of side-stream smoke
 Weight reduction/maintenance at optimal
– Healthy choices
– Portion control
– Dietary supplements
 Aerobic and strength fitness
Optimal Medical Therapy for Atherosclerosis
 Reduction in LDL-C
 Reduction in non-HDL-C
 Blood pressure control without hypotension
– RAS blockers
– Others
 Reduction in platelet aggregation
– ASA
– Thienopyridine
 Glycemic control without hypoglycemia
 Smoking cessation/avoidance of side-stream smoke
 Weight reduction/maintenance at optimal
– Healthy choices
– Portion control
– Dietary supplements
 Aerobic and strength fitness
How to Achieve these New Targets
Multi-drug treatment for Atherosclerosis
 High dose statin
Targets: LDL-C, ApoB
 Bile acid sequestrants
 Ezetimibe
 Niacin
 Fenofibrate
Target: Non-HDL
 Omega-3 Fatty Acids
 Wait for new drugs
 Niacin/laropiprant
 Anacetrapib
 Darapladib/Varespladib
 Mipomersen
 Others
Non-HDL Reduction and CHD Risk
Nicotinic Acid: 2010 Meta-Analysis

Seven trials, 5137 patients met inclusion criteria

Compared to placebo group, niacin therapy significantly reduced
 Coronary artery revascularization (RR [relative risk]: 0.307
with 95% CI: 0.150-0.628; P = .001),
 Nonfatal myocardial infarction ([MI]; RR: 0.719; 95% CI:
0.603-0.856; P = .000),
 Stroke, and TIA ([transient ischemic attack] RR: 0.759;
95%CI: 0.613-0.940; P = .012),
 Cardiac mortality (RR: 0.883: 95% CI: 0.773-1.008; p=
0.066).
J CARDIOVASC PHARMACOL THER June 2010 vol. 15 no. 2 158-166
Fibrates: 2010 Meta-analysis

Randomized controlled trials to evaluate the role of fibrates in
the prevention of cardiovascular events in patients with type 2
diabetes mellitus.

A total of 11,590 patients from 6 published randomized placebocontrolled trials

The use of fibrates did not significantly affect the risk of allcause mortality or cardiac mortality, and also did not affect the
risk of stroke, unstable angina, or invasive coronary
revascularization.

However, the relative risk of non-fatal myocardial infarction was
significantly reduced by about 21% (pooled relative risk 0.79,
p=0.006) with the use of fibrates.
Int J Cardiol Volume 141, Issue 2, Pages 157-166 (28 May 2010)
Fibrates in Hypertriglyceridemic Subgroups
Current Atherosclerosis Reports 2006, 8:356–364, Diabetes Care 32:493–498, 2009. N Engl J Med 2010. DOI:
10.1056/
Optimal Medical Therapy for Atherosclerosis
 Reduction in LDL-C
 Reduction in non-HDL-C
 Blood pressure control without hypotension
– RAS blockers
– Others
 Reduction in platelet aggregation
– ASA
– Thienopyridine
 Glycemic control without hypoglycemia
 Smoking cessation/avoidance of side-stream smoke
 Weight reduction/maintenance at optimal
– Healthy choices
– Portion control
– Dietary supplements
 Aerobic and strength fitness
Quadruple endpoint: myocardial infarction, stroke, heart failure, and cardiovascular death
Journal of Hypertension 2010, 28:1356–1365
NHANES III: Poor SBP Control Underlies Inadequate BP Control Overall
Published Guidelines Have Set
Clear Treatment Goals
JNC 7 / ADA / NKF / ISHIB Guidelines
for Hypertension and Patients at High Risk
Condition
mmHg
Essential hypertension
<140/90
Diabetes mellitus
<130/80
Chronic renal disease
<130/80
High-risk* hypertension
<130/80
ADA=American Diabetes Association.
NKF=National Kidney Foundation.
ISHIB=International Society on Hypertension in Blacks.
*History
of CVD event, stroke, transient ischemic attack, evidence of target-organ damage (e.g., left
ventricular hypertrophy, microalbuminuria), CHD, or high-risk for CHD (e.g., metabolic syndrome).
Chobanian AV et al. JAMA. 2003;289:2560–2572. Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82.
Douglas JG et al. Arch Intern Med. 2003;163:525–541. Bakris GL et al. Am J Kidney Dis. 2000;36:646–661.
Optimal Medical Therapy for Atherosclerosis
 Reduction in LDL-C
 Reduction in non-HDL-C
 Blood pressure control without hypotension
– RAS blockers
– Others
 Reduction in platelet aggregation
– ASA
– Thienopyridine
 Glycemic control without hypoglycemia
 Smoking cessation/avoidance of side-stream smoke
 Weight reduction/maintenance at optimal
– Healthy choices
– Portion control
– Dietary supplements
 Aerobic and strength fitness
NEJM
352;16, April
21, 2005
Optimal Medical Therapy for Atherosclerosis
 Reduction in LDL-C
 Reduction in non-HDL-C
 Blood pressure control without hypotension
– RAS blockers
– Others
 Reduction in platelet aggregation
– ASA
– Thienopyridine
 Glycemic control without hypoglycemia
 Smoking cessation/avoidance of side-stream smoke
 Weight reduction/maintenance at optimal
– Healthy choices
– Portion control
– Dietary supplements
 Aerobic and strength fitness
All-Cause Mortality
0.15
Known DM
0.10
New DM
IGT
0.05
IFG
0.00
NGT
0
2
4
6
Cumulative Incidence of
CVD Mortality
Cumulative Incidence of
All-cause Mortality
Unadjusted Mortality According to
Glucose Metabolism: Data from AusDiab
CVD Mortality
0.05
Known
DM
0.04
New DM
0.03
IFG
0.02
IGT
0.01
0.00
NGT
0
Time (years)
2
4
Time (years)
AusDiab = Australian Diabetes, Obesity, and Lifestyle Study; CVD = cardiovascular;
KDM = known diabetes mellitus; NDM = newly diagnosed diabetes mellitus; IFG =
impaired fasting glucose; IGT = impaired glucose tolerance; NGT = normal glucose
tolerance
Reprinted from Barr EL, et al. Circulation. 2007;116:151–157,
with permission from Lippincott Williams & Wilkins.
6
Intensive Office Glycemic Control: 2009
Meta-analysis
Risk of Severe Hypoglycemia with
Intensive DM Management
Optimal Medical Therapy for Atherosclerosis
 Reduction in LDL-C
 Reduction in non-HDL-C
 Blood pressure control without hypotension
– RAS blockers
– Others
 Reduction in platelet aggregation
– ASA
– Thienopyridine
 Glycemic control without hypoglycemia
 Smoking cessation/avoidance of side-stream smoke
 Weight reduction/maintenance at optimal
– Healthy choices
– Portion control
– Dietary supplements
 Aerobic and strength fitness
33 vs 9% Abstinence Achieved
Optimal Medical Therapy for Atherosclerosis
 Reduction in LDL-C
 Reduction in non-HDL-C
 Blood pressure control without hypotension
– RAS blockers
– Others
 Reduction in platelet aggregation
– ASA
– Thienopyridine
 Glycemic control without hypoglycemia
 Smoking cessation/avoidance of side-stream smoke
 Weight reduction/maintenance at optimal
– Healthy choices
– Portion control
– Dietary supplements
 Aerobic and strength fitness
Optimal Dietary Habits Reduce Mortality in
Prevention Studies
2002
Physician’s Health Study
(N = 20,551)*
2003
2002
Nurses’ Health Study
(N = 84,688)
Cardiovascular Health Study
(N = 5,201)*
2003
2005
European Prospective
Investigation into Cancer
and Nutrition–Greek cohort
(N = 22,043)†
European Prospective
Investigation into Cancer
and Nutrition–elderly cohort
(N = 74,607)†
2004
The Healthy Aging:
A Longitudinal Study in Europe
(N = 2339)
*Blood levels of n-3 fatty acids inversely
related to death
†Greater adherence associated with lower mortality
Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87.
Trichopoulou A et al. BMJ. 2005;330:991-7.
Knoops KTB et al. JAMA. 2004;292:1433-9.
Optimal Diet for CVD Prevention and Treatment
Miller WM, McCullough PA. Chapter 21. Obesity, p209-218. Pollock’s Textbook of Cardiovascular Disease and
Rehabilitation. Durstine JL, Moore GE, LaMonte MJ, Franklin BA, Editors. Human Kinetics, 2008.
Nonfatal MI and CV Death
Weight Loss and Risk Factors
Janosz KE, Zalesin KC, Miller WM, McCullough PA, Franklin BA. Impact of surgical and
nonsurgical weight loss on diabetes resolution and cardiovascular risk reduction. Curr Diab Rep.
2009 Jun;9(3):223-8.
Optimal Medical Therapy for Atherosclerosis
 Reduction in LDL-C
 Reduction in non-HDL-C
 Blood pressure control without hypotension
– RAS blockers
– Others
 Reduction in platelet aggregation
– ASA
– Thienopyridine
 Glycemic control without hypoglycemia
 Smoking cessation/avoidance of side-stream smoke
 Weight reduction/maintenance at optimal
– Healthy choices
– Portion control
– Dietary supplements
 Aerobic and strength fitness
VBWG
Exercise reduces CV and all-cause mortality
N = 9791, moderate exercise vs little or no exercise
NHANES I Epidemiological Follow-up Survey (1971-1992)
Favors exercise Favors no exercise
HR
Normal BP
All-cause death
0.75
0.76
CV death
Prehypertension
All-cause death
0.79
0.79
CV death
Hypertension
All-cause death
0.88
0.84
CV death
0
0.5
1.0
1.5
2.0
Hazard ratio
Fang J et al. Am J Hypertens. 2005;18:751-8.
We need individualization not
generalization in clinical management
of coronary disease
Frequency (%) of Elective, Urgent, and
Emergent PCI in the United States
15.7
26.7
56.7
Elective
Urgent
Emergent
Courtesy Robert AM For the Dartmouth Dynamic Registry Investigators et al, in press, 2009
Chronic Stable CAD: PCI vs
Conservative Medical Management
Meta-analysis of 11 randomized trials; N=2950
Favors medical
management
Favors PCI
P value
Death
0.68
Cardiac death or MI
0.28
Nonfatal MI
0.12
CABG
0.82
PCI
0.34
0
1
2
Risk ratio (95% Cl)
CI, confidence interval; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention
Katritsis DG, et al. Circulation. 2005;111:2906-2912.
Survival Free of Death from Any
Cause and Myocardial Infarction
Optimal Medical Therapy (OMT)
1.0
0.9
0.8
PCI + OMT
0.7
Hazard ratio: 1.05
95% CI (0.87-1.27)
P = 0.62
0.6
0.5
0.0
0
1
2
3
Years
4
5
6
7
Number at Risk
Medical Therapy
PCI
1138
1149
1017
1013
959
952
834
833
638
637
408
417
N Engl J Med. 2007 Apr 12;356(15):1503-16.
192
200
30
35
BARI-2D Trial
~10 year history of DM
Positive stress test
82.1% symptomatic with classic angina
95% treated with statin
LDL-C ~ 80 mg/dl
Non-HDL-C ~ 90 mg/dl
BP ~ 125/70 mm Hg
Glycohemoglobin 7.2%
BARI 2D: All-cause death for medical therapy vs
type of revascularization
BARI 2D: Death, MI, stroke for medical therapy vs
type of revascularization
Summary: Optimizing Outcomes in Patients
with CVD
Traditional
risk factors
Enhanced Risk
Stratification
-Apo B
Clinical
trials
-hs CRP
-PLAC™
Multifactorial Risk Reduction
Improved Clinical Outcome
Conclusions
• Multiple therapies beyond statins reduce “hard” CVD
endpoints
• Non-HDL is a viable treatment target
• Optimal medical therapy manages “residual risk”
– Simultaneous multiple risk factor reduction
– Involves behavior change and drugs in every case
– Avoids adverse events (hypoglycemia, hypotension)
• When applied with modest achievement of goals
– Makes elective PCI and revascularization truly “optional”
– Reduces but does not completely avoid future ACS