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Review

Angina pectoris in women: Focus on microvascular disease☆

Cinzia Zuchi, Isabella Tritto, Giuseppe Ambrosio ⁎Department of Cardiology, University of Perugia School of Medicine, Perugia, Italy

a b s t r a c ta r t i c l e i n f o

Article history:Received 24 August 2011Received in revised form 7 July 2012Accepted 7 July 2012Available online 21 July 2012

Keywords:Angina pectorisWomenIschemic heart diseaseAntianginal drugsMicrocirculation

Ischemic heart disease (IHD) is the leading cause of death among women in Western countries, and it isassociated with higher morbidity and mortality than in men. Nevertheless, IHD in women remainsunderdiagnosed and undertreated, and the misperception that females are “protected” against cardiovas-cular disease leads to underestimation of their cardiovascular risk; instead, women with chest pain have ahigh risk of cardiovascular events. Women suffering from angina pectoris tend to have different character-istics compared to men, with a high prevalence of non-significant coronary artery disease. Angina inwomen is more commonly microvascular in origin than in men, and therefore standard diagnostic algo-rithms may be suboptimal for women. This different pathophysiology impacts clinical management ofIHD in women. While response to medical therapy may differ in women, they are scarcely represented inclinical trials. Therefore, solid data in terms of gender efficacy of antianginal drugs are lacking, and partic-ularly when angina is microvascular in origin women often continue to be symptomatic despite maximaltherapy with classical antianginal drugs. Recently, newmolecules have shown promising results in women.In conclusion, women with angina are a group of patients in whom it seems appropriate to concentrateefforts aimed at reducing morbidity and improving quality of life.

© 2012 Elsevier Ireland Ltd. All rights reserved.

1. The underappreciated prevalence of ischemic heart diseasein women

Ischemic heart disease (IHD) is the leading cause of death inWesterncountries. Over the past 30 years, substantial progress has been achievedin this area. Yet, whilemortality rate for IHD has steadily declined inmen,it has remained largely unchanged in women [1]; indeed, contrary to thecommon perception that coronary artery disease affects mainly men,more women than men die from coronary artery disease in the U.S.A.[1] and in Europe [2].

In addition to being a major cause of death, IHD is also a majorcause of morbidity. Stable angina is a very common condition, witha prevalence around 5% of general population in Western countries[3], which impacts quality of life and ability to work, and withsignificant economic consequences. This manifestation of IHD hasnot declined, or it has even increased in prevalence in recent years[1]. Again, women score worse than men also in this respect. In arecent meta-analysis of both cross-sectional and prospective studiesfrom 31 countries world-wide, encompassing 13,331 cases of angina

in women and 11,511 cases in men, a substantial female excess wasconsistently shown, with a pooled random-effect sex ratio of 1.20(95% confidence interval 1.14–1.28; pb0.0001) [3].

2. Women with ischemic heart disease: a different breed?

Women suffering from angina pectoris differ substantially frommen with this disease. It is well known that women with IHD areolder, and tend to have a greater burden of comorbidities and morefunctional disability than men [4,5]; it is also established that IHD isless prevalent in premenopausal women, its incidence lagging10–15 years behind that of men until approximately the seventhdecade of life. Much less appreciated, instead, is the fact that patho-physiology of angina pectoris may often be different in women. Onein two women referred for elective coronary angiography becauseof angina actually do not show evidence of significant coronary arterystenosis [4,6–11] (Fig. 1). In a very large cohort of patients referred forangiographic evaluation of stable angina (n=375,886; 45% women)at 388 US hospitals, the risk-adjusted OR for significant coronaryartery stenosis was only 0.34 for women compared to men (pb0.0001)[4,8]. Lower prevalence of obstructive coronary artery disease (CAD) inwomen with angina holds true across all age group [8]; however, itbecomes astonishingly low at relatively young ages, as almost 80% ofb60 years old women referred for elective, diagnostic coronary angiog-raphy with suspected stable angina had no significant coronary arterystenosis [8] (Fig. 1).

International Journal of Cardiology 163 (2013) 132–140

☆ Grant support: None.⁎ Corresponding author at: Department of Cardiology, Ospedale S. Maria della

Misericordia, Piazzale Menghini, 1, 06132, Perugia, Italy. Tel.: +39 075 5782394; fax:+39 0755271244.

E-mail address: giuseppe.ambrosio@ospedale.perugia.it (G. Ambrosio).

0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ijcard.2012.07.001

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3. Impact of different pathophysiology on clinical management ofischemic heart disease in women

These peculiar demographic and angiographic findings may influ-ence clinical presentation and diagnosis of IHD in women. These dif-ferences may actually lead to substantially underdiagnosing IHD inwomen, due to the following several major factors.

3.1. Inappropriate perception of cardiovascular risk

There is widespread underappreciation of cardiovascular risk inwomen, not just among lay people but among physicians as well. Inthe Euro Heart Survey of Stable Angina, women with anginal painwere less likely to undergo an exercise electrocardiogram, and lesslikely to be referred for coronary angiography [12]. Interestingly,there are reasons for this misconception which partly stem from theuse of risk algorithms originally derived from predominantly malepopulations. Indeed, by this approach, even up to age 80, three quar-ters of women would have a 10-year Framingham Risk Score of b10%[13]. However, the assessment may change if one uses a more refinedstrategy. A novel, specifically tailored risk score was tested in 24,558women involved in the Women Health Study [14]; this new algo-rithm, the Reynolds Risk Score, which includes age, systolic bloodpressure, hemoglobin A1c if diabetic, current smoking, total andHDL-C, hsCRP, and parental history of myocardial infarction beforeage 60, reclassified 15% of women predicted to be at intermediaterisk (according to Adult Treatment Panel III criteria) into high-riskcategory [14]. Among the new risk factors examined in the ReynoldsRisk Scores, hsCRP, a marker of inflammation, seems to be ofparticular importance. Indeed, among postmenopausal hypertensivewomen, a high peripheral neutrophil count has recently beenshown to be an independent predictor of cardiovascular events [15],highlighting that inflammation may be of relevance in identifyingwomen at increased risk of cardiovascular disease.

3.2. Inappropriate evaluation of symptoms

Definition of what constitutes “typical” anginal symptoms is largelyderived from observations made in predominantly male populations;thus, one may ask whether symptoms in women should be judged bythe same criteria used to diagnose stable IHD in men. In this respect,the very recently-issued NICE guidelines on stable angina state that dif-ferences in symptomatic presentation between men and women aresmall and it is the pre-test likelihood of coronary atherosclerosiswhich should influence management, not gender alone [16]. This rec-ommendation is in line with current understanding and treatment ofIHD, which is based on the “significant stenosis” approach, and un-doubtedly it is appropriate for a large number ofwomenwith stable an-gina due to coronary artery disease. However, it should be consideredthat possible gender differences in presenting symptoms may stillexist with respect to characteristics, frequency, and quality of

symptoms noted during chest pain [17–20], which at times may makeit difficult to properly evaluate chest pain in women. These differenceson the one hand hinge around description of symptoms, which maybe influenced by the characteristics of the population investigated,while on the other hand the “trigger” of symptoms sometimes may dif-fer between genders.

With respect to clinical characteristics, in patients with documentedcoronary artery stenosis – as reviewed in NICE guidelines [16] – typicaleffort angina is indeed the main complaint of both men and women. In5125 patients with chronic stable angina and documented coronaryartery disease (53% female), angina with physical activity was presentin 90%, without significant differences between men and women [18].In another cohort of patients with coronary artery stenosis, Kimble etal. [19] reported similar physical limitation related to angina inwomen compared tomen by Seattle Angina Questionnaire (SAQ). How-ever, if one considers all patientswho complain of angina– regardless ofcoronary anatomy – most women actually refer atypical symptoms,more so than men. In a Caucasian population (2676 women and 2929men) Zaman et al. found significant difference in symptoms, 53.6% ofwomen reporting atypical chest pain [17]. This may have substantialpractical implications, since as mentioned significant coronary arterystenosis is often absent in women.

On the trigger side, women complain more often than men ofmental-stress evoked angina [18,20], or angina unrelated to physicalexercise [18]. Women with stable angina and documented CAD aremore likely than men to report chest pain during rest, sleep, or epi-sodes of mental stress [18]; indeed, female sex has been associatedwith significant excess risk for mental stress angina (RR 1.28), andrest angina (RR 1.09) [18]. Similarly, women with documented CADrefer angina during mental stress more frequently than men (19% vs3.6%, pb0.01) [20]. Interestingly, microvascular angina – which ismuch more common in women [10,21–27] (see below) – may haveatypical features, such as pain at rest, prolonged duration of attacks,poor response to sublingual nitrates [23].

Together, these findings suggest that mechanisms other than clas-sical demand-vs-supply imbalance due to coronary artery stenosismay at times be involved in women with IHD; thus, episodes ofchest pain not clearly related to exercise, or presence of during exer-tion symptoms other than typical angina, while less likely to accom-pany significant coronary artery stenosis, should not allow thephysician to rule out IHD altogether in women. As summarized in2010 NICE guidelines [28], when discussing gender differences insymptoms “Cardiovascular risk factors are at least as important inwomen as in men, if not more so, [i.e., compared to symptoms] in deter-mining the likelihood of women having coronary events”.

3.3. Inappropriate assessment

According to Bayes theorem, the predictive value of a diagnostictest depends on the prevalence of disease in the population tested,and on sensitivity and specificity of the test itself. Non-invasivetools currently used to diagnose IHD, namely exercise stress test, per-fusion imaging, stress-echo, all rely on the possibility of inducing anddetecting regional ischemia. While this approach is useful for the pur-pose of revealing discrete flow-limiting stenoses, it may be ill-suitedto detect ischemia in the absence of a significant stenosis. So, thelower prevalence of obstructive coronary artery disease in womenmakes diagnostic testing designed to detect focal areas of relativeunderperfusion less sensitive and specific in this population [5]. Sim-ilarly, the interpretation of results of an exercise ECG stress test as“false positive” when there is no angiographic evidence of significantCAD has to be made with caution in women, as it may derive frommicrovascular alterations. Also, sensitivity and specificity of exercisestress testing are not in favor of women. Indeed, in a meta-analysisof exercise testing in women, sensitivity and specificity of ST-segmentdepression in symptomatic, intermediate risk women were just 61%

Fig. 1. Angiographic findings in 168,180 women and 207,706 men subjected to electivecoronary angiography because of anginal pain. Data are from the American College ofCardiology–National Cardiovascular Data Registry.Replotted from Barey-Merz et al. [4] and Shaw LJ et al. [8].

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and 70%, respectively [29]. ECG changes during exercise have beenreported to be of diminished accuracy in women as a result of morefrequent resting ST–T wave changes, lower ECG voltage, and hormonalfactors such as endogenous estrogens in premenopausal women andhormone replacement therapy in postmenopausal women [30–34].Handberg et al., analyzing data from190womenenrolled in theNationalHeart, Lung, and Blood Institute (NHLBI)-sponsored Women's IschemiaSyndrome Evaluation (WISE) study, showed that women with reducedcoronary flow reserve were significantly more likely to have reducedfunctional capacity [35]. A Consensus Statement indicates that the diag-nostic and prognostic accuracy of exercise ECG stress test in symptomaticwomen with suspected IHD can be enhanced by the inclusion ofadditional parameters (e.g., functional capacity, treadmill scores)to the interpretation of the ST-segment response to exercise [34].

4. Different pathophysiology

An even greater contributor to the peculiar characteristics of anginain women could be represented by specific mechanisms. We tend toequate angina pectoris with underlying significant coronary stenoses,but chest discomfort due to myocardial ischemia can also occur inother conditions. Women show structural and functional differencesin the coronary circulation [36]. Indeed, coronary arteries in womenare smaller than men, independent of body size [37]; this might be ofsome relevance, since it has been shown that even in the absence of dis-crete stenosis diffuse narrowing of vessel lumen by atherosclerosis mayresult in abnormal resistance, limiting myocardial flow [38]. Of greaterrelevance is the finding that angina in women is less likely to be associ-ated with angiographically significant coronary artery stenosis than inmen, microvascular disease of coronary arteries being more commonin women than men.

As already mentioned, substantial amount of observational andregistry data indicate that a majority of women (from 51% to 65%)referred for a diagnostic cath for evaluation of angina actually haveno significant coronary artery stenosis [4,6–11]. Furthermore, grow-ing evidences suggest that coronary microvascular dysfunction canbe an etiological factor for IHD, and it frequently explains the pres-ence of chest pain in the absence of significant coronary obstruction,configuring the so called “microvascular angina”, or cardiac “syn-drome X” [21,23–27,39–46]. In this regard, studies that specificallylooked into patients with microvascular angina consistently report alarge female excess (ranging from 54% to 100%) of enrolled patients[10,21–23,25–27]. A recent systematic review on this topic [24] of47 studies on microvascular angina (accruing 1934 patients), founda significantly higher proportion of women, with a pooled relativefemale frequency of 56%.

One lingering question is whether chest pain in those patients withmicrovascular angina is indeed due to true myocardial ischemia.Women with angina and non-significant coronary artery stenosis mayshow impaired cardiac energy metabolism by nuclear magnetic reso-nance spectroscopy, unequivocally documenting exercise-induced ische-mia [47,48]. Furthermore, evidence of blunted coronary vasodilatorreserve has been documented in patients (mostly women) with angio-graphically normal coronary arteries and microvascular angina[25–27,42–46,49], thus providing evidence of coronary microvascu-lar dysfunction in patients with otherwise angiographically normalcoronary arteries.

5. Prognosis

The common belief that women suffering of angina in the absenceof significant coronary artery stenosis are characterized by good prog-nosis may not always hold true. Earlier studies reported very few car-diac events in these patients [23,50,51]. However, more recently ithas been shown that prognosis in such patients may be less benign.Johnson et al. reported that cumulative incidence of cardiovascular

events (death,myocardial infarction, heart failure, stroke, hospitalizationfor unstable angina) at 3 yearswas not negligible forwomenwith anginaand no angiographic alterations (13%), and it got even higher (43%) inthe subgroup of these women in whom evidence of impaired energymetabolism (by NMR spectroscopy) could be elicited by exercise [48].In another study, among 412womenwithout CAD, thosewith persistentepisodes of chest pain in spite of medical therapy (PChP) at a medianfollow-up period of 5.2 years hadmore than twice the rate of compositeCV events (non-fatal myocardial infarction, stroke, congestive heartfailure, CV death), than women without PChP (p=0.03) [52]. Finally,in a large retrospective analysis of 11,223 patients referred for coronaryangiography with stable angina [11], almost half (5183 patients; 59% ofwhom women) had angiographically normal coronary arteries (3479patients), or just diffuse non-obstructive CAD (1,704 patients). Com-pared with a reference population, after multivariable-adjusted analysispatientswith angina andnormal coronary arteries showed a significantlygreater Hazard Ratio of coronary events (HR 1.52; 1.27–1.83 95% confi-dence interval), as well as of all-cause mortality (HR 1.29; CI 1.07– 1.56); interestingly, patients with diffuse non-obstructive CAD showed a fur-ther increase in the risk of coronary events and of all-cause mortality(HR 1.85; CI 1.51–2.28; and 1.52; CI 1.24–1.88, respectively), consistentwith the notion that a great proportion of acute coronary events involvesatherosclerotic plaques without significant stenosis. Thus, while obvious-ly lower thanpatientswith frank coronary artery disease, a substantial ex-cess risk of coronary events and mortality seems to be conferred byangina symptoms even in patients with no, or only subtle alterations atcoronary angiography.

Altered functional response of coronary microcirculation seems tobe a major player in risk stratification of such patients. Among 167women referred for coronary angiography because of suspectedIHD, and found to be mostly (75%) free of obstructive disease,impaired coronary vasodilation to acetylcholine was independentlylinked to adverse cardiovascular outcomes, regardless of CAD severity[53]. Data from the WISE study demonstrate a 2.5% annual risk of ad-verse cardiac events, including death, in women with microvascularcoronary dysfunction [45,48]. Very recently, Pepine et al. [54] haveinvestigated 189 womenwith suspected ischemia and atherosclerosisrisk factors; most (81%) women had either no or b50% obstructiveCAD. In this cohort, assessment of coronary microvascular reactivityto adenosine significantly improved prediction of major adverse out-comes over angiographic CAD severity and CAD risk factors: during a5.4 year follow-up; 42% of women had an adverse outcome (Fig. 2);impaired CFR provided the best prediction for major adverse out-comes (CFR b2.32 outcome rate 27.0%; ≥2.32 outcome rate 12.2%,X2=6.73, p=0.010). Predictive role of impaired CFR remainedconsistent after adjusting for risk factors (SBP, CAD severity, age,diabetes, smoking) (Fig. 2). Importantly, similar results were obtainedwhen restricting the analysis to women without obstructive CAD, aswomen with low CFR experienced significantly more major adverseevents (CFR b2.32 outcome rate 26.6% vs. 9.3%, X2=5.84; p=0.016)(Fig. 2).

In another study, Halcox et al. assessed coronary vascular function in308 patients, of whom 143 women, undergoing cardiac catheterizationbecause of chest pain [55]. Among female patients, 22% had normal cor-onary arteries at angiography. At a mean follow up of 46±3 months,after multivariable analysis change in coronary vascular resistancewith acetylcholine (p=0.02), and epicardial vessel constriction withacetylcholine (p=0.003), together with increasing age, CAD, andbody mass index, were independent predictors of adverse events inthe whole cohort [55].

Suwaidi et al. studied 157 patients with “mildly diseased” coro-nary arteries who had undergone coronary vascular reactivity evalu-ation by intracoronary acetylcholine, adenosine, and nitroglycerin,and intracoronary ultrasound, at the time of diagnostic cath [56].Over an average 28-month follow-up, none of the patients with nor-mal or mildly abnormal endothelial function had cardiac events,

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while 14% of those with severe endothelial dysfunction had cardiacevents (myocardial infarction, coronary revascularization, and/orcardiac death; pb0.05).

Thus, while obviously lower than patients with overt coronaryartery disease, a substantial risk of coronary events seems to be con-ferred by angina symptoms even in patients with no, or subtle alter-ations at coronary angiography. These patients should not be easilydismissed, and may need accurate risk stratification. Assessment ofmicrovascular function might help identify among patients withangina and angiographically normal coronary arteries those athigher risk for future cardiac events.

6. Treatment of stable angina in women

More complex pathophysiology of angina in womenmay also leadto lower response to therapy. Angina pectoris is also considerablyundertreated in women [12]. In the Euro Heart Survey of Stable Angi-na, antiplatelet and statin therapies were used significantly less inwomen than in men, even when there was direct documentation ofcoronary artery disease [12]. Women with confirmed coronary dis-ease were less likely to be revascularized than men, and were twiceas likely to suffer death or nonfatal myocardial infarction duringfollow-up, even after multivariable adjustment for age, abnormalventricular function, severity of coronary artery disease, and diabetes[12].

More extensive use of revascularization procedures, however, mayreduce the burden of ischemic symptoms in women only to someextent, since: a) PCI or CABG do not eradicate symptoms in many suchpatients, as a sizable number of women remain symptomatic in spiteof successful revascularization [57–60]; b) as already pointed out,angina in the absence of significant stenosis of native coronary arteries(i.e., microvascular dysfunction) is particularly prevalent in women[8,10,21–27], and women in this latter group quite frequentlycontinue to have symptoms in spite of therapywith classical antianginaldrugs [52,61]; and c) drugs currently available tend to be less effectivein women, due to specific pathophysiology which may not favortreatment of angina following the traditional “supply-vs-demand”approach [62]. Indeed, consistent with the notion that women withangina tend to have symptoms less linked to degree of physicalactivity [19,63], exercise stress test in women is a less sensitive indi-cator of treatment efficacy than angina frequency or nitroglycerinconsumption [64].

Response to medical therapy may differ in women when com-pared with men because there may be gender-specific physiologicaldifferences [65], and differences in the activity of drug-metabolizing

enzymes [65]. For example, significantly lower therapeutic effect onstress-induced angina pectoris was reported in women with coro-nary artery disease treated with metoprolol compared with men[62], in spite of the fact that greater plasma concentrations of meto-prolol are achieved in women [66].

6.1. Classical antianginal drugs

Besides small studies, women are poorly represented in largerandomized clinical trials on stable angina [67,68], and data ongender differences on the effect of anti-ischemic drugs are lacking.A metanalysis of 90 studies on stable angina treatment with“classical antianginal” drugs (beta-blockers, calcium antagonists,and nitrates) shows that less than 20% of enrolled patients werewomen [68].

The picture becomes even fuzzier when ischemia, although docu-mented by chest pain and ST-segment depression during exercise stresstest, is not accompanied by evidence of obstructive coronary arterydisease at angiography. Regrettably, intervention studieswith antianginaldrugs in patients affected by microvascular angina (summarized inTable 1) tend to be small, and too short, to firmly establish whether thebenefit observed remains stable over time. Among classical anti-anginaldrugs, onlyβ-blockers have been consistently shown to effectively reducechest pain episodes during daily life in this condition [69–71]. Ca++antagonists seem to do little to prevent chest pain in patientswith “nor-mal” angiograms [69,72,73], and they fail to ameliorate the diminishedcoronary blood flow reserve of these patients [72]. Nitrates are anecdot-ally reported to be of help in some patients but not in others [23], butrandomized, placebo-controlled trials on nitrates are lacking. Interest-ingly, benefits on various parameters of exercise tolerance have beenobtained in patients with microvascular angina through a substantiallydifferent approach, namely trying to influence microcirculation func-tion, either via potentiation of endogenous adenosine (by aminophyl-line [74,75]), or secondary to a putative increase in the activity ofnitric oxide with ACE-inhibitors [76–79], or statins [80,81]. However,none of these studies went past the “proof-of-concept” stage, withonly a handful women treated for a few weeks. Recently, the NICEguidelines on stable angina reviewed the interventional studies on Car-diac Syndrome X [16]. They state that only evidence for limited out-comes over short periods of time is available and the evidence doesnot support use of standard antianginal drugs for long term benefit[16], and concluded that drug treatment for stable angina in patientsalready on treatment should be continued only if it improves symptoms[16]. Thus, there is an unmet need for effectively treating angina inwomen with specifically tailored drugs.

Fig. 2. Coronary flow reserve (CFR) and event-free survival in women with stable angina. Left panel: CFR and event-free survival in the whole cohort; Right panel: CFR andevent-free survival in those without CAD. Note the significantly worse prognosis in women with impaired CFR, regardless of presence or not of coronary artery stenosis. Data rep-resent unadjusted Kaplan–Meier curves for absence of: death, nonfatal MI, nonfatal stroke, or hospitalization for congestive heart failure during follow-up.Modified from Pepine et al. [54].

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6.2. Ranolazine

Ranolazine, a novel molecule approved in the USA and Europe fortreatment of stable angina [82], may represent one such possibility.Unlike classical antianginal drugs, it shows anti-ischemic actions atconcentrations that have negligible effect on heart rate, blood pressure,or O2 consumption [83]. During ischemia there is an elevation in intracel-lular Na+ in myocytes [84–86] secondary to increase in the late Na+

inward current (INa) [84,86]; this condition induces intracellularCa++ overload [86], which in turn increases actin/myosin filamentinteraction and LV diastolic tension [87]. As a consequence, on theone hand there is abnormal increase in contractile work and O2 con-sumption, and on the other hand compression of vasculature, bothleading to further ischemia. By inhibiting myocyte INa; ranolazinewould reduce [Na+]i-dependent Ca++ overload induced by ischemia.Consistent with this mechanism, in patients with IHD ranolazine causesa downward shift of LV pressure–volume relationship, increasespeak filling rate and wall lengthening of ischemic regions of LV[88,89]. Recently, a small mechanistic study on ranolazine has beenperformed in women with microvascular angina, no obstructive

coronary artery disease, and evidence of ischemia as perfusion abnor-malities on adenosine stress cardiac magnetic resonance imaging [90].Compared with placebo, women on ranolazine scored significantly bet-ter on SAQ, including physical functioning (p=0.046), angina stability(p=0.008), and quality of life (p=0.021); interestingly, in womenwith reduced baseline CFR (i.e., reduced microvascular perfusion)ranolazine significantly improved myocardial perfusion reserve index.

Ranolazine has been tested overall in 1737 patientswith stable anginaenrolled in 4 randomized clinical trials (MARISA; CARISA; ERICA;RAN080) [91–94], showing effective anti-anginal activity. Kass-Wengeret al. [95] have recently performed gender comparison of efficacy andsafety of ranolazine in patients with stable angina and a similar genderdistribution of concomitant treatment with ACE-inhibitors, α- andβ-blockers, and statins. Study designs are summarized in Table 2. The ef-fect of ranolazine on exercise tolerancewas less pronounced in women,whereas it afforded comparable reduction of angina frequency andnitroglycerin consumption in women and men (Fig. 3). Patients whocompleted the MARISA or CARISA trials were then enrolled in TheRanolazine Open Label Experience (ROLE) [96], where the safety ofranolazine was assessed. It should be acknowledged that these findings

Table 1Clinical studies on treatment of microvascular angina. W = women; C = Hypercholesterolemia; MI = previous myocardial infarction; ND = non diabetic; CFR = coronary flowreserve; CBF = coronary blood flow; FMD = flow mediated dilatation; SAQ = Seattle Angina Questionnaire.

Author Year N W Drug Study design Length Effects

Lanza GA[70]

1999 10 6 Atenolol 100 mg/dayAmlodipine 10 mg/dayISMN 50 mg/day

Cross-over, double blind,randomized

4 weekseachtreatment

↓ angina episodes only with atenolol

Fragasso G[71]

1997 22 16 Atenolol 100 mg/day Single-blind, randomised, crossovertrial, placebo-controlled

10 days ↓ angina episodes, prevention ofexercise-induced ischemia, improvement ofDoppler-derived indices of ventricular filling

Cannon RO[107]

1985 26 15 Verapamil 40–160 mg ×4/day ornifedipine 10–30 mg ×4/day

Randomized, double-blind,placebo-controlled outpatient study

1 month ↓angina episodes and ↑ exercise duration

Sutsch G[72]

1995 16 7 Diltiazem 10 mg iv Case–control Acute study No effect on CFR

Montorsi P[108]

1990 18 12 Nifedipine 10 mg slNifedipine 10 to 20 mg ×4/day

Double blind, placebo controlled Acute and4 weeks

Acute: ↑CBF, ↓ST-shift during exercise stress test,↑norepinephrine plasma concentrationsAfter 4 weeks: further ↓ in effort ST-segment shift

Cannon RO[109]

1990 22 12 Lidoflazine 240 or 360 mg/day Randomized, double blind, placebocontrolled

7 weeks ↑ exercise duration and ↓ chest pain at stress test,↑ CFR

BugiardiniR [69]

1989 16 Verapamil 320 mg/dayPropranolol 120–160 mg/day

Randomized double-blind crossoverplacebo-controlled trial

7 days eachtreatment

↓ ischemic episodes at Holter ECG with Propranolol

Lanza GA[110]

1994 51 22 ISDN 5 mg sl Case–control Acute study ↓exercise duration and no prevention of anginaduring exercise stress test

Radice M[111]

1996 20 19 Nitroglycerin 0.3 mg slAminophylline 400 mg os

Randomized 3 exercisetests

↑ time to ischemic threshold and angina onlywith aminophylline

Yoshio [74] 1995 12 10 Aminophylline 6 mg/kg iv Single-blind, placebo-controlled Acute study ↑ ischemic threshold and ↑ exercise durationElliot PM[75]

1997 13 11 Aminophylline 350 or 225 mg×2/day

Randomized, double-blind,cross-over, placebo-controlled

3 weeks ↑ time to angina during exercise stress test

Kaski JC[77]

1994 10 7 Enalapril 10 mg/day Randomized, single-blind, crossover,placebo-controlled study

2 weeks ↑exercise duration and ↓ exercise-induced ischemia

Chen [78] 2002 20 5 Enalapril 20 mg ×2/day Randomized, double-blind, placebocontrolled

8 weeks ↑ exercise duration, ↑ CFR, ↓ plasma vWF, ↓ ADMA,↑NOx, ↑ ratio L-arginine/ADMA

Nalbantgil I[79]

1998 18 15 Cilazapril 5 mg /day Randomized double-blind crossoverplacebo-controlled trial

3 weeks ↑exercise duration and ↓ ST-shift during exercise

Russel SJ[112]

2007 28 25 Irbesartan 150 mg daily300 mgdaily

Double-blind, randomised,placebo-controlled, two periodscrossover

1 week No effect on exercise duration and onischemia episodes at Holter ECG

Pizzi C[76]

2004 45 40 Ramipril 10 mg/day andAtorvastatin 40 mg/day

Randomized, placebo-controlled 6 months ↓ SOD levels, ↑ exercise duration and improved SAQ

Fabian E[80]

2004 40C

15 Simvastatin 20 mg/day Randomized, placebo controlled 12 weeks ↓ exercise-induced ischemia

Kayikcioglu[81]

2003 40 22 Pravastatin 40 mg/day Single-blind, randomized,placebo-controlled

3 months Improvement of FMD, ↑ exercise durationand time to 1 mm-ST depression

Rosano GM[113]

1996 25MI

25 17-beta-estradiol cutaneouspatches 100 micrograms/day

Double-blind, placebo-controlled,cross-over

8 weeks ↓chest pain episodes, no effect on exercise duration

Lerman[114]

1998 26 13 L-arginine 3 g ×3/day Double-blind, randomized,placebo-controlled

6 months ↓ symptoms, ↑CFR, ↓ endothelin

Botker HE[115]

1998 16 14 Doxazosin 1–4 mg/day Double-blind, placebo controlled,crossover study

10 weeks No effect on angina, exercise duration andexercise-induced ischemia

Jadhav S[22]

2006 33ND

33 Metformin 500 mg ×2/day Double-blind, randomized,placebo-controlled

8 weeks Improvement in forearm (skin) endotheliumdependent microvascular function, maximalST-segmentdepression, Duke score and chest pain incidence

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have been obtained using different doses of ranolazine, and withdifferent comparator drugs; type of exercise protocol used also dif-fered among studies.

In MERLIN-TIMI36 trial, the efficacy and safety of ranolazine wastested during long-term treatment of patients with non-ST elevationacute coronary syndrome [97]. Women were more represented thanin other trials, comprising 35% of study population (n=2291) [98];again,womenwere less likely to have significant epicardial coronary ar-tery disease. Interestingly, incidence of worsening angina did not differbetween women with and without obstructive epicardial disease;women treated with ranolazine reported less angina and required less

intensification of their antianginal medical regimen during follow up[98].

6.3. Ivabradine

This drug inhibits the If current of sinus node, and as such it slowsheart rate, particularly during exercise, without negative inotropic ef-fects [99]. In clinical trials of patients with effort angina and docu-mented CAD, ivabradine improved exercise performance [100–103];the drug was non-inferior to atenolol, and conferred additional benefitwhen added on top of beta-blockers [101,102]. Ivabradine shows

Table 2Study design of randomized clinical trials on ranolazine treatment in chronic stable angina. ACE = angiotensin-converting enzyme; BID = 2 times daily; BB = β-blocker; CCB = calciumchannel blocker; ER = extended release; IR = immediate release; LAN = long-acting nitrate; NTG = nitroglycerin; QD = 1 time daily; SAQ = Seattle Angina Questionnaire; TID = 3times daily.

Study design N ofpatients

Treatments Primary efficacymeasurements

Secondary efficacy measurements Concomitant medications

MARISA[91]

Double-blind,4-periodcrossover

191randomized

Ranolazine ER 500, 1000,1500 mg and placebo BID for1 week each

Exercise duration ontreadmill at troughranolazineconcentration

Time to angina, time to 1-mm ST-segmentdepression at trough and peak; exerciseduration at peak

None permitted

CARISA[92]

Double-blind,parallelgroup

823randomized

Ranolazine ER 750 or 1000 mgor placebo BID for 12 weeks

Exercise duration ontreadmill at troughranolazineconcentration

Time to angina, time to 1-mm ST-segmentdepression at trough and peak; exerciseduration at peak; angina frequency; NTGuse

Required: diltiazem 180 mgQD, atenolol 50 mg QD, oramlodipine 5 mg QD.

RAN080[94]

Double-blind,three periodscrossover

158randomized

Ranolazine IR 400 mg TID,atenolol 100 mg QD, and place-bo for 1 week each

Time to onset ofangina during ETT atpeak ranolazineconcentration

Time to angina, time to 1-mm ST-segmentdepression at trough and peak

CCBs and LANs permitted

ERICA[93]

Double-blindparallelgroup

565randomized

Ranolazine ER 500 mg BID orplacebo for 1 week; ranolazine1000 mg BID or placebo for6 weeks

Average weeklyfrequency of anginaattacks

Average weekly NTG consumption; SAQscores

Required: amlodipine 10 mgQD; permitted: LANs, ACEinhibitors; other antianginalexcluded

Fig. 3. Gender comparisons of efficacy of ranolazine on angina episodes and nitroglycerin consumption per week in CARISA, RAN080, and ERICA trials.Modified from Kass-Wenger et al. [95].

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comparable efficacy to amlodipine in improving exercise tolerance,with a greater effect on rate-pressure product (a marker of myocardialO2 consumption) [103]. However, presence of women in these trialswas low (10–15%) [100–102], nor was subgroup analysis for genderperformed. A large observational study showed effective treatment ofstable angina by ivabradine in patients mainly not taking beta-blockersdue to contraindications or intolerance [104]; of 4954 patients, 41%werewomen, and therefore thosefindings could be translated to a femalepopulation; however, because of its open-label design and absence of aplacebo-controlled group, those data are not definitive.

6.4. Outcomes

Very little information is availablewith respect to the effects of “clas-sical” antianginal drugs on long termoutcomes. This comes to as no sur-prise. On the one hand, those drugs were mostly tested at a time whenless attention was being paid to the outcome issues, as compared tothese days; on the other hand, intervention studies with antianginaldrugs understandably focus on improvement of exercise tolerance andof symptoms, and as such a rather short follow up is required. Ametanalysis by Heidenreich et al. of clinical trials in 6144 patientswith stable angina reports that length of follow up is typically lessthan 6 months [68]. Within that time frame, OR for risk of cardiac deathand/or myocardial infarction was 0.97 (95% CI, 0.67–1.38, p=0.85) inpatients treated either with beta-blockers or calcium antagonists [68].

With respect to newer compounds, data about the effect of ivabradineon hard end points are relative to patients enrolled in the setting ofreduced left ventricular function [105,106]. BEAUTIFUL found no impactof ivabradine on outcomes in patients with stable coronary artery disease(CAD) and left ventricular systolic dysfunction [105]. However, in apost-hoc analysis among patients with limiting angina at baseline at amean follow-up of 18 months, there was a significant reduction in theprimary endpoint, mostly in the subgroup of patients with heart rate≥70 bpm (73% reduction in hospitalization for MI and 59% reduction incoronary revascularization) [106].

As for ranolazine, as yet there is no direct evidence of its long termbenefits on mortality and cardiovascular events in patients withstable angina. Indirect evidence can be gathered from the ROLE(Ranolazine Open Label Experience) program, which involvedpatients who completed theMARISA or CARISA trials in a subsequentopen-label extension program [96]. Ranolazine was titrated tooptimal dosages between 500 and 1000 mg; 76.7% of patients com-pleted 2 years of open-label ranolazine therapy. For mortality analy-sis, follow-up data of the 942 patients exposed to ranolazine throughrandomization in the MARISA or CARISA trials or in the ROLE pro-gram were used [96]. Annual incidence of death was 2.8%, substan-tially lower than expected for a similar population [96]. It shouldbe pointed out that due to its open-label design, the ROLE programdoes not allow for a rigorous analysis of mortality; moreover therewas no comparison cohort.

In summary, data with respect to the effects of antianginal drugson outcomes are disappointingly scarce, and virtually non-existentin terms of gender-based analysis. Future clinical research should fillin this knowledge gap.

7. Conclusions

Ischemic heart disease is a major cause of death in women, and itis largely underrecognized and undertreated; indeed, greater aware-ness of possible differences in presentation and pathophysiology ofangina in women is in order. Appropriate therapeutic strategiesneed to be properly evaluated, as solid data for classical antianginaldrugs do not exist in terms of gender efficacy. Of equal or greaterimportance, the approach to ischemic heart disease in women shouldchange, the aim being at identifying patients at high risk for cardio-vascular events, rather than patients with obstructive coronary artery

disease. In this context, postmenopausal women with angina are agroup of patients in whom it seems appropriate to concentrate effortsaimed at reducing morbidity and improving quality of life. This can beconsidered amajor unmet need in terms of modern-day cardiovasculartherapy. The current focus of randomized trials and clinical guidelines inangina onmale patients ignores the substantial burden of this disease inwomen.

Disclosure of potential conflict of interest

Prof. Ambrosio has served as a consultant, and on the speaker'sbureau of Menarini International.

Acknowledgment

The authors of this manuscript have certified that they complywith the Principles of Ethical Publishing in the International Journalof Cardiology.

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