Dr Tali Porter,

Head of intermediate ICCU - Dept. of Cardiology, Rabin Medical Center- Belinson Campus, Petah Tikva, Tel Aviv University

Case presentation

-STATINS

.Kannel WB et al. Am Heart J. 1986;112:825-836.

Multiple Risk Factor Intervention Trial (MRFIT) N=325,346

Correlation Between Serum Cholesterol and CVD Mortality

6-Y

ear

CV

D D

eath

Rat

e P

er

100

0

0

5

10

15

20

25

30

Q1

<(182)

Q2

(182-202)

Q3

(203-220)

Q4

(221-244)

Q5

>(244)

35-39 years

40-44 years

45-49 years

50-54 years

55-57 years

Serum Cholesterol Quintile (mg/dL)

Untreated Patients

Lifetime Risk of CHD Lifetime Risk of CHD Increases with Increases with Serum CholesterolSerum Cholesterol

0

10

20

30

40

50

60

Per

cent

Men Women

<200 mg

200-239 mg

>240 mg

Framingham Study: Subjects age 40 years

DM Lloyd-Jones et al Arch Intern Med 2003; 1966-1972

34

44

57

19

2933

Cholesterol

___________________________________________________________________________

_______________________________________________________________________________

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

How we assess risk?

The Framingham risk score

Gender and CVD risk factor assessment

♠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 score20% 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

Small LDL particlesElevated serum homocysteineElevated serum lipoprotein (a) Elevated FibrinogenElevated CRPCalcium 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.

“The panel acknowledged that nearly all women are at risk for CVD, which underscores the importance of a heart-healthy lifestyle”.

◦ AHA Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women: 2007 Update

After the age of 50, cholesterol levels plateau in men.

In women age 40-60 , LDL increases an average 0.05mmol/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%

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 LDL-C levels

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.

HPS*ALL-HAT LLT*

ASCOT LLA*

PROSPER*

WOSCOP

AFCASP/TExCAPS

% of women

24.748.818.851.7015

Treatment

Simvastatn 40 mg

Pravastatin 20-40 mg

Atorvaststin 10 mg

Pravastatin 40 mg

Pravaststin 40 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?

OutcomeStatinControl

RR (95%CI)

Total mortality

6.66.90.95)0.88-1.02(

Total MI and Stroke

7.38.70.84) 0.78-0.90(

Total SAE44.243.91.01)0.97-1.05(

Prosper, ALLHAT,Ascot-LLA, AFCAPS, WOSCOP

JUPITERAHA 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 )hsCRP(:

The JUPITER Trial

Paul Ridker*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest,*

Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby,*

Alberto Lorenzatti*, Jean MacFadyen, Borge Nordestgaard ,*James Shepherd*, James Willerson, and Robert Glynn *

on behalf of the JUPITER Trial Study Group

An Investigator Initiated Trial Funded by AstraZeneca, USA

•These authors have received research grant support and/or consultation fees from one or more

•.

JUPITERWhy Consider Statins for Low LDL, high hsCRP Patients?

However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP 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

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.00.5

[A]

[B]

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.00.5

AFCAPS/TexCAPS Low LDL Subgroups

RR

JUPITERBaseline Blood Levels )median, interquartile range(

Rosuvastatin

hsCRP, mg/L 4.2 (2.8 - 7.1) 4.3 (2.8 - 7.2) LDL, mg/dL 108 (94 - 119) 108 (94 - 119)

HDL, mg/dL 49 (40 – 60) 49 (40 – 60)

Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169)

Total Cholesterol, mg/dL 186 (168 - 200) 185 (169 - 199)

Glucose, mg/dL 94 (87 – 102) 94 (88 – 102)

HbA1c, % 5.7 (5.4 – 5.9) 5.7 (5.5 – 5.9)

Ridker et al NEJM 2008

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69P < 0.00001

Number Needed to Treat )NNT5( = 25

-44%

0 1 2 3 4

0.0

00

.02

0.0

40

.06

0.0

8

Cu

mu

lati

ve In

cid

ence

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Ridker et al NEJM 2008

Jupiter – the gender aspectIn 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?

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

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2003

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.

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%.

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

non-significant 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 differencesMechanism of differencesSeveral 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:b4531

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 (I2=62.2%; P=0.02) and stroke (I2=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 reductionThe net effect on stroke was non significant.Vascular mortality was not affected significantlyIn 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 analysesActual numbers for aspirin-allocated trial participants, and adjusted numbers for control-allocated trial participants, are presented, together with the corresponding mean yearly event rates (in parentheses). Rate ratios (RRs) for all trials are indicated by squares and their 99% CIs by horizontal lines. Subtotals and their 95% CIs are represented by diamonds. Squares or diamonds to the left of the solid line indicate benefit. A global test for heterogeneity (χ2 on 11 degrees of freedom) is provided. Unknown values are not plotted. SBP=systolic blood pressure. DBP=diastolic blood pressure. BMI=body-mass index. CHD=coronary heart disease. *Excluding patients with a history of vascular disease.

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

Summary of the meta-analysisA 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 WomenAspirin—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 MIMosca L, et al. Circulation 2007

Dosecurrent 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 primary-prevention situation.

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