Case Study II Does Gender Matter in Cardiovascular Risk Assessment?

JR is a 69-year-old white female with longstanding, well-controlled hypertension treated with an ACE-inhibitor who comes in for a cardiovascular risk evaluation. She denies a personal history of diabetes, tobacco abuse, psoriasis, collagen vascular disease, or chronic kidney disease. There is no family history of premature vascular disease. She is moderately active and has no clinical symptoms referable to the cardiovascular system. Her medications also include anti-depressants and supplemental thyroid.

Her blood pressure is 135/85. Her physical examination and electrocardiogram are normal. There are no findings of left ventricular hypertrophy.

Routine chemistries reveal normal renal function, fasting blood glucose, and thyroid stimulating hormone. On fasting lipid profile total cholesterol is 260 mg/dL, triglycerides 156 mg/dL, HDL-C 72 mg/dL, LDL-C 157 mg/dL and non-HDL-C 188 mg/dL.

Does she need an aspirin and what are her lipid goals?

In the Women’s Health Study, 39,856 women over the age of 45 without baseline cardiovascular disease (CVD) were randomized to low dose aspirin versus placebo and followed for an average of 10 years. In this study, there was no advantage to the use of aspirin 100 mg every other day in the reduction of a combined endpoint of stroke, non- fatal myocardial infarction (MI), or cardiovascular death. However, there was a significant 17% reduction in the risk of stroke. There was a 24% reduction in ischemic stroke risk and a non-statistically significant increase in hemorrhagic stroke risk. In a subgroup analysis of women over the age of 65, aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and MI.¹

The 2011 American Heart Association (AHA) Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women recommends the use of aspirin therapy in women 65 years of age or older (81 mg daily or 100 mg every other day) if blood pressure is controlled and the benefit for ischemic stroke and MI prevention is likely to outweigh the risk of gastrointestinal bleeding and hemorrhagic stroke. These guidelines also note that aspirin may be reasonable for women less than 65 years of age for ischemic stroke prevention.²

It is important to note the gender differences in the benefit of aspirin, as the data from the Physicians Health Study, although older, demonstrated a 44% reduction in the risk of MI in men who took 325 mg of aspirin every other day compared with those who received placebo.³ This gender difference in the effectiveness of aspirin may be related to differences in vascular pathophysiology, and is highlighted by demographic trends. In 2008, there were 419,700 women and 392,200 men who died of CVD.⁴ Death from coronary heart disease (CHD) or MI was more common in men (73% of the men versus 59% of the women). However, death from stroke, hypertension, or congestive heart failure was more common in women (35% of the women versus 26% of the men).⁴

The 2009 U.S. Preventive Services Task Force (USPSTF) recommends the use of aspirin in women ages 55 to 79 for stroke prevention when the potential benefit outweighs the potential risk of gastrointestinal bleeding. Specifically, for women ages 60-69, aspirin is recommended when the 10 year risk of stroke is 8% or greater.⁵ For comparison, the USPSTF recommends the use of aspirin for prevention of MI in men ages 45 to 79 years when the potential benefit outweighs the potential harm.⁵

JR’s risk of developing a stroke in the next ten years is 8%, which exceeds the average risk in the United States of 7.2%.^6,7 Based on both the USPSTF recommendations and the AHA Prevention Guidelines for Women, low dose aspirin is a very reasonable recommendation for JR.

How about a statin?

Statins have been proven to reduce the risk of stroke in both primary and secondary prevention trials. In the Heart Protection Study, 20,536 high-risk patients were randomized to moderatedose statin versus placebo. In this trial, statin use was associated with a 25% relative risk reduction in the occurrence of a first stroke event, regardless of baseline LDL-C level.⁸ A recent metaanalysis by the Cholesterol Treatment Trialists’ Collaborators also demonstrated a significant reduction in stroke risk with statin use and subsequent LDL-C reduction, regardless of baseline risk level.⁹

Although stroke risk is lowered with statins, we generally consider the recommendation for statin therapy based on a patient’s overall cardiovascular risk and the benefit of reducing all CVD events.

Based on JR’s traditional Framingham risk factors (age and hypertension, minus one for having an HDL-C > 60 mg/dL), she would fall into the low risk category (0-1 risk factor) with a LDL-C treatment target of less than 160 mg/dL and a non-HDL-C target of less than 190 mg/dL.¹⁰ Following the step-wise approach recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), we would not be expected to calculate a Framingham risk score. Even if we did, her 10-year risk of coronary death or MI would also fall into the low risk category at 6%, notably lower than her estimated 10-year stroke risk of 8%.

Therefore, JR’s LDL-C of 156 mg/dL seems to be within her treatment goal as does her non-HDL-C. Should we really stop here or are we missing something?

It is now well-recognized that the traditional Framingham risk assessment has limitations and can underestimate risk in women, especially in young women. Some of these limitations include: the focus on short-term (ie.10-year) risk of "hard" coronary outcomes only (MI or CHD death), the lack of inclusion of family history in risk calculators, overestimation or underestimation of risk in nonwhite populations, and the fact that subclinical CVD can have a relatively high prevalence among women who are scored as being at low risk.² In order to address some of these limitations, alternative risk stratification schemes have been adopted in certain guidelines such as the AHA Prevention Guidelines for Women.² Indeed the AHA guidelines propose three risk categories: high risk, at risk, and ideal risk. JR would fall into the "at risk" category based on her risk factors of hypertension and elevated total cholesterol. Of note, this "at risk" category also includes nontraditional risk factors, which JR doesn’t have, such as poor exercise capacity, lupus or rheumatoid arthritis, and evidence of subclinical CVD. For "at risk" women, the AHA guidelines do recommend calculating a Framingham risk score using the newest Framingham risk calculator in order to further refine treatment targets.

As noted above, one of the limitations of the traditional Framingham risk calculation is that it only estimates the 10-year risk of CHD death or MI, and does not account for other vascular events. A newer risk assessment model, also based on Framingham data, expands the risk calculation to include all first cardiovascular events such as coronary artery disease, stroke, manifestations of peripheral vascular disease, or heart failure.¹¹ If we calculate JR’s "general cardiovascular risk score," she actually falls into the moderate risk category with a 13.7% risk of developing a major vascular event in the next 10 years.^11,12 This general CVD risk profile also calculates a "vascular age," which is a translation of the patient’s general CVD risk points to the equivalent age assuming all other risk factors are optimal. JR’s vascular age is greater than 80, over 10 years older than her biologic age. Based on her general CVD risk score, JR’s LDL-C goal would be less than 130 mg/dL with an optional goal of less than 100 mg/dL, and she would qualify for a statin as first line therapy in addition to lifestyle counseling to achieve her LDL-C target.¹³

One other important concept for assessing and communicating cardiovascular risk is that of "lifetime risk." For many patients, especially young patients, 10-year risk is relatively short term, and the Framingham risk score may be very low unless there are multiple uncontrolled risk factors. Lifetime risk or 30-year risk has emerged as a tool that better reflects the cumulative burden of risk factors over a much longer period of time. A high lifetime risk can identify patients who may be at low short-term risk, but would certainly benefit from additional lifestyle counseling or even preventive pharmacotherapies. Based on data from the Cardiovascular Lifetime Risk Pooling Project, JR’s lifetime risk (to the age of 90) of any event related to atherosclerotic CVD is estimated at 38.7% based on her age and the presence of 2 major risk factors (treated hypertension and total cholesterol greater than 240 mg/dL). For comparison, her risk would be 12.4% if all risk factors were optimal.¹⁴

For JR, a statin should be recommended in addition to aspirin to lower her overall risk of CVD, including both coronary events and stroke. Her recommended LDL-C goal should be less than 130 mg/dL with an optional goal of less than 100 mg/dL, and a moderate dose statin should be prescribed to achieve this goal.

Disclosure statement: Dr. Duffy has received grants from Roche/Genentech, Forest Laboratories, and Abbott Laboratories. Dr. Goldenberg has received honoraria related to speaking from Takeda Pharmaceuticals, Boehinger-Ingelheim, Abbott Laboratories, and Merck & Co. Dr. Goldenberg has received consulting fees from Amarin Corporation.