8 acc prevention ineffective therapies

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



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


*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


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


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


B Vitamins and Folic Acid GuidelinesB Vitamins and Folic Acid Guidelines

I IIa IIb IIISecondary Prevention



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


I IIa IIb III

Hormone Replacement TherapyHormone Replacement TherapyGuidelinesGuidelines


I IIa IIb III



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

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.


Nonsteroidal Anti-inflammatoryNonsteroidal Anti-inflammatoryDrug GuidelinesDrug Guidelines

I IIa IIb III

I IIa IIb III

NSAIDs=Nonsteroidal anti-inflammatory drugs


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


Nonsteroidal Anti-inflammatoryNonsteroidal Anti-inflammatoryDrug Guidelines (Continued)Drug Guidelines (Continued)

COX-2-Cyclooxygenase 2, NSAIDs=Nonsteroidal anti-inflammatory drugs

I IIa IIb III


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.


Nonsteroidal Anti-inflammatoryNonsteroidal Anti-inflammatoryDrug Guidelines (Continued)Drug Guidelines (Continued)

I IIa IIb III


I IIa IIb III

COX-2-Cyclooxygenase 2, NSAIDs=Nonsteroidal anti-inflammatory drugs, NSTE-ACS=Non-ST-segment elevation acute coronary syndrome



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

8 acc prevention ineffective therapies

Health & Medicine