Aspirin and Statins for primary preventionWhat is new anddoes gender really matters? Dr Tali Porter, Head of intermediate ICCU - Dept. of Cardiology, Rabin Medical Center- Belinson Campus, Petah Tikva, Tel Aviv University
Correlation Between Serum Cholesterol and CVD Mortality Multiple Risk Factor Intervention Trial (MRFIT) N=325,346 30 Untreated Patients 25 55-57 years 50-54 years 20 15 6-Year CVD Death Rate Per 1000 45-49 years 10 40-44 years 35-39 years 5 0 Q1 (<182) Q2 (182-202) Q3 (203-220) Q4 (221-244) Q5 (>244) Serum Cholesterol Quintile (mg/dL) . Kannel WB et al. Am Heart J. 1986;112:825-836.
______________________________________________________________________________________________________________________________________________________________ Lifetime Risk of CHD Increases with Serum Cholesterol ___________________________________________________________________________ Cholesterol 57 44 34 33 29 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
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 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
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: • Coronary calcification • 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 heart-healthy 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 0.05mmol/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 withinthe 1-year interval before and after the final menstrual period, consistent withmenopause-induced changes. This pattern was similar across ethnicgroups • Women experience a unique increase in lipids at the time ofthe FMP. “
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 AtorvastatinTrial 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 LDL-C levels
AFCASP/TExCAPS • 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. Only 17% of pts had NCEP criteria for Rx
Trials of statin therapy (* high risk patients)-Primary prevention 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 preventiontrials Prosper, ALLHAT,Ascot-LLA, AFCAPS, WOSCOP
Total mortality was not reduced by statin therapy 71primary preventionpts 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 (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 • .
JUPITER Why Consider Statins for Low LDL, high hsCRP Patients? AFCAPS/TexCAPS Low LDL Subgroups Low LDL, Low hsCRP Low LDL, High hsCRP Low LDL, Low hsCRP Low LDL, High hsCRP [A] [B] 0.5 2.0 1.0 0.5 2.0 1.0 RR Statin Effective Statin Not Effective Statin Effective Statin Not Effective 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
JUPITER Baseline Blood Levels (median, interquartile range) Ridker et al NEJM 2008 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)
JUPITER Primary Trial Endpoint :MI, Stroke, UA/Revascularization, CV Death Ridker et al NEJM 2008 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Placebo 251 / 8901 0.08 Number Needed to Treat (NNT5) = 25 - 44 % 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 0 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
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%
BMJ2009- 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
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 enhanceprimary prevention of CHD. “
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%.
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 non-significant effect with respect to the primary end-points