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Transcript
Valvular Heart Disease: A Primer for the Clinical Pharmacist Tammy J. Bungard, Pharm.D., and Brian Sonnenberg, M.D. Valvular heart disease is a commonly encountered clinical condition that is not taught in most undergraduate and graduate pharmacy programs, leaving the practicing pharmacist without basic knowledge to expand on and subsequently apply to direct patient care. Unlike other areas of cardiology in which thousands of patients are recruited in many well-designed randomized clinical trials, data assessing treatments for valvular heart disease are limited and often consist of retrospective case series or observations. Our goal is to provide a basic overview of chronic valvular heart disease, with emphasis on describing the common conditions requiring surgery and the available options, as well as common pharmacologic therapies used in this patient population. Anomalies in valves can be broadly classified as stenosis and regurgitation. Depending on the valve and the type of anomaly, the impact on the cardiovascular system will vary. Understanding the hemodynamic consequences of aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation is imperative to effectively counsel patients surrounding disease progression and self-monitoring, use of vasodilators, and prophylaxis for endocarditis and rheumatic fever. Further, patient characteristics factored into the choice of implanting either a bioprosthetic (tissue) or prosthetic (metal) valve encompass patient choice, life expectancy, and willingness or ability to accept lifelong anticoagulation therapy. The evolution of metal valves has resulted in newer generations under clinical study that have more laminar flow (minimizing interaction with blood products) and improved pyrolytic carbon (minimizing infection and interaction with blood products). Although antithrombotic therapy with warfarin is now mandatory in North America for all patients receiving metal valves, research is ongoing to assess the need with the most recent generation of valves. Key Words: valvular heart disease, VHD, stenosis, regurgitation, prosthetic valve, bioprosthetic valve. (Pharmacotherapy 2011;31(1):76–91) OUTLINE Overview of Hemodynamics Diagnostic Testing and Evaluation Aortic Valve Disease From the Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (both authors). For reprints, visit http://www.atypon-link.com/PPI/loi/phco. For questions or comments, contact Tammy J. Bungard, B.S.P., Pharm.D., EPICORE Centre, University of Alberta, 220 College Plaza, Edmonton, Alberta, Canada T6G 2C8; e-mail: [email protected]. Stenosis Regurgitation Mitral Valve Disease Stenosis Regurgitation Patient Counseling Bioprosthetic versus Prosthetic Valve Monitoring and Follow-up After Surgery Antithrombotic Therapy Endocarditis Prophylaxis Rheumatic Fever Prophylaxis Conclusion VALVULAR HEART DISEASE Bungard and Sonnenberg Valvular heart disease is a commonly encountered clinical condition that is not taught in most undergraduate and graduate pharmacy programs, leaving the practicing pharmacist without basic knowledge to expand on and subsequently apply to direct patient care. Unlike other areas of cardiology in which thousands of patients are recruited in multiple well-designed randomized clinical trials, data assessing therapeutic approaches in valvular heart disease are limited and, when available, consist of retrospective case series or observations. Our goal with this article is to provide a basic overview of chronic valvular heart disease, with emphasis on describing the common conditions requiring surgery and the available options, as well as common pharmacologic therapies used in this patient population. Overview of Hemodynamics The heart is a muscular pump with two atria and two ventricles.1 Deoxygenated blood flows through the inferior and superior vena cava into the right atrium. It then flows across the tricuspid valve into the right ventricle. From the right ventricle, blood is pumped into the pulmonary artery to the lungs, becomes oxygenated, and flows through the pulmonary vein into the left atrium. Once in the left atrium, blood flows across the mitral valve into the left ventricle. Blood is expelled across the aortic Coronary cusp 77 valve to the aorta and out to the rest of the body. There are two types of valves within the heart: semilunar and atrioventricular.2 The aortic and pulmonic valves are the semilunar valves and consist of three valve leaflets (Figure 1). The mitral and tricuspid valves are atrioventricular valves and differ in structure from the semilunar valves. The atrioventricular valves consist of leaflets—mitral having two leaflets (bicuspid) and tricuspid having three leaflets—attached to chordae tendinea, which are thin strands of connective tissue that attach to papillary muscles that attach to the ventricular wall (Figure 2). With ventricular contraction, the papillary muscles contract and prevent valves from billowing back into the atria, maintaining valve closure and preventing backleak. The heart sound S1 (lub) signifies the nearly simultaneous closure of the mitral and tricuspid valves, with S2 (dub) being the closure of the aortic and pulmonic valves. Accordingly, the time interval between S 1 and S 2 is systole, whereas the interval between S 2 and S 1 is diastole. Systole usually is one third of the time interval, with diastole taking two thirds of this time. The cardiovascular system is a closed loop driven by changes of pressure (Figure 3).3 The period of systole begins with isovolumic contraction after closure of the mitral and tricuspid valves (the aortic and pulmonic valves Aortic Annulus Left atrium Primary chords Papillary muscles Figure 1. The aortic valve (viewed from above) is a semilunar valve and consists of three valve leaflets. Figure 2. Mitral valve anatomy. The mitral valve is an atrioventricular valve, which consists of two leaflets (bicuspid) attached to the chordae tendineae, which are thin strands of connective tissue that attach to papillary muscles that attach to the ventricular wall. With ventricular contraction, the papillary muscles contract and prevent valves from billowing back into the atria, maintaining valve closure and preventing backleak. PHARMACOTHERAPY Volume 31, Number 1, 2011 78 Table 1. Murmurs with Common Forms of Valvular Heart Disease Phase of Valve Disease Cardiac Cycle Classic Findings on Physical Examination Aortic stenosis Systole Midsystolic murmur that peaks in late systole and radiates to the carotids; single or paradoxically split S2; low-amplitude, delayed carotid upstroke confirms presence of severe aortic stenosis Mitral stenosis Diastole Often early diastolic opening snap as thickened mitral valve “pops” open, followed by low-pitched rumble of turbulent atrial inflow into left ventricle Aortic regurgitation Diastole Hyperkinetic central and peripheral pulses; diastolic blowing murmur radiating from aortic valve area down toward apex, S3 and S4 often heard as a manifestation of volume or pressure load Mitral regurgitation Systole Displacement of left ventricular apical impulse (indicates severe and chronic mitral regurgitation with left ventricular dilation); murmur at mitral area heard throughout systole, S3 indicating diastolic flow load usually present (does not indicate heart failure) Mitral valve prolapse Systole Midsystolic click (high-pitched sound of short duration); may be followed by late systolic murmur (medium-high pitch, loudest at the cardiac apex) S2, S3, and S4 = second, third, and fourth heart sound, respectively. are closed also). During this period, ventricular pressure rapidly increases while the volume remains unchanged. Once ventricular pressure exceeds aortic (pulmonic) pressure, the aortic (and pulmonic) valve opens and blood begins to be ejected from the ventricle. Once systole is finished, the pressure in the ventricle falls below that in the aorta, the aortic (and pulmonic) valve closes, and diastole begins. During diastole, left ventricular pressure falls well below aortic pressure, allowing coronary flow to reach even the innermost layers of ventricular myocardium. Pressure - Volume Tracings Great V e ssel P ressur e 3 Ventrr i cular c ull ar Pressure 2 1 Atrial 4 Time Ventricular Systole Isovolumic Contraction time Ventricular Diastole Isovolumic Relaxation time End-diastolic volume Volume 1 End-systolic volume Figure 3. Pressure cycle of the heart. 1 = closure of mitral and tricuspid valves (aortic and pulmonic also closed); 2 = opening of aortic and pulmonic valves (mitral and tricuspid closed); 3 = closure of aortic and pulmonic valves (mitral and tricuspid closed); 4 = opening of mitral and tricuspid valves (aortic and pulmonic closed). Diastole consists of four phases: isovolumic relaxation, rapid filling, diastasis, and atrial contraction. 3 Isovolumic relaxation is a brief phase where the aortic and mitral valves are closed; the ventricular volume does not change, but the pressure in this chamber declines dramatically as ventricular muscle fibers relax. The rapid filling phase begins with the opening of the mitral (and tricuspid) valve, with pressure in the ventricle falling below the atrium and passive flow from atria to ventricles beginning. Most ventricular filling (80%) occurs during this phase, and once most of the atrial emptying has occurred, the pressure difference between atria and ventricles drops, and inflow slows. At this point, minimal further filling of ventricles occurs, and during this period of diastasis only about 5% of ventricular filling occurs. Finally, if in normal rhythm, atrial systole occurs and generates a higher atrial pressure leading to resumption of ventricular filling. In general, atrial systole accounts for about 15% of the ventricular filling. At onset of ventricular systole, ventricular pressure exceeds atrial pressure, the mitral (and tricuspid) valve closes, and diastole is complete. Anomalies in valve function can be broadly classified as stenosis (valve is too tight) or regurgitation, sometimes termed insufficiency (valve leaks).2 Both types of valve dysfunction cause turbulent blood flow, which can be heard on auscultation in the form of a murmur. Screening for valve dysfunction is performed by physical examination (including listening for murmurs). Murmurs range from having no functional clinical significance to being a hallmark in identifying cardiovascular disease VALVULAR HEART DISEASE Bungard and Sonnenberg 79 Table 2. Glossary of Hemodynamic Terms Term Definition Afterload Force against which the ventricle ejects blood once contraction of the muscle fibers begins Annulus Ring-like structure that forms the base of the heart valve and anchors the valve leaflets Balloon Procedure in which a narrow valve is stretched open by inflating a deflated balloon inside the tight valvuloplasty valve, usually introduced percutaneously through a catheter from percutaneous venous or arterial access, thereby negating the need for open-heart surgery Cardiac output Quantity of blood pumped per unit of time (cardiac output = stroke volume x heart rate) Concentric Enlargement of the muscle mass inward, encroaching on inner chamber volume, with no outward expansion of chamber (response to pressure overload) hypertrophy Commissure Distinct area where the leaflets of the valve come together and insert into the annulus Doppler Technique for recording the flow of red blood cells through the cardiovascular system by means of echocardiography Doppler ultrasonography, either continuous wave or pulsed waves, generating either color images that show areas of blood flow inside the regular sonogram (color Doppler) or spectral displays of the blood flow directions and velocities from a focused part of the image. Doppler relies on detecting a change in the reflected sound wave frequency when the sound beam hits moving blood. The degree of frequency shift correlates with velocity of moving blood and can be used to calculate the driving pressure creating the flow by means of the modified Bernouilli equation. Eccentric Enlargement of the chamber volume with elongation and some thickening of muscle fibers, with hypertrophy resultant increase in mass of the myocardium (response to volume overload) Echocardiography Examination of the heart by using ultrasonographic techniques to image structural and functional abnormalities of the heart Ejection fraction Fraction of blood pumped out of the ventricle with each heart beat; a normal ejection fraction is considered to be ≥ 60%, whereas significant systolic dysfunction is usually defined as an ejection fraction ≤ 40% Preload Stretch imposed on the heart muscle due to ventricular and diastolic volume, or stretch imposed on the heart muscle due to venous return emptying into ventricles from atria Stenosis Constriction or narrowing of a duct or passage Transesophageal Diagnostic test using an ultrasound device that is passed into the esophagus of the patient to create a echocardiography clear image of the heart muscle and other parts of the heart. A tube with a device called a transducer is passed down into the patient’s throat and into the esophagus. The transducer directs ultrasound waves into the heart, and the reflected sound waves picked up by the transducer are translated into an image of the heart. Valvotomy Surgical cutting of a constricted cardiac valve to relieve obstruction (Table 1). Tests to confirm or establish the diagnosis include a variety of noninvasive tests (electrocardiography, echocardiography, exercise testing) and invasive tests (catheterization).4, 5 The definitions of many of these common hemodynamic terms are provided in Table 2. Diagnostic Testing and Evaluation Cardiac imaging is commonly used for cardiac diseases, and echocardiography (including Doppler echocardiography) remains the test of choice for valve disease.4, 5 No other imaging modality has the extremely high frame rates (typically 30–60 Hz) and resolution (0.5–1 mm) that allows for accurate real-time imaging of fastmoving, thin valvular structures. Combined with Doppler techniques, echocardiography can assess most valve lesions accurately in terms of their severity and etiology (Table 3). Doppler echocardiography assesses flow velocity by measuring the change in ultrasound frequency when the sound beam reflects off moving blood. Doppler techniques create color images that show the area of flow disturbance caused by stenosis or regurgitation, and can also be used to estimate the pressure gradients driving blood flow, thereby allowing calculation of area of the valve. If needed, transesophageal echocardio-graphy can help assess valve morphology and function extremely accurately without interference from chest wall structures. Cardiac magnetic resonance imaging (MRI) and computed tomography are improving resolution in assessing valves but cannot achieve very high resolution real-time images, especially if a major irregular rhythm disturbance does not allow averaging multiple cardiac cycles to “sum up” a representative image. 4 Cardiac MRI is evolving to become the gold standard for assessment of ventricular volumes and function but still is somewhat technically limited in assessing severity of valve stenosis. It also has some difficulties with assessing valve regurgitation (especially in the presence of rhythm irregularities).4 Cardiac catheterization used to be the gold 80 PHARMACOTHERAPY Volume 31, Number 1, 2011 Table 3. Echocardiographic Findings with Valve Lesions Valve Area Pressure Gradient (mm Hg)a 2 Severity of Lesion (cm ) Peak Mean Aortic stenosis Mild < 2.0 < 15 < 15 Moderate 1–1.5 < 64 < 40 Severe < 1.0 > 64 > 40 b Aortic regurgitation Mild Normal Normal Normal Moderate Normal Variable Variable Severe Normal Mildly Mildly increased increased Mitral stenosis Mild < 2.0 Variable <5 Moderate 1–1.5 Variable 5–10 Severe < 1.0 Variable > 10 b Mitral regurgitation Mild Normal Normal Normal Moderate Normal Normal Normal Severe Normal Mildly May be mildly increased increased Chamber Enlargement None None None None Left ventricle Left ventricle and left atrium Left atrium, then right ventricle and right atrium Left atrium, then right ventricle and right atrium Left atrium, then right ventricle and right atrium None Left atrium and left ventricle may be enlarged Left atrium and left ventricle, then right ventricle and right atrium a Pressure gradients assume normal cardiac flow state and heart rates within normal range. Use of ultrasensitive modern echocardiographic techniques has found that trivial valve regurgitation, especially mitral regurgitation, is extremely common in healthy adults, often progressing to mild mitral or aortic regurgitation in many older patients in our population. b standard for assessing heart valve disease, but it currently is almost exclusively reserved for preoperative assessment of coronary arteries in patients deemed to be high enough risk to have developed coronary atherosclerosis.5 Very rarely, invasive assessment of valve regurgitation or stenosis is used to resolve discrepancies between clinical impression and echocardiographic data. Routine testing, such as chest radiography, may be done to very crudely assess chamber size and valve calcification, but this type of testing is best reserved to confirm the presence of high left heart filling pressures that present as varying degrees of left heart failure. Further, electrocardiograms are routinely obtained at follow-up visits to assess rhythm as well as offer nonspecific information, such as ventricular enlargement. Stress tests can be very useful to objectively assess whether patients still have intact functional capacity, especially if there is concern that patients have reduced their exercise gradually without recognizing their subclinical cardiac decompensation. However, stress testing should not be performed if patients are believed to have symptomatic severe aortic stenosis. Aortic Valve Disease Stenosis Aortic stenosis is the most common form of valvular disease.6 It most often occurs as a result of calcification (a process described as being similar to that of atherosclerosis) of the valve that occurs with age, typically manifesting in patients aged 60–90 years.5, 7 It may be evident earlier (30–50 yrs old) among patients having a congenitally malformed bicuspid aortic valve. One to two percent of the population is born with a bicuspid aortic valve, and this congenital anomaly often leads to premature calcification of the valve resulting in stenosis.8 Calcific aortic stenosis occurs when solid calcium is deposited within the cusps of the valve.9 In contrast, a very rare cause of stenosis of the aortic valve may occur by commissural fusion, typically in patients with rheumatic heart disease who already have mitral valve disease. Regardless of a calcific or rheumatic etiology, aortic stenosis is typically slowly progressive over decades, with symptoms presenting only when the heart’s ability to adapt has been exhausted.5 The increase in afterload as a result of the stenotic aortic valve results in an increase in left ventricle systolic pressure that is initially compensated for quite well by the development of concentric hypertrophy.4, 7, 9 This compensatory response is initially appropriate and beneficial to compensate for high intracavity pressures. The hypertrophy, however, requires gene expression that eventually is toxic to the myocardium. With VALVULAR HEART DISEASE Bungard and Sonnenberg time, this compensatory response increases oxygen requirements of the myocardium, and eventually the response is no longer able to overcome increasing afterload nor compensate for high left ventricular systolic pressures. As a result, cardiac output declines and left atrial enlargement to accommodate increased pressure on the left side of the heart is evident. In a critically narrowed aortic valve (critical aortic stenosis), the heart cannot increase its output. A vasodilator that decreases peripheral resistance would therefore lead to potentially deadly hypotension, since the heart would not be able to increase cardiac output (blood pressure = cardiac output x peripheral resistance).5, 7, 9 Concordantly, reducing the preload excessively would also decrease cardiac output, thus excessive venodilators should be avoided. However, treating marked hypertension may be beneficial, since high aortic pressure only adds to the already high afterload facing the left ventricle. Symptoms, Prognosis, Monitoring The symptoms of aortic stenosis consist of angina, syncope, and heart failure or dyspnea, almost exclusively in patients with severe aortic stenosis.4, 7 With milder aortic stenosis, symptoms may occur only during states of exertion, such as exercise, emotional stress, infection, pregnancy, or atrial fibrillation with rapid ventricular response rate. This prolonged latent period with minimal symptoms, if any, carries low rates of mortality and associated morbidity. Aortic stenosis has an unpredictable rate of progression. As such, depending on the degree of stenosis, echocardiographic assessment is indicated as little as every 5 years for patients with mild aortic stenosis to as frequently as every year or sooner in those with severe asymptomatic aortic stenosis (especially if symptoms change). As stenosis progresses, the cardiac output is impaired at rest, resulting in the occurrence of symptoms without exertion. Once patients experience severe symptoms, survival is limited to 2–3 years with a high risk of sudden death.10 Signs of severe aortic stenosis include a very dampened downstream central pulse (low volume, slowly rising carotid pulse) and a latepeaking systolic murmur.5 Treatment and Outcomes Symptomatic patients with aortic stenosis have exhausted the physiologic adaptations to severe afterload from the mechanical obstruction of 81 aortic stenosis.5 There are no proven therapies that improve the natural history or that are known to alter the adaptative processes favorably. Basic science work has suggested a similar vascular atherosclerotic process occurs within the valve leaflet, leading investigators to assess the effect of lipid-lowering therapy in this disease process.11, 12 Small, retrospective studies using surrogate end points derived from echocardiography or cardiac computed tomography have indicated benefit, but two randomized, prospective studies with clinical end points showed no benefit.5, 13, 14 Many clinicians, however, believe the major challenge with these data is that patients are likely receiving statin therapy too late in the disease process after the valve is already heavily calcified.15 In theory, concomitant hypertension adds further workload to the already afterloaded heart, and many elderly patients have a stiff aorta with increased impedance. Theoretically, it may help to reduce blood pressure to nonhypertensive levels, but the target blood pressure is not known.16 In a randomized study, among patients with symptomatic aortic stenosis without heart failure, enalapril was well tolerated and improved effort tolerance and reduced dyspnea. 17 This study, however, provided follow-up for only 3 months and did not provide survival information. However, excessive vasodilation is theoretically lethal, since a major decrease in peripheral vascular resistance would require a compensatory increase in cardiac output to maintain aortic and blood pressure (blood pressure = cardiac output x mean vascular resistance), and there may be a limit to how much more cardiac output can increase with very tight aortic stenosis (fixed cardiac output). In a small study, patients already experiencing pulmonary edema who were not treated with diuretics or nitrates and had severe left ventricular systolic dysfunction were given intravenous nitroprusside to maintain mean systemic blood pressure above 60 mm Hg.18 In these patients, the elevated left heart filling pressures decreased more toward normal, and cardiac output improved. These patients, however, were in frank heart failure and were not treated with standard therapies known to confer benefit. Thus, all patients with aortic stenosis may not benefit from vasodilation, especially given that standard heart failure therapies were not used in this study. Once patients have severe aortic stenosis with symptoms, the only treatment is replacement of 82 PHARMACOTHERAPY Volume 31, Number 1, 2011 Table 4. Indications for Valve Surgery5 Indication for Surgery Valve Disease Aortic stenosis Symptomatic, severe aortic stenosis Asymptomatic aortic stenosis and abnormal exercise response (symptoms unmasked) Severe asymptomatic aortic stenosis and high likelihood of rapid progression or long surgical delays Moderate or severe aortic stenosis if undergoing other open-heart surgery Aortic regurgitation Symptomatic, severe aortic regurgitation Asymptomatic, severe aortic regurgitation and left ventricular systolic dysfunction (ejection fraction < 50% or major left ventricular dilation) Moderate-to-severe aortic regurgitation if undergoing other open-heart surgery Mitral stenosis Percutaneous mitral Symptomatic NYHA functional classes II–IV, moderate-to-severe mitral stenosis, suitable valve balloon valvuloplastya Symptomatic NYHA functional classes II–IV, mild mitral stenosis, if evidence that mitral stenosis is causing symptoms (high left atrial or pulmonary pressures during exercise), suitable valve Asymptomatic moderate-to-severe mitral stenosis, with pulmonary hypertension, suitable valve Atrial fibrillation with moderate-to-severe mitral stenosis, suitable valve Symptomatic NYHA functional classes III and IV with less than ideal valve, but high surgical risk Surgery Repair (if possible) or replacement if symptomatic (NYHA functional classes III and IV) moderate-to-severe mitral stenosis when percutaneous mitral balloon valvuloplasty is unavailable or contraindicated Mitral regurgitation Symptomatic severe mitral regurgitation Severe mitral regurgitation with new-onset atrial fibrillation Asymptomatic severe mitral regurgitation with signs of left ventricular dysfunction (ejection fraction 30–60%, or major left ventricular dilation) or pulmonary hypertension Asymptomatic severe mitral regurgitation if > 90% chance of repair with experienced surgeon Asymptomatic severe mitral regurgitation if undergoing other open-heart surgery Consider if severe mitral regurgitation and secondary severe left ventricular dysfunction (ejection fraction < 30%) if high chance of repair Repair is recommended over replacement in majority with severe chronic mitral regurgitation NYHA = New York Heart Association. a Ideally pliable, noncalcified valve, no major mitral regurgitation or left atrial clot. the aortic valve (Table 4). 5 Debate exists surrounding aortic valve replacement in the asymptomatic patient.19, 20 Some are reluctant to proceed with surgery given that 50% will continue to be symptom free in 5 years, whereas others are concerned about progression of the disease with irreversible myocardial dysfunction.5 Among patients with left ventricular dysfunction, the degree of reversibility of systolic function depends on the extent to which the impaired cardiac output is dependent on the increased afterload imposed by the stenotic valve relative to the degree of impaired myocardial contractility as a result of increased pressure (i.e., the remodeling within the ventricle). Although improved symptoms and survival occur in both settings, patients who have left ventricular dysfunction due to exaggerated afterload may have complete improvement in left ventricular function. 5 It should be noted that in the setting of aortic stenosis, age is not a contraindication for surgery—the very elderly have similar outcomes to those of age-matched controls.5, 19, 20 Recently, percutaneously delivered balloon-expandable bioprosthetic (tissue) valves were implanted in patients too sick to undergo open-heart valve replacement. It is still too early, however, to know whether this technique, compared with palliative drugs, will have better outcomes, and whether it will ever replace open-heart surgical aortic valve replacement.21 Regurgitation Aortic regurgitation is either due to abnormal valve leaflets (congenitally malformed bicuspid aortic valve, or due to age-related degeneration, endocarditis, or rheumatic fever) or from a dilated root of the aorta pulling normal leaflets apart (due to hypertension, collagen vascular disorder, Marfan’s syndrome, or idiopathic dilation of the aorta).22 Like aortic stenosis, the onset of aortic regurgitation is gradual and progression continues over decades.5, 22 With aortic regurgitation, end diastolic volume increases in the left ventricle due to a progressively increasing retrograde flow of blood across the aortic valve.5, 19 The left ventricle responds to VALVULAR HEART DISEASE Bungard and Sonnenberg this volume load by increasing its compliance to accept a larger volume without a major filling pressure increase. As aortic regurgitation worsens, the left ventricle has to eject increasingly large volumes in order to ensure enough net forward output. This high output into the relatively stiff aorta raises aortic pressure and thus left ventricular afterload. The combined volume and pressure overload contribute to dramatic hypertrophy, and eventual left ventricular systolic dysfunction. Earlier in the disease, the systolic dysfunction is primarily related to excess afterload, and subsequently full recovery of ventricular function is achievable with correction of the aortic regurgitation. Uncorrected, alterations in ventricular chamber size (spherical geometry) and reduced myocardial contractility predominate as the cause of systolic dysfunction over the excessive afterload. Once these changes have occurred, left ventricular recovery and survival benefit may not occur after correction of the aortic regurgitation.5 Symptoms, Prognosis, and Monitoring Aortic regurgitation has a gradual onset.5, 22 The left ventricle has tremendous reserve dealing with aortic regurgitation volume and afterload, leaving many patients asymptomatic for decades. However, more than 25% of patients who die or develop systolic dysfunction do so before the onset of warning symptoms, emphasizing that thorough patient questioning is insufficient in serial evaluation of asymptomatic patients. 5 Routine echocardiography is recommended as little as every 2–3 years, and often more frequently (at least annually with severe aortic regurgitation 5 and perhaps every 4–6 mo if alterations in left ventricular shape or function are present). Once left ventricular dysfunction is evident, patients are likely to have symptoms begin at a rate of about 25%/year, and the disease progresses more rapidly.22 Symptoms are typical for that of left-sided heart failure, although angina can also occur due to higher oxygen demands from the workload or left ventricular hypertrophy. After experiencing symptoms, most patients will require surgical aortic valve replacement, as with aortic stenosis (Table 4). Untreated, mortality increases dramatically with symptoms of angina (> 10%/yr) and heart failure (> 20%/yr).5, 22 Treatment Vasodilator therapy can reduce the hemodynamic 83 burden in some patients by reducing systemic vascular resistance and enhancing forward flow while reducing regurgitation driving pressure and lowering the regurgitant volume and left ventricle afterload.5, 23, 24 Although earlier data suggested that nifedipine delayed the need for aortic valve replacement in patients with normal left ventricular function and asymptomatic severe aortic regurgitation, 25 a randomized trial comparing nifedipine 20 mg every 12 hours with enalapril 20 mg/day and placebo revealed no benefit to vasodilator therapy either in terms of slowing the need for surgery or reducing left ventricular volume loading or severity of regurgitation.23 It may be, however, that these randomized trials lacked large enough sample sizes to have statistical power to detect true benefits or perhaps that there was an inadequate drug effect to achieve necessary vasodilation.24 Thus, vasodilators are only recommended in severe aortic regurgitation for the following circumstances: long-term treatment of those deemed poor candidates for surgery because of cardiac or noncardiac factors, short-term use to improve the hemodynamic profile in preparation for aortic valve replacement among those with severe heart failure symptoms or severe left ventricular dysfunction, and to prolong the compensated phase of asymptomatic patients with normal systolic function.5 Clearly, surgery is the only known corrective option (Table 4), as there is no certainty that vasodilators dramatically change the natural history of this valve problem. Mitral Valve Disease Stenosis Mitral stenosis is almost exclusively caused by rheumatic heart disease, an inflammation of all of the endocardium, myocardium, and pericardium in response to a group A Streptococcus infection.5, 26 Several years after the infection, the initial damage predisposes to leaflet thickening, commissural fusion, and chordal shortening and fusion.5, 27 After the acute episode of rheumatic fever, a slow stable course, with a latent period of 20–40 years, ensues, followed by progressive acceleration later in life. The mean onset of progression is 50–60 years of age, and it is twice as likely in women. The more group A streptococcal infections, however, the faster the process. With mitral stenosis, blood flow relies on the transmitral pressure gradient. 5, 22, 27 The left atrium enlarges as afterload increases with progressive mitral stenosis, and this leads to an 84 PHARMACOTHERAPY Volume 31, Number 1, 2011 increase in pressure in the pulmonary venous circulation. Eventually, the right ventricle bears the burden of propelling blood across the mitral valve. The right ventricle becomes compromised by afterload imposed on it by high left atrial pressures that secondarily causes pulmonary vasoconstriction and will eventually lead to fixed pulmonary hypertension. Furthermore, due to the increase in left atrial pressure and dilation of the left atrium, 30–40% of patients with mitral stenosis will develop atrial fibrillation.22 The development of atrial fibrillation is correlated with the severity of mitral stenosis and left atrial pressure. With atrial fibrillation in the setting of mitral stenosis, systemic embolization may occur at much higher rates than in nonvalvular atrial fibrillation, 20–30%/year. 22 About 65% of all embolic events occur within the first year of the onset of atrial fibrillation.19, 22 Symptoms, Prognosis, and Monitoring The symptoms of mitral stenosis are due to the high left atrial pressure needed to drive blood across the tight valve, mimicking left-sided heart failure (without any actual left ventricular failure).5, 19, 22 As with aortic stenosis, symptoms early in mild mitral stenosis are elicited by exertional states. Later, atrial fibrillation may cause dramatic worsening of heart failure symptoms (tachycardia and loss of atrial “kick” helping to drive blood across the valve), and eventual right-sided heart failure (edema, fatigue, ascites, and abdominal distension) may follow. The 10-year survival rate for patients having either mild or no symptoms with mitral stenosis is 80%.22 All patients with mitral stenosis should be assessed at least annually, with a history, physical examination, and electrocardiogram.5 Routine follow-up with echocardiography is necessary, and its frequency is dictated by the severity of clinical and echocardiographic findings (ranging from yearly or more often if symptoms develop to as little as every 5 yrs). From the onset of symptoms, it is typical for a decade to pass before the occurrence of disabling symptoms. Once limiting symptoms are present, the 10-year survival rate declines to 0–15%. Data reveal that death in untreated patients is often due to progressive heart failure (60–70%), systemic embolism (20–30%), pulmonary embolism (10%), or infection (1–5%). 5, 19, 22 Furthermore, once patients experience severe pulmonary hypertension, mean survival is less than 3 years. Treatment Given that a mechanical narrowing of the mitral valve orifice is central to all pathology related to this disease process, no medical therapy will provide complete resolution.5, 19, 27 Hydrochlorothiazide or low-dose furosemide (gentle diuresis) may help patients with high back-pressure from the tight mitral stenosis. In addition, heart rate slowing is critical to help increase the percentage of time the heart spends in diastole, allowing more time for left atrial emptying into the venticle (tachycardia actually causes the heart to spend longer in systole than in diastole, dramatically raising the mitral pressure gradient needed to push the same flow through the heart). -Blockers and rate-slowing calcium channel blockers remain the backbone of rate-slowing therapy in these situations. In atrial fibrillation, adding digoxin may further help heart rate slowing, whereas warfarin is crucial to decrease the otherwise extremely high embolic risk for patients with mitral stenosis and atrial fibrillation. 28 Attempting to prevent atrial fibrillation with antiarrhythmics is theoretically attractive but remains limited by the relative lack of effectiveness of these drugs to fully suppress atrial fibrillation. Even in patients with nonvalvular atrial fibrillation, treatment with the most effective antiarrhythmic amiodarone had an incomplete success rate of only 70% of patients after 1 year.29 In addition, major concerns about toxicity (including potentially lethal proarrhythmia) remain for almost all antiarrhythmics. Although dronedarone might not have these potential mortality concerns, there are worries about its relative lack of effectiveness even in nonvalvular atrial fibrillation.30 Ultimately, mechanical intervention is required for patients with moderate mitral stenosis (Table 4). The options include percutaneous mitral balloon valvotomy or surgical mitral valve repair or replacement.5, 19 With balloon valvotomy, a catheter is inserted into the femoral artery and a deflated balloon is pushed across the mitral valve. The end of the catheter contains the hourglass-shaped balloon that is inflated across the valve orifice and “cracks open” the valve, usually doubling the valve area with a 50–60% decline in the transmitral gradient. This procedure, however, is technically challenging, and medical centers that perform large volumes of this procedure have better success with fewer complications.5 Surgical or open commissurotomy is the surgical division of fibrous chords or VALVULAR HEART DISEASE Bungard and Sonnenberg commissures of the mitral valve to relieve the stenosis. If neither balloon nor surgical mitral valve repair is possible, then mitral valve replacement remains the final option.31 In general, the type of intervention performed takes into account the morphology of the mitral valve apparatus, patient comorbidities, and center-specific practices and expertise.5, 19 The timing of the procedure is dictated by the severity of the disease. 5, 19 Outcomes of mitral valve replacement surgery correlate directly with age. Morbidity and mortality rates are less than 5% for a young healthy person and as high as 10–20% in older patients with concomitant medical problems or pulmonary hypertension. 19 Both younger and older patients have lower operative mortalities and superior outcomes with mitral valve repair compared with replacement. 32 Preservation of the subvalvular apparatus, as done with repair and not always feasible with replacement, aids in maintaining left ventricular function.5 This, however, is particularly unlikely in the setting of rheumatic mitral stenosis.5 Mitral Regurgitation Chronic mitral regurgitation is commonly caused by the syndrome of mitral valve prolapse ([MVP] hypermobile “floppy” chordae or leaflets that cause leakage), distorted papillary muscles from myocardial damage due to coronary artery disease (so-called ischemic mitral regurgitation), or from simple dilation of the left ventricle pulling apart the mitral apparatus (functional mitral regurgitation). 5, 33–35 Less commonly, rheumatic heart disease often combined with stenosis may cause mitral regurgitation. 5, 33 Whatever the initial cause, mitral regurgitation often leads to progressive enlargement of the left ventricle, with the ventricle becoming more spherical, causing more papillary muscle displacement and further worsening mitral regurgitation (mitral regurgitation begets mitral regurgitation). 33 In general, ischemic mitral regurgitation is prognostically worse that nonischemic mitral regurgitation.35, 36 Mitral valve prolapse, a nonischemic form of mitral valve disease, is common in the general population, affecting 1–2.5%. 5, 34, 37 Although MVP is typically benign, because of its prevalence in the population, it is the leading cause of mitral regurgitation today.34 In most of these patients, MVP has no effect on their life expectancy, but rarely MVP can significantly affect morbidity and mortality. With MVP, the leaflet(s) billows into 85 the left atrium (must be > 2 mm above the mitral annulus).5, 34 Regardless of the cause of chronic mitral regurgitation, the hemodynamic compensation and progression are the same. 5, 34, 38 Ejection from the left ventricle into the low pressure and generally very compliant left atrium is easier than normal forward ejection through the aortic valve, and provides a low afterload. Because of the large amount of left ventricle ejection lost back into the left atrium, both the left atrium and left ventricle must have substantially higher filling (preload) to maintain adequate net forward output. Thus, in the setting of normal myocardial function, the ejection fraction should appear above normal. Once mitral regurgitation becomes severe, over 50% of the left ventricular output regurgitates backward, requiring doubling of left ventricular output, and thus leads to left ventricular and left atrial dilation with eccentric hypertrophy. This increase facilitates a greater stroke volume with each ventricular contraction, thereby allowing sufficient cardiac output to allow some patients to remain asymptomatic, even with vigorous exercise. Patients having mild-to-moderate mitral regurgitation remain asymptomatic for several years, having little to no hemodynamic compromise. However, continued volume overload eventually results in left ventricular contractile dysfunction, perhaps because the same factors that promote dilation and hypertrophy are also, in the long term, toxic to myocardium.39 Due to the favorable loading conditions, however, ejection fractions are often maintained within the low normal range (50–60%), despite substantial muscle damage. Allowed to progress, pulmonary hypertension will develop, conferring a poor prognosis.5, 19 Symptoms, Prognosis, and Monitoring The symptoms of mitral regurgitation are consistent with left-sided heart failure (e.g., pulmonary congestion).5, 36 After severe mitral regurgitation is detected, patients are likely to develop symptoms or have left ventricular dysfunction within 6–10 years.5, 36 With mitral regurgitation, assessing a patient’s exercise tolerance or occurrence of or change in symptoms is crucial given the insidious progression of this disease. Monitoring with echocardiography for those with moderate-to-severe mitral regurgitation should occur either annually or sooner if symptoms change, with ongoing assessment of ventricular dimensions and 86 PHARMACOTHERAPY Volume 31, Number 1, 2011 volumes given that the ejection fraction typically is above normal. Correction of mitral regurgitation should be considered before substantial decline in left ventricular function (ejection fraction < 60%) as progressive deterioration in myocardial function confers a poorer prognosis. Prognosis worsens as the disease ensues and manifests with pulmonary hypertension.5, 19, 33 Treatment Differentiation between ischemic and nonischemic mitral regurgitation is important in the medical management of this population.5, 35 Those with mitral regurgitation due to dilated or ischemic cardiomyopathy may benefit from pharmacologic agents reducing preload given the pathophysiology of this disease process.5, 33 If left ventricular dysfunction is evident, standard treatments for heart failure are beneficial in reducing the severity of functional mitral regurgitation. 5, 37, 40 For patients having nonischemic mitral regurgitation, no widely accepted recommendations have been made surrounding medical management. 5 Once patients develop symptoms, however, surgical options should be considered for both ischemic and nonischemic mitral regurgitation, even if left ventricular function is normal.5, 19 Three types of operations for mitral valves in the setting of mitral regurgitation are used: mitral valve repair, mitral valve replacement with preservation of part or all of the mitral apparatus, and mitral valve replacement with removal of the mitral apparatus.5, 19, 38 In general as with mitral stenosis, mitral valve repair confers lower operative mortality and superior late outcomes in comparison with mitral valve replacement.5, 37, 38 The mitral apparatus consists of chordae tendineae attaching the cusps of the valve to the papillary muscles that are part of the left ventricular wall (Figure 2). This apparatus is an integral part of the left ventricle, important in maintaining normal shape, volume, and function. As such, removal of this apparatus (as seen with many older valve replacements) leads to poorer postoperative left ventricular function and survival compared with leaving it intact. 5, 33 Repairing the mitral valve, however, requires that the valve morphology is suitable and that the appropriate surgical skill and expertise are available; these procedures are technically challenging, usually most often for MVP than for other causes of mitral regurgitation.5, 37, 38 When replacing the mitral valve is mandatory, surgeons will always consider preserving the chordae tendineae (if possible), as this procedure tends to relieve symptoms and maintain preoperative left ventricular function. Replacing the mitral valve with removal of the mitral apparatus is only done when absolutely necessary—that is, in situations in which the native preoperative morphology simply cannot be spared, as in patients with rheumatic disease.5 If possible, in patients with rheumatic mitral regurgitation, artificial chordal reconstruction is done to preserve the mitral apparatus.5 With ischemic mitral regurgitation, concomitant surgery may be indicated for coronary revascularization, as data show that correction of only the valve anomaly by means of ring annuloplasty offers short-term benefit.5, 19, 33, 35 Many patients continue to have mitral regurgitation as the ventricle continues to remodel after the procedure. Patients with ischemic mitral regurgitation have poorer prognoses than those with nonischemic mitral regurgitation and have a greater rate of mitral regurgitation recurrence after valve repair.35, 36 In contrast to ischemic mitral regurgitation, those with MVP tend to have exceptional long-term survival beyond 10 years and up to 20 years after surgical repair of the valve.5, 32 The indications for surgery for MVP and mitral regurgitation parallel those for other forms of severe ischemic mitral regurgitation (Table 4).5 Patient Counseling Patients with any of the four valve lesions discussed should be informed of the slow yet variable progression of their disease.5 With MVP, recognition of a typical benign prognosis, with encouragement to have a normal lifestyle, should be emphasized.5 Routine questioning surrounding changes in symptoms, most likely to occur initially with increased activity or exercise, should be done in patients with any type of valvular heart disease to serve as a surrogate for disease progression. Patients should be encouraged to report deterioration or changes in their symptoms, as objective reassessment through echocardiography may be warranted. Specific symptoms for each lesion are identified in Table 5. With mitral stenosis, the pharmacist should be alerted to the increased likelihood for development of atrial fibrillation and be prepared to discuss concordant symptoms of atrial fibrillation with the patient. In contrast, with mitral regurgitation (and aortic regurgitation) patient VALVULAR HEART DISEASE Bungard and Sonnenberg 87 Table 5. Topics for Counseling of Patients with Valvular Heart Disease Valve Lesion Danger Symptoms Exercise Recommendations Aortic stenosis Angina, syncope, dyspnea Asymptomatic-to-mild disease: unrestricted exercise (on exertion, later frank heart Moderate-to-severe disease: avoid high-intensity or competitive failure with orthopnea or PND) sports, consider exercise testing before beginning exercise program Aortic Dyspnea (on exertion, Asymptomatic, mild, or moderate disease with normal left ventricular regurgitationa shape and function: encourage exercise, including competitive orthopnea, PND), angina, palpitations sports Severe disease: limit exercise to mild or moderate aerobic activitiesb Mitral stenosis Dyspnea (on exertion, Symptom-limited exercising orthopnea, PND) Avoid tachycardia-provoking situationsc If moderate-to-severe disease: avoid competitive sports Mitral Dyspnea (on exertion, Symptom-limited exercisingb regurgitationa orthopnea, PND) If moderate-to-severe disease: avoid competitive sports PND = paroxysmal nocturnal dyspnea. a Symptom-related progression is often delayed, imparting the importance of serial objective assessment of valve lesion. b Activities increasing aortic pressure (i.e., isometric exercises such as yoga or weight lifting) are strongly discouraged due to the likely increase in the aortic regurgitation driving pressure. c Sudden onset of pulmonary edema may occur in an asymptomatic patient if there is rapid onset of atrial fibrillation; hence, patients should be counseled to seek medical attention if shortness of breath develops, as this could be life-threatening. Table 6. Characteristics of the Ideal Valve Design42 Factor Ideal Valve Flow Unobstructed, laminar flow Comments Subsequent generations have improved flow across the valve Gradient across valve Low, to not cause stenosis or damage blood cells Rigid leaflets interact with blood cells Inert material Avoid interaction with blood components (i.e., activation of clotting cascade or shear force activation of platelets) Avoid infection Tissue valves are more biocompatible compared with prosthetic Newer materials, such as pyrolytic carbon, may be superior in minimizing interaction with blood components and minimizing infection Durability Strong Metal valve components do not wear out, tissue valves will eventually wear out education surrounding the insidious progression is paramount and must encompass a conscious effort to gauge the patient’s baseline exercise tolerance in order to allow detection of subtle changes from a patient’s baseline. Various recommendations surrounding exercise for each valve lesion are included in Table 5. 5, 41 Concordant with recommendations for specific valve lesions, any patient taking anticoagulants (e.g., for atrial fibrillation or metal heart valves) should avoid contact sports.41 Bioprosthetic versus Prosthetic Valves In the 1960s with the introduction of cardiopulmonary bypass, the ability to replace valves with good outcomes became evident. 5, 19, 34 Worldwide, approximately 300,000 valve replace- ments are performed annually.19 Characteristics of the ideal valve are described in Table 6. 42 There are two types of valves for implantation: bioprosthetic (tissue) valves and prosthetic (mechanical, metal) valves (Table 7). 5, 42, 43 Bioprosthetic valves are heterografts derived from either a porcine or bovine source.43 Mechanical valves are composed of plastic and metal components. The decision to implant a tissue versus a metal prosthetic valve is made in conjunction with the patient, considering life expectancy and ability or willingness to accept lifelong anticoagulation therapy. 5, 19, 42, 43 Overall, bioprosthetic valves are less thrombogenic and hence do not mandate lifelong anticoagulation therapy; however, the trade-off is that they are less durable than metal valves. Bioprosthetic valves are preferred in situations 88 PHARMACOTHERAPY Volume 31, Number 1, 2011 Table 7. Bioprosthetic and Prosthetic Valves Type of Valve Description Bioprosthetic Trileaflet tissue (bovine and porcine) (tissue) Nonstented (free porcine aortic root) Trade Namea Carpentier-Edwards, Hancock, Medtronic Mosaic Freestyle Prosthetic (mechanical, metal) First generation Second generation Third generation Potential Starr-Edwards Bjork-Shiley, Medtronic-Hall, Omnicarbon St. Jude, Carbomedic, Edwards-Duromedics On-X valve Ball and cage Single tilting disk (monoleaflet) Bileaflet tilting disk Bileaflet tilting disk a Manufacturers are as follows: Carpentier-Edwards: Edwards Lifesciences, Irvine, CA; Hancock: Medtronic, Minneapolis, MN; Medtronic Mosaic: Medtronic; Freestyle: Medtronic; Starr-Edwards: Edwards Lifesciences; Bjork-Shiley: Pfizer, New York, NY; Medtronic-Hall: Medtronic; Omnicarbon: Medical CV, Inver Grove Heights, MN; St. Jude: St. Jude Medical, St. Paul, MN; Carbomedic: Carbomedics Inc., Austin, TX; Edwards-Duromedics: Baxter Healthcare Corp., Edwards Division, Santa Ana, CA; On-X valve: On-X Life Technologies, Inc., Austin, TX. of limited life expectancy (< 10–15 yrs) given their limited durability.5, 19, 43 Native valves have the unique ability to become rigid under stress (when they close) but become very pliable when they need to open, and, as living tissue, can selfrepair.2 Unfortunately, nonliving tissue cannot be made to mimic this alternating rigidity and pliability. Thus, eventually tissue valves degenerate, especially in younger patients with presumably higher cardiac output across the valves. Ten-year failure rates exceed 42% when implanted in patients younger than 40 years.43 In contrast, patients older than 70 years have a 10% chance of the tissue valve failing in 10 years, and 50% are still functioning adequately at 15–17 years.43 Tissue valves have reduced thrombogenicity; thus, patients do not have to receive lifelong anticoagulation therapy. As such, bioprosthetic valves should be considered in patients unable or unwilling to take vitamin K antagonists (e.g., patients desiring pregnancy, those with contraindications to warfarin therapy). Mechanical metal valves should be considered in patients whose life expectancy exceeds 10–15 years and who are able and willing to take vitamin K antagonists.19, 43 Three generations of mechanical valves have been marketed, with each subsequent generation having improvements in flow patterns across the valve and reduced thrombogenicity (Table 7).42–44 Earlier generation valves (ball and cage) encouraged more lateral blood flow, whereas recent ones (bileaflet) have more central blood flow that parallels the physiologic pattern.42 With improved blood flow and synthetic materials, the rates of thromboembolic complications for later generations of valves are reduced. Given this, most patients having metal valves implanted today receive a bileaflet valve. To date, in North America, all patients having metal valves implanted have required full-intensity warfarin therapy.42 In January 2006, the On-X prosthetic valve (On-X Life Technologies, Inc., Austin, TX) was approved for use based on an investigational device exemption.45 This valve is promoted as having superior material (pure pyrolytic carbon) and design (inlet flares mimicking the native valve) and is purported to have a better life span (i.e., lifetime) and fewer complications.45 The Prospective Randomized On-X Valve Anticoagulation Trial (PROACT) is under way.46 This trial is recruiting and will assess the ability to use aspirin alone or lower-intensity warfarin therapy (international normalized ratio [INR] target 1.5–2.0) against standard of care with 5 years of follow-up. An intermediate follow-up report of European patients receiving aortic (184 patients) or mitral (117 patients) On-X valves having an INR range of 3.0–4.5 reported rates of thromboembolism of 0.88% and 1.76%/patientyear, respectively. 47 Given the target of anticoagulation, these results are comparable to current valve options. We will, however, await data from PROACT. If positive, these results have the potential to revolutionize the care of patients with prosthetic heart valves. Monitoring and Follow-up After Surgery Both bioprosthetic and metal valves require regular postoperative follow-up. 5 A baseline echocardiogram should be obtained within the first half year after implantation to ensure no early valve complications are evident (e.g., undersized valve leading to residual stenosis, or valve dysfunction with major residual regurgitation). Fortunately, mechanical failure of metal valves is rare, especially in the first years after surgery. Mechanical failure accelerates especially VALVULAR HEART DISEASE Bungard and Sonnenberg 89 Table 8. Antithrombotic Therapy for Bioprosthetic and Prosthetic Valves49 Duration of Antithrombotic Therapy and Indication INR Other Treatment Options Bioprosthetic (tissue) valves Mitral valve 2.0–3.0 3 mo, then aspirin 50–100 mg/day Aortic value NA Aspirin 50–100 mg/day Atrial fibrillation or left atrial thrombus 2.0–3.0 Until risk of left atrial thrombus is gone during surgery (often indefinite) 2.0–3.0 > 3 mo History of systemic embolism Additional thromboembolic risk factors 2.0–3.0 Long term; add aspirin 50–100 mg/day (atrial fibrillation, hypercoagulable if history of atherosclerotic vascular state, or low ejection fraction) disease (avoid if age > 80 yrs and history of gastrointestinal bleed) Prosthetic (mechanical, metal) valves Mitral valve Aortic valvea Additional thromboembolic risk factors (atrial fibrillation, hypercoagulable state, low ejection fraction, history of atherosclerotic disease) Systemic embolism despite a therapeutic INR 2.5–3.5 2.5–3.5 2.5–3.5 Long term Long term Add aspirin 50–100 mg/day unless age > 80 yrs or history of gastrointestinal bleed 2.5–3.5 or 3.0–4.0 Add aspirin 50–100 mg/day, or up-titration only INR = international normalized ratio; NA = not applicable. a For aortic bileaflet valve or Medtronic-Hall monoleaflet valve (Medtronic, Minneapolis, MN) and normal sinus rhythm and no left atrial enlargement, INR range is 2.0–3.0. in bioprosthetic values after about 10 years, and annual echocardiography should be performed starting at 7 years in patients with a bioprosthetic value. Even metal valves can develop mechanical failure if scar tissue (pannus) starts to grow and encroach on the valve orifice, creating prosthetic stenosis or regurgitation. The rate of prosthetic valve infective endocarditis is similar for both types of valves (1%/yr).48 In addition, the annual thromboembolism rate with bioprosthetic values is similar to that with fully anticoagulated metal valves at 1–2%. 49 Thus, despite the fact that bioprosthetic valves do not require long-term anticoagulation (although many surgeons require anticoagulation in patients for the first 3 mo), both types of valves can be associated with potentially serious embolism. Patients should therefore be regularly followed by a specialist to monitor valve function. Antithrombotic Therapy The risk of thromboembolism in patients with valve replacements is dependent on the position of the valve (aortic or mitral), the type of valve (bioprosthetic or prosthetic), as well as other clinical and echocardiographic characteristics.5, 49, 50 Overall, mitral valves are more thrombogenic than aortic valves because of the flow patterns around the valve and the increased likelihood of the development of atrial fibrillation with mitral valve disease.49, 50 Concomitant risk factors, such as atrial fibrillation, low ejection fractions, and history of atherosclerotic disease, often encompass an indication for concomitant aspirin therapy.49 An overview of current recommendations for antithrombotic therapy in patients with bioprosthetic and metal valves is provided in Table 8.49 Endocarditis Prophylaxis Infective endocarditis is defined as an infection of the endocardial (inside) layer of the heart, which usually affects the heart valves.5, 48 Both native and artificial valves may be affected. The pathophysiologic process occurs initially as a result of turbulence or trauma to the endothelial surface of the heart that encourages platelet and fibrin deposition with resultant formation of nonbacterial thrombotic endocardial lesions. Subsequently, transient bacteremia may lead to the seeding of these lesions with bacteria adhering and multiplying within them, creating an infective vegetation.48 As such, consideration should be given to antibiotic prophylaxis for procedures (primarily dental) exposing patients with valvular heart disease to systemic infections. For dental procedures, this encompasses any procedure likely to cause gingival bleeding or penetration of the mucosa.5 When these occur, 90 PHARMACOTHERAPY Volume 31, Number 1, 2011 antibiotic prophylaxis is indicated for patients with prosthetic heart valves or valve repairs containing prosthetic material.5 A single dose of amoxicillin 2 g is recommended for adults; clindamycin 600 mg is an alternative for those with penicillin allergy.48 Antibiotic prophylaxis is not necessary for procedures that do not perforate the mucosa, such as transesophageal echocardiography, diagnostic bronchoscopy, esphagogastroscopy, or colonoscopy. 5, 48 Furthermore, prophylaxis is unnecessary for all patients with native valve disease (whether stenosis or regurgitation), MVP, innocent murmurs, and those with abnormal echocardiographic findings without an audible murmur. According to the American College of Cardiology–American Heart Association guidelines, only patients with prosthetic valves, previous endocarditis, unrepaired complex cyanotic heart disease, or heart transplant recipients with major valve lesions should receive endocarditis prophylaxis.5, 48 Rheumatic Fever Prophylaxis Rheumatic fever is a systemic inflammatory disease that may occur weeks after an untreated infection with group A Streptococcus, as with “strep throat” or scarlet fever, and is believed to be caused by antibody cross-reactivity. 5, 26 Typically, the inciting infection occurs early in life (ages 5–15 yrs) and manifests later in life with clinical sequelae. Valvular heart disease occurs with time, with repeated inflammation with fibrous resolution, causing valve leaflet thickening, commissural fusion, and shortening and thickening of the tendinous cords. As such, prompt recognition and treatment are paramount for the primary episode, whereas for those having a history of rheumatic fever (including those with mitral stenosis), secondary antistreptococcal prophylaxis is warranted for recurrent fever. 5 Various regimens that are penicillin based are appropriate for these purposes.5 Conclusion Although pharmacists commonly encounter patients with valvular heart disease, the disease is often not well understood and subsequently patients are denied reinforcement of pertinent information. Understanding the cardiac cycle and the valve anomaly allows a logical progression of consequences to the cardiovascular system. With this understanding, pharmacists can effectively counsel patients surrounding disease progression and self-monitoring, use of vasodilator therapy, and prophylaxis for endocarditis and rheumatic fever. Where appropriate, important therapies (e.g., for atrial fibrillation, heart failure, hyperlipidemia) to reduce overall risk should be implemented in this patient population. Knowledge of the differences between bioprosthetic (tissue) values and prosthetic (mechanical, metal) valves is important in the provision of antithrombotic therapy, and this area continues to be evaluated in clinical trials. References 1. Baume P. Heart. In: Currie W, Baume P, Tracey DJ, et al, eds. Anatomica: the complete medical encyclopedia, 12th ed. Vancouver, Canada: Raincoast Books, 2000:344–50. 2. Otto KM, Bonow RO. Valvular heart disease. In: Libby P, Bonow RO, Zipes DP, Mann DL, eds. Braunwald’s heart disease: a textbook of cardiovascular medicine, 8th ed. Philadelphia, PA: Saunders/Elsevier, 2007:1625–93. 3. Johnson JA. Diastolic dysfunction in congestive heart failure. Clin Pharm 1991;10:850–61. 4. Constantine G, Shan K, Flamm SD, Sivananthan MU. Role of MRI in clinical cardiology. Lancet 2004;363:2162–71. 5. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118:e523–661. 6. Rahimtoola SH, Frye RL. Valvular heart disease. Circulation 2000;102:IV24–33. 7. Aronow WS. Aortic stenosis. Compr Ther 2007;33:174–83. 8. Fedak PWM, Verma S, David TE, Leask RL, Weisel RD, Butany J. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation 2002;106:900–4. 9. Carabello BA, Paulus WJ. Aortic stenosis. Lancet 2009;373:956–66. 10. Carabello BA, Crawford FA. Valvular heart disease. N Engl J Med 1997;337:32–41. 11. Rajamannan NM. Reassessment of statins to retard the progression of aortic stenosis. Curr Cardiol Rep 2007;9:99–104. 12. Rabus MB, Kayalar N, Sareyyupoglu B, Erkin A, Kirali K, Yakut C. Hypercholesterolemia association with aortic stenosis of various etiologies. J Card Surg 2009;24:146–50. 13. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–56. 14. Cowell SJ, Newby DE, Prescott DJ, et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389–97. 15. Rosenhek R. Statins for aortic stenosis. N Engl J Med 2005;352:2441–3. 16. Briand M, Dumesnil JG, Kadem L, et al. Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis. J Am Coll Cardiol 2005;46:291–8. 17. Chockalingam A, Venkatesan S, Subramaniam T, et al. Safety and efficacy of angiotensin-converting enzyme inhibitors in symptomatic severe aortic stenosis: symptomatic cardiac obstruction—pilot study of enalapril in aortic stenosis (SCOPEAS) [online exclusive article]. Am Heart J 2004;147:e19. Available from http://www.ahjonline.com/article/ VALVULAR HEART DISEASE Bungard and Sonnenberg PIIS0002870303007336/fulltext. 18. Khot UN, Novaro GTM, Popovi ZP, et al. Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis. N Engl J Med 2003;348:1756–63. 19. Gallegos RP. Selection of prosthetic heart valves. Curr Treat Options Cardiovasc Med 2006;8:443–52. 20. Piper C, Hering D, Kleikamp G, Korfer R, Horstkotte D. Valve replacement in octogenarians: arguments for an earlier surgical intervention. J Heart Valve Dis 2009;18:239–44. 21. Grube E, Buellesfeld L, Mueller R, et al. Progress and current status of percutaneous aortic valve replacement: results of three device generations of the CoreValve Revalving system. Circ Cardiovasc Interv 2008;1:167–75. 22. Bhandari S, Subramanyam K, Trehan N. Valvular heart disease: diagnosis and management. J Assoc Physicians India 2007;55:575–84. 23. Evangelista A, Tornos P, Sambola A, Permanyer-Miralda G, Soler-Soler J. Long-term vasodilator therapy in patients with severe aortic regurgitation. N Engl J Med 2005;353:1342–9. 24. Carabello BA. Vasodilators in aortic regurgitation—where is the evidence of their effectiveness? N Engl J Med 2005;353: 1400–3. 25. Scognamiglio R, Rahimtoola SH, Fasoli G, Nistri S, Dall Volta S. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular dysfunction. N Engl J Med 1994;331:689–94. 26. Cunningham MW. Pathogenesis of group A streptococcal infections and their sequelae. Adv Exp Med Biol 2008;609: 29–42. 27. Carabello BA. Modern management of mitral stenosis. Circulation 2005;112:432–7. 28. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association task force on practice guidelines and the European Society of Cardiology committee for practice guidelines. Circulation 2006;114:e257–354. 29. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861–72. 30. Zimetbaum P J. Dronedarone for atrial fibrillation: an odyssey. N Engl J Med 2009;360:1811–13. 31. Gammie JS, Sheng S, Griffith BP, et al. Trends in mitral valve surgery in the United States: results from the Society of Thoracic Surgeons adult cardiac database. Ann Thorac Surg 2009;87:1431–9. 32. Ailawadi G, Swenson BR, Girotti ME. et al. Is mitral valve repair superior to replacement in elderly patients? Ann Thorac Surg 2008;86:77–86. 33. Le H, Thys DM. Ischemic mitral regurgitation. Semin Cardiothorac Vasc Anesth 2006;10:73–7. 34. Hayek E, Gring CN, Griffin BP. Mitral valve prolapse. Lancet 2005;365:507–18. 91 35. Carabello BA. The current therapy for mitral regurgitation. J Am Coll Cardiol 2008;52:319–26. 36. Ahmed MI, McGiffin DC, O’Rourke RA, Dell’Italia LJ. Mitral regurgitation. Curr Probl Cardiol 2009;34:93–136. 37. Verma S, Mesana TG. Mitral valve repair for mitral valve prolapse. N Engl J Med 2009;361:2261–9. 38. Foster E. Mitral regurgitation due to degenerate mitral-valve disease. N Engl J Med 2010;363:156–65. 39. Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA. Controversies in ventricular remodelling. Lancet 2006;267:356–67. 40. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2005;112:1825–52. 41. Bonow RO, Cheitlin MD, Crawford MH, Douglas PS. American College of Cardiology/American Heart Association consensus document on athletes and heart disease. Task force 3: valvular heart disease. J Am Coll Cardiol 2005;45:1334–40. 42. Kidane AG, Burriesci G, Cor nejo P, et al. Current developments and future prospects for heart valve replacement therapy. J Biomed Mater Res B Appl Biomater 2009;88:290–303. 43. Vongpatanasin W, Hillis D, Lange RA. Prosthetic heart valves. N Engl J Med 1996;335:407–16. 44. Mercadante N. Management of patients with prosthetic heart valves: potential impact of valve site, clinical characteristics, and comorbidity. J Thromb Thrombolysis 2000;10:29–34. 45. Health Central. Heart valve replacement education center. Available from http://www.healthcentral.com/heart-disease/ valve/benefits_of_onx_valve.html. Accessed November 17, 2009. 46. Medical Carbon Research Institute, LLC. Prospective randomized On-X anticoagulation clinical trial (PROACT). ClinicalTrials.gov. Bethesda, MD: National Library of Medicine. Available from http://clinicaltrials.gov/ct2/show/ NCT00291525?term=PROACT&rank=5. Accessed November 17, 2009. 47. Palatianos GM. Laczkovics AM, Simon P, et al. Multicentered European study on safety and effectiveness of the On-X prosthetic heart valve: intermediate follow-up. Ann Thorac Surg 2007;83:40–6. 48. Nishimura RA, Faxon DP, Lytle BW, et. al. ACC/AHA 2008 guideline update on valvular heart disease: focused update on infective endocarditis. A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2008;118:887–96. 49. Salem DN, O’Gara PT, Madias C, Pauker SG. Valvular and structural heart disease. Chest 2008;133:S593–629. 50. Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJM, Vanden Broucke JP, Briët E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995;333:11–17.