Abstract
The different responses of women and men to cardiovascular drugs reflect gender –specific variances in pharmacokinetic profiles and drug sensitivities coupled to inherent differences in the underlying physiology of each sex. Thus, many common cardiovascular drugs exhibit gender -specific therapeutic and adverse effects. For example, the QT interval of the electrocardiogram is longer in women compared to men, and accordingly, drugs that prolong the QT interval are more likely to cause lethal ventricular arrhythmias in female than male patients. As more clinical drug trials include women subjects, our improved knowledge base for assessing the risk/benefit ratio for cardiovascular drugs in women will enable us to consider gender as one factor in prescribing drugs and adjusting drug loading and maintenance dosages. This short review will present evidence for gender- related differences in the responses to common cardiovascular drugs including statins, antiplatelet and antithrombotic agents, β-blockers, digoxin, vasodilator therapies, and drugs associated with the Long QT Syndrome.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Women take more medications than men, but these therapies are less likely to follow evidence-based guidelines [1, 2]. For example, the use of aspirin and statins as primary and secondary prevention against cardiovascular events is less common in women compared to men across all races and ethnicities [3]. Women also show lower adherence to medication regimens compared to men [1, 2]. The reasons for disparities between women and men in prescribed medications and adherence to them are poorly understood, but may relate to a complex interplay of many societal, economic and physiological factors. For example, under-representation of women in clinical trials may be a factor contributing to limited recognition of gender-based differences in medication responses, thereby preventing optimization of therapeutics for women of all ages. The 1.5 to 1.7 -fold higher risk of adverse drug events in women may partially relate to less risk recognition in addition to gender-based differences in immune responses [2, 4, 5]. Additionally, men and women show differences in pharmacokinetics and pharmacodynamics of cardiovascular medications [6–8], including altered patterns of absorption, distribution, metabolism and excretion (Table 1).
Pharmacokinetics
Absorption of medications in women may be slower due to reduced gastric acid secretion and gastrointestinal motility [6–11]. Therefore, drugs designed for absorption in the duodenum, including enteric-coated formulations, may exhibit diminished or delayed absorption, especially following a meal [10, 11]. Examples of cardiovascular medications that are reported to show delayed or reduced availability in women due to slowed or attenuated absorption include verapamil, captopril, felodipine, and enteric-coated aspirin [6–11]. To ensure adequate bioavailability of medications recommended to be taken on an empty stomach, women should take these medications prior to breakfast or wait longer than prescribed after eating a meal if the medication is taken more than once daily [6].
Women also may have a smaller drug volume of distribution due to lower body weight and smaller intravascular, organ, and muscle volumes as compared to men [6–8]. For this reason, special attention should be given when administering loading doses or intravenous boluses of cardiovascular medications with narrow therapeutic indexes to prevent adverse events in women. Weight-based dose adjustments are routinely recommended for class I and class III antiarrhythmic agents, digoxin, heparin and other cardiovascular drugs [6–8]. Another consideration is that despite lower body weight, women generally have a higher percent of body fat, which favors a higher volume of distribution normalized to body weight for lipophilic drugs [6].
Several metabolic enzymes are reported to have higher activity in men compared to women. These enzymes include CYP1A2, CYP2E1, P-glycoprotein (drug efflux pump), and certain isoforms of glucuronyltransferases and sulfotransferases [7]. On the other hand, CYP2D6 and CYP3A are reported to have slightly higher activity in women of childbearing years [7, 12, 13]. No specific gender differences have been reported for CYP2C9 or CYP2C19 [7, 12, 13]. The potential for gender-based metabolic differences to importantly impact the availability and half-lives of cardiovascular drugs in women is poorly understood. In addition, renal clearance or glomerular filtration rate in women is 10 to 25 % slower than in men even after adjusting for body size [6–8]. Thus, cardiovascular medications that undergo primary renal elimination, such as digoxin, will be cleared more slowly [6, 7, 14].
The remainder of this chapter will highlight emerging evidence for the unique pharmacology of cardiovascular drugs in women. Pregnancy represents a condition unique to women that not only affects drug choice due to teratogenicity concerns, but also can alter the pharmacokinetics/pharmacodynamics of medications. This topic is reviewed elsewhere [15], and we have chosen to focus more globally on providing a short review of the pharmacokinetics and pharmacodynamics of several important cardiovascular drug categories. These categories of drugs include the statins, antiplatelet and antithrombotic agents, digoxin, β-adrenergic receptor blockers (β-blockers), vasodilator therapies, and drugs that can induce long QT syndrome as they pertain to women. A summary of gender-related therapeutic and toxic effects is provided in Table 2.
Statins
Elevated serum cholesterol levels, specifically low density lipoprotein cholesterol (LDL-C), have long been associated with an increased incidence of cardiovascular events [16, 17]. Statins directly inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a key enzyme for cholesterol synthesis in the liver, and thereby reduce circulating LDL-C levels [17]. Statins also exhibit beneficial pleiotropic effects associated with decreased inflammation, improved endothelial function, and enhanced atherosclerotic plaque stability [17–21]. Cardiovascular benefits derived from statin use are attributed to a combination of these effects [17–21].
Several meta-analyses offer conflicting data on the protective effects of statins for primary cardiovascular disease prevention in women [17]. The discrepancies may be related to ill-defined risk stratification or under-utilization of guidelines in women compared to men. Recent guidelines issued by the American College of Cardiology/American Heart Association, while generally more inclusive of women, fail to make a distinction in risk stratification between women and men for initiating and maintaining statin therapy [17]. In addition, some reports suggest that the lower metabolism, reduced muscle mass, and lower body weight of women compared to men predispose to statin-induced myalgias and diabetes [8, 22, 23]. The risk of these adverse events is highest in older women with low body weight [8, 22]. However, health providers are advised to avoid over-emphasizing these adverse effects and determine individual risk versus benefit for the use of statins in primary prevention of cardiovascular events in women. Meanwhile, the use of intensive statin therapy for secondary prevention of cardiovascular events in women is routinely recommended, since it has demonstrated significant decreases in myocardial infarction, unstable angina, heart failure and death [16–24].
Antiplatelet Agents: Aspirin
Platelets are crucial to the pathogenesis of atherosclerosis, and their role in the etiology of cardiovascular disease is confirmed indirectly by the clinical benefits of antiplatelet agents, such as aspirin and clopidogrel [25]. Aspirin inhibits platelet function and aggregation by inactivating the enzyme cyclooxygenase (COX)-1, which results in decreased synthesis of prostaglandins and thromboxane A2 [26]. Studies suggest that aspirin significantly reduces the risk of myocardial infarction in men with little change in risk of stroke [8, 27]. Conversely, aspirin was ineffective as primary prevention of myocardial infarction in women [25, 27], but showed significant protection against stroke [25, 27, 28]. There are several potential reasons for this gender disparity in the benefit conferred by aspirin therapy. First, uncoated aspirin exhibits altered pharmacokinetics in women, displaying faster absorption, a larger volume of distribution and more rapid hydrolysis [29], potentially compromising its beneficial effect. Alternatively, aspirin’s differential effects could relate to differing platelet functions and disease pathogenesis between men and women. For example, a recent study identified gender-specific responses to stress in patients with stable ischemic heart disease [30]. These researchers reported that men are more likely to respond to stressors by increasing blood pressure, whereas women exhibit higher platelet aggregation not only after pharmacologic stress with serotonin or epinephrine, but also in response to mental stress [30].
Genetic polymorphisms in platelet glycoproteins (Gp) also are linked to increased cardiovascular events. However, the gender distribution of these polymorphisms has not been defined [25]. Some evidence suggests that women who carry at least one Gp Ib-alpha5C allele exhibit a higher risk of cardiovascular events compared to women homozygous for the Gp Ib-alpha5T allele [31]. However, hormone replacement therapy was associated with reduced cardiovascular events in women who carried at least one Gp Ib-alpha5C allele compared to women homozygous for the Gp Ib-alpha5T allele [31]. This finding may align with other reports that estrogen decreases platelet reactivity in women [32, 33]. Future studies are clearly needed to determine gender-specific mechanisms of platelet action and potential differences in antiplatelet therapeutic outcomes. Currently, aspirin is recommended for use in women for the secondary prevention of cardiovascular events [25, 27].
Antithrombotics
Atherothrombosis is the leading cause of unstable angina, myocardial infarction and cardiovascular death [34]. Two pharmacologic strategies are available to decrease thrombosis in patients: anticoagulation and fibrinolytics. Anticoagulants inhibit thrombus or clot formation, while fibrinolytics break up already formed clots [34]. Both strategies have displayed similar reductions in myocardial infarction and cardiovascular death in men and women [35]. However, they were associated with an increased risk of adverse bleeding in women [35]. Specifically, women who received the anticoagulant heparin for acute myocardial infarction were more likely to achieve higher activated partial thromboplastin time (aPTT) than men, a finding associated with increased bleeding risk [36]. Two randomized controlled trials demonstrated that women using thrombolytic therapy for treatment of acute myocardial infarction, which included a combination of heparin with either streptokinase and/or alteplase, have a greater risk for both fatal and nonfatal complications compared to men [37, 38]. In other studies, the female gender was independently associated with higher bleeding rates following fibrinolytic treatment for acute myocardial infarction [39, 40].
Digoxin
Digoxin is a cardiac glycoside with positive inotropic and parasympathetic effects, properties useful for the treatment of heart failure and to slow conduction through the atrioventricular node, respectively [41]. As previously discussed, digoxin has a different pharmacokinetic profile in women compared to men, displaying a reduced volume of distribution and slower renal clearance [6–8]. These pharmacokinetic differences may partially explain the increased mortality risk seen in women taking digoxin for heart failure. A post hoc analysis of the 1997 Digitalis Investigation Group study determined that female heart failure patients using digoxin had a significantly higher mortality risk compared to those taking placebo [42, 43]. These women also exhibited a 5.8 % higher mortality rate compared to men treated with digoxin [42, 43]. Although there was a trend linking higher serum digoxin concentrations to all-cause mortality in women, the small number of women participating in the trial limited the ability to reach statistical significance [8]. Widely accepted therapeutic serum concentrations for digoxin are 0.8 to 2 ng/mL. However, recent American College of Cardiology Foundation/ American Heart Association (ACCF/AHA) guidelines recommend lower serum concentrations (0.5 to 0.9 ng/mL) to reduce mortality in heart failure patients regardless of gender [44]. Although data are limited in women, it is recommended clinicians adopt the lower serum digoxin concentration range of 0.5-0.9 ng/mL, particiularly when treating female patients [44].
β-Blockers
The beta-adrenergic receptor blockers (β-blockers) are used to treat a wide range of cardiovascular diseases including hypertension, heart failure, angina, arrhythmias, and post-myocardial infarction. These drugs block the ability of endogenous catecholamines (epinephrine and norepinephrine) released from the sympathetic nervous system to bind to β-adrenergic receptors located in the heart, kidney, smooth muscle, and other sites [45]. There are three isoforms (β1, β2, β3) of the β receptor, which exhibit tissue –specific expression and actions, with the β1 receptor the primary target of β-blocker drugs. The β1 receptors in the heart are responsible for enhancing heart rate and force of contraction, and in the kidney, β1 receptors are responsible for renin secretion. Therefore, β1-receptor blockers lower heart rate, decrease force of contraction, attenuate renin secretion, and reduce blood pressure [45]. Evidence suggests β-blockers display gender-specific pharmacokinetics and may confer different survival benefits to men and women. A study of normal healthy volunteers receiving oral metoprolol twice daily revealed no gender-related difference in elimination half-life, but women showed a greater reduction in heart rate and systolic blood pressure during exercise as compared to men [46]. These effects were attributed to increased serum drug concentrations facilitated by enhanced absorption of metoprolol in women [46]. However, despite these presumed higher serum drug concentrations, metoprolol has failed to show increased anti-ischemic effects in women with chronic stable angina compared to men [47]. Moreover, inadequate inclusion of women in large clinical trials has led to conflicting data on the survival benefits of β-blockers in women diagnosed with heart failure after myocardial infarction [8]. Neither the Metoprolol CR/XL study nor the COPERNICUS trial showed decreased mortality associated with the use of β-blockers in women with heart failure [48, 49]. Conversely, a gender-specific analysis of data in the CIBIS II study revealed that treatment with bisoprolol significantly decreased mortality in women compared to men with heart failure [50, 51]. When the mortality data from these three trials were pooled, men and women with heart failure both showed survival benefits associated with β-blocker use [51, 52]. This finding further emphasizes the importance of adequate representation of women in clinical trials.
Drug-Induced Long QT Syndrome
The QT interval of the electrocardiogram accounts for the duration of electrical activity for cardiac muscle cell contraction and ventricular repolarization in the cardiac cycle. Prolongation of the QT interval (Long QT Syndrome) caused by slowed ventricular repolarization is generally regarded as a pro-arrhythmic state, which can predispose to Torsades de Pointes (TdP), a rare but often fatal polymorphic ventricular arrhythmia [53, 54]. The female gender has been identified as an independent risk factor for QT prolongation and TdP [55, 56], which may be partially explained by the fact that women have longer QT intervals at baseline compared to men even after correction for heart rate [57, 58]. This gender-related difference is most pronounced at the onset of puberty and gradually declines with age. By age 50, there appears to be no significant difference in QT intervals between genders [59].
Several studies have sought to determine the influence of sex hormones and the menstrual cycle on QT intervals [59–62]. Findings demonstrate that endogenous testosterone decreases the cardiac action potential, thereby shortening the QT interval [59–62]. This action of testosterone may contribute to the baseline difference in QT interval between men and women [60]. Endogenous progesterone also decreases the duration of the cardiac action potential [60–62]. Progesterone concentrations fluctuate throughout the menstrual cycle, with the highest levels occurring during the luteal phase and much lower levels during the follicular phase. A study utilizing 24-h electrocardiograms in healthy Japanese women, who pursued normal daily activities during the luteal and follicular phases of their menstrual cycle, found a shorter QT interval during the luteal phase, which correlated with a higher serum concentration of progesterone [61].
In addition to these physiological differences between men and women, which may predispose women to long QT intervals, many common cardiovascular medications can prolong the QT interval and lead to TdP [63]. In a meta-analysis of 93 publications involving at least one identified case of TdP associated with the use of Class IA or Class III anti-arrhythmic or anti-anginal agents (quinidine, procainamide, disopyramide, amiodarone, sotalol, bepridil, or prenylamine), women accounted for 64 to 75 % of cardiovascular drug -induced TdP [55]. A subsequent meta-analysis of 22 clinical trials with a total of 3135 patients treated with d,l-sotalol revealed that women had a three-fold higher risk of developing TdP even after adjusting for additionally identified risk factors (ventricular arrhythmias, congestive heart failure, and d,l-sotalol dose >320 mg/day) [56]. It is possible that the increased risk of drug-induced long QT intervals with the use of anti-arrhythmic and anti-anginal agents in women can be attributed to higher serum drug concentrations due to lower body weight and decreased volume of distribution compared to men. However, considering that there is no defined relationship between serum drug concentration and QT prolongation with certain anti-arrhythmic agents, including quinidine and sotalol, this factor cannot be the only contributing influence [64, 65]. A recent open-label non-randomized trial in healthy young adults demonstrated that women show a higher sensitivity to sotalol-induced prolonged QT interval compared to men even across similar drug serum concentrations [65].
Other studies focused on gender-related differences in autonomic tone demonstrated significant QT prolongation in response to use of β-blockers in healthy women compared to men [66]. Also women with LQTS1, a mutation in the KCNQ1 gene that increases the QT interval, showed significant QT prolongation compared to men with LQTS1 after administration of a β-blocker agent [67]. Thus, mechanisms underlying the increased risk of prolonged QT and TdP in women cannot be fully explained by increased serum drug concentrations or differences in autonomic tone, but may vary depending on menstrual cycle phase. Future studies determining the potential arrhythmogenicity of pharmacological compounds should take this factor into account when establishing the study design.
Calcium Channel Blockers
Calcium channel blockers (CCBs) are indicated in a variety of cardiovascular diseases including hypertension, angina and supraventricular tachyarrhythmias. In arterial smooth muscle cells, the CCBs block voltage-gated “L-type” calcium channels to reduce Ca2+ influx and Ca2+-activation of contractile proteins, thereby mediating vasodilation. In the sinoatrial (SA) and atrioventricular (AV) nodes of the heart, CCBs slow the Ca2+-dependent upstroke of the action potential, thereby reducing automaticity of the SA node and slowing impulse conduction through the AV node. Gender-related pharmacokinetic differences for several CCBs, including amlodipine and verapamil, have been described [68, 69]. Women achieve higher plasma concentrations of amlodipine and display faster oral elimination rates for verapamil compared to men. This difference can be partially attributed to the lower body weight, higher activity of CYP3A4 and lower activity of P-gp in women compared to men [68, 69]. An 18 week, open-labeled, prospective study demonstrated that amlodipine exerted a greater antihypertensive effect in women compared to hypertensive men across all age groups [70, 71]. However this enhanced blood pressure lowering effect of amlodipine was accompanied by an increased incidence of peripheral edema in women compared to men [70, 71], potentially resulting in decreased adherence and discontinuation of therapy, thereby negating the beneficial effects of CCBs in women.
Isosorbide Mononitrate
Isosorbide mononitrate is a nitric oxide donor used to dilate blood vessels and relieve anginal pain. In a pharmacokinetic study to determine bioequivalence of a fixed dose of two different extended release formulations of isosorbide dinitrate, women had significantly higher serum plasma concentrations compared to men [72]. This difference was attributed solely to the significantly lower body weights in the female study population, suggesting that doses of extended release isosorbide mononitrate should be based on body weight rather than fixed regimens [72]. However the clinical significance of these findings has yet to be determined.
Other Cardiovascular Agents
Many other medications exist for the treatment of cardiovascular diseases, including diuretics and inhibitors of the renin-angiotensin-aldosterone system (RAAS). The latter family of drugs includes the angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and the renin inhibitor, aliskiren. Although no gender differences in pharmacokinetics or pharmacodynamics have been described for RAAS inhibitors or diuretics [73, 74], prescribing differences in these medications appear to be gender related [75, 76]. Among hypertensive patients, men are more likely to be treated with RAAS inhibitors, while women are more likely to be prescribed a diuretic, even after controlling for age and comorbidities [75, 76]. One reason for these differences may relate to the potential teratogenic and abortive effects of RAAS inhibitors in women of child bearing years, and the reluctance of health providers to prescribe such RAAS –targeting medications without assurances of adequate birth control [77–80]. It also has been reported that women have an increased risk of adverse events while taking these medications compared to men, including a higher incidence of cough with ACEIs [81], and increased incidence of hyponatremia with diuretics [82]. Thus, women should be monitored carefully for such outcomes after prescribing these drugs.
Summary
Women and men are physiologically different and present with gender-specific clinical manifestations of cardiovascular disease. Therefore, it stands to reason that cardiovascular drugs will exhibit different pharmacological and pharmacokinetic profiles between women and men, and it is insufficient to extrapolate data from drug trials conducted almost exclusively in males to a female patient population. This chapter highlights the importance of adequate inclusion of both genders in drug safety and efficacy trials, and Table 2 summarizes some of the cardiovascular drugs with gender-specific therapeutic and adverse effects. The package inserts for a growing number of cardiovascular drugs, including simvastatin, atorvastatin, lovastatin, heparin, enoxaparin, and sotalol, now recognize gender- related differences in drug profiles, which may guide the adjustment of loading or maintenance doses for female patients. The results of studies reviewed in this chapter suggest that the practice of considering gender as one factor in prescribing drugs will become common, as more studies emerge to improve our knowledge base for weighing risk/benefit of cardiovascular drugs in women and men.
References
Manteuffel M, Williams S, Chen W, Verbrugge RR, Pittman DG, Steinkellner A. Influence of patient sex and gender on medication use, adherence, and prescribing alignment with guidelines. J Women’s Health. 2014;23(2):112–9.
Bugiardini R, Yan AT, Yan RT, Fitchett D, Langer A, Manfrini O, et al. Factors influencing underutilization of evidence-based therapies in women. Eur Heart J. 2011;32:1337–44.
Johansen, ME Hefner JL, Foraker RE. Antiplatelet and statin use in US patients with coronary artery disease categorized by race/ethnicity and gender, 2003 to 2012. Am J Cardiol. 2015.
Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol. 2001;2(6):349–51.
Oertelt-Prigione S. The influence of sex and gender on the immune response. Autoimmun Rev. 2012;11(6-7):A479–85.
Whitley HP, Lindsey W. Sex-based differences in drug activity. Am Fam Physician. 2009;80(11):1255–8.
Anderson GD. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Women’s Health. 2005;14(1):19–29.
Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov. 2006;5(5):425–38.
Kimura T, Higaki K. Gastrointestinal transit and drug absorption. Biol Pharm Bull. 2002;25(2):149–64.
Fleisher D, Li C, Zhou Y, Pao LH, Karim A. Drug, meal, and formulation interactions influencing drug absorption after oral administration. Clin Implications Clin Pharmacokinet. 1999;36(3):233–54.
Mojaverian P, Rocci Jr ML, Conner DP, Abrams WB, Vlasses PH. Effect of food on the absorption of enteric coated aspirin: correlation with gastric residence time. Clin Pharmacol Ther. 1987;41(1):11–7.
Schwartz JB. The current state of knowledge on age, sex, and their interactions on clinical pharmacology. Clin Pharmacol Ther. 2007;82(1):87–96.
Hagg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol. 2001;51:169–73.
Yukawa E, Honda T, Ohdo S, Higuchi S, Aoyama T. Population-based investigation of relative clearance of digoxin in Japanese patients by multiple trough screen analysis: an update. J Clin Pharmacol. 1997;37(2):92–100.
Mattison D. Cardiovascular medications during pregnancy. In: Clinical Pharmacology During Pregnancy, Mattison D. (ed), Academic Press, 2013, Chpt 18, pp 275–294.
Desai H, Hollingsworth PW, Chugh AR. Statins and aspirin: do they really work in women? Am J Cardiovasc Drugs. 2015. doi:10.1007/s40256-015-0111x.
Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118.
Stead LG, Vaidyanathan L, Kumar G, Fellolio MF, Brown RD, Suravaram S, et al. Statins in ischemic stroke: just low-density lipoprotein lowering or more? J Stroke Cerebrovasc Dis. 2009;18(2):124–7.
Pawelczyk M, Chmielewski H, Kaczorowska B, Przybyla M, Baj Z. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke. Arch Med Sci. 2015;11(1):115–21.
Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012;18:1519–30.
Blanco-Colio LM, Tunon J, Martin-Ventura JL, Egido J. Anti-inflammatory and immunomodulatory effects of statins. Kidney Int. 2003;63:12–23.
Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012;172(2):144–52.
Bang CN, Okin PM. Statin treatment, new-onset diabetes, and other adverse effects: a systematic review. Curr Cardiol Rep. 2014;16(3):461–4.
Truong QA, Murphy SA, McCabe CH, Armani A, Cannon CP, Group TS. Benefit of intensive statin therapy in women: results from PROVE IT-TIMI 22. Circ Cardiovasc Qual Outcomes. 2011;4(3):328–36.
Basili S, Raparelli V, Proietti M, Tanzilli G, Franconi F. The impact of sex and gender on the efficacy of antiplatelet therapy: the female perspective. J Atheroscler Thromb. 2015;22:109–25.
Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101:1206–18.
Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295(3):306–13.
Meyer DM, Eastwood JA, Copton MP, Gylys K, Zivin JA, Ovbiagele B. Sex differences in antiplatelet response in ischemic stroke. J Womens Health (Lond). 2011;7(4):465–74.
Buchanan MR, et al. Rischke JA, Butt R, Turpie AG, Hirsh J, Rosenfeld J. The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects. Thromb Res. 1983;29:125–39.
Samad Z, Boyle S, Ersboll M, Vora AN, Zhang Y, Becker RC, et al. Sex differences in platelet reactivity and cardiovascular and pyschological response to mental stress in patients with stable ischemic heart disease. J Am Coll Cardiol. 2014;64:1669–78.
Bray PF, Howard TD, Vittinghoff E, Sane DC, Herrington DM. Effect of genetic variations in platelet glycoproteins Iba and VI on the risk of coronary heart disease events in postmenopausal women taking hormone therapy. Blood. 2007;109(5):1862–9.
Nakano Y, Oshima T, Ozono R, Ueda A, Oue Y, Matsuura H, et al. Estrogen replacement suppresses function of thrombin stimulated platelets by inhibiting Ca2+ influx and raising cyclic adenosine monophosphate. Cardiovasc Res. 2002;53:634–41.
Miller VM, Jayachandran M, Hashimoto K, Heit JA, Owen WG. Estrogen, inflammation, and platelet phenotype. Gend Med. 2008;5(Suppl A):S91–102.
Viles-Gonzalez JF, Fuster V, Badimon JJ. Atherothrombosis: a widespread disease with unpredictable and life-threatening consequences. Eur Heart J. 2004;25:1197–207.
Capodanno D, Angiolillo DJ. Impact of race and gender on antithrombotic therapy. Thromb Haemost. 2012;104:471–84.
Granger CB, Hirsh J, Califf RM, Col J, White HD, Betriu A, et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction. Circulation. 1996;93:870–8.
Weaver WD, White HD, Wilcox RG, Aylward PE, Morris D, Guerci A, et al. Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. GUSTO-I Investigators. JAMA. 1996;275(10):777–82.
Woodfield SL, Lundergan CF, Reiner JS, Thompson MA, Rohrbeck SC, Deychak Y, et al. Gender and acute myocardial infarction: is there a different response to thrombolysis? J Am Coll Cardiol. 1997;29:35–42.
Van de Werf F, Barron HV, Armstrong PW, Granger CB, Berioli S, Barbash G, et al. Fox NL; ASSENT-2 Investigators. Assessment of the safety and efficacy of a new thrombolytic. Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents: a comparison of TNK-tPA and rt-PA. Eur Heart J. 2001;22:2253–61.
Berkowitz SD, Granger CB, Pieper KS, Lee KL, Gore JM, Simons M, et al. Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO) I Investigators. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation. 1997;95:2508–16.
Gheorghiade M, Adams KF, Colucci WS. Digoxin in the management of cardiovascular disorders. Circulation. 2004;109:2959–64.
The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525–33.
Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347(18):1403–11.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–239.
Helfand M, Peterson K, Christensen V, Dana T, Thakurta S. Drug class review: Beta adrenergic blockers: final report update 4. Portland (OR): Oregon Health & Science University; 2009. http://www.ncbi.nlm.nih.gov/books/NBK47172/.
Luzier AB, Killian A, Wilton JH, Wilson MF, Forrest A, Kazierad DJ. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharm Ther. 1999;66(6):594–601.
Cocco G, Chu D. The anti-ischemic effect of metoprolol in patients with chronic angina pectoris is gender-specific. Cardiology. 2006;106:147–53.
The MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERITHF). Lancet. 1999;353:2001–7.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U. S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–55.
Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex differences in the prognosis of congestive heart failure: results from the cardiac insufficiency bisoprolol study (CIBIS II). Circulation. 2001;103:375–80.
CIBISII. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13.
Ghali JK, Pina IL, Gottlieb SS, Deedwania PC, Wikstrand JC. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol extended-release randomized intervention trial in heart failure (MERIT-HF). Circulation. 2000;105:1585–91.
Leenhardt A, Coumel P, Slama R. Torsades de pointes. J Cardiovasc Electrophysiol. 1992;3:281–92.
Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndrome: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis. 1988;31:115–72.
Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA Clin Cardiol. 1993;270(21):2590–7.
Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. Sex difference in risk of torsade de pointes with d, l-sotalol. Circulation. 1996;94:2535–41.
Merri M, Benhorin J, Alberti M, Locati E, Moss A. Electrocardiographic quantitation of ventricular repolarization. Circulation. 1989;80:1301–8.
Stramba-Badiale M, Locati EH, Martinelli A, Courville J, Schwartz PJ. Gender and the relationship between ventricular repolarization and cardiac cycle length during 24-h Holter recordings. Eur Heart J. 1997;18:1000–6.
Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992;8:690–5.
Sadlak T, Shufelt C, Iribarren C, Bairey Merz CN. Sex hormones and the QT interval: a review. J Women’s Health. 2012;21(9):933–41.
Nakagawa M, Ooie T, Takahashi N, Taniguchi Y, Anan F, Yonemochi H, et al. Influence of menstrual cycle on QT interval dynamics. PACE. 2006;29:607–13.
Rodriguez I, Kilborn MJ, Liu XK, Pezzullo JC, Woosley RL. Drug-induced QT prolongation in women during the menstrual cycle. JAMA. 2001;285:1322–6.
Fazio G, Vernuccio F, Grutta G, Lo RG. Drugs to be avoided in patients with long QT syndrome: focus on the anaesthesiological management. World J Cardiol. 2013;5(4):87–93.
Thompson KA, Murray JJ, Blair IA, Woosley RL, Roden DM. Plasma concentrations of quinidine, its major metabolites, and dihydroquinidine in patients with torsades de pointes. Clin Pharmacol Ther. 1988;43:636–42.
Darpo B, Karnad DR, Balilini F, Florlan J, Garnett CE, Korthari S, et al. Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol. Br J Clin Pharmacol. 2013;77(3):522–31.
Nakagawa M, Ooie T, Ou B, Ichinose M, Takahashi M, Hara M, et al. Gender differences in autonomic modulation of ventricular repolarization in humans. J Cardiovasc Electrophysiol. 2005;16:278–84.
Conrath CE, Wilde AAM, Jongbloed RJE, Alders M, van Langen IM, van Tintelen JP, et al. Gender differences in the long QT syndrome: effects of β-adrenocepter blockade. Cardiovasc Res. 2002;53:770–6.
Dadashzadeha S, Javadiana B, Sadeghianb S. The effect of gender on the pharmacokinetics of verapamil and norverapamil in humans. Biopharm Drug Dispos. 2006;27:329–34.
Abad-Santos F, Novalbos J, Gálvez-Múgica MA, Gallego-Sandín S, Almeida S, Vallée F, et al. Assessment of sex differences in pharmacokinetics and pharmacodynamics of amlodipine in a bioequivalence study. Pharmacol Res. 2005;51(5):445–52.
Kloner RA, Sowers JR, DiBona GF, Gaffney M, Wein M. Sex- and age-related antihypertensive effects of amlodipine. The Amlodipine Cardiovascular Community Trial Study Group. Am J Cardiol. 1996;77(9):713–22.
Spratt KA. Sex- and age-related antihypertensive effects of amlodipine. Am J Cardiol. 1997;79(6):843–4.
Vree TB, Dammers E, Valducci R. Sex-related differences in the pharmacokinetics of isosorbide-5-mononitrate (60 mg) after repeated oral administration of two different original prolonged release formulations. Int J Clin Pharmacol Ther. 2004;42(8):463–72.
Li EC, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev. 2014;8, CD009096.
Olde Engberink RH, Frenkel WJ, van den Bogaard B, Brewster LM, Vogt L, van den Born BJ. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertens. 2015;65(5):1033–40.
Ljungman C, Kahan T, Schioler L, Hjerpe P, Hasselstrom J, Wettermark B, et al. Gender differences in antihypertensive drug treatment: results from the Swedish Primary Care Cardiovascular Database (SPCCD). J Am Soc Hypertens. 2014;8(12):882–90.
Ljungman C, Kahan T, Schiöler L, Hjerpe P, Wettermark B, Boström KB, Manhem K. Antihypertensive treatment and control according to gender, education, country of birth and psychiatric disorder: the Swedish Primary Care Cardiovascular Database (SPCCD). J Hum Hyperten. 2014.
Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ. 2011;343:d5931.
Walfisch A, Al-maawali A, Moretti ME, Nickel C, Koren G. Teratogenicity of angiotensin converting enzyme inhibitors or receptor blockers. J Obstet Gynaecol. 2011;31(6):465–72.
Moretti ME, Caprara D, Drehuta I, Yeung E, Cheung S, Federico L, Koren G. The fetal safety of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Obstet Gynecol Int. 2012.
Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354(23):2443–51.
Os I, Bratland B, Dahl€of B, Gisholt K, Syvertsen JO, Tretli S. Female preponderance for lisinopril-induced cough in hypertension. Am J Hypertens. 1994;7:1012–5.
Barber J, McKeever TM, McDowell SE, Clayton JA, Ferner RE, Gordon RD, et al. A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation? Br J Clin Pharmacol. 2015;79(4):566–77.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Stolarz, A.J., Rusch, N.J. Gender Differences in Cardiovascular Drugs. Cardiovasc Drugs Ther 29, 403–410 (2015). https://doi.org/10.1007/s10557-015-6611-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10557-015-6611-8