Vitamins in the Prevention of Cardiovascular Diseases : Vitamins in the Prevention of Cardiovascular Diseases Eva Lonn
McMaster University
Oxidation of LDL - Essential Step in Atherogenesis : Oxidation of LDL - Essential Step in Atherogenesis Libby et al. Circulation 2002;105:1135-1143. E-Selectin, P-Selectin LDL OxLDL L-Selectin, Integrins VCAM-1, ICAM-1 M-CSF MCP-1 Macrophage
Activation & Division Monocyte Intima Media Smooth Muscle Cell
Migration Other inflammatory triggers
Antioxidant Vitamins in CVD : Antioxidant Vitamins in CVD Oxidized LDL is atherogenic
Antioxidant Vitamins
Vitamin E – major lipid soluble natural antioxidant
Beta-carotene – lipid soluble
Vitamin C – water soluble Ox
LDL Foam Cells Direct cytotoxic to EC Attracts macrophages
to the subintima Inflammation Increased Vascular Tone Procoagulant
Food Sources of Antioxidants : Food Sources of Antioxidants AHA Nutrition Committee. Circulation 1999;99:591-595.
Vitamin E and Platelet Function : Vitamin E and Platelet Function
Scanning electron micrographs in
controls, platelets from individuals
supplemented with Vitamin E 200 IU
and 400IU x 2 weeks
Vitamin E reduces the release
of platelet granules and inhibits
platelet aggregation and adhesion
Steiner M. Clin Cardiol 1993
Epidemiology Antioxidant Vitamins and CV Risk : Epidemiology Antioxidant Vitamins and CV Risk Diets rich in fruit and vegetables associated with decreased CVD risk
Randomized Trials of Antioxidant Vitamins : Randomized Trials of Antioxidant Vitamins Vitamin E improves endothelial function, measured by FMD of the brachial artery, in people with type 1 DM
Skyme-Jones RAP, et al. J Am Coll Cardiol; 2000
Vitamin E improves endothelial function, measured by FMD of the brachial artery, in people with type 1 DM
Pinkney JH. Et al. Diabet Med; 1999
Vitamin E has no effect on endothelial function, measured by forearm venous occlusion plethysmography, in people with type 2 DM
Pinkney JH. Et al. Diabet Med; 1999
Vitamin C improves endothelial function, measured by FMD of the brachial artery, shortly after administration, but the effect is lost with chronic administration
Celermajer DS et al. J Am Coll Cardiol 2000 Endothelial Function
Atherosclerosis Progression Trials : Atherosclerosis Progression Trials * Decreased the benefit attained with Simvastatin+Niacin; Vit E+C+beta-carotene+selenium
Slide9 : Effect of Vitamin E on Carotid Atherosclerosis Lonn EM, et al. Circulation 2001; 103:919-25. 0.025
0.020
0.015
0.010
0.005
0 Mean max. carotid IMT slope (mm/year) Placebo Vitamin E Not significant
Nutrition Intervention Trial in Linxian (China) : Nutrition Intervention Trial in Linxian (China) 29,584 adults
Intervention : 2x4 factorial design
Beta-carotene + selenium + vitamin E group (30 mg)
Lower mortality: RR=0.91 (0.84-0.99); p=0.03 mainly due to lower cancer rates
523 cerebrovascular deaths - lower rates in vitamin E arm - RR=0.90
Vitamin E in End-Stage Renal Disease : Vitamin E in End-Stage Renal Disease * No differences in stroke, PVD, total mortality ,CV deaths
Boaz M, et al. Lancet 2000;356:1318
The SPACE trial
196 patients with ESRD on hemodialysis with pre-existent CVD MI/Stroke/
PVD/UAP
MI 33/99 15/97 17/99
5/97
Randomized Controlled Trials of Vitamin C : Randomized Controlled Trials of Vitamin C 3 small randomized controlled clinical trials of vitamin C in CVD prevention:
538 patients admitted to a geriatric unit
Vitamin C 200 mg/day; duration: 6 months
297 elderly people with low Vitamin C levels
Vitamin C 150 mg/day; duration: 2 years
199 elderly patients
Vitamin C 200 mg/day; duration: 6 months
RRI = 8% (95% CI= -7% to 26%)
Large Randomized Controlled Trials of Beta- Carotene : Large Randomized Controlled Trials of Beta- Carotene Vivekananthan DP. Lancet 2003;361:2017
Effect of Beta-Carotene on All Cause Death : Effect of Beta-Carotene on All Cause Death Vivekananthan DP. Lancet 2003;361:2017
Effect of Beta-Carotene on Cardiovascular Death : Effect of Beta-Carotene on Cardiovascular Death Vivekananthan DP. Lancet 2003;361:2017
Large Randomized Trials of Vitamin E : Large Randomized Trials of Vitamin E Vivekananthan DP. Lancet 2003;361:2017
Effects of Vitamin E on All Cause Death : Effects of Vitamin E on All Cause Death
Effect of Vitamin E on CV Death : Effect of Vitamin E on CV Death Vivekananthan DP. Lancet 2003;361:2017
Effect of Vitamin E on Stroke : Effect of Vitamin E on Stroke Vivekananthan DP. Lancet 2003;361:2017
Effect of Vitamin E on CV Death/ Fatal or Non-Fatal MI : Effect of Vitamin E on CV Death/ Fatal or Non-Fatal MI
Slide21 : HOPE: Effect of Vitamin E on Major Vascular Events 0.20
0.15
0.10
0.05
0 0 500 1,000 1,500 Proportion of Patients Days of follow-up Vitamin E Placebo RR: 1.05 (95% CI, 0.95-1.16) p=0.33 The HOPE Investigators. N Engl J Med 2000; 342:154-60.
Slide22 : Effect of Vitamin E on Major Vascular Outcomes in Diabetic Patients 0.25
0.20
0.15
0.10
0.05
0 0 500 1,000 1,500 2,000 Kaplan-Meier Rate Days of follow-up Lonn E, et al. Diabetes Care 2002; 25:1919-27. Placebo Vitamin E RR: 1.03 (95% CI, 0.88-1.21) p=0.70
Effect of Vitamin E on Diabetic Complications Microvascular Disease : Effect of Vitamin E on Diabetic Complications Microvascular Disease No effect on urinary albumin/ creatinine ratio
No effect on the incidence of self-reported diabetes
Slide24 : Effect of Vitamin E on Major Vascular Outcomes in Patients with Mild-Moderate Renal Insufficiency 0.30
0.20
0.10
0 0 Kaplan-Meier Rate Follow-up (Days) Mann J, et al. Kidney International 2004; 65:1375-80. Placebo Vitamin E 500 1000 1500 2000 RR: 1.03 (95% CI, 0.79-1.34) p=0.82
Slide25 : HOPE Extension 0.30
0.25
0.20
0.15
0.10
0.05
0 0 Kaplan-Meier Rate Time, y The HOPE and HOPE-TOO Investigators. JAMA 2005; 293:1338-47. Placebo 0.30
0.25
0.20
0.15
0.10
0.05
0 0 Time, y 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Vitamin E Placebo Vitamin E Incident Cancer Major CV Events No. at Risk:
Vitamin E 4761 4617 4441 4279 3946 2972 2168 1783
Placebo 4780 4638 4452 4266 3957 2895 2130 1754
4761 4548 4328 4130 3810 2874 2091 1714
4780 4571 4355 4142 3854 2883 2091 1732 Main HOPE Trial Ends Main HOPE Trial Ends
Effect of Vitamin E on CV Outcomes and on All Cause Death : Effect of Vitamin E on CV Outcomes and on All Cause Death Vitamin E Placebo
(N=4761) (N=4780)
Effect off Vitamin E on Heart Failure : Effect off Vitamin E on Heart Failure
HOPE-TOO Outcomes: Vitamin E Arm : HOPE-TOO Outcomes: Vitamin E Arm Aspirin and Other Antiplatelets
Beta-Blockers Lipid-Lowering Agents
Diuretics
Calcium Channel Blockers % Risk Increase No effect on cancer, major CV events or all-cause death Effect Beyond HOPE *Statistically significant
Lonn E et al. JAMA 2005.
*13% *19% *21% *40%
Vitamin E increases the Risk of Developing Heart Failure after Myocardial Infarction: Results from the GISSI-Prevenzione Trial : Vitamin E increases the Risk of Developing Heart Failure after Myocardial Infarction: Results from the GISSI-Prevenzione Trial Marchioli R et al. for the GISSI-Prevenzione Investigators. J Cardiovasc Med 2006:7:347-350.
Vitamin E increases the Risk of Heart Failure after MI: Results from the GISSI-Prevenzione Trial : Vitamin E increases the Risk of Heart Failure after MI: Results from the GISSI-Prevenzione Trial Marchioli R et al. for the GISSI-Prevenzione Investigators
Meta-analysis of Antioxidant Supplements for Prevention of Gastrointestinal Cancers : Bjelakovic G et al. Lancet 2004;364:1219-1228
Meta-analysis of Antioxidant Supplements for Prevention of Gastrointestinal Cancers 14 randomized trials; n-179525
No benefit for beta-carotene, vitamins A, C, E and selenium alone or in combination vs. placebo
In some analyses beta-carotene increased mortality
Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality : Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality Miller ER et al. Ann Intern Med 2004;141
Conclusions : Conclusions The available evidence derived from large RCTs shows no benefit for the use of antioxidant vitamin supplements in CV prevention.
Antioxidant vitamins should not be used in CV prevention.
The use of antioxidant vitamin supplements is associated with potential harm.
The available evidence does not refute the “oxidative hypothesis of atherosclerosis”.
There is a need for the study of new antioxidants and of novel strategies to reduce oxidative stress.
Slide34 : AHA Science Advisory
Antioxidant Vitamin Supplements and
Cardiovascular Disease
Penny M. Kris-Etherton, PhD, RD; Alice H. Lichtenstein, DSc; Barbara V. Howard, PhD;
Daniel Steinberg, MD, PhD; Joseph L. Witztum, MD; for the Nutrition Committee of the American
Heart Association Council on Nutrition, Physical Activity, and Metabolism
Summary
At this time, the scientific data do not justify the use of antioxidant vitamin supplements for CVD risk reduction. CVD risk reduction can be achieved by the long-term consumption of diets consistent with the AHA Dietary Guidelines; the long-term maintenance of a healthy body weight through balancing energy intake with regular physical activity; and the attainment of desirable blood cholesterol and lipoprotein profiles and blood pressure levels. No consistent data suggest that consuming micronutrients at levels exceeding those provided by a dietary pattern consistent with AHA Dietary Guidelines will confer additional benefit with regard to CVD risk reduction
..
Circulation 2004; 110:637-641
Why Did the Randomized Controlled Trials of Antioxidant Vitamins Fail? : Why Did the Randomized Controlled Trials of Antioxidant Vitamins Fail? “Fooled” by epidemiology
Vitamin E dose used in trials
Vitamin E preparation
Did we do the right trials? Pro-oxidant in an oxidative milieu
Displacement of gamma-tocopherol
Decrease in HDL2
Homocysteine Production and Metabolism : Methionine S-Adenosyl- methionine Acceptor Methylated
Acceptor Protein (B12) Serine Glycine THF S-Adenosyl- homocysteine Homocysteine 5-Methyl THF 5,10-Methylene THF* MTHFR (B2 ) MS Homocysteine Production and Metabolism (B6) Folate Cycle DMG Betaine BHMT Cystathionine Serine Cysteine (B6) SO42- CBS Transsulfuration Methionine Cycle Remethylation * THF: Tetrahydrofolate
Homocysteine Theory of Atherosclerosis : Homocysteine Theory of Atherosclerosis Severe hyperhomocysteinemia with homocystinuria - rare inborn errors of metabolism caused by several different genetic deficiencies of enzymes in the metabolism homocysteine
Clinical features: Variable, but early neurologic complications and arterial and venous thromboses are common
Biochemical features: High levels of homocysteine (> 100 µmol/L) in plasma and urine
Histopathological features: endothelial injury, arterial stenosis, SMC proliferation
Homocysteine and Atherogenesis : Homocysteine and Atherogenesis In experimental animal models and in human studies homocysteine
Increases oxidative stress
Causes endothelial dysfunction and vascular injury
Increases inflammation
Smooth muscle cell proliferation
Enhances thrombogenicity
Homocysteine and CVD : Homocysteine and CVD Mild to moderate hyperhomocysteinemia is common
Genetic factors – “thermolabile MTHFR”
B Vitamin deficencies
Increased methionine consumption
Age
Male sex
Postmenopausal state
Tobacco use
Renal dysfunction
Hypothyroidism
Diabetes
Severe inflammatory disorders
Drugs
Meta-analysis of Cross-Sectional and Retrospective Case-Control Studies : Meta-analysis of Cross-Sectional and Retrospective Case-Control Studies 0.6 0.7 0.8 0.9 1 2 3 4 5 6 7 8 Coronary Artery Disease—Males Coronary Artery Disease—Females Study Alfthan Stampfer Pancharuniti Israelsson Wu Malinow Genest Ubbink von Eckardstein Summary, All Alfthan Wu Malinow Summary, All Odds Ratio (95% Confidence Interval) Boushey CJ et al. JAMA. 1995;274:1049-1057. CHD: OR=1.7 (1.5-1.9)
CeVD: OR=2.5 (2.0-3.0)
PAD: OR=6.8 (2.9-15.8)
5 μmol/L increase in tHcy
similar risk to 0.5 mmol/L
increase in LDL-C
5 μmol/L decrease in tHcy
→ 1/3 decrease in CHD risk
Homocysteine, Mortality and CAD : Homocysteine, Mortality and CAD 0.70 0.75 0.80 0.85 0.90 0.95 1.00 0 1 2 3 4 5 6 9.0–14.9 µmol/L n=335 15.0–19.9 µmol/L n=44 Years Proportion Surviving P<0.001 for trend Nygård O, et al. N Engl J Med. 1997;337:230-236. <9.0 µmol/L n=125 20.0 µmol/L n=19
Homocysteine A Modifiable CV Risk Factor : Homocysteine A Modifiable CV Risk Factor Graded continuous relationship between homocysteine and CV risk
Even mild to moderate elevations in homocysteine levels are associated with increased CV risk
Evidence from mendelian randomization
Mild to moderate elevations in homocysteine levels are common
Homocysteine levels can be lowered with simple, safe and inexpensive therapy
Folic Acid Lowers Homocysteine Concentrations : Folic Acid Lowers Homocysteine Concentrations Homocysteine Lowering Trialists Collaboration. BMJ 1998;316:896-98.
Potential Impact of Homocysteine Lowering Vitamin Therapy : Potential Impact of Homocysteine Lowering Vitamin Therapy “The lowering of the population mean level of total homocysteine is estimated to have prevented 17,000 deaths from coronary causes each year”
AHA 2005
Homocysteine – a component of the polypill
Wald, Law 2003
HOPE-2 Study Design : HOPE-2 Investigators. N Engl J Med. 2006;354: 157;1567-77. HOPE-2 Study Design Randomized Double-blind Main Study Objective:
To evaluate the effects of homocysteine lowering
with B Vitamins on major CV events
HOPE-2: Baseline Characteristics : HOPE-2: Baseline Characteristics Folate food-fortification status *2.5-mg folic acid/50-mg B6/1-mg B12 % Patients Fortification program
HOPE-2: Baseline Prevalence of CVD : HOPE-2: Baseline Prevalence of CVD Placebo Active* N = 5522 Other CVD history <10% *2.5-mg folic acid/50-mg B6/1-mg B12
HOPE-2: Baseline Prevalence of CV Risk Factors : HOPE-2: Baseline Prevalence of CV Risk Factors Placebo Active* Patients (%) *2.5-mg folic acid/50-mg B6/1-mg B12
N = 5522
Plasma Homocysteine Levels : Plasma Homocysteine Levels 0 1 2 3 4 5 0 2 4 6 8 10 12 14 16 Years Folic Acid + Vitamins B6 and B12 Placebo μmol/L 12.2 13.2 12.9 12.2 9.9 9.7 Difference in change from baseline in homocysteine
levels of 3.3 µmol/L at 2 years and of 3.2 µmol/L at study end Plasma Folate, Pyridoxal and Vitamin B12 levels increased > 2 – 4 fold
Primary Outcome and All-Cause Death : Primary Outcome and All-Cause Death * All patients with this outcome are included
Treatment Effect on the Primary Outcome CV Death, Myocardial Infarction or Stroke : Treatment Effect on the Primary Outcome CV Death, Myocardial Infarction or Stroke
Effect on CV Death and Myocardial Infarction : Effect on CV Death and Myocardial Infarction 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0 1 2 3 4 5 Years 2764 2660 2515 2386 2246 1000 2758 2650 2506 2367 2227 978 No. at Risk Active Placebo Log-Rank P=0.823 Cardiovascular Death Myocardial Infarction Folic Acid + Vitamins B6 and B12 Placebo Proportion of Patients 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0 1 2 3 4 5 Years 2764 2699 2600 2501 2391 1084 2758 2702 2587 2486 2376 1059 No. at Risk Active Placebo Log-Rank P=0.585
Treatment Effect on Stroke : Treatment Effect on Stroke Proportion of Patients 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0 1 2 3 4 5 Years 2764 2671 2562 2442 2315 1048 2758 2686 2560 2442 2326 1030 No. at Risk Active Placebo Log-Rank P=0.025 Folic Acid + Vitamins B6 and B12 Placebo
Blood Pressure : Blood Pressure * p=0.01
Secondary Outcomes : Secondary Outcomes
Other Outcomes : Other Outcomes
Renal HOPE-2: Study Design : Renal HOPE-2: Study Design History of vascular disease or diabetes plus additional atherosclerotic risk factor(s) N = 5522 Randomized Double-blind Folic acid 2.5 mg + vitamins B6 50 mg + B12 1 mg qd n = 307 Placebo n = 312 Random sample with blood sample N = 3310 Estimated GFR (MDRD)* < 60 ml/min N = 619 Primary and secondary outcomes 5 years *eGFR according to the formula developed in the Modification of Diet in Renal Disease (MDRD) study
Baseline Laboratory Values : Baseline Laboratory Values * p<0.01
Plasma Homocysteine Levels in People with Renal Insufficiency : Plasma Homocysteine Levels in People with Renal Insufficiency 0 1 2 3 4 5 0 2 4 6 8 10 12 14 16 Years Folic Acid + Vitamins B6 and B12 Placebo μmol/L Difference in change from baseline in homocysteine
levels of 3.6 µmol/L at 2 years and of 3.8 µmol/L at study end 15.7 16.1 15.5 15.9 12.7 11.9 Plasma Folate, Pyridoxal and Vitamin B12 levels increased > 2 – 4 fold
CV Event Rates (/100pyrs) in Patients with and without Renal Insufficiency : CV Event Rates (/100pyrs) in Patients with and without Renal Insufficiency
Risk of Major CV Events and Death by Quintiles of GFR : Risk of Major CV Events and Death by Quintiles of GFR 1.Q ≥ 90.46
2.Q 80.14 to 90.45
3.Q 80.13 to 71.38
4.Q 80.13 to 71.38
5.Q <60.78 GFR ml/min
Primary Outcome and All-Cause Death in Patients with Renal Insufficiency : Primary Outcome and All-Cause Death in Patients with Renal Insufficiency * All patients with this outcome are included
Treatment Effect on the Primary Outcome in Patients with Low GFR : Treatment Effect on the Primary Outcome in Patients with Low GFR Years Proportion of Patients 0.0 0.10 0.20 0.30 0.40 0 1 2 3 4 5 312 295 276 246 220 112 307 279 258 234 204 100 No. at Risk Placebo Active Folic Acid + Vitamins B6 and B12
Placebo
Secondary and Other Outcomes in Patients with Renal Insufficiency : Secondary and Other Outcomes in Patients with Renal Insufficiency
Treatment Effect on Heart Failure in Patients with Low GFR : Treatment Effect on Heart Failure in Patients with Low GFR Years Proportion of Patients 0.0 0.05 0.10 0.15 0.20 0 1 2 3 4 5 312 300 281 262 241 122 307 280 260 244 218 109 No. at Risk Placebo Folate Folic Acid + Vitamins B6 and B12
Placebo
Clinical Trials of Hcy Lowering : Clinical Trials of Hcy Lowering
Slide68 : Probability of No Recurrent Stroke by Treatment Group VISP O’Toole J. JAMA 2004;291:565-575
Cumulative Risk of Primary Endpoint by Treatment Group : Cumulative Risk of Primary Endpoint by Treatment Group NORVIT Bøona KH et al. N Engl J Med 2006;354
Evidence from Randomized Controlled Trials : Evidence from Randomized Controlled Trials
Evidence from Randomized Controlled Trials : Evidence from Randomized Controlled Trials
How Can We Explain the Results of the Homocysteine Lowering Clinical Trials? : How Can We Explain the Results of the Homocysteine Lowering Clinical Trials? Folate food fortification
“Fooled” by epidemiology
Studies underpowered to show a small (10% RRR) treatment effect
Treatment with folic acid and B vitamins reduces Hcy but causes deleterious effects that offset potential benefits of Hcy lowering
Cell proliferation
DNA methylation → atherogenesis
Asymmetric dimethylarginine → inhibits NOS → endothelial dysfunction
Slide73 : Loscalzo J. N Engl J Med 2006;354:1629-1632 Homocysteine and the Methylation Cycle
Conclusions : Conclusions Current evidence from randomized controlled trials does not support the use of B vitamins in CV prevention
Effects on stroke require further exploration especially in regions without mandatory folate food fortification and in subjects with high homocysteine levels
Complementary and Alternative Medicines CAM : Complementary and Alternative Medicines CAM http://nccamnih.gov-accessed Oct19th ,2006
CAM Therapies Included in the 2002 NHIS : CAM Therapies Included in the 2002 NHIS
Use of CAM : Use of CAM
CAM - Efficacy : CAM - Efficacy Over the past few decades, thousands of studies of various dietary supplements have been performed.
To date, however, no single supplement has been proven effective in a compelling way. http://nccamnih.gov-accessed Oct19th ,2006
CAM - Costs : CAM - Costs The U.S. public spent an estimated $36 billion to $47 billion on CAM therapies in 1997.
In 2002, sales of dietary supplements increased to an estimated $18.7 billion per year, with herbs/botanical supplements accounting for an estimated $4.3 billion in sales.
http://nccamnih.gov-accessed Oct19th, 2006