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ACC Prevention Ineffective Therapies
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The Evidence for Current Cardiovascular Disease
Prevention Guidelines:
Ineffective Therapies in Cardiovascular Disease
American College of Cardiology Best Practice Quality Initiative Subcommittee
and Prevention Committee
Classification of Classification of Recommendations and Levels Recommendations and Levels of Evidenceof Evidence
*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.
†In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level.
I IIa IIb III
I IIa IIb III
I IIa IIb III
I IIa IIb III I IIa IIb III
I IIa IIb III
I IIa IIb III
I IIa IIb III
I IIa IIb III
I IIa IIb III
I IIa IIb III
I IIa IIb III
Icons Representing the Classification and Icons Representing the Classification and Evidence Levels for RecommendationsEvidence Levels for Recommendations
Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease
Prevention GuidelinesPrevention Guidelines
Antioxidant Vitamins Evidence Antioxidant Vitamins Evidence and Guidelinesand Guidelines
Nurses Health Study 34% in CHD1 28% in CHD2 --
Health Professionals Follow-Up Study 41% in CHD3** 25% in CHD3** 29% in CHD3**
NHANES 1 -- 42% in CVD4* --
Study Vitamin E Vitamin C Beta-Carotene
Largest Observational Studies
Sources: 1Stampfer MJ et al. NEJM 1993;328:1444-1449
2Osganian SK et al. JACC 2003;42:246-2523Rimm EB et al. NEJM 1993;328:1450-1456
4Enstrom JE et al. Epidemiology 1992;3:194-202
* Applies to men in this study. Women in this study had a 25% relative risk reduction in CVD.
** These finding apply to men only.
CHD=Coronary heart disease, CVD=Cardiovascular disease, NHANES=National Health and Nutrition Examination Survey
Pre-2007 Data on AntioxidantPre-2007 Data on AntioxidantVitamins in Cardiovascular PreventionVitamins in Cardiovascular Prevention
Study Vitamin E Vitamin C Beta-Carotene
ATBC 10% in CHD1 -- 1% in CHD1
Cambridge Heart Antioxidant Study (CHAOS) 47% in CVD2 -- --
GISSI 5% in CVD3 -- --
HOPE NS4 -- --
Beta-Carotene and Retinol Efficacy Trial (CARET)
-- -- 26% in CVD5
Physican’s Health Study (PHS) -- -- 0% in CVD6
Heart Protection Study (HPS) NS7 NS7 NS7
Primary Prevention Project (PPP) 6% in CVD8 -- --
Women’s Health Study 7% in CVD9 -- 17% in CVD10
Largest Randomized Studies
ATBC=Alpha-Tocopherol Beta-Carotene Cancer Prevention study, CHD=Coronary heart disease, CVD=Cardiovascular disease, GISSI=Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico, HOPE=Heart Outcomes Prevention Evaluation study, NS=Non-significant
1Virtamo J et al. Arch Intern Med 1998;158:668-6752Stephens NG et al. Lancet 1996;347:781-786
3GISSI Investigators. Lancet 1999;354:447-5554Yusuf S et al. NEJM 2000;342:154-160
5Omenn GS et al. NEJM 1996;334:1150-11556Hennekens CH et al. NEJM 1996’334:1145-1149
7HPS Collaborative Group Lancet 2002;360:23-338PPP Study Group. Lancet 2001;357:89-95
9Lee IM et al. JAMA 2005;294:56-6510Lee IM et al. J Natl Cancer Inst 1999;92:2102-106
Pre-2007 Data on AntioxidantPre-2007 Data on AntioxidantVitamins in Cardiovascular PreventionVitamins in Cardiovascular Prevention
Physicans’ Health Study II (PHS II)
Sesso HD et al. JAMA 2008;300:2123-2133
*Beta-carotene intervention was stopped by the data and safety monitoring board prior to study
completion
Vitamin C
10.812
8
4
0
HR=0.99P=0.91
Num
ber
of
card
iovasc
ula
r events
**/1
00
0 p
ers
on-
years
10.9
Placebo Vitamin E Placebo
10.8
HR=1.01P=0.86
10.9
**Includes nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death
14,641 men (>50 years) randomized (2 x 2 x 2 x 2) to Vitamin C (500 mg/day), Vitamin E (400 IU every other day), a multivitamin, or beta-
carotene (50 mg every other day)* for a mean of 8 years
Antioxidants provide no benefit to men without cardiovascular disease
Vitamin C and E:Vitamin C and E:Primary PreventionPrimary Prevention
Cook NR et al. Arch Intern Med 2007;167:1610-8
Women’s Antioxidant Cardiovascular Study (WACS)
Vitamin C
731
800
750
700
0
HR=1.02P=0.71
Num
ber
of
majo
r ca
rdio
vasc
ula
r events
*
719
Placebo Vitamin E Placebo
708
HR=0.94P=0.23
742
Beta-Carotene
Placebo
731
HR=1.02P=0.71
719
*Includes myocardial infarction, stroke, coronary reveascularization, or cardiovascular disease death
8,171 women with known CV disease or with >3 CV risk factors randomized (2 x 2 x 2) to Vitamin C (500 mg/day), Vitamin E (600 IU every other day),
or beta carotene (50 mg every other day) for a mean of 9.4 years
Antioxidants provide no benefit to women with CV disease
Vitamin C, E, and Beta Carotene:Vitamin C, E, and Beta Carotene:Secondary PreventionSecondary Prevention
CV=Cardiovascular
Antioxidant vitamin supplements (e.g., vitamins E, C, or beta carotene) should not be used for secondary prevention in NSTE-ACS.
NSTE-ACS=Non-ST-segment elevation acute coronary syndrome
Anderson JL et al. JACC 2007;50:652-726
Antioxidant Vitamin GuidelinesAntioxidant Vitamin Guidelines
I IIa IIb III
Secondary Prevention
Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease
Prevention GuidelinesPrevention Guidelines
B Vitamins and Folic AcidB Vitamins and Folic AcidEvidence and GuidelinesEvidence and Guidelines
Cofactors of Homocysteine
Metabolism
• Vitamin B6
• Vitamin B12
• Folic acid
B Vitamins, Folic Acid, and B Vitamins, Folic Acid, and Homocysteine:Homocysteine:Mechanism of ActionMechanism of Action
Welch G et al. NEJM 1998;338:1042-1050
Wald DS et al. BMJ 2006;333:1114-1117
Pre-2006 Data on B VitaminsPre-2006 Data on B Vitaminsand Folic Acid in CV Preventionand Folic Acid in CV Prevention
Randomized Trials of Lowering Homocysteine Levels
CV=Cardiovascular
Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS)
227
300
200
100
0
HR=1.03P=0.65
Num
ber
of
card
iovasc
ula
r events
*/1
00
00
pers
on-
years
220
Placebo
Albert CM et al. JAMA 2008;299:2027-2036
B-vitamins/Folic acid
12.1
14
12
10
0
P=0.001
Media
n h
om
ocy
stein
e
level (m
icro
mole
s/L)
9.8
Placebo
12.5
P=0.99
11.8
B-vitamins/Folic acid
*Includes myocardial infarction, stroke, coronary revascularization, or cardiovascular disease mortality
5,442 women with known cardiovascular disease or >3 cardiovascular risk factors randomized to folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin
B12 (1 mg) or placebo for 7.3 years
B-vitamins and folic acid provide no benefit in 1o/2o Prevention
B Vitamins and Folic Acid:B Vitamins and Folic Acid:Primary and Secondary PreventionPrimary and Secondary Prevention
HOPE 2 Investigators. NEJM 2006;354:1567-1577
Heart Outcomes Prevention Evaluation (HOPE)-2 Study
DM=Diabetes mellitus
B-vitamins/Folic acid
12.2
14
12
10
0Mean h
om
ocy
stein
e
level (m
icro
mole
s/L)
9.7
Placebo
12.2
12.9
5,522 patients with vascular disease or DM randomized to folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) or placebo for 5 years
B-vitamins and folic acid provide no benefit in 2o Prevention
B Vitamins and Folic Acid:B Vitamins and Folic Acid:Secondary PreventionSecondary Prevention
Bonna KH et al. NEJM 2006;354:1578-1588
• Vitamin B6 (40 mg), Vitamin B12 (0.4 mg), and Folic acid (0.8 mg)†
• Vitamin B12 (0.4 mg) and Folic acid (0.8 mg)‡
• Vitamin B6 (40 mg)^
• Placebo
Treatment Arms
*Includes recurrent myocardial infarction, stroke, and sudden death attributed to coronary artery disease†HR=1.22, P=0.05 compared to placebo, ‡HR=1.08, P=0.31 compared to placebo,
^HR=1.14, P=0.09 compared to placebo
*
Baseline 13.1 12.9 13.3 13.2
Study End 9.5 9.8 13.3 13.6
Homocysteine Level
Vit B6/12 Folic acid
Vit B12 Folic acid
Vit B6 Placebo
B Vitamins and Folic Acid:B Vitamins and Folic Acid:Secondary PreventionSecondary Prevention
Norwegian Vitamin (NORVIT) Trial3,749 patients with a recent myocardial infarction randomized in a 2 x 2
factorial design to B-vitamins + folic acid or placebo for 40 months
B-vitamins and folic acid provide no benefit in 2o Prevention
House AA et al. JAMA 2010;303:1603-1609
*Secondary end point which includes composite of MI, stroke, revascularization, and all-cause mortality
B-vitamins/Folic acid
15.5
20
15
10
0Mean h
om
ocy
stein
e
level (m
icro
mole
s/L)
13.3
Placebo
15.5
18.1 *
P<0.001
B Vitamins and Folic Acid:B Vitamins and Folic Acid:Primary and Secondary PreventionPrimary and Secondary Prevention238 diabetic patients randomized to folic acid (2.5 mg), vitamin B6 (25 mg),
and vitamin B12 (1 mg) or placebo for 31.9 months
B-vitamins and folic acid provide no benefit in diabetics
Folic acid, with or without B6 and B12, should not be used for secondary prevention in NSTE-ACS
NSTE-ACS=Non-ST-segment elevation acute coronary syndrome
Anderson JL et al. JACC 2007;50:652-726
B Vitamins and Folic Acid GuidelinesB Vitamins and Folic Acid Guidelines
I IIa IIb IIISecondary Prevention
Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease
Prevention GuidelinesPrevention Guidelines
Hormone Replacement TherapyHormone Replacement TherapyEvidence and GuidelinesEvidence and Guidelines
Women’s Health Initiative (WHI)
CHD=Coronary heart disease, HRT=Hormone replacement therapy, MI=Myocardial infarction
HR=1.24, 95% CI 0.97-1.60
Hormone Replacement Therapy:Hormone Replacement Therapy:Primary PreventionPrimary Prevention
16,608 postmenopausal women aged 50-79 years randomized to conjugated equine estrogen (0.625 mg) plus medroxyprogesterole
acetate (2.5 mg) or placebo for 5.2 years
HRT provides no cardiovascular benefit
Years of follow up
Non
fata
l MI o
r C
HD
dea
th (
%)
Manson JE et al. NEJM 2003;349:523-534
**P=0.009 for trend-time analysis
Hulley S et al. JAMA 1998;280:605-613
Heart and Estrogen/progestin Replacement Study (HERS)
*Includes coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, transient ischemic attack
or stroke, peripheral arterial disease, and all-cause mortality
2,763 postmenopausal women with known CAD randomized to conjugated equine estrogen (0.625 mg) and medroxyprogesterone acetate (2.5 mg)
or placebo for 4.1 years
HRT provides no CV benefit in women with known CAD
CAD=Coronary artery disease, CV=Cardiovascular, HRT=Hormone replacement therapy
Hormone Replacement Therapy:Hormone Replacement Therapy:Secondary PreventionSecondary Prevention
0
40
50
60
Year 1 Year 2 Year 3 Year 4 + 5
Num
ber
of C
V E
vent
s*
PlaceboHRT
Year RR
123
4+5
1.521.000.870.67
**
Sare GM et al. Eur Heart J 2008;29:2031-2041
Hormone Replacement Therapy:Hormone Replacement Therapy:Primary and Secondary PreventionPrimary and Secondary Prevention
HRT provides no cardiovascular benefit in primary and secondary prevention
Meta-analysis of 35 randomized clinical trials evaluating the effect of hormone replacement therapy on cardiovascular outcomes
HRT with estrogen plus progestin, or estrogen alone, should not be given de novo to postmenopausal women after NSTE-ACS for secondary prevention of coronary events.
Postmenopausal women who are already taking estrogen plus progestin, or estrogen alone, at the time of NSTE-ACS in general should not continue HRT. Women who are more than 1-2 years past the initiation of HRT who wish to continue therapy for another compelling indication should weigh the risks and benefits, recognizing the greater risk of CV events and breast cancer (combination therapy) or stroke (estrogen).
CV=Cardiovascular, HRT=Hormone replacement therapy, NSTE-ACS=Non-ST-segment elevation acute coronary syndrome
Anderson JL et al. JACC 2007;50:652-726
I IIa IIb III
Hormone Replacement TherapyHormone Replacement TherapyGuidelinesGuidelines
Secondary Prevention
I IIa IIb III
Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease
Prevention GuidelinesPrevention Guidelines
Nonsteroidal Anti-inflammatory DrugsNonsteroidal Anti-inflammatory DrugsEvidence and GuidelinesEvidence and Guidelines
Meta-analysis of 121 randomized trials evaluating the CV effects of COX-2 inhibitors
COX-2 NSAIDs increase the risk of adverse CV events
CV=Cardiovascular, COX-2=Cyclooxygenase 2, NSAIDs=Nonsteroidal anti-inflammatory drugs
Nonsteroidal Anti-inflammatory Drugs:Nonsteroidal Anti-inflammatory Drugs:Primary PreventionPrimary Prevention
Kearney PM et al. BMJ 2006;332:1302-1306
*Predominantly includes myocardial infarction and sudden cardiac death
McGettigan P et al. JAMA 2006;296:1633-1644
CV=Cardiovascular, COX-2=Cyclooxygenase 2, NSAIDs=Nonsteroidal anti-inflammatory drugs
Meta-analysis of 23 studies evaluating the CV effects* of NSAIDs
COX-2 NSAIDs increase the risk of adverse CV events
Nonsteroidal Anti-inflammatory Drugs:Nonsteroidal Anti-inflammatory Drugs:Primary and Secondary PreventionPrimary and Secondary Prevention
*Predominantly includes myocardial infarction and sudden cardiac death
McGettigan P et al. JAMA 2006;296:1633-1644
CV=Cardiovascular, COX-2=Cyclooxygenase 2, NSAIDs=Nonsteroidal anti-inflammatory drugs
Meta-analysis of 23 studies evaluating the CV effects* of NSAIDs
COX-2 NSAIDs increase the risk of adverse CV events
Nonsteroidal Anti-inflammatory Drugs:Nonsteroidal Anti-inflammatory Drugs:Primary and Secondary PreventionPrimary and Secondary Prevention
CV=Cardiovascular
Meta-analysis of 6 randomized trials evaluating the CV effects of celecoxib
There is a dose dependent increase in CV risk with celecoxib
Nonsteroidal Anti-inflammatory Drugs:Nonsteroidal Anti-inflammatory Drugs:Primary and Secondary PreventionPrimary and Secondary Prevention
Cel
ecox
ib r
egim
en
Solomon SD et al. Circulation 2008;117:2104-2013
CV=Cardiovascular, NSAIDs=Nonsteroidal anti-inflammatory drugs, MI=Myocardial infarction
Nonsteroidal Anti-inflammatory Drugs:Nonsteroidal Anti-inflammatory Drugs:Secondary PreventionSecondary Prevention
Case-crossover analysis of the death rate relative to NSAIDs in 58,432 patients discharged following an acute MI
NSAIDs in patients with previous MI increase the risk of adverse CV events
Gislason GH et al. Circulation 2006;113:2906-2913
CV=Cardiovascular, COX-1=Cyclooxygenase 1, COX-2=Cyclooxygenase 2, GI=Gastrointestinal
Nonsteroidal Anti-inflammatory Drugs:Nonsteroidal Anti-inflammatory Drugs:Balance of CV and GI RisksBalance of CV and GI Risks
Grosser T et al. JCI 2006;116:4-15
ASA=Aspirin, CV=Cardiovascular, COX-2=Cyclooxygenase 2, NSAIDs=Nonsteroidal anti-inflammatory drugs
Stepwise Approach to PharmacologicStepwise Approach to PharmacologicTherapy for Musculoskeletal DiseaseTherapy for Musculoskeletal Disease
Antman EM et al. Circulation 2007;115:1634-1642
At hospital discharge, the patient’s need for treatment of chronic musculoskeletal discomfort should be assessed, and a stepped-care approach to treatment should be used, starting with acetaminophen, small doses of narcotics, or nonacetylated salicylates.
It is reasonable to use nonselective NSAIDs, such as naproxen, if initial therapy with acetaminophen, small doses of narcotics, or nonacetylated salicylates is insufficient.
Anderson JL et al. JACC 2007;50:652-726
Nonsteroidal Anti-inflammatoryNonsteroidal Anti-inflammatoryDrug GuidelinesDrug Guidelines
I IIa IIb III
I IIa IIb III
NSAIDs=Nonsteroidal anti-inflammatory drugs
Secondary Prevention
It is reasonable to use nonselective NSAIDs, NSAIDs with increasing degrees of relative COX-2 selectivity may be considered for pain relief only for situations in which intolerable discomfort persists despite attempts at stepped-care therapy with acetaminophen, small doses of narcotics, nonacetylated salicylates, or nonselective NSAIDs. In all cases, the lowest effective doses should be used for the shortest possible time
Anderson JL et al. JACC 2007;50:652-726
Nonsteroidal Anti-inflammatoryNonsteroidal Anti-inflammatoryDrug Guidelines (Continued)Drug Guidelines (Continued)
COX-2-Cyclooxygenase 2, NSAIDs=Nonsteroidal anti-inflammatory drugs
I IIa IIb III
Secondary Prevention
NSAIDs with increasing degrees of relative COX-2 selectivity may be considered for pain relief only for situations in which intolerable discomfort persists despite attempts at stepped-care therapy with acetaminophen, small doses of narcotics, nonacetylated salicylates, or nonselective NSAIDs. In all cases, the lowest effective doses should be used for the shortest possible time.
NSAIDs with increasing degrees of relative COX-2 selectivity should not be administered to NSTE-ACS patients with chronic musculoskeletal discomfort when therapy with acetaminophen, small doses of narcotics, nonacetylated salicylates, or nonselective NSAIDs provides acceptable levels of pain relief.
Anderson JL et al. JACC 2007;50:652-726
Nonsteroidal Anti-inflammatoryNonsteroidal Anti-inflammatoryDrug Guidelines (Continued)Drug Guidelines (Continued)
I IIa IIb III
Secondary Prevention
I IIa IIb III
COX-2-Cyclooxygenase 2, NSAIDs=Nonsteroidal anti-inflammatory drugs, NSTE-ACS=Non-ST-segment elevation acute coronary syndrome
Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease
Prevention GuidelinesPrevention Guidelines
Other TherapyOther TherapyEvidence and GuidelinesEvidence and Guidelines
Cardiovascular Health Study (CHS) Substudy
Ginkgo Biloba:Ginkgo Biloba:Primary and Secondary PreventionPrimary and Secondary Prevention
10.5
30
20
10
0
HR=1.16P=0.30
Rat
e of
ca
rdio
vasc
ular
eve
nts
per
1000
per
son-
year
s (%
)
12.1
5.0
HR=1.06P=0.78
5.3
Myocardial infarction
22.2
HR=1.04P=0.70
23.0
CHD Death Total Death
Ginko bilobaPlacebo
3,069 patients (>75 years) randomized to Ginkgo biloba (120 mg/day) or placebo for a mean of 6.1 years
Ginkgo biloba has no effect on the rate of MI or death
Kuller LH et al. Circ Cardiovasc Qual Outcomes 2010;3:41-47
CHD=Coronary heart disease, MI=Myocardial infarction
Multivitamin:Multivitamin:Primary and Secondary PreventionPrimary and Secondary Prevention
Placebo Multivitamin
Physicians’ Health Study II14641 men randomized to a daily multivitamin or placebo for a
median of 11.2 years
A multivitamin had no effect on the rate of adverse CV events
Sesso HD et al. JAMA 2012;308:1751-1760
CV=Cardiovascular