ARDITH DOMINGUEZ-TAN, MD, FPCC

•Diplomate and Fellow, Philippine College of Physicians Diplomate and Fellow, Philippine College of Cardiology•Assistant Professor, Dept. of Medicine , DLS-Health Sciences Institute College of Medicine•Consultant Cardiologist, De La Salle University Medical Center•Unit Head, Dr. RP Ariniego Cardiovascular Laboratory-De La Salle University Medical Center• Cancer survivor (Non-Hodgkins Lymphoma)

“Statins and Aspirin for Primary Prevention?

What are the current recommendations and risk

stratification measures for its administration?”

Ardith Dominguez-Tan, MD, FPCC

Disclosures:

• Currently lecture for Astra-Zeneca, Sanofi-Aventis, MSD, Hospira

SESSION OBJECTIVES:1. Review existing data on randomized trials

on statins and aspirin in the primary prevention of CV events

2. Review current recommendations on the use of statins and aspirin in primary prevention

3. Propose risk stratification measures to adopt for the use of statins and aspirin in primary prevention

Cardiovascular Disease:• Ranked as the number one cause of

mortality and is a major cause of morbidity worldwide

• In the Philippines, heart disease is the number one cause of death among Filipinos (DOH, Phil. Health Statistics 2004)

• Important goal of medical treatment is to reduce high blood cholesterol

• Statins are the agents of first choice

STATINS

• Benefit of statins proven in secondary prevention trials

• For people without a past history of cardiovascular disease (CVD) the evidence is less clear

• Recommendations for statin use in primary prevention ? Clinical benefit in high vs. lower risk populations?

Framingham Heart Study Prediction

• Separate score sheets are used for men and women and the factors used to estimate risk include • age, blood cholesterol (or LDL cholesterol), HDL

cholesterol, blood pressure, cigarette smoking, and diabetes mellitus.

• Relative risk for CHD is estimated by comparison to low risk Framingham participant

Framingham Heart Study Prediction

• Limitations — Risk assessments that stratify patients according to the number of defined risk factors can identify high-risk persons, but they tend to falsely reassure persons deemed to be at low risk who may have multiple marginal abnormalities. Since the segment of the population with borderline abnormalities of blood pressure and lipids has most of the coronary events, it is important not to overlook these subjects.

SCORE-European High Risk Chart10 year risk of fatal CVD in high risk regions of Europe

SCORE European High Risk ChartCardiovascular Risk Estimation:• 10 yr CV risk should be calculated and used

as the basis to reduce the risk• A total CVD risk of > 20% over 10 years is

defined as HIGH RISK• People with moderate to high risk more

likely to be compliant w/ lifestyle changes and preventive medication

• Intermediate to low-risk ?

LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC)

and Drug Therapy in Different Risk CategoriesNCEP ATP III

Risk CategoryLDL Goal(mg/dL)

LDL Level at Which to Initiate

Therapeutic Lifestyle Changes

(TLC) (mg/dL)

LDL Level at Which

to ConsiderDrug Therapy

(mg/dL)

CHD or CHD Risk Equivalents

(10-year risk >20%)<100 100

130 (100–129: drug

optional)

2+ Risk Factors (10-year risk 20%)

<130 130

10-year risk 10–20%: 130

10-year risk <10%: 160

0–1 Risk Factor <160 160

190 (160–189: LDL-lowering drug

optional)

European guidelines on cardiovascular disease prevention

in clinical practice: Fourth Joint Task Force of the European

Society of Cardiology and Other Societies on Cardiovascular

Disease Prevention in Clinical Practice

Trials on Primary Prevention“Statins for Primary prevention: At what

coronary risk is safety assured?” ( Jackson et al B J Cl Pharm, Oct 2001)

• Methodology- Automated and manual literature search • Major placebo controlled statin outcome trials• Outcome measure - all cause mortality and baseline

values of standard coronary risk factors abstracted for each trial

• Results: • Statin use could be associated with an increase in mortality of 1%

in 10 years• Sufficiently large to negate statins beneficial effect on CHD

mortality in patients w/ event risk < 13% over 10 yrs• CONCLUSION: Absolute safety of statins not demonstrated for

patients at LOW RISK of CHD

“The Benefits of Statins in People without established Cardiovascular Disease but with Cardiovascular Risk Factors: Meta-analysis of

Randomized Controlled Trials” (Brugts et al BMJ 2009)• 10 RCTs, n= 70,388 persons ( women= 34%, DM=23% )• Mean ff-up= 4.1 years• Results: statins reduced the risk of

• All cause mortality OR 0.88 (95% CI: 0.81 to 0.96)• Major coronary events OR 0.70 (95% CI: 0.61 to 0.81)• Major cerebrovascular events OR 0.81 (95% CI: 0.71-0.93)

• No significant heterogeneity in clinical subgroups• CONCLUSION: In patients WITHOUT established CVD but with

cardiovascular risk factors, STATIN use was associated with significantly improved survival and large reductions in the risk of major CV events

“Statin prescription to men and women at cardiovascular risk: to whom and when?” ( Brugts, JJ and Deckers, JW Curr Op in Cardiol 2010)

• Reviewed clinical trials of statins in patients at relatively low risk of cardiovascular disease but w/ CV risk factors

• WOSCOPS, AFCAPS, PROSPER, ALLHAT-LLT, ASCOT-LLA, HPS, CARDS, ASPEN, MEGA, JUPITER

• CONCLUSION: Statins reduce the cardiovascular risk and mortality in low-risk patients without CVD. However, the overall ARR and cost-effectiveness of long-term statin prescription should be kept in mind before prescribing statins to relatively healthy individuals

“Efficacy of statins for primary prevention in people at low cardiovascular risk : a meta-analysis”

(Tonelli M, Lloyd A et al CMAJ Nov 2011)• MEDLINE and EMBASE registries (to Jan. 28 2011 )• Included trials of participants at low CV risk (10 yr risk of

<20%)• Statin vs. placebo or no statin• Results: 29 eligible trials (n=80,711)

• Reduction in: -all-cause mortality

• RR 0.90 (95% CI: 0.84- 0.97) –10 yr risk <20%• RR 0.83 (95% CI: 0.73-0.94)- 10 yr risk <10%

-NFMI RR 0.64 (95% CI: 0.49-0.84)-Non-fatal stroke RR 0.81 (95% CI: 0.68-0.96)

• CONCLUSION: Statins efficacious in preventing death and CV morbidity in people at low CV risk

“Primary Prevention of Cardiovascular Mortality and Events with statin treatments: a network meta-analysis involving more than 65,000 patients”

(JACC Nov. 2008)• Comprehensive search of 10 electronic databases from inception to

May 2008• RCTs of at least 12 month duration • Primary prevention population• Results: 20 RCTs- Reduction in:• 19 trials – all cause mortality RR 0.93 (95% CI: 0.87 to 0.99, p=0.03)• 18 trials - cardiovascular deaths RR 0.89 (95% CI: 0.81 to 0.9, p=0.01)• 17 trials- major cardiovascular events RR 0.85 (95% CI: 0.77 to 0.95,

p=0.004)• 17 trials- MI RR 0.77 (95% CI: 0.63 to 0.95, p=0.01)• CONCLUSION: Statins have a clear role in primary prevention of CVD

mortality and major events

“Statins for the Primary Prevention of Cardiovascular Disease”

(Taylor F, Ward K et al The Cochrane Library 2011)• Cochrane Central Register of Controlled Trials (Issue 1,

2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007)

• To avoid duplication- checked reference lists of previous systematic reviews

• RCTs of statins with minimum duration of 1 yr and ff-up of 6 months• Adults w/ no restrictions on LDL or HDL levels • History of CVD <10%

• Results: 14 RCTs (16 trial arms; 34, 272 participants) 11 RCTs- (raised lipids, diabetes, HPN,

microalbuminuria)• Reduction in:

-all-cause mortality RR 0.84 (95% CI: 0.73-0.96) -combined fatal and nonfatal CVD endpoints RR 0.70 (95% CI: 0.61-0.79) -revascularization rates RR 0.66 (95% CI: 0.53-

0.83)• Reduction in TC and LDL in all trials with evidence of

heterogeneity of effects• No clear evidence of any significant harm caused by statin

prescription of effects on patient quality of life

CONCLUSION: • Reductions in all-cause mortality, major vascular

events and revascularization were found with no excess of cancers or muscle pain among people without evidence of CV disease treated with statins

• Only limited evidence showed that primary prevention with statins may be cost-effective and improve patient quality of life

• Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk

“Statins and All-Cause Mortality in High Risk Primary Prevention” A Meta-analysis of 11

RCTs involving 65, 229 Participants” (Ray et al Arch Intern Med June 2010)

• Computerized literature search of MEDLINE and Cochrane databases (January 1970- May 2009)

• Prospective RCTs of statin therapy in individuals free from CVD at baseline with data on all-cause mortality

• Results: 11 RCTs (n=65, 229) --244,000 person-years• No statistically significant reduction in

• All cause mortality RR 0.91 (95% CI: 0.83-1.01)• No statistical evidence of heterogeneity among studies • CONCLUSION: This literature-based meta analysis did not

find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up

“Statins for the primary prevention of cardiovascular events in older adults: a

review of the evidence” (Ali R, Am J Geriatr Pharmacother Mar 2007)

• Computerized literature search of PubMed database (Jan 1980 to June 2006)

• Results: 6 published trials only 3 included subjects aged >75 yrs

• Data suggests but does not confirm benefit in the elderly subgroup (i.e. >65 yrs old)

• CONCLUSION: Prospective RCTs that better define tolerability, safety and efficacy of statin therapy in older adults w/ elevated cholesterol and intermediate CV risk are needed

“PROSPER: Pravastatin Reduces Cardiovascular Events in the Elderly”

(Lancet 2002)• N=5804 men and women, aged 70-82 yrs• History or risk factors for vascular dse• Pravastatin 40 OD vs. placebo• Ff-up : 3.5 yrs• Results: reduction in

• coronary death, MI or stroke -15%• Coronary mortality- 24%

“Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated CRP”

JUPITER Trial(Ridker et al NEJM Nov 2008)

• n= 17,802 • healthy men and women

• low LDL levels (<130 mg/dL/3.4 mmol/L) • hs CRP > 2.0 mgs/L

• Rosuvastatin 20 mgs vs placebo• Trial stopped after 1.9 years • Results:

• Rosuvastatin reduced LDL=50% and hs CRP=37%

• Reduction in• First major vascular event (NFMI, NF stroke, Hosp for

UA, AR, or confirmed death fr cardiovasc causes)- HR 0.56 (95% CI; 0.46-069; p<0.00001)

• MI HR 0.46 (95% CI;0.3-0.7; p<0.00002)• Stroke HR 0.52 (95% CI;0.34-0.79; p<0.002)• Revasc or UA HR 0.53 (95% CI; 0.4-0.7; p,0.00001)

• CONCLUSION: In apparently healthy persons without hyperlipidemia but with elevated hs CRP levels, rosuvastatin significantly reduced the incidence of major cardiovascular events

Statins in Primary PreventionSummary1. While there is conflicting evidence on the beneficial

effect of the long-term use of statins in primary prevention we cannot ignore the fact that statins do play a role in the reduction of mortality and major events even in the low cardiovascular risk population

2. In estimating an individual/s risk for CHD we need to look beyond the lipid level

3. Additional markers for assessing overall CHD risk (e.g. hsCRP) may need to be put into guidelines especially when assessing the risk of seemingly “healthy” subjects

4. The exact threshold of baseline risk of CVD has not been determined yet and is a challenge for emerging treatment guidelines in primary prevention

5. Despite the fact that scoring systems are available to estimate CHD risk, a thorough medical exam is still warranted

ASPIRIN

• Aspirin is widely recognized and currently approved by BFAD :• to reduce the risk of recurrent ischemic stroke and stroke after transient ischemic attack, • For suspected AMI, and prevention of recurrent MI, • for unstable angina pectoris, • for chronic stable angina pectoris, • for revascularization procedures in selected patients• Primary prevention of CVD in patients with hypertension or diabetes

• In spite of these approvals, aspirin continues to be underutilized in many of these populations. *

• One possible explanation for the underuse of aspirin by patients and physicians is concern regarding the potential for adverse effects and difficulty in assessing aspirin's benefit-to-risk relationship.

1. Stafford RS. Circulation. 2000;101:1097-1101.

Population NFMI Vascular Event

Vascular Death

Source ASA Placebo

ASA Placebo

ASA Placebo

ASA Placebo

PHS1988

11,037

11,034

1.2% 1.9% 2.8% 3.4% 0.7% 0.8%

BDT1991

3,429 1,710 2.3% 2.4% 8.4% 8.5% 4.3% 4.6%

TPT1998

2,545 2,540 3.7% 5.4% 9.0% 10.2%

4.0% 3.2%

HOT1998

9,399 9,391 NR NR 3.4% 3.9% 1.4% 1.5%

PPP2001

2,226 2,269 0.7% 0.8% 6.3% 8.2% 0.8% 1.4%

WHS 2005

19,934

19,942

0.92%

0.90%

2.4% 2.6% 0.6% 0.63%

JPAD 2008

1,262 1,277 1.0% 0.7% 2.2% 2.5% 0.08%

0.8%

POPADAD 2008

638 638 8.6% 8.8% 18.2% 18.3%

6.8% 5.6%

AAA 2010

1,675 1,675 3.7% 4.1% 10.8% 10.5%

2.1% 1.8%

Total 50,868

49,170

1.0% 1.3% 3.6% 4.0% 1.2% 1.1%

Trials on Aspirin for Primary Prevention

Am J Cardiol 2011;107:1796–1801

Results: Aspirin in primary prevention

End point Odds ratio (95% CI)

p

Total CHD 0.85 (0.69-1.06) 0.154

Nonfatal MI 0.81 (0.67-0.99) 0.042

Total CV events

0.86 (0.80-0.93) 0.001

Stroke 0.92 (0.83-1.02) 0.116

CV mortality 0.96 (0.80-1.14) 0.619

All-cause mortality

0.94 (0.88-1.01) 0.115

Bartolucci AA, Tendera M, and Howard G. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol 2011

0.5 0.8 1 2 5

9 randomized trials of aspirin in patients without CHD/CVD

Gastrointestinal Bleeding for the 9 study

Study Aspirin Control Absolute increase

WHS 4.5% 3.8% 0.7%

BMD 0.3% 0.4% -0.1%

PHS 4.0% 3.8% 0.2%

HOT 0.8% 0.4% 0.4%

PPP 0.8% 0.2% 0.6%

TPT 1.4% 0.9% 0.5%

AAAT 0.5% 0.5% 0

JPAD 0.8% 0.3% 0.5%

POPADAD 4.4% 4.9% -0.5%

Mean 1.9% 1.6% 0.3%

Modified from Am J Cardiol 2011;107:1796–1801

Benefit/risk ratio of antiplatelet prophylaxis with aspirin in

different settingsClinical setting Benefita Riskb

Benefit/risk ratio

Number of patients in

whom a major vascular event is avoided per

1000/year

Number of patients in

whom a major GI bleeding

event is caused per 1000/year

Men and women at low-

cardiovascular risk

1–2 1–2 1

Essential hypertension

1–2 1–2 1

High risk for CHD 10 1–2 5–10Modified from Patrono et al., Chest 2008

Patient application:

• If the patient meets all inclusion criteria and has violated none of the exclusion criteria• the results can be applied with considerable confidence.

• Look at the baseline characteristics

• the patient before you may have different attributes or characteristics from those enrolled in the trial. • age, severity of disease, co morbid condition• health-seeking behavior, predicament, values and preferences

“Aspirin for primary prevention of cardiovascular events in people with diabetes: Meta-analysis of

RCTs”(De Berardis BMJ 2009)

• Literature search• 6 RCTs in DM with no known cardiovascular dse.• ASA vs. placebo/no aspirin• Results: • No statistically significant differences in the risk of major

cardiovascular events, CV mortality, all- cause mortality, MI or stroke and “inconsistent” harm from aspirin use.

• By sex, ASA appeared to significantly reduce the risk of MI by 43% but no significant reduction in MI seen in women

• Randomized trials are needed to answer the question about risk and benefit of aspirin in primary prevention in diabetic subjects• A Study of Cardiovascular Events in Diabetes

(ASCEND)• Aspirin and Simvastatin Combination for

Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D)

Benefits of aspirin in cancer• Review of an analyses of published clinical trials

on aspirin • ASA user had a 38% reduction in the risk of

colorectal and other GI cancers compared w/ non-users

• regular ASA users-15% lower CA mortality - 35-40% less metastasis

Jasmer R, MedPage Today March 21, 2012

• However, did not include results from The Women’s Health Initiative and the Physicians Health Study- 2 largest clinical evaluations of ASA effect on cancer risk

• did not demonstrate an effect of aspirin on cancer risk

Aspirin in Primary PreventionSummary

1. the widespread use of aspirin in primary prevention should be weighed carefully in terms of benefit vs. harm especially in the light of its possible beneficial effects in cancer

2. The benefit of aspirin use in the diabetic population remains in question until large scale clinical trial results are in. In the meantime approaches known to minimize CV risk (e.g. avoidance of smoking, use of ACE-I and good glucose control) should be used

Thank You for your Attention!