ASPIRIN AND STATINS FOR PRIMARY PREVENTION

• ASPIRIN AND STATINS FOR PRIMARY PREVENTION WHAT IS NEW AND DOES GENDER REALLY MATTERS? Dr Tali Porter, Head of intermediate ICCU Dept. of Cardiology, Rabin Medical Center- Belinson Campus, Petah Tikva , Tel Aviv University

Case presentation

STATINS -

Correlation Between Serum Cholesterol and CVD Mortality 6 -Year CVD Death Rate Per 1000 30 Multiple Risk Factor Intervention Trial (MRFIT) N=325, 346 Untreated Patients 25 55 -57 years 20 50 -54 years 15 45 -49 years 10 40 -44 years 35 -39 years 5 0 Q 1 (<182) Q 2 (182 -202) Q 3 (203 -220) Q 4 (221 -244) Q 5 (>244) Serum Cholesterol Quintile (mg/d. L) . Kannel WB et al. Am Heart J. 1986; 112: 825 -836.

____________________________________ fetime Risk of CHD Increases with Serum Cholesterol __________________________________ Cholesterol 57 44 34 29 33 19 Framingham Study: Subjects age 40 years DM Lloyd-Jones et al Arch Intern Med 2003; 1966 -1972 ____

Although there are special considerations for the management of high blood cholesterol in women, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) does not recommend different guidelines for men and women

Lipids- women prevention guidelines 2007

How we assess risk ?

The Framingham risk score

Gender and CVD risk factor assessment

The INTERHEART study- Lancet 2004

LIMITATIONS OF CURRENT CARDIOVASCULAR RISK ASSESSEMENT ♠ According to the Framingham cohort, 98%of asymptomatic primary prevention women <59 and 92% of those 60 -69 years ARE CLASSIFIED AS LOW RISK FOR CHD • ♠ Emphasis on life-time risk and not on short- term risk

there has been a growing appreciation of the limitations of risk stratification with the Framingham risk function in diverse populations of women: The Framingham global risk score 20% could be used to identify a woman at high risk but a lower score is not sufficient to ensure that an individual woman is at low risk. Even the presence of a single risk factor at 50 years of age is associated with a substantially increased lifetime absolute risk for CVD and shorter duration

Novel risk factors Small LDL particles Elevated serum homocysteine Elevated serum lipoprotein (a) Elevated Fibrinogen Elevated CRP Calcium score The role of new risk factors as well as new screening modalities may have a strong implication on women cardiovascular risk assessment

Unknown risks A woman found to have: 1) Coronary calcification 2) Increased carotid intimal thickness may be at low absolute risk of CHD on the basis of the Framingham score, but she may actually be at intermediate or high risk of a future CVD event.

? Which women are at risk The panel acknowledged that nearly all women are at risk for CVD, which underscores the importance of a hearthealthy lifestyle”. “ ◦ AHA Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women: 2007 Update

Profile of Dyslipidemia and gender After the age of 50, cholesterol levels plateau in men. In women age 40 -60 , LDL increases an average 0. 05 mmol/L per year. HDL is lower in men, but does not change over the years In menopause women HDL levels decreases

Are Changes in Cardiovascular Disease Risk Factors in Midlife Women Due to Chronological Aging or to the Menopausal Transition? JACC 2009; 54 “total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B demonstrated substantial increases within the 1 -year interval before and after the final menstrual period, consistent with menopause-induced changes. This pattern was similar across ethnic groups Women experience a unique increase in lipids at the time of the FMP. “

SUMMARY OF DATA

Lipid-Lowering Efficacy – does gender matters? The efficacy of atorvastatin in reducing LDL-C levels was evaluated using a pooled dataset of clinical studies. . The data show a consistent dose-related response in both men and women, with improved LDL-C lowering efficacy with increasing doses of atorvastatin. At each dose evaluated, women had slightly higher baseline LDL-C levels. Women also had a slightly better LDL-C lowering effect at most doses compared with the response in men. The difference in mean percent reduction between men and women at a given atorvastatin dose, ranged from 0% to 4%

WATCH –Women Atorvastatin Trial on Cholesterol- Atherosclerosis 1999 The 16 -week study, conducted at 43 centers across Canada with women aged 18 to 75 years of age, enrolled 318 women with CHD and/or risk factors for CAD or other atherosclerotic diseases Under Lipitor Rx (10 mg to 80 mg), 87 percent of women with risk factors for CAD and 81 percent of women with established CAD reached target LDLC levels

AFCASP/ TEx. CAPS The first prevention trial of a statin included men (≥ 45 years) and women (≥ 55 years) with no evidence of atherosclerotic cardiovascular disease. Participants were randomized to either lovastatin 20 – 40 mg/day (n = 3304) or placebo (n = 3301) for a mean follow-up period of 5. 2 years. At 1 year, in the lovastatin group TC, LDL-C, and TG were reduced by 18. 4%, 25. 0%, and 15%, respectively. HDL-C increased by 6. 0%. At 5 years, there was a 37% decrease in the relative risk for having a first acute coronary event Women showed similar relative risk reduction as men.

Trials of statin therapy (* high risk patients)Primary prevention HPS* % of women Treatme nt ALL-HAT LLT* 24. 7 48. 8 ASCOT LLA* 18. 8 PROSPER* WOSCOP AFCASP/ TEx. CAPS 51. 7 0 15 Simvastat Pravastatin Atorvast Pravastatin Pravaststi n 40 mg 20 -40 mg stin 10 40 mg n 40 mg mg Lovaststin 20 -40 mg In: ACOT HPS and POSPER actually most pts had either atherosclerotic manifestation or many risk factors including DM, L----ALHAT-no benefit of statins, underpowered?

Meta-analysis of major outcomes from 5 statin primary prevention trials Outcome Statin. Control RR (95%CI) Total mortality 6. 6 6. 9 0. 95(0. 88 -1. 02) Total MI and Stroke 7. 3 8. 7 0. 84 (0. 78 -0. 90) Total SAE 44. 2 43. 9 1. 01(0. 97 -1. 05) Prosper, ALLHAT, Ascot-LLA, AFCAPS, WOSCOP

Total mortality was not reduced by statin therapy 71 primary prevention pts have to be treated for 3 -5 years to prevent 1 MI or stroke

JUPITER AHA November 9, 2008 A Randomized Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among 17, 802 Apparently Healthy Men and Women With Elevated Levels of C-Reactive Protein (hs. CRP): The JUPITER Trial Paul Ridker*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*, Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*, Alberto Lorenzatti*, Jean Mac. Fadyen, Borge Nordestgaard*, James Shepherd*, James Willerson, and Robert Glynn* on behalf of the JUPITER Trial Study Group An Investigator Initiated Trial Funded by Astra. Zeneca, USA These authors have received research grant support and/or consultation fees •

JUPITER Why Consider Statins for Low LDL, high hs. CRP Patients? AFCAPS/Tex. CAPS Low LDL Subgroups Low LDL, Low hs. CRP [A] Low LDL, High hs. CRP [B] 0. 5 Statin Effective 2. 0 1. 0 RR Statin Not Effective However, while intriguing and of potential public health importance, the observation in AFCAPS/Tex. CAPS that statin therapy might be effective among those with elevated hs. CRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Ridker et al, New Engl J Med 2001; 344: 1959 -5

JUPITER Baseline Blood Levels (median, interquartile range) Ridker et al NEJM 2008 Rosuvastatin hs. CRP, mg/L 4. 2 (2. 8 - 7. 1) 4. 3 (2. 8 - 7. 2) LDL, mg/d. L 108 (94 - 119) HDL, mg/d. L 49 (40 – 60) Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169) Total Cholesterol, mg/d. L 186 (168 - 200) 185 (169 - 199) Glucose, mg/d. L 94 (87 – 102) 94 (88 – 102) Hb. A 1 c, % 5. 7 (5. 4 – 5. 9) 5. 7 (5. 5 – 5. 9)

Ridker et al NEJM 2008 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death HR 0. 56, 95% CI 0. 46 -0. 69 P < 0. 00001 0. 08 JUPITER Placebo 251 / 8901 0. 04 0. 06 - 44 % Rosuvastatin 142 / 8901 0. 00 0. 02 Cumulative Incidence Number Needed to Treat (NNT 5) = 25 0 1 2 4 Follow-up (years) Number at Risk Rosuvastatin Placebo 3 8, 901 8, 631 8, 621 8, 412 8, 353 6, 540 6, 508 3, 893 3, 872 1, 958 1, 963 1, 353 1, 333 983 955 544 534 157 174

Jupiter – the gender aspect In the AHA 11/09, pre-specified gender analysis of the Jupiter trial showed: Treating women with low LDL, but high CRP with rosurvastatin, cut their risk of cardiovascular events in half. The combined end points (MI, stroke, revascularization , hospitalization for ACS and CVD death) was reduced by 46%

BMJ 2009 - new promising meta-analysis Total of 70, 388 pts (34% women), w/o established CAD, with risk factors Statin therapy significantly reduced: ◦ All cause mortality (12%) ◦ Major coronary events (30%) ◦ Major cardiovascular events 19% ◦ No association to increased risk of cancer ◦ No difference was found for end points in men and women

Who should be treated with statins?

Statins- summary When making decisions about initiating lipid- lowering therapy in women, clinicians should consider a woman’s overall risk for CHD. Decisions about treatment of hyperlipidemia and other CHD risk factors will thus depend not only on the woman’s lipid levels, but also her other risk factors for heart disease and her overall risk of experiencing a CHD event

An editorial published in JACC 2009: "It is important for women to understand that their cardiovascular risk factors change during the perimenopausal years and that they need to be vigilant to do everything that they can do to prevent any adverse changes related to lifestyle” “It is important for physicians to assess perimenopausal women to determine whether they now meet treatment thresholds for lipids. “ Monitoring lipids in perimenopausal women should enhance primary prevention of CHD. “

Aspirin

2003 Contact Us Sitemap Bayer filed a Citizen's Petition with the FDA to broaden the professional labeling of aspirin to include an indication for prevention of a first heart attack in individuals at moderate or greater risk of coronary heart disease. defined by a 6 -10% or greater risk over a 10 -year period. Save $1. 00 on any Bayer Aspirin Product (24 ct. or larger) Save $1. 50 on any Bayer Quick Release Crystals (10 ct. or larger) Save up to $3. 00 Contact Us Where to Buy Bayer Links Bayer Global Bayer US Bayer Consumer Care General Conditions of Use Privacy Statement Imprint Aspirin for Pain After all this time, no other OTC analgesic has been proven to be more effective than aspirin in relieving tough pain and, taken under a doctor's direction, reducing inflammation. HOME OUR PRODUCTS THE WONDERS OF ASPIRIN FOR PAIN ASPIRIN FOR THE HEART EMERGING SCIENCE INTERACTIVE TOOLS WORKING WONDERS FAQS HEALTHCARE PROFESSIONALS Copyright © 2009 Bayer Health. Care LLC. All Rights Reserved Unless otherwise indicated, all trademarks are owned by Bayer Health. Care LLC or licensed for its use. Aspirin and Heart Disease Bayer Aspirin can help fight heart disease. Bayer Aspirin can help Aspirin in the Future prevent a heart attack Science continues to or recurrent stroke. discover that aspirin Aspirin is not may potentially hold appropriate for answers to other everyone, so be sure to ailments like certain talk to your doctor cancers and Alzheimer's. before you begin or In fact, aspirin is one of modify an aspirin the most studied drugs regimen. Taken during in the world. a heart attack, aspirin can help save your life by reducing damage to your heart.

Can aspirin therapy help prevent recurrent heart attacks or strokes? Is it true? “Aspirin has been shown to reduce the risk of heart attacks or ischemic strokes in certain people. Aspirin also may help people who suspect they are having a heart attack. Both men and women may benefit from aspirin use. Studies in tens of thousands of women demonstrate aspirin's effectiveness in preventing heart attacks and their adverse consequences. The Nurses Health Study, one of the first large-scale evaluations of the effect of aspirin on women, found that women who regularly take aspirin reduced their chance of a heart attack by 30%.

Aspirin prevention guidelines- 2007 IIB recommendtaion , level of evidence B III recommendation , level of evidence B

A randomized trial of low-dose Aspirin in the primary prevention of CVD in women- Ridker et al NEJM 2005 39, 876 healthy women, > 45 years, received 100 mg aspirin on alternate day or placebo. Follow-up 10 years Results: Non significant reduction in all events (RR 0. 91; 0. 82 -1. 03) 17 % reduction of stroke (RR 0. 83; 0. 69 -0. 99, p=0. 04) Non significant effect on fatal and non-fatal MI, or death from CVD. Non- significant increase in hemorrhagic stroke More frequent significant GI bleeding (RR 1. 4; 1. 07 -1. 83, P= 0. 02) In this trial lowered the risk of ischemic stroke, but had a nonsignificant effect with respect to the primary end-points

Based on the absolute risk reduction of 0. 30% and 0. 37% in women and men, respectively, the number needed to treat to prevent 1 cardiovascular event over the mean follow-up of 6. 4 years was 333 women and 270 men Aspirin therapy for an average of 6. 4 years results in an average absolute benefit of approximately 3 cardiovascular events prevented per 1000 women and 4 cardiovascular events prevented per 1000 men.

Mechanism of differences Several possibilities may explain the differences in cardioprotection observed between the sexes: Evidence exists that there is a difference in aspirin metabolism. Several studies have suggested a reduced pharmacological effect of aspirin among women compared with men. Event rates of stroke and MI differ. Women have a greater proportion of strokes compared with MIs, whereas men have a greater proportion of MIs compared with strokes. Based on the number of events recorded in our analysis, it would be easiest to find a statistically meaningful difference in the risk of stroke among women and in the risk of MI among men. Aspirin resistance tends to be more common among women than men

Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomized controlled trials BMJ 2009; 339: b 4531 When aspirin was compared with placebo there was no statistically significant reduction in the risk of major cardiovascular events, cardiovascular mortality , or all cause mortality Significant heterogeneity was found in the analysis for myocardial infarction (I 2=62. 2%; P=0. 02) and stroke (I 2=52. 5%; P=0. 08). Aspirin significantly reduced the risk of myocardial infarction in men (0. 57, 0. 34 to 0. 94) but not in women (1. 08, 0. 71 to 1. 65; P for interaction=0. 056).

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials The Lancet, , Pages 1849 - 1860, 30 May 2009 In the primary prevention trials, aspirin yielded a 12% proportional reduction in serious vascular events. The main effect was seen on non-fatal MI reduction The net effect on stroke was non significant. Vascular mortality was not affected significantly In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. The proportional hazard reduction was similar among genders

Serious vascular events in primary prevention trials—subgroup analyses Actual numbers for aspirin-allocated trial participants, and adjusted numbers for control-all

Figure 3 Selected outcomes in primary prevention trials of aspirin, by sex Actual numbers for aspirin-allocated trial participants, and adjusted numbers for controlallocated trial participants,

Summary of the meta-analysis A 12% reduction in CVD events (CI 0. 82 -0. 94, p=0. 0001), with no significant heterogeneity among sub-groups. In the primary prevention trials aspirin had no net effect on stroke of known cause. There was no significant reduction in all CVD death The reduction in serious vascular events did not differ among genders

Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U. S. Preventive Services Task Force. Ann Int Med 2009 aspirin use reduces the number of CVD events in patients without known CVD. Men in these studies experienced fewer myocardial infarctions and women experienced fewer ischemic strokes. Aspirin does not seem to affect CVD mortality or all-cause mortality in either men or women. The use of aspirin for primary prevention increases the risk for major bleeding events, primarily gastrointestinal bleeding events, in both men and women. Men have an increased risk for hemorrhagic strokes with aspirin use. A new RCT and meta-analysis suggest that the risk for hemorrhagic strokes in women is not statistically significantly increased.

What have we learned this year? “It's only really since the summer that it's been possible to look at the question with reliable data, “ “ the balance of benefit and risk is really very marginal, especially if you give aspirin on top of safer forms of primary prevention. . It is likely of benefit for preventing MI in men age 45 to 79 and preventing stroke in women 55 to 79, when the benefits outweigh the gastrointestinal risks on an individual-patient basis.

Aspirin—At Risk or Healthy Women Consider aspirin therapy (81 mg daily or 100 mg qod) IF: ● Age > 65 years BP controlled and Benefit for ischemic stroke and MI prevention is likely to outweigh risk of GI bleeding and hemorrhagic stroke Age < 65 years, use aspirin when benefit for ischemic stroke prevention is likely to outweigh adverse effects of therapy Routine use of aspirin in healthy women <65 years is not recommended to prevent MI Mosca L, et al. Circulation 2007

Dose current guidelines recommend 75 mg/d to 162 mg/d of aspirin for primary prevention The Women’s Health Study used a lower dose (100 mg every other day) than currently recommended. However, 100 mg every other day has been found to be as effective as 81 mg/d at inhibiting thromboxane and prostacyclin levels

The take-home message Women are presenting with cardiovascular disease, at a later age, so we can't wait until they are 80 and intervene just then We tailor our intervention based on their risk, so for the higher-risk women, we have to identify them by the traditional risk factors and treat. When traditional risk score is limited, we have to look for other risk factors to see if this is somebody we should start to intervene on more aggressively or if this is somebody for whom we should just recommend less-aggressive therapies Regarding aspirin: We should be careful not to give the impression that aspirin doesn't work. It works, but the balance of benefit/hazard is not good enough for a primaryprevention situation.

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