Preventing Coronary Heart Disease in Women:

Q: Many of my older women patients think theyare at much higher risk for breast cancer thancoronary heart disease (CHD). How can we raise women'sawareness about their risks of CHD and therebyencourage them to take measures to prevent it?

A: All clinicians have to educate women about their vulnerabilityto CHD and recommend ways to lower theircoronary risk. Almost a quarter of a million American womendie of CHD each year, compared with 40,000 who die of breastcancer.¹ Postmenopausal women have a 31% lifetime risk ofdying of CHD, compared with a 2.8% risk each from hip fracture(as a surrogate for osteoporosis) or breast cancer. One in3 women older than 65 years has clinical evidence of CHD.

Q: Acute myocardial infarction (MI) is underdiagnosedin women far more frequently than in men. Whatare the chief diagnostic pitfalls?

A: In both sexes, chest pain is by far the most prevalentpresenting symptom. But an atypical presentationis much more common in women than in men.Women with MI may describe pain in the neck, arms,back, shoulder, or abdomen. A presentation that involvessuch diffuse pain can complicate the diagnosis. Generally,however, even such nonspecific symptoms havean acute onset and should not be discounted. A womanmay experience such symptoms and not understandtheir potential ominous significance. If she makes anappointment to see her physician 2 or 3 days later, theacute phase may have passed and the MI may never bediagnosed. Or worse -she may not live to keep thatappointment.

Furthermore, a subgroup of older patients of bothsexes -many of whom are women with diabetes -may notexperience any pain during an MI. They may feel extremefatigue, shortness of breath, or a sensation of being "totallywashed-out." Even in this group, however, the onset ofsymptoms is relatively abrupt, and patients may thereforego to the emergency department(ED). In this setting, ahigh index of suspicion among health care professionals isabsolutely crucial.

ED physicians sometimes follow the patient's leadand take the wrong diagnostic path. Some women whodo not understand the nature of their symptoms willclutch their chests and say, "I'm having indigestion."Incontrast, a man with the same symptoms and presentationwill say, "I'm having a heart attack," and will be managedappropriately. If we educate women to realize thatthey are vulnerable to CHD and MI, many more will realizethat their symptoms may be far more serious thanindigestion.

Q: Does underdiagnosis of MI in women accountfor the fact that women are also undertreatedfor CHD?

A: Unfortunately, yes. Women in an ED are treated less frequently than they should be with thrombolytic therapyand less often than men with ß-blockers, aspirin, angiotensin-converting enzyme inhibitors, and other drugs.³This is not because physicians choose to undertreat women;it's simply that MI is often not suspected, and therefore urgentECG and other diagnostic tests are not done. This results inomission or delay of life-saving therapies.

Also, women typically present to the hospital later thantheir male counterparts following symptom onset. This istrue not only with a first MI, but with recurrent MI as well.Delayed hospital admission means that women may missthe window of opportunity for certaininterventions, particularly coronarythrombolysis.

Q: Women have worse outcomesthan men after treatmentfor MI. Is this a result of inherentbiologic differences, of age atpresentation, or other factors?

A: Women aged 60 to 70 yearshave higher mortality after MIthan age-matched men, both duringhospitalization and in the first 2 yearsafter the event. It is not yet clearwhether this is a function of biologicdifferences, risk factors, treatment issues,or comorbidity. Women with afirst MI are likely to have a higher riskfactor burden than men -that is, theytend to have concomitant diabetes,hypertension, and/or dyslipidemia.When we adjust the data for these conditions,the differences in mortality decrease,but the higher incidence ofdeath in women does not disappear.The obvious challenge, then, becomes primary prevention:if we address risk factors earlier and more aggressively, wemight significantly reduce women's cardiovascular risk.

Although the absolute risk of coronary events in bothsexes increases with age and although CHD is most commonin older women, younger women are at risk as well -andthese younger women have worse outcomes than their malecounterparts after both MI and coronary artery bypass graft(CABG>) surgery. The reasons for this are unclear. Amongwomen younger than 50 years, post-MI mortality is more thantwice as high as among men of the same age ⁴.Following MI,a young woman is also at very high risk for recurrence.

Mortality for men and women after MI is similaramong those older than 75 years. Among the very elderly,however, women with MI tend to do slightly betterthan men. These differences have not been explained.One possible reason for the fact that women generallyoutlive men is that women seem to incur most of their seriousdiseases later in life, whereas men are more likelyto be afflicted in middle age. Perhaps this is another reasonthat CHD in women has been neglected: the preponderanceof CHD is in elderly women. These women areno longer at the peak of their family or career responsibilities;perhaps they're retired. Their illness is not as visibleas in men with CHD, who may be stricken at thepeak of their career and family obligations.

Q: Which risk factors for CHDshould I be especiallyconcerned about in my femalepatients?

A: Cigarette smoking and diabetesare strongly associated with anincreased risk of CHD in women. Cigarettesmoking seems to be a particularlyimportant risk factor in youngerwomen, possibly because smoking isoften their major risk factor. Smokingis strongly associated with plaque erosionin premenopausal women. ⁵Moreyoung women take up the smokinghabit than any other subgroup. Thisputs them at greatly increased risk.

Diabetes virtually abolishes thesex-based cardiovascular protectionthat is presumed in women. Womenwith diabetes are at much higher riskfor MI than diabetic men; their risk isthe same as that of women who've alreadyhad an MI. Diabetes appears togreatly magnify the adverse effects ofother risk factors, such as smoking, hypercholesterolemia,and hypertension.⁶ Moreover, women with diabetes aremore likely to have unfavorable lipid profiles and to be hypertensiveand obese. The reasons and the mechanismshave yet to be completely elucidated.

Q: What constitutes optimal medical treatment ofwomen with diabetes who are approachingmenopause?

A: Precise control of blood glucose levels is imperative,as is aggressive management of associated dyslipidemiaand hypertension. Since diabetes is considered acoronary risk equivalent, the goal levels for blood pressure and for lipids in patients with diabetes are the same as forpersons with known CHD. Lifestyle modification is also important.Women with diabetes must quit smoking, eat aheart-healthy diet, lose weight if necessary, and engage indaily moderate-intensity physical activity.

Q: Do women fare better with CABG surgeryor percutaneous transluminal coronaryangioplasty (PTCA)?

A: CABG surgery is the only option for some women(and men), primarily because of the nature of theircoronary anatomy. However, a sizeable database from theSociety of Thoracic Surgeons showsthat women die at nearly twice therate of men who have had CABGsurgery. Again, it's unclear whetherthis is related to sex or risk factors.Many women who require CABGsurgery present in a more urgent setting,which obviously increases therisk. Perhaps we have to considersurgery earlier, following more timelyevaluation of symptoms and riskstratification procedures. Nevertheless, women who requirebut do not undergo CABG surgery have muchworse short- and long-term outcomes with medical therapythan women who have had the surgery.The saga of elective PTCA is an evolving one. In theearlier registries from the National Heart, Lung, andBlood Institute (1985/1986 and 1993/1994), the incidenceof procedural morbidity and mortality was higher in women than men. An analysis of data from the 1997/1998registry shows that for the first time women and menhad similar outcomes.⁷ Newer data from the dynamicPTCA registry are even more favorable for women.Even though the women are older and sicker, they do aswell as the younger and less sick women in the earlierregistries. This success is probably attributable to acombination of factors, including increased operator experience;the selection of women who are more appropriatecandidates for PTCA; the use of equipment that isbetter suited to women's coronary anatomy; the use ofstents; and adjunctive medical therapy, particularly antiplateletagents.

Q: In the setting of acute MI, dowomen have better outcomeswith thrombolysis or PTCA?

A: An increasing body of evidencedemonstrates that all patientsseem to do somewhat better with primaryPTCA in terms of both morbidityand mortality. Women seem to domuch better with this procedure, becausethey have a higher incidence of bleeding and hemorrhagicstroke with thrombolysis. It's unclear whether theincreased bleeding is associated with the thrombolyticagent, heparin, or a combination, because much of the olderdata was accumulated before weight-based heparin dosingbecame the norm. Obviously, if the same dosages wereused for women and men, many women received inappropriatedoses.

Q: The International Position Paper on Women'sHealth and Menopause: A ComprehensiveApproach, which you edited, has just been published bythe NIH and the Giovanni Lorenzini Medical ScienceFoundation in Milan, Italy.⁸ How will this paper enableus to optimize our management of women in menopauseand beyond?

A: The strength of this paper -which took an expertpanel almost 4 years to prepare -is that it provides evidence-based global recommendations for menopausalhealth (Table). As new clinical trial evidence emerged, wemodified the level of recommendations. Only when stringentevidence was not available did we cite expert opinion. Referencesthrough 2001 are included.

The expert panel emphasizes that menopause is a lifecycleevent. It is not a disease, and should not be treated assuch. Menopause offers the opportunity for a woman andher physician to explore preventive care for the remainder ofthat woman's life. The approach of the expert panel involvesmany aspects of women's health, not just hormonal function.

Q: A number of my colleagues have long prescribedhormone replacement therapy (HRT) forcardioprotection and other health benefits -eventhough the "evidence"appeared to be basedprimarily on observational studies. Many in the medicalcommunity were shocked when the HRT arm ofthe Women's Health Initiative (WHI) was stopped inJuly because of a documented increase in invasivebreast cancer, heart attack, stroke, and pulmonaryembolism.⁹The researchers recommended thatHRT not be initiated or continued for primaryprevention of CHD. How can we sort out these latestdata in a rational way?

A: Most of us practice evidence-based medicine.Numerous studies have confirmed that HRT doesnot provide benefit in certain areas where once it wasthought to be effective and in fact may sometimes beharmful, particularly in regard to cardiovascular disease.¹⁰For example, many clinicians prescribed HRT for urinaryincontinence. But randomized trials have shown thathormones worsened this condition^8,11 Another recent studyfound that HRT worsens dry eye syndrome12 Studies of theeffects of HRT on cognition and Alzheimer disease havefailed to show benefit.^8,13 HRT has been shown to improvemood and feelings of well-being only in some women whohave very severe vasomotor symptoms and insomnia.The WHI results refer only to the hormone regimenstudied -that is, conjugated equine estrogens, 0.625 mg/d,plus medroxyprogesterone acetate, 2.5 mg/d. Other regi-mens, dosages, and modes of administration requireinvestigation.

Q: Based on the latest evidence -including the WHIresults -what is the appropriate role for HRT?

A: HRT is by far the most effective intervention for themanagement of menopausal symptoms, such as hotflashes and vaginal dryness. It has no peer in that regard. Itis also effective for the prevention of osteoporosis. These areits only indications. Each woman must discuss with her caregiverthe risks and benefits of all options for osteoporosisprevention, both hormonal and nonhormonal. HRT shouldbe used in the lowest effective dose for the shortest durationfeasible.

Estrogen was previously indicated for both the preventionand treatment of osteoporosis; in earlier years, itwas the only treatment available. However, in 1999 the FDAremoved the treatment indication because there were norandomized, controlled trials supporting treatment benefit.We now have evidence-based data that show benefit for fractureprevention and treatment with the bisphosphonates,calcitonin, and the selective estrogen receptor modulatorraloxifene.^14-17 These are the only agents approved for thetreatment of osteoporosis. However, the WHI resultsshowed fracture benefit for HRT; this requires a reexaminationof approved therapies.

Q: What are women's best choices for preventionof heart disease and osteoporosis?

A: measures are crucial. These include smokingcessation; regular, moderate-intensity physical activity;and weight control, preferably by means of a hearthealthydiet and exercise. Fat should be restricted to lessthan 30% of total daily calories, and saturated fat to less than10% of calories from fat. For women at risk for osteoporosis,calcium and vitamin D are imperative. Weight-bearing, muscle-building, and balance exercises can help prevent fracture.In addition, women should avoid sedatives and excessalcohol intake, correct visual impairment, and make theirhomes as fall-proof as possible.

We have to evaluate each woman's risk factors andcheck her blood pressure and cholesterol levels. If nonpharmacologicmeasures do not get these to target levels,drug therapy is in order.

At the beginning of the last decade, and up to the mid1990s, the American Heart Association (AHA), the AmericanCollege of Cardiology (ACC), and Adult TreatmentPanel (ATP) II of the US National Cholesterol EducationProgram (NCEP) (1993 and 1994) all recommended intheir clinical practice guidelines that HRT be used as first-line lipid-lowering therapy for women. Since then, theserecommendations have changed because a number of verylarge, randomized, controlled clinical trials with statinshave shown clinical outcome benefits for women -as wellas a better side-effects profile -that were never demonstratedwith HRT.¹⁸ The AHA, ACC, and NCEP (in the ATPIII guidelines released last year) now all recommendstatins as first-line lipid-lowering therapy for women.^19,20

Q: What about the subset of older women who havehigh high-density lipoprotein (HDL) cholesterollevels -say, 70 to 80 mg/dL -total cholesterol levels inthe mid 200 mg/dL range, and no other risk factor forheart disease? Would you treat these women with astatin?

A: It depends on their low-density lipoprotein (LDL)levels.The NCEP ATP III guidelines continue to identifyelevated LDL cholesterol -rather than total cholesterol -as the primary target of cholesterol lowering therapy. Recentdata from the British Heart Protection Study -whichexamined data from more than 20,000 patients -did not addressHDL and showed benefit even in patients with lowLDL levels.²¹ The study, which assessed long-term use(more than 5 years) of simvastatin, 40 mg/d, in patients athigh risk for CHD, found a survival benefit in the drug-treatedgroup -regardless of age, sex, or baseline cholesterolvalues. Results included a 12.9% reduction in total mortality,an 18% reduction in coronary mortality, and a 24% reductionin major vascular events.

References:

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