Reference: Glick H, et al. (1995). J Card Fail 1:371 \200\223380. MAJOR TRIALS IN CARDIOLOGY 639 Scandinavian Simvastatin Survival Study SSSS (4S) Purpose: To evaluate the impact of 20 mg simvastatin in patients with total serum cholester ol 5.5 \200\2238 mmol/L (after 8 weeks of dietary therapy) on mortality and the incidence o f major coronary artery disease. 4444 patients aged 35 \200\22369 years were in the study. Follow-up: Median 5.4 years Results: There was a 30% relative risk reduction in all-cause mortality, 42% reduction in c oronary mortality, 34% reduction in coronary events, 32% reduction in cost of hospitalizati on, and 37% reduction in revascularization procedures in the simvastatin group. Simvastatin signi \201 cantly reduced the risk of major coronary events in all quartiles of baseline total, LDL, and HDL cholesterol to a comparable degree in each quartile. There was one case of reversible myopathy that was the most serious drug-related adverse event. Reference: J nsson B, et al. (1996) Eur Heart J 17: 1001 \200\2231007. Trials evaluating a slow-release paclitaxel-eluting stent (TAXUS) for coronary lesions TAXUS TAXUS 1: This trial was to evaluate the safety and feasibility of a TAXUS stent delivering paclitaxel locally to coronary plaques via a slow-release polymer coating, compared to a ba re-metal control stent. 61 patients with de novo or restenotic lesions ((cid:100)12 mm) wer e randomized to receive a TAXUS stent or control stent that was non-drug eluting (diameters 3.0 or 3.5 mm). The primary end point, 30-day major adverse clinical event (MACE), rate wa s 0% in both groups. At 12 months, the MACE rate was 3% in the TAXUS group and 10% in the c ontrol. The restenosis rate measured by QCA was 0% in the TAXUS group vs. 10% in controls a t 6 months. IVUS showed signi \201 cant improvements in normalized neointimal hyperplasia in the TAXUS group compared to controls. TAXUS 2: A comparison of slow-release (SR) and moderate- release (MR) paclitaxel-eluting st ents with control bare- metal stents (BMS). All 536 patients had post-procedure and 6-month follow-up with IVUS. There was signi \201 cant reduction in MACE rates, in-stent restenos is (ISR), and in-stent volume reduction with SR or MR stents compared to controls. There wa s no signi \201 cant difference between the TAXUS groups. TAXUS 3: 28 patients with ISR with lesions <30 mm in length and 50% \200\22399% diameter st enosis in 3.0 \200\2233.5 mm vessels were treated with one or more TAXUS stents. 25 people completed the angiographic follow-up at 6 months. The MACE rate was 29% (8 patients). IVUS was recommended to ensure good stent deployment and complete coverage of target lesion. CHAPTER 15 Major trials in cardiology 640 TAXUS 4: This trial evaluated the safety and ef \201 cacy of slow-release polymer-based pa clitaxel stents after implantation in de novo coronary lesions after 1 year. 1314 patients with de novo coronary lesions 10 \200\22328 mm length, diameter 2.5 \200\2233.75 mm, covera ble by a single stent, were randomized to a TAXUS or bare metal (EXPRESS) stent. At 1 year, MACE rates and target vessel revascularization rates were lower in the TAXUS group. Rates of cardiac death, MI, and subacute thrombosis were not signi \201 cantly different. TAXUS References: Grube E, et al. (2003). Circulation 107:38 \200\22342; Columbo A, et al. (2003) Circulation 108:788 \200\223794; Tanabe K, et al. (2003). Circulation 107:559 \200\223564; Stone GW, et al. (2004) Circulation 109:1942 \200\2231947. Ef \201 cacy of tPA (with IV heparin) was compared to streptokinase in achieving reperfusi on in 290 patients presenting with acute STEMI <6 hours after symptom onset. All patients u nderwent baseline coronary angiography after randomization. Signi \201 cantly higher rates of perfusion were found in the TPA arm. Patients with a patent artery at 90 minutes after starting reperfusing therapy had lower 6-month and 1-year mortality regardless of treatment group. TIMI 1 Patients with acute MI were given tPA within 4 hours of symptom onset and randomized to an immediate invasive (angiogram within 2 hours), delayed invasive (within 18 \200\22348 hours ), and conservative (angiogram if ETT positive at 6 weeks or further ischemia) strategy. Th ey were then given a predischarge angiogram and 6-week ETT, and followed up at 1 year. At 6 weeks there was no difference between the groups in death or reinfarction. Infarct-related artery patency at time of discharge was similar in all groups, with more complications in the invasive arms. TIMI 2A 3339 patients with AMI were given tPA within 4 hours of symptom onset and randomized to an invasive strategy (angiogram within 18 \200\22348 hours) or a conservative strategy (angiog ram if ETT positive at 6 weeks or further ischemia). Patients were also randomized to immed iate IV followed by oral B-blockade, or deferred B-blockade. There was no difference in the composite end point of death or recurrent MI at 42 days between the invasive and conservat ive groups. But those in the invasive arm were twice as likely to need PTCA or CABG at 1 ye ar. In the early B-blockade group, there was signi \201 cantly lower reinfarction and recu rrent ischemia at 6 weeks. TIMI 2B MAJOR TRIALS IN CARDIOLOGY 641 391 patients with unstable angina or NQWMI were given aspirin, IV heparin, B-blockers, nitr ates and calcium antagonists, and then randomized to receive tPA or placebo after baseline angiography had excluded patients with left main stem disease or no coronary disease. They then underwent repeat angiography at 18 \200\22336 hours and were followed up at 6 weeks wi th an ETT. Baseline angiography showed 35% had apparent thrombus, and 30% had possible thro mbus, with no difference in the degree of lesion improvement at angiography after randomiza tion (25% tPA vs. 19% placebo). TIMI 3A 1473 patients with unstable angina or NQWMI were treated with maximal medical therapy and r andomized in a 2x2 factorial design to receive tPA or placebo, and to follow invasive or co nservative strategies. There was no difference in composite end points of death, infarction , or ischemia in tPA and placebo groups, although the risk of MI, death, or cerebral bleedi ng was higher in the tPA group. Similarly, there was no difference between the conservative and invasive groups in the primary end points, although the invasive group required more r eadmission to the hospital for angina. The TIMI 3 registry showed that ST deviation was a p rognostic indicator in unstable angina, whereas new T-wave inversion was not. TIMI 3B 382 patients with AMI <6 hours were randomized to tPA, APSAC, or a combination of the two ( at reduced dosage). Each underwent angiograms at 90 minutes, and at 18 \200\22336 hours. tP A was shown to have higher patency than APSAC or the combination, fewer unsatisfactory outc omes prior to discharge, and lower mortality at 1 year. TIMI 4 Patients with AMI <6 hours were randomized to hirudin (a direct thrombin inhibitor) or unfr actionated heparin, combined with aspirin and tPA, followed by angiography at 90 minutes an d 18 \200\22336 hours. The hirudin arm had higher TIMI 3 \202 ow rates and fewer re-occlu sions. TIMI 5 This study compared different doses of hirudin and unfractionated heparin in AMI patients i n combination with streptokinase and aspirin. There was a lower incidence of death, recurre nt MI, or new-onset CHF in the hirudin groups than in the heparin groups. TIMI 6 Hirulog was used to treat 250 patients with unstable angina at a high and low dose. The inc idence of death and MI was lower using higher doses of hirulog. TIMI 7 This follow-up trial compared hirulog and heparin in a multicenter, double-blind, randomize d study. The sponsor stopped it for business reasons after enrollment. TIMI 8 CHAPTER 15 Major trials in cardiology 642 This trial evaluated the safety and ef \201 cacy of hirudin compared to heparin as an adju nct to thrombolysis with tPA or streptokinase. As there were higher rates of bleeding than expected with hirudin, TIMI 9B was designed using lower hirudin doses. TIMI 9A This was similar to TIMI 9A but using lower doses of hirudin. No signi \201 cant differenc e in death or reinfarction was seen between the hirudin and heparin groups. TIMI 9B This was a dose-ranging trial of TNK-tPA with aspirin and unfractionated heparin for treati ng acute STEMI. TIMI 10A Using TIMI 10A data, bolus doses of 30, 40, and 50 mg of TNK-tPA were chosen for comparison with accelerated tPA in conjunction with aspirin and IV heparin. A single bolus of TNK 40 mg achieved similar TIMI 3 \202 ow to tPA at 90 minutes. TIMI 10B This dose-ranging trial for IV enoxaparin treated patients with unstable angina/NQWMI. Due to a higher than expected bleeding rate, the trial was recon \201 gured to look at a 1 mg/ kg of enoxaparin to give bleeding rates similar to those in heparin plus placebo arm of TIM I 3B. TIMI 11A This was a comparison of enoxaparin and unfractionated heparin to treat unstable angina/NQW MI looking at the bene \201 t of an extended courses of enoxaparin compared to a shorter c ourse (8 vs. 43 days). Those randomized to unfractionated heparin continued on placebo. The enoxaparin group had reduced death, MI, and revascularization at both time points. TIMI 11B This was a dose-ranging study for the gpIIb/IIIa inhibitor sibra \201 ban in patients 1 \200\2237 days after presenting with acute coronary syndrome. Results showed a dose-depende nt rise in platelet inhibition. TIMI 12 Abciximab was evaluated for treatment of STEMI, in combination with tPA, streptokinase, ret eplase, or with no thrombolytic drug, compared to a group receiving tPA and heparin only. T he combination of abciximab and half-dose tPA achieved the highest rates of reperfusion. TIMI 14 This dose-ranging study of the GpIIb/IIIa inhibitor Klerval (avail-able both orally and IV) for acute coronary syndrome showed a dose-dependent increase in platelet inhibition. The d ata were used in selecting the dose for the TIMI 15B trial. TIMI 15A This dose-ranging trial examined IV Klerval for 24 \200\22396 hours then oral Klerval for 4 weeks in the management of acute coronary syndromes (unstable angina, NSTEMI, STEMI), vs. placebo. Results showed potent predictable dose-related platelet inhibition with intravenou s use, but moderate inhibition only with oral use. TIMI 15B MAJOR TRIALS IN CARDIOLOGY 643 (OPUS TIMI 16) Patients with acute coronary syndrome were randomized to two dosing strategi es of oral orbo \201 ban vs. placebo to evaluate the bene \201 t of orbo \201 ban in add ition to standard therapy. No signi \201 cant bene \201 t was observed. TIMI 16 (InTIME II) A multicenter trial of bolus lanoteplase vs. accelerated tPA was conducted for 15087 patients with STEMI. No signi \201 cant difference was observed in mortality at 30 d ays between the two groups. TIMI 17 (TACTICS TIMI-18) Treat angina with aggrastat and determine cost of therapy with an invasiv e or conservative strategy TIMI 18 TIMI 18 2220 patients with an unstable angina or NQWMI had baseline troponin measured and were give n aspirin, heparin, and tiro \201 ban. They were then randomized to an early invasive (ang iogram in 4 \200\22348 hours) or early conservative strategy, and would proceed to PCI or C ABG depending on their symptoms, treadmill testing, or other evidence of ischemia. They wer e followed up for 6 months. The combined primary end point of death, MI, and rehospitalizat ion at 6 months was 19.4% in the conservative arm and 15.9% in the invasive arm. The reduct ion in patients who reached the primary end point was most marked in the 54% who were tropo nin positive (>0.01 ng/mL) and in patients who had an intermediate- and high-risk TIMI scor e. There was no signi \201 cant difference in stroke, although major bleeding rate was hig her in the invasive group. Hence there was bene \201 t for \200\234upstream \200\235 use of tiro \201 ban in early intervention, using troponin levels and TIMI scores to guide pot ential usefulness of an early interventional approach. Pravastatin or atorvastatin evaluation and infection therapy (PROVE IT) TIMI 22 This study aimed to evaluate whether statins are effective in reducing events in patients w ith an acute coronary syndrome (ACS) and to see whether intensive lipid lowering of LDL-C ( to an average 65 mg/dL) achieves greater reduction in clinical events than standard lowerin g (to an average 95 mg/ dL). 4162 patients with an ACS within 10 days were given standard t herapy and randomized to pravastatin 40 mg (standard therapy) or atorvastatin 80 mg (intens ive therapy), as well as gati \202 oxacin vs. placebo in a 2x2 factorial manner. There was a mean 2-year follow-up after which the following primary end points were measured: death, MI, documented unstable angina requiring hospitalization, revascularization (>30 days afte r randomization), and stroke. The \201 ndings were that for the atorvastatin group, the r isk of all-cause mortality or major cardiac events was reduced by 16% (p = 0.005). The bene \201 ts emerged at 30 days post-ACS and were maintained throughout follow-up and were con sistent across all cardiovascular end points except stroke, and most clinical subgroups. CHAPTER 15 Major trials in cardiology 644 The role of clopidogrel in early and sustained arterial patency after \201 brinolysis for ST-segment elevation myocardial infarction TIMI 28 CLARITY This trial evaluated treatment with clopidogrel compared with placebo among patients with S T elevation myocardial infarction initial medical management strategy. In patients with STE MI treated with an early medical management strategy, use of clopidogrel was associated wit h a reduction in the primary composite end point compared with placebo, driven by the reduc tion in infarct-artery occlusion. It should be noted that patients in the study were treate d with an early medical management strategy and did not undergo coronary angiography for a median of 3.5 days. The risk of TIMI major bleeding did not differ signi \201 cantly betwe en the clopidogrel and placebo groups. (STEMI) treated with an VANQWISH Veterans Affairs Non-Q Wave Infarction Strategies in Hospital Purpose: To compare the role of early invasive vs. conservative management strategies in pa tients with NQWMI with or without prior MI. The background of this study was that patients with a \201 rst NQWMI have a better prognosis than those with prior myocardial infarction who suffer another NQWMI. 920 patients were enrolled; 396 had had prior MI, 524 had not. T hese two groups were randomly assigned to an invasive strategy or conservative strategy, wi th subsequent invasive management if there was spontaneous or inducible ischemia within 72 hours of the NQWMI. The combined primary end point was death or nonfatal MI. Follow-up: Mean 23 months Results: Mortality did not differ signi \201 cantly between the invasive and conservative strategy groups. Those with previous MI were identi \201 ed as a high-risk subset of NQWMI patients who have similar outcomes regardless of the strategy used. But patients with a \201 rst infarct had better prognosis if managed conservatively, or with an ischemia- guide d approach. Reference: VANQWISH Trial Investigators (1998). N Engl J Med 338:1785 \200\2231792. MAJOR TRIALS IN CARDIOLOGY 645 Vasodilator Heart FailureTrial II V-HEFT II Purpose: To compare the impact of enalapril with the combination of hydralazine plus isosor bide dinitrate in treating 804 patients with chronic congestive cardiac failure. Follow-up: Mean 2.5 years Results: The enalapril group had signi \201 cantly lower mortality attributable mainly to a reduction in sudden cardiac death. Blood pressure reduction was greater in the enalapril group in the \201 rst 13 weeks. There was increased incidence of symptomatic hypotension and cough in the enalapril group, and increased headache in the hydralazine plus isosorbide dinitrate group. Reference: Cohn JN, et al. (1991) N Engl J Med 325: 303 \200\223310. West of Scotland Coronary Prevention Study WOSCOPS Purpose: A primary prevention study to evaluate the effect of 5 years of once-daily 40 mg p ravastatin on the risk of MI, in 6595 men aged 45 \200\22364 years with LDL cholesterol 4 \200\2236 mmol/L and no history of MI, in a randomized, double- blind, placebo-controlled t rial. Follow-up: Mean 4.9 years Results: Total cholesterol and LDL cholesterol were lowered by 20% and 26%, respectively, i n the pravastatin group. There was a 31% relative risk reduction in the number of de \201 nite coronary events in the pravastatin group, and a 31% reduction in nonfatal MI, 33% redu ction in death from coronary heart disease, and 32% reduction in death from all cardiovascu lar causes. All-cause mortality was reduced by 22% in the pravastatin group (p = 0.051). Reference: The WOSCOPS Study Group (1996). Eur Heart J 17:163 \200\223164. This page intentionally left blank 647 Chapter 16 Special populations: women and elderly Women and heart disease 648 The elderly and heart disease 656 CHAPTER 16 Special populations: women and elderly 648 Women and heart disease Background Cardiovascular disease in women is a health problem of e pidemic pro- portions throughout the world. In the United States, cardiovascular dis- ease (CVD) affects over 37 million American women, representing over one-third of the American f emale population, with coronary heart disease (CHD) affecting 5.9 million women. By age 55, the prevalence of cardiovascular disease in women exceeds that in men. Cardiovas cular disease accounts for 1 in 2.5 female deaths compared to 1 in 30 deaths attributable t o breast cancer. Despite the high prevalence and mortality rate of cardiovascular disease, only 13% of women consider it to be their greatest health risk. Although the past two to three decades have seen a decline in the overall mortality rate fr om CVD in men, the mortality rates for women have remained stable. In addition, when women do present with a new diagnosis of stable angina, they are less often referred for noninvas ive or invasive studies and are less likely to undergo revascularization or given optimal s econdary prevention medication even in the presence of con- \201 rmed obstructive coronar y artery disease than are men. Many studies have been done that highlight the discrepancies in the recognition and appropr iate treatment of CHD between women and men and underscore the importance of appropriately identifying women who are at risk for CHD. Diagnosis and prognosis Exercise treadmill testing (ETT) Women generally manifest CHD about 10 years later than men, present more commonly with atypical chest pain or dyspnea, and ha ve a lower prevalence of luminal obstructive coronary disease by angiography. However, when women do present with obstructive coronary disease, they have higher morbidity and mortali ty rates than those of age-matched men. It is therefore imperative to not only \201 nd effective primary and second- ary preventi on measures in women but also appropriately identify and risk stratify women with CHD. Hist orically, the noninvasive diagnostic workup in women has been underused, secondary to a lac k of physician con \201 - dence in the accuracy of the test results. While exercise stress testing is the most commonly used noninvasive diagnostic modality for detecting coronary artery disease in men, many studies have demonstrated a low sensitivity and speci \201 city for exercise treadmill testing in women. In fact, women are 5 to 20 t imes more likely than men to have a false-positive exercise ECG. Several mechanisms for the reduced speci \201 city of exercise ECG test- ing in women have been proposed. These mechanisms include a lower prevalence of disease in women tested, low er achieved workload, the digoxin-like effect of estrogen, an inappropriate catecholamine r esponse to exercise in women, a higher incidence of mitral valve prolapse, and dif- ferent chest wall anatomy. WOMEN AND HEART DISEASE 649 In addition, it is important to note that the standards for an abnormal exercise ECG test were developed in a male population. Perfusion imaging and stress echocardiography in women As a result of the high false-positi ve rate in exercise ECG testing in women, various imaging modalities have been evaluated in the diagnosis and risk strati \201 cation of CHD in women. Myocardial perfusion imaging h as been shown to have a signi \201 cantly higher sensitivity and speci \201 city than tha t of ETT for detecting CAD in men. Nevertheless, the small size of the left ventricle in women and breast artifact have led to some concerns regarding its utility in women. Studies evaluating the utility of myocardial perfusion imaging (MPI) in women with both Tc-99m sestamibi and Tl-201, however, have con \201 rmed their value in diagnosing CAD in women. The use of gated SPECT imaging further i ncreased the speci \201 city of MPI \201 ndings in women. Exercise echocardiography has also been shown to be an accurate modality to noninvasively d iagnose CAD in men. There have, however, been con \202 icting reports regarding its utilit y in women, with speci \201 cities ranging from 46% to 93%. In a study dedicated to evaluating the diagnostic accuracy of stress echocardiography compa red to cardiac catheterization in 161 women, the sensitivity of exercise echocardiography f or detecting CAD (>50% ste- nosis) was 80%, the speci \201 city was 81%, the positive pred ictive value was 71%, and the negative predictive value was 87%. Based on these studies, it is clear that exercise ECG is a less than ideal test for detecti ng CAD in women, with a very high false-positive rate, which in turn leads to many unnecess ary invasive coronary angiograms. The addition of perfusion imaging or echocardiography to the exercise ECG provides an effective and cost-ef \201 cient way to diagnose women with s uspected CAD without a high rate of false positives. What is the prognostic utility of stress testing in women? Both myocardial perfusion imagin g and stress echocardiography have been evaluated for their roles in risk strati \201 cati on of women with suspected CAD. It has been demonstrated that abnormal MPI is a more powerf ul predictor of future cardiac events in women than in men, with women Table 16.1 Sensitivity and speci \201 city of stress test modalities (for detecting stenos es >50%) Test Sensitivity Speci \201 city ETT (men) 70% 77% ETT (women) 61% 70% Tl-201 MPI 75% 61.9% Tc-99m MPI 71.9% 85.7% Gated Tc-99m MPI N/A 94.1% Exercise ECHO 80% 81% CHAPTER 16 Special populations: women and elderly 650 having a greater than twofold higher event rate than that of men with a similar scan result . The nuclear scan information added 17% and 37% addi- tional prognostic information in men and women, respectively. Exercise and dobutamine stress echocardiography have also been proven bene \201 cial in ri sk stratifying both men and women with a relative risk of a cardiac event (nonfatal MI or c ardiac death) in patients with an abnormal stress ECHO of 1.45. Based on these studies, both exercise and pharmacological myocar- dial perfusion imaging an d stress echocardiography are valuable tools in women for risk strati \201 cation. The cho ice of imaging modality will need to be based on each individual woman \200\231s risk facto rs, body habitus, and local expertise. Hormone replacement therapy (HRT) Proposed mechanism for estrogen \200\231s cardiovascular protection The rates of coronary heart disease in po stmenopausal women are two to three times greater than in premenopausal women of the same a ge. This is thought to be secondary to the cardioprotective effects of estrogen. In the bas ic science arena, researchers have demonstrated that estrogen has sys- temic effects as wel l as direct effects on the vasculature (see Box 16.1). Data from observational trials \200\224initial support for HRT The role for estrogen replac ement therapy (ERT) and hormone replace- ment therapy was initially supported by numerous o bservational epide- miological studies. A meta-analysis of these initial studies published from 1970 through the 1990s showed a signi \201 cant reduction (35% \200\22340%) in risk o f CHD in women taking HRT. Based on these observational data, the use of HRT/ERT in the primary and secondary preventi on of CHD in women was the standard of care until 1998, when results from large, randomized controlled trials (RCTs) contradicted the \201 ndings of earlier observational studies. Data from randomized controlled trials \200\224increased risk with HRT in primary and secon dary prevention When HRT was evaluated in a large, randomized controlled study in post- men opausal women with known CHD (HERS trial), there was no differ- ence in recurrent CHD event s between the placebo group and the HRT Box 16.1 Effects of estrogen \200 Alteration in lipoprotein pro \201 le: decrease in total cholesterol, LDLc, and Lp(a); inc rease in HDLc and triglycerides Regulate expression of \201 brinogen and ATIII and protei n S Rapid effects on vasculature: vasodilation and increased nitric oxide (NO) synthesis Lo ng-term effects on vasculature: alterations in gene expressions that decrease atheroscleros is, decrease vascular injury, decrease smooth muscle cell growth, and increase endothelial cell growth Proin \202 ammatory: increase in C-reactive protein (CRP) \200 WOMEN AND HEART DISEASE 651 group. In fact, a post-hoc time trend analysis showed a 52% increase in CHD events during t he \201 rst year of HRT use compared to placebo and a trend toward a decrease in CHD even ts in years 3 and 4. Further stud- ies looking at the bene \201 t of estrogen replacement therapy alone in the secondary prevention of CHD also did not show a bene \201 t in reduci ng cardiac events. Similarly, a large randomized controlled trial of HRT in the primary pre- vention of CHD in postmenopausal women (Women \200\231s Health Initiative) did not show a reduction in CHD e vents. In fact, there was a trend toward an increase in CHD events, with the greatest amoun t of risk occurring in the \201 rst year after randomization with a hazard ratio of 1.81 (95% CI 1.09 \200\2233.01). Interestingly, a subgroup analysis of women strati \201 ed according to years since menopa use revealed a nonsigni \201 cant trend toward a reduction in CHD in women less than 10 ye ars since menopause (HR 0.89, 95% CI 0.5 \200\2231.7). When estrogen replacement alone was evaluated in the primary prevention of CHD, there was also no signi \201 cant difference i n CHD events between the active treatment arm and the placebo. Possible future role for HRT in prevention of CHD Regardless of the type of estrogen used, the method of hormone delivery or the combination of hormone replacement with estrogen and progestin, no signi \201 cant bene \201 t in CHD prevention was found in the aforemention ed randomized trials. In the randomized trials, however, the average time between menopause and enrollment in the studies ranged from 16 years to over 20 years. The initiation of hormone or estrogen therapy at this late stage may not truly represent ph ysiological replacement and may contribute to lack of bene \201 t in both primary and seco ndary prevention of CHD. The delay in HRT/ERT may have allowed subclinical atherosclerosis to develop and may have reduced the cardiovascular bene \201 ts of estrogen. The trend toward a reduction in CHD events in the subgroup analysis in the Women \200\231s Health Initiative of women who began HRT/ERT within 10 years of menopause and results from a series of experiments in primates, which showed a bene \201 t of ERT on atherogenesis pr ogression only when started immediately post-oophorectomy, lend support to this theory. These observations have kept the door open for a possible role of HRT in primary prevention in women at the inception of menopause and are the basis for the ongoing Kronos Early Estr ogen Prevention Study (KEEPS). For now, however, there is no clear role of HRT or ERT for e ither primary or secondary prevention of CHD in postmenopausal women. Dietary and vitamin supplements Role of antioxidant vitamin supplements in women As with th e debate over HRT in the primary and secondary prevention of CHD in women, the role of anti oxidant vitamins has been investigated over the past two decades. Like estrogen, vitamin E had a plausible biologi- cal basis for a postulated role in atherosclerosis prevention. This theory was based on the hypothesis that oxidative modi \201 cation of low-density lip oprotein (LDL) initiates atherosclerosis and on the idea that CHAPTER 16 Special populations: women and elderly 652 antioxidant vitamins, such as vitamin E, could inhibit lipid peroxidation, thereby preventi ng the development or progression of atherosclerosis and CHD. Observational data from the Nurses Health Study and Iowa Women \200\231s Study initially su pported this hypothesis. However, the positive bene \201 t of vitamin E supplements noted in observational studies has not been con- sistently supported by subsequent randomized pla cebo-controlled clinical trials. The GISSI-Prevenzione trial, the Heart Protection Study (H PS), and the WAVE trial found no bene \201 t of vitamin E in the secondary prevention of C HD events or in the angiographic progression of coronary atheroscle- rosis. The ability to apply these results to a female population, however, is limited because of the low proporti on of women (19% in GISSI, 25% in HPS) in the majority of these trials. Similarly, data for the role of vitamin E supplements in the primary pre- vention of CHD in women have also not been borne out in randomized placebo-controlled studies. In subgroup a nalyzes of the HOPE and HOPE- TOO trials, there was no reduction in CHD events in women ass igned to vitamin E supplementation. However, a study dedicated to addressing this issue in women, the Women \200\231s Health St udy, found a nonsigni \201 cant 7% reduction in major car- diovascular events (nonfatal MI , nonfatal stroke, cardiovascular death), and a signi \201 cant reduction in major cardiov ascular events in the subgroup of women aged 65 years or older, suggesting a possible role in the primary prevention of CHD events in this elderly subset of women. The use of vitamin E in this subgroup of women needs to be investigated further. While data regarding the use of antioxidant vitamins, speci \201 cally vitamin E, in the p rimary and secondary prevention of CHD have been contradic- tory, the bulk of the data does not support the use of vitamin E in the prevention of CHD in women. At this point in time, vitamin E should not be recommended for the primary or secondary prevention of CHD in wome n. Role of folic acid or vitamin B6 in CHD prevention in women Plasma homocysteine levels h ave been shown to be a strong, independent predictor of cardiovascular disease in both men and women. The correla- tion between homocysteine and CHD mortality (r = 0.71) suggests tha t homocysteine may play an important role in determining CHD mortality among different popu lations. Several plausible mechanisms by which homocysteine could increase risk of CHD (direct toxic ity to endothelial cells, increased coagulation, decreased endothelial reactivity, and stim ulation of smooth muscle cell proliferation) have been previously elucidated. Folate and vitamin B6 are important cofactors in the metabolism of homocysteine, and changi ng the intake of folic acid and vitamin B6 can modify homocysteine levels. Accordingly, stu dies have shown that low dietary intake of vitamin B6 is also associated with increased ris k of CHD. Based on these observations, some investigators have hypothesized that lowering l evels of homocysteine via folate and vitamin B6 supplementa- tion would translate into a re duction in cardiovascular events. Support for this hypothesis in women was initially offere d from observations from the WOMEN AND HEART DISEASE 653 Nurse \200\231s Health Study, which showed a relationship between folate and B6 intake and incidence of CHD events. The concern that the observed relation of homocysteine and vitamin B6/folate to CHD risk ma y actually represent unrecognized confounders rather than a true causal relationship has le d to the development of rand- omized clinical trials. Similar to the HRT and vitamin E stor y, randomized controlled studies evaluating the role of vitamin B6 and folate in the sec- o ndary prevention of CHD have been negative (NORVIT trial). The role of these vitamins in the primary prevention of CHD, however, is still a question. Until a randomized, clinical trial addresses this issue, the routine use of these supplemen ts in primary prevention of CHD in women is not recommended. Role of omega 3 fatty acid supplements The observation that populations with a high intake of \201 sh have a lower rate of cardiovascular disease initially led to the hypothesis th at \201 sh con- sumption may have a protective effect for atherosclerosis (Box 16.2). Several prospective epidemiological studies in men have lent support to this hypothesis. Si milar risk reductions were also observed in women in the Nurse \200\231s Health Study cohor t. Although these epidemiological data are compelling, to date, there are no randomized con trolled clinical trials to support the role of \201 sh or \201 sh oil in the primary pr evention of CHD events in women. Currently, the JELIS investigators are following 10,796 postmenopausal women and 4204 men w ho were free of CHD, in a trial of eicosapentae- noic acid (EPA), a component of \201 sh oil, in addition to treatment with a statin in hyperlipidemic patients for 5 years. The pri mary end points in this trial are major coronary events (sudden cardiac death, fatal and no nfatal MI, unstable angina, and coronary revascularization). The initial results of this trial, which were presented at the American Heart Association s cienti \201 c session in 2005, revealed a 19% risk reduction in major cardiovascular event s (RR 0.81, 95% CI 0.69 \200\2230.95) in the group treated with EPA plus statin therapy, co mpared to statin therapy alone, and a 24% risk reduction in unstable angina (RR 0.76, 95% C I 0.62 \200\2230.95). In contrast to the dearth of data from randomized controlled trials on the role of \201 s h oil in the primary prevention of CHD, there have been sev- eral observational trials and randomized controlled clinical trials showing Box 16.2 Proposed biological mechanisms for omega 3 fatty acid CV protective effects \200 \200 \200 \200 Reduced susceptibility of the heart to ventricular arrhythmias Antithrombogenic properties Lowering of triglyceride levels Retardation of atherosclerotic plaque growth via reduced ad hesion molecule expression Reduction in platelet derived growth factor Anti-in \202 ammato ry mediator Promotion of NO-induced endothelial relaxation \200 \200 CHAPTER 16 Special populations: women and elderly 654 a bene \201 t of \201 sh oil on the secondary prevention of CHD events (GISSI- Prevenzio ne trial). The low number of female subjects participating in these trials, however, limits the applicability of the results to women. Although the data are limited in women at this time, it is reasonable to recommend the use of n-3 omega fatty acids for the secondary preven- tion of CHD events in women who have rec ently had an MI. The recent results from the JELIS study also support the recommendation of adding \201 sh oil to the treatment of hyperlipidemics in the primary prevention of CHD events. Aspirin use in women Aspirin for primary prevention in women The role of aspirin in the sec ondary prevention of cardiovascular events is well established in both men and women. The r ole of aspirin in the pri- mary prevention of cardiovascular disease in women, on the other hand, is not clear. The Physician \200\231s Health Study, which was the \201 rst trial to uncover a sig- ni \201 cant 44% reduction in \201 rst MI with aspirin use only included men in its subject population. The data from the Hypertension Optimal Treatment Study (HOT) and the Primary Pr evention Project, (each trial included about 50% women) present a less than convincing argu ment for the use of aspirin in the primary prevention of MI in women. The Women \200\231s Health Study sought to \201 nally answer this question in women. This study enrolled 39,876 women who were free of cardiovas- cular disease and had low-risk car diovascular pro \201 les. The investigators found a nonsigni \201 cant 9% risk reduction in major cardiovascular events, with no signi \201 cant effect on fatal or nonfatal MI and with a concomitant increase in the rate of bleeding complications in those taking aspirin. Only in the subgroup of women over the age of 65 did they \201 nd a signi \201 cant red uction in major cardiovascular events and in MI event rate. Based on these data, there does not appear to be a clear role for aspi- rin in the primary prevention of cardiovascular disease in women in the low-risk female population. There may be a bene \201 t in the elderly female population. However, given the risk of bleeding complications, this needs to be fur- ther evaluated wit h a large-scale trial dedicated to answering this question. Although there is no clear role of aspirin use in the primary prevention of CHD events in women, this does not negate its use in women with estab- lished coronary artery disease, especially in the setting of acute myocardial infarction or post-angioplasty and stenting. Cholesterol and in \202 ammatory biomarkers of CHD in women Optimal lipid levels in women for secondary prevention of CHD The role of LDL cholesterol in the development of atheroscl erosis has been well established. However, the best lipid parameter for predicting CHD even ts in women continues to be an issue of some debate. In a nested case \200\223control study from the Nurse \200\231s Health Study cohort, the data suggest that measurements of both L DL and HDL are essential in the prediction of CHD events in women. WOMEN AND HEART DISEASE 655 A similar contribution to the prediction model was seen when the ratio of total cholesterol to HDL was added (ROC increased to 0.72). This ratio re \202 ects the proportion of ather ogenic-to-antiatherogenic lipid fractions and appears to be a powerful tool for predicting CHD in postmenopausal women. From these data it follows that lowering LDL cholesterol and rais- ing HDL cholesterol shou ld play a role in CHD prevention in women. Accordingly, the data from secondary prevention randomized controlled trials of statin therapy have shown reduced risks of CHD events in wo men placed on statin therapy. The female subgroup analyzes of the 4S trial, the CARE trial, and the PROVE-IT-TIMI22 trial have all shown signi \201 cant reductions in major coronary events in women with known CA D who are placed on statins. Based on observational and clinical trial data, the goal LDL i n women with a history of CHD or diabetes should be (cid:100)70 mg/dL. Role of CRP in predi cting CHD risk in women In addition to LDL and HDL cholesterol, recent data have shown that vari- ous markers of in \202 ammation are also potent predictors of CHD events in women. Women in general have higher CRP levels than those in men, and black women have signi \201 cantly higher CRP levels than white, Hispanic, or Asian women.