**2. Medical treatment**

The standard therapy for symptomatic patients with severe aortic stenosis (AS) due to any cause is replacement of the valve. Since the prognosis dramatically worsens once the symptoms of AS develop, this is a late stage for an effective medical treatment. Patient education regarding the disease course and typical symptoms is an important priority. Current man‐ agement of patients with AS comprises monitoring disease progression. Unfortunately, in patients with AS medical therapy may not prolong life nor improve progression and has limited utility in alleviating symptoms. Severe AS is adversely affected by changes in preload

© 2013 Oz et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and afterload. In patients with severe AS, drugs that reduce preload or afterload should be used with caution because any medical treatment option used in these patients may worsen the patients' conditions. Meanwhile, there is a growing body of evidence about TAVI which is currently used mainly in patients with multi-morbidity and high surgical risk. In patients with rheumatic valve disease, rheumatic fever prophylaxis is strongly recommended to prevent repetitive valve scarring [1]. It has been hypothesized that some of the risk factors and pathophysiologic mechanisms in atherosclerosis play an important role in the development of calcific AS. Therefore theoretically, anti-inflammatory and anti-proliferative agents might slow or prevent disease progression. Because patients with severe AS are mostly older adults, some important and common issues like kidney insufficiency (KI), autonomic dysfunction, conduction disturbances, propensity to falls, and osteoporosis should always be kept in mind in the medical management of these patients.

years or older [9]. A recently published article reported the outcomes of percutaneous coronary intervention (PCI) in patients with concomitant severe AS and CAD [10]. In this well-matched trial, 30-day mortality after PCI was similar in patients with and without severe AS. In this study AS patients with low EF (≤30) and high Society of Thoracic Surgeons score (≥10) were associated with significantly increased 30-day mortality after PCI. Patients with mild AS should not be restricted from physical activity. Patients with severe AS should avoid compet‐ itive or vigorous activities that involve high dynamic and static muscular demands, although other forms of exercise are safe. Exercise may also improve functional capacity and may

Current Treatment Options in Aortic Stenosis

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381

Valvular heart disease, particularly left-sided valvular lesions precipitate the development of atrial fibrillation (AF). Although it has been less well studied in AS compared to mitral valve disorders, AF often complicates uncorrected aortic valve disorders [11]. In the recently published SEAS study, baseline or prior was present in approximately 9% of patients with mild-to-moderate AS [12]. The study excluded the patients with baseline and prior AF and sought the effect of simvastatin plus ezetimibe on new-onset AF. During an average of 4.3±0.8 years of follow up, 6% of the patients developed AF and the rate was similar between the simvastatin plus ezetimibe and placebo groups. In this study, increased age and left ventricular mass index were independent predictors of new onset AF. New-onset AF was associated with two-fold higher risk of AF related outcomes and four-fold higher risk of nonfatal nonhemor‐ rhagic stroke. In a previously asymptomatic patient, new onset AF may cause overt heart failure symptoms due to the noncompliant left ventricle which is associated with a relative shift of left ventricular filling to the later part of diastole with a greater dependence upon atrial contraction. Similar treatment approaches for AF in patients with AS can be used as in patients without AS. Heart rate control is important to enable an adequate diastolic filling time. Although guidelines generally recommend rate control over rhythm control in patients with AS, there is a trend towards preference of rhythm control with the benefits of early rhythm control and options of left atrial catheter ablation and new anti-arrhythmic drugs [13, 14]. Within the current ECS guidelines on AF, severe AS is stated as a contraindication for verkalant usage [14]. It is also important to screen for coronary disease in patients with AS before the initiation of class Ic anti-arrhythmic drugs for rhythm control for AF [11]. Significant ventric‐ ular hypertrophy or dysfunction increases the risk of proarrhythmia associated with class Ic and most class III anti-arrhythmic drugs. In such patients amidodarone is the preferred agent [11]. However, when medications for heart rate control such as beta blockers and nondihydropridine calcium channel blockers are used, their potential to depress LV systolic function and cause clinical deterioration should be kept in mind. Specific considerations about drug choices to control heart-rate are depicted in the following specific drug classes section. Specific considerations about warfarin treatment are depicted in the following specific drug

prevent skeletal muscle mass loss (i.e. sarcopenia).

**2.3. Atrial fibrillation**

classes section.

#### **2.1. Hypertension**

Hypertension is not uncommon in patients with AS and approximately 40 percent of patients have hypertension [2]. In patients with concomitant hypertension and AS, left ventricular afterload is elevated as result of the "double-load" of increased systemic vascular resistance and valve stenosis [3]. For this reason reducing afterload may improve the degree of valvular opening and stroke volume. Therefore treatment of hypertension is recommended in patients with asymptomatic AS by many clinicians. There are a few studies assessing the safety of antihypertensive treatment in patients with AS [4]. Angiotensin converting enzyme (ACE) inhibitors seem to be well tolerated both in patients with mild-to-moderate and severe AS [5, 6]. Recently, ACE inhibitors and angiotensin receptor blockers (ARBs) were reported to be associated with improved survival and reduced cardiovascular (CV) events [7]. On the other hand, the recently published Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study reported an increased risk of CV events associated with antihypertensive treatment. However, this study was not a dedicated study on HT in AS and the only type of anti-hypertensive drug group associated with increased CV events was alpha-blockers [4]. This finding is in accord‐ ance with the results of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [8]. Blood pressure lowering agents should be initiated at low doses and gradually titrated with frequent monitoring, especially in older patients with increased risk of falls and osteoporotic fractures. Especially older patients given alpha blockers or diuretics should be informed about orthostatic hypotension to avoid falls.

#### **2.2. Coronary artery disease**

Coronary artery disease (CAD) is rather common in patients with AS and evaluation regarding conventional atherosclerotic risk factors is recommended in these patients. Tobacco use should be discouraged. The current US Preventive Services Task Force recommends usage of low dose aspirin for primary prevention when CV risk outweighs the risk of gastrointestinal hemor‐ rhage in men between 45-79 years and when the risk of ischemic stroke outweighs the risk of gastrointestinal hemorrhage in women between 55-79 years [9]. It is also stated that the current evidence is insufficient to assess the balance of benefits and harms of aspirin in patients 80 years or older [9]. A recently published article reported the outcomes of percutaneous coronary intervention (PCI) in patients with concomitant severe AS and CAD [10]. In this well-matched trial, 30-day mortality after PCI was similar in patients with and without severe AS. In this study AS patients with low EF (≤30) and high Society of Thoracic Surgeons score (≥10) were associated with significantly increased 30-day mortality after PCI. Patients with mild AS should not be restricted from physical activity. Patients with severe AS should avoid compet‐ itive or vigorous activities that involve high dynamic and static muscular demands, although other forms of exercise are safe. Exercise may also improve functional capacity and may prevent skeletal muscle mass loss (i.e. sarcopenia).

#### **2.3. Atrial fibrillation**

and afterload. In patients with severe AS, drugs that reduce preload or afterload should be used with caution because any medical treatment option used in these patients may worsen the patients' conditions. Meanwhile, there is a growing body of evidence about TAVI which is currently used mainly in patients with multi-morbidity and high surgical risk. In patients with rheumatic valve disease, rheumatic fever prophylaxis is strongly recommended to prevent repetitive valve scarring [1]. It has been hypothesized that some of the risk factors and pathophysiologic mechanisms in atherosclerosis play an important role in the development of calcific AS. Therefore theoretically, anti-inflammatory and anti-proliferative agents might slow or prevent disease progression. Because patients with severe AS are mostly older adults, some important and common issues like kidney insufficiency (KI), autonomic dysfunction, conduction disturbances, propensity to falls, and osteoporosis should always be kept in mind

Hypertension is not uncommon in patients with AS and approximately 40 percent of patients have hypertension [2]. In patients with concomitant hypertension and AS, left ventricular afterload is elevated as result of the "double-load" of increased systemic vascular resistance and valve stenosis [3]. For this reason reducing afterload may improve the degree of valvular opening and stroke volume. Therefore treatment of hypertension is recommended in patients with asymptomatic AS by many clinicians. There are a few studies assessing the safety of antihypertensive treatment in patients with AS [4]. Angiotensin converting enzyme (ACE) inhibitors seem to be well tolerated both in patients with mild-to-moderate and severe AS [5, 6]. Recently, ACE inhibitors and angiotensin receptor blockers (ARBs) were reported to be associated with improved survival and reduced cardiovascular (CV) events [7]. On the other hand, the recently published Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study reported an increased risk of CV events associated with antihypertensive treatment. However, this study was not a dedicated study on HT in AS and the only type of anti-hypertensive drug group associated with increased CV events was alpha-blockers [4]. This finding is in accord‐ ance with the results of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [8]. Blood pressure lowering agents should be initiated at low doses and gradually titrated with frequent monitoring, especially in older patients with increased risk of falls and osteoporotic fractures. Especially older patients given alpha blockers or diuretics should be

Coronary artery disease (CAD) is rather common in patients with AS and evaluation regarding conventional atherosclerotic risk factors is recommended in these patients. Tobacco use should be discouraged. The current US Preventive Services Task Force recommends usage of low dose aspirin for primary prevention when CV risk outweighs the risk of gastrointestinal hemor‐ rhage in men between 45-79 years and when the risk of ischemic stroke outweighs the risk of gastrointestinal hemorrhage in women between 55-79 years [9]. It is also stated that the current evidence is insufficient to assess the balance of benefits and harms of aspirin in patients 80

in the medical management of these patients.

informed about orthostatic hypotension to avoid falls.

**2.2. Coronary artery disease**

**2.1. Hypertension**

380 Calcific Aortic Valve Disease

Valvular heart disease, particularly left-sided valvular lesions precipitate the development of atrial fibrillation (AF). Although it has been less well studied in AS compared to mitral valve disorders, AF often complicates uncorrected aortic valve disorders [11]. In the recently published SEAS study, baseline or prior was present in approximately 9% of patients with mild-to-moderate AS [12]. The study excluded the patients with baseline and prior AF and sought the effect of simvastatin plus ezetimibe on new-onset AF. During an average of 4.3±0.8 years of follow up, 6% of the patients developed AF and the rate was similar between the simvastatin plus ezetimibe and placebo groups. In this study, increased age and left ventricular mass index were independent predictors of new onset AF. New-onset AF was associated with two-fold higher risk of AF related outcomes and four-fold higher risk of nonfatal nonhemor‐ rhagic stroke. In a previously asymptomatic patient, new onset AF may cause overt heart failure symptoms due to the noncompliant left ventricle which is associated with a relative shift of left ventricular filling to the later part of diastole with a greater dependence upon atrial contraction. Similar treatment approaches for AF in patients with AS can be used as in patients without AS. Heart rate control is important to enable an adequate diastolic filling time. Although guidelines generally recommend rate control over rhythm control in patients with AS, there is a trend towards preference of rhythm control with the benefits of early rhythm control and options of left atrial catheter ablation and new anti-arrhythmic drugs [13, 14]. Within the current ECS guidelines on AF, severe AS is stated as a contraindication for verkalant usage [14]. It is also important to screen for coronary disease in patients with AS before the initiation of class Ic anti-arrhythmic drugs for rhythm control for AF [11]. Significant ventric‐ ular hypertrophy or dysfunction increases the risk of proarrhythmia associated with class Ic and most class III anti-arrhythmic drugs. In such patients amidodarone is the preferred agent [11]. However, when medications for heart rate control such as beta blockers and nondihydropridine calcium channel blockers are used, their potential to depress LV systolic function and cause clinical deterioration should be kept in mind. Specific considerations about drug choices to control heart-rate are depicted in the following specific drug classes section. Specific considerations about warfarin treatment are depicted in the following specific drug classes section.

### **2.4. Heart failure**

In patients with severe AS, aortic valve replacement (AVR) is indicated when symptomatic heart failure develops. Even when severe AS is present, transvalvular pressure gradients may not be found high because of left ventricular systolic dysfunction. Reduced EF is associated with worse clinical outcome. A recent study compared the outcomes of severe AS patients with an EF of ≤30 or >30 who was followed with medical treatment or underwent TAVI [15]. While an EF of ≤30 was associated with worse prognosis in the medically treatment group, TAVI was associated with an improvement in EF and functional class and patients who underwent TAVI had better prognoses irrespective of their baseline EF. When patients with mild or moderate AS have HF, there is generally other causes of HF like coronary heart disease and medical therapy of HF is preferable to AVR. Vasodilator therapy and beta blockers may be started with careful dose titration and closely monitoring. Volume status of patients should also be determined and followed up carefully [3, 16].

which is not specific for malnutrition. Wang et al demonstrated the correlation of fetuin-A, which has recently been identified as an important circulating inhibitor of calcification, with

Current Treatment Options in Aortic Stenosis

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383

There is also data indicating undernutrition is associated with worse outcomes after cardiac valve surgery. In a retrospective study, impact of BMI and albumin levels on morbidity and mortality after cardiac surgery was assessed in 5168 patients undergoing coronary artery bypass or valve operations [25]. Preoperative low albumin (<2.5 g/dl) and low BMI (<20 kg/m2) were independently associated with increased postoperative mortality. Tepsuwan et al. assessed the impact of cardiac cachexia retrospectively in 353 patients who underwent cardiac valve surgery [26]. The study population was relatively young and mitral stenosis and mitral regurgitation were the most frequent valve disorders. They found significant association between cachexia and worse New York Heart Association functional class and worse postop‐ erative outcomes. Thourani et al investigated the impact of body mass index (BMI) on outcomes after cardiac valve surgery in 4247 patients [27]. Most of the procedures were isolated AVR (47.2%). They showed increased in-hospital and all-cause long-term mortality in patients with a BMI of less than 25 compared to patients with a BMI of 25-35 or higher than 35. In this

Patients with AS may suffer from dietary restriction due to reduced physical capacity and depressive mood. When concomitant mesenteric vessel atherosclerosis is present, abdominal angina may cause avoidance from eating. All these factors may render these patients suscep‐ tible to infectious diseases, osteoporosis, skeletal muscle loss (i.e. sarcopenia) and fall related fractures. Unfortunately, there is no study evaluating the role of nutritional intervention, which may potentially improve muscle and bone mass, muscle functions, and functional

Later-life depression (LLD) is associated with disability and poor outcomes [28]. Among various chronic medical conditions, cardiac disease and arthritis are the most commonly ones associated with depression [29]. Underlying medical problems may affect the prognosis of depression and depression may decrease compliance to medical treatment thus delay recovery from medical illnesses [28]. The importance of screening for depression in patients with heart disease is well established, but identifying patients with depression may be difficult. Organic somatic symptoms possibly unrelated to mood may increase the score on depression scales and patients with depression may deny and do not report their depressive symptoms [28]. Furthermore, there are many shared symptoms of heart disease and depression like insomnia, fatigue, shortness of breath, weight loss, palpitations, and exercise intolerance. Vascular depression is associated with late onset, treatment-resistant symptoms, vascular disease, vascular risk factors, and extensive cerebrovascular lesions [28]. Although there is no specific data about the association of vascular depression and AS in the elderly, atherosclerosis has

Beta blocker treatment, which is being used commonly in patients with heart disease, may potentially precipitate depression. Although there is conflicting data about the association of

the presence and degree of malnutrition in patients on peritoneal dialysis [24].

study, no laboratory or clinical data about nutritional status was reported.

capacity, on clinical outcomes in patients with AS.

pivotal role in the pathogenesis of both.

**2.7. Depression**

Invasive hemodynamic monitoring in the intensive care unit should be considered for decompensated patients with severe AS [3]. Nitroprusside rapidly and markedly improves cardiac function in patients with decompensated HF due to severe left ventricular systolic dysfunction and severe AS. It provides a safe and effective bridge to AVR or oral vasodilator therapy in these critically ill patients [17].

Phosphodiesterase type 5 inhibition had beneficial effects on pressure overload in preclinical models and a preliminary study of oral sildenafil in 20 patients with severe symptomatic AS showed that it was associated a reduction in systemic and pulmonary vascular resistance and pulmonary artery and wedge pressures [18]. Although sildenafil was also resulted in 11% decrease in mean systemic arterial pressure, it was not associated with any episodes of symptomatic hypotension.

#### **2.5. Metabolic syndrome**

Metabolic syndrome (MS) is a worldwide problem with increased risk of CV events. The results of Multi-Ethnic Study of Atherosclerosis (MESA) and another recent prospective trial suggest that MS is independently associated with progression of AS, particularly in younger individ‐ uals [19, 20]. Although these findings need to be confirmed in larger studies, studies assessing the effects of lifestyle modification and reduction of insulin resistance on the incidence and progression rate of AS could be of value.

#### **2.6. Malnutrition**

Malnutrition is a common and important health problem in the older adults and being underweight is associated with a worse prognosis than being overweight in this population [21]. Association of malnutrition and heart valve disorders is rarely reported in the literature. Otto et al reported increased long-term mortality independently associated with cachexia in 674 elderly patients who underwent balloon aortic valvuloplasty for AS [22]. Another obser‐ vational study showed association of heart valve calcification with malnutrition in patients on hemodialysis [23]. In this study evaluation of malnutrition was done only with albumin level which is not specific for malnutrition. Wang et al demonstrated the correlation of fetuin-A, which has recently been identified as an important circulating inhibitor of calcification, with the presence and degree of malnutrition in patients on peritoneal dialysis [24].

There is also data indicating undernutrition is associated with worse outcomes after cardiac valve surgery. In a retrospective study, impact of BMI and albumin levels on morbidity and mortality after cardiac surgery was assessed in 5168 patients undergoing coronary artery bypass or valve operations [25]. Preoperative low albumin (<2.5 g/dl) and low BMI (<20 kg/m2) were independently associated with increased postoperative mortality. Tepsuwan et al. assessed the impact of cardiac cachexia retrospectively in 353 patients who underwent cardiac valve surgery [26]. The study population was relatively young and mitral stenosis and mitral regurgitation were the most frequent valve disorders. They found significant association between cachexia and worse New York Heart Association functional class and worse postop‐ erative outcomes. Thourani et al investigated the impact of body mass index (BMI) on outcomes after cardiac valve surgery in 4247 patients [27]. Most of the procedures were isolated AVR (47.2%). They showed increased in-hospital and all-cause long-term mortality in patients with a BMI of less than 25 compared to patients with a BMI of 25-35 or higher than 35. In this study, no laboratory or clinical data about nutritional status was reported.

Patients with AS may suffer from dietary restriction due to reduced physical capacity and depressive mood. When concomitant mesenteric vessel atherosclerosis is present, abdominal angina may cause avoidance from eating. All these factors may render these patients suscep‐ tible to infectious diseases, osteoporosis, skeletal muscle loss (i.e. sarcopenia) and fall related fractures. Unfortunately, there is no study evaluating the role of nutritional intervention, which may potentially improve muscle and bone mass, muscle functions, and functional capacity, on clinical outcomes in patients with AS.

#### **2.7. Depression**

**2.4. Heart failure**

382 Calcific Aortic Valve Disease

determined and followed up carefully [3, 16].

therapy in these critically ill patients [17].

progression rate of AS could be of value.

symptomatic hypotension.

**2.5. Metabolic syndrome**

**2.6. Malnutrition**

In patients with severe AS, aortic valve replacement (AVR) is indicated when symptomatic heart failure develops. Even when severe AS is present, transvalvular pressure gradients may not be found high because of left ventricular systolic dysfunction. Reduced EF is associated with worse clinical outcome. A recent study compared the outcomes of severe AS patients with an EF of ≤30 or >30 who was followed with medical treatment or underwent TAVI [15]. While an EF of ≤30 was associated with worse prognosis in the medically treatment group, TAVI was associated with an improvement in EF and functional class and patients who underwent TAVI had better prognoses irrespective of their baseline EF. When patients with mild or moderate AS have HF, there is generally other causes of HF like coronary heart disease and medical therapy of HF is preferable to AVR. Vasodilator therapy and beta blockers may be started with careful dose titration and closely monitoring. Volume status of patients should also be

Invasive hemodynamic monitoring in the intensive care unit should be considered for decompensated patients with severe AS [3]. Nitroprusside rapidly and markedly improves cardiac function in patients with decompensated HF due to severe left ventricular systolic dysfunction and severe AS. It provides a safe and effective bridge to AVR or oral vasodilator

Phosphodiesterase type 5 inhibition had beneficial effects on pressure overload in preclinical models and a preliminary study of oral sildenafil in 20 patients with severe symptomatic AS showed that it was associated a reduction in systemic and pulmonary vascular resistance and pulmonary artery and wedge pressures [18]. Although sildenafil was also resulted in 11% decrease in mean systemic arterial pressure, it was not associated with any episodes of

Metabolic syndrome (MS) is a worldwide problem with increased risk of CV events. The results of Multi-Ethnic Study of Atherosclerosis (MESA) and another recent prospective trial suggest that MS is independently associated with progression of AS, particularly in younger individ‐ uals [19, 20]. Although these findings need to be confirmed in larger studies, studies assessing the effects of lifestyle modification and reduction of insulin resistance on the incidence and

Malnutrition is a common and important health problem in the older adults and being underweight is associated with a worse prognosis than being overweight in this population [21]. Association of malnutrition and heart valve disorders is rarely reported in the literature. Otto et al reported increased long-term mortality independently associated with cachexia in 674 elderly patients who underwent balloon aortic valvuloplasty for AS [22]. Another obser‐ vational study showed association of heart valve calcification with malnutrition in patients on hemodialysis [23]. In this study evaluation of malnutrition was done only with albumin level Later-life depression (LLD) is associated with disability and poor outcomes [28]. Among various chronic medical conditions, cardiac disease and arthritis are the most commonly ones associated with depression [29]. Underlying medical problems may affect the prognosis of depression and depression may decrease compliance to medical treatment thus delay recovery from medical illnesses [28]. The importance of screening for depression in patients with heart disease is well established, but identifying patients with depression may be difficult. Organic somatic symptoms possibly unrelated to mood may increase the score on depression scales and patients with depression may deny and do not report their depressive symptoms [28]. Furthermore, there are many shared symptoms of heart disease and depression like insomnia, fatigue, shortness of breath, weight loss, palpitations, and exercise intolerance. Vascular depression is associated with late onset, treatment-resistant symptoms, vascular disease, vascular risk factors, and extensive cerebrovascular lesions [28]. Although there is no specific data about the association of vascular depression and AS in the elderly, atherosclerosis has pivotal role in the pathogenesis of both.

Beta blocker treatment, which is being used commonly in patients with heart disease, may potentially precipitate depression. Although there is conflicting data about the association of beta blockers and depression, and individual susceptibility to depression may be important, patients with risk factors for depression should be followed up in terms of development of depression [30]. Lipophilic beta blockers like propranolol, timolol, pindolol, metoprolol, carvedilol and nebivolol are more strongly associated with depression than hydrophilic beta blockers like atenolol, nadolol, practolol and sotalol [30]. When there are strong indications like CAD and CHF for beta blocker treatment are present, depression should not be considered as an absolute contraindication. SSRI are among the most commonly used medications in the treatment of depression. There is some data that indicate use of SSRI in patients with CAD and depression may improve CV outcomes [31]. Because treatment with SSRI may reduce platelet functions as severe AS do, bleeding complications of surgical procedures may be increased in patients with severe AS under SSRI treatment. Sodium levels should be monitored in older patients under SSRI treatment, especially if concomitant diuretic use is present because both of them may be associated with hyponatremia.

**2.9. Perioperative medical treatment for non-cardiac surgery**

recommended to stop them before the surgery.

Renal insufficiency (defined as a preoperative serum creatinine of greater than 2 mg/dL)

It has been considered that the valve lesion in calcific AS might share similar pathogenetic mechanisms with atherosclerosis and progression may be related to known atherosclerotic risk factors [39]. Statins are now well established in the primary and secondary prevention of CAD. Several studies have suggested that statins may cause regression of CAD and reduce the calcific volume of coronary plaques [40]. In accordance with this finding, presence and progression of aortic valve calcification are reported to be increased in patients with a serum

While some earlier studies indicate that statin therapy is associated with a slower rate of hemodynamic progression of AS [42-45], some more recent trials have inconsistent results of different statin preparations on the progression of AS [46-49]. SALTIRE (Scottish aortic stenosis

**Table 1.** Clinical risk factors for perioperative cardiovascular complications

History of ischemic heart disease

History of cerebrovascular disease

**2.10. Specific drug classes**

LDL cholesterol >130 mg/dL [41].

Diabetes Mellitus

*2.10.1. Statins*

History of compensated or prior heart failure

Beta blocker treatment is recommended in patients with CAD or more than one of the cardiac risk factors which are listed in Table 1 [37]. However, the multicenter POISE trial showed an increased rate of death associated with perioperative beta blocker treatment despite a signif‐ icant reduction in the primary composite endpoint of CV death, nonfatal MI or nonfatal cardiac arrest [38]. This trial resulted in the following recommendation in the current guidelines: "Routine administration of high-dose beta blockers in the absence of dose titration is not useful and may be harmful to patients not currently taking beta blockers who are undergoing noncardiac surgery" [37]. Titration of beta blockers to heart rate and blood pressure is recommended if the patient will undergo high- or intermediate-risk surgery [37]. Like it is recommended for many drug classes, starting beta blockers in low doses and careful titration is important in elderly patients who are at increased risk for bradycardia and hypotension. The role of beta blockers in intermediate- and low-risk patients is not well known. Optimal type, dose, timing, duration, and titration of beta blockers are also lacking [37]. Withdrawal of beta blockers in the preoperative period may be associated with adverse events and should not be performed unless necessary. Metformin and renin-angiotensin-aldosterone system (RAS) blockers increase the risk of postoperative lactic acidosis and KI respectively and it is

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385

#### **2.8. Perioperative medical treatment**

Careful manipulation of hemodynamics in the perioperative period is crucial in patients with AS [32]. Maintaining sinus rhythm, a relatively slow heart rate, and adequate preload and afterload are important goals to minimize the perioperative CV risk [32]. Ideal heart rate is between 60 and 70 beats per minute and bradicardia should be avoided. Careful assessment of hydration status and providing adequate hydration is also important to maintain preload which these patients are dependent upon. Careful monitoring of the arterial blood and central venous pressures is also important. Hypotension should be controlled with pure α agonists because they do not cause tachycardia. Routine antibiotic prophylaxis is not recommended unless the patient has a previous history of infective endocarditis [33]. Severe AS may be associated with markedly reduced platelet functions. One recent double-blind placebo controlled trial investigated effects of infusion of desmopressin (0.3 μg/kg) on platelet functions and postoperative blood loss [34]. The authors recommend assessing of platelet functions in the preoperative period in patients with severe AS and usage of desmopressin to avoid increased blood loss in patients with reduced platelet functions.

Delirium is rather common after cardiac valve surgery and is independently associated with increased risk of short and long term morbidity and mortality [35, 36]. Hyperactive delirium is easily recognized because of agitation, hallucinations and delusions. Routine assessment of attention and orientation is crucial to detect hypoactive delirium because it is easily and frequently overlooked. Providing adequate volume status, following up of renal functions and electrolyte levels, controlling postoperative pain and rational selection of medications may reduce the risk of delirium. Many drugs like anticholinergics, antihistaminics, narcotics and central acting drugs may precipitate delirium. Maldonado et al. investigated the effects of postoperative sedation on the development of delirium in patients undergoing cardiac valve surgery [35]. In this open label study, dexmedetomidine was associated with a significantly decreased rate of delirium with compared to propofol and midazolam (rates of delirium 3%, 50% and 50% respectively).

#### **2.9. Perioperative medical treatment for non-cardiac surgery**

Beta blocker treatment is recommended in patients with CAD or more than one of the cardiac risk factors which are listed in Table 1 [37]. However, the multicenter POISE trial showed an increased rate of death associated with perioperative beta blocker treatment despite a signif‐ icant reduction in the primary composite endpoint of CV death, nonfatal MI or nonfatal cardiac arrest [38]. This trial resulted in the following recommendation in the current guidelines: "Routine administration of high-dose beta blockers in the absence of dose titration is not useful and may be harmful to patients not currently taking beta blockers who are undergoing noncardiac surgery" [37]. Titration of beta blockers to heart rate and blood pressure is recommended if the patient will undergo high- or intermediate-risk surgery [37]. Like it is recommended for many drug classes, starting beta blockers in low doses and careful titration is important in elderly patients who are at increased risk for bradycardia and hypotension. The role of beta blockers in intermediate- and low-risk patients is not well known. Optimal type, dose, timing, duration, and titration of beta blockers are also lacking [37]. Withdrawal of beta blockers in the preoperative period may be associated with adverse events and should not be performed unless necessary. Metformin and renin-angiotensin-aldosterone system (RAS) blockers increase the risk of postoperative lactic acidosis and KI respectively and it is recommended to stop them before the surgery.


**Table 1.** Clinical risk factors for perioperative cardiovascular complications

#### **2.10. Specific drug classes**

#### *2.10.1. Statins*

beta blockers and depression, and individual susceptibility to depression may be important, patients with risk factors for depression should be followed up in terms of development of depression [30]. Lipophilic beta blockers like propranolol, timolol, pindolol, metoprolol, carvedilol and nebivolol are more strongly associated with depression than hydrophilic beta blockers like atenolol, nadolol, practolol and sotalol [30]. When there are strong indications like CAD and CHF for beta blocker treatment are present, depression should not be considered as an absolute contraindication. SSRI are among the most commonly used medications in the treatment of depression. There is some data that indicate use of SSRI in patients with CAD and depression may improve CV outcomes [31]. Because treatment with SSRI may reduce platelet functions as severe AS do, bleeding complications of surgical procedures may be increased in patients with severe AS under SSRI treatment. Sodium levels should be monitored in older patients under SSRI treatment, especially if concomitant diuretic use is present because both

Careful manipulation of hemodynamics in the perioperative period is crucial in patients with AS [32]. Maintaining sinus rhythm, a relatively slow heart rate, and adequate preload and afterload are important goals to minimize the perioperative CV risk [32]. Ideal heart rate is between 60 and 70 beats per minute and bradicardia should be avoided. Careful assessment of hydration status and providing adequate hydration is also important to maintain preload which these patients are dependent upon. Careful monitoring of the arterial blood and central venous pressures is also important. Hypotension should be controlled with pure α agonists because they do not cause tachycardia. Routine antibiotic prophylaxis is not recommended unless the patient has a previous history of infective endocarditis [33]. Severe AS may be associated with markedly reduced platelet functions. One recent double-blind placebo controlled trial investigated effects of infusion of desmopressin (0.3 μg/kg) on platelet functions and postoperative blood loss [34]. The authors recommend assessing of platelet functions in the preoperative period in patients with severe AS and usage of desmopressin to

Delirium is rather common after cardiac valve surgery and is independently associated with increased risk of short and long term morbidity and mortality [35, 36]. Hyperactive delirium is easily recognized because of agitation, hallucinations and delusions. Routine assessment of attention and orientation is crucial to detect hypoactive delirium because it is easily and frequently overlooked. Providing adequate volume status, following up of renal functions and electrolyte levels, controlling postoperative pain and rational selection of medications may reduce the risk of delirium. Many drugs like anticholinergics, antihistaminics, narcotics and central acting drugs may precipitate delirium. Maldonado et al. investigated the effects of postoperative sedation on the development of delirium in patients undergoing cardiac valve surgery [35]. In this open label study, dexmedetomidine was associated with a significantly decreased rate of delirium with compared to propofol and midazolam (rates of delirium 3%,

avoid increased blood loss in patients with reduced platelet functions.

of them may be associated with hyponatremia.

**2.8. Perioperative medical treatment**

384 Calcific Aortic Valve Disease

50% and 50% respectively).

It has been considered that the valve lesion in calcific AS might share similar pathogenetic mechanisms with atherosclerosis and progression may be related to known atherosclerotic risk factors [39]. Statins are now well established in the primary and secondary prevention of CAD. Several studies have suggested that statins may cause regression of CAD and reduce the calcific volume of coronary plaques [40]. In accordance with this finding, presence and progression of aortic valve calcification are reported to be increased in patients with a serum LDL cholesterol >130 mg/dL [41].

While some earlier studies indicate that statin therapy is associated with a slower rate of hemodynamic progression of AS [42-45], some more recent trials have inconsistent results of different statin preparations on the progression of AS [46-49]. SALTIRE (Scottish aortic stenosis and lipid lowering therapy, impact on regression) trial was the first double blind randomized controlled trial of lipid lowering treatment in patients with calcific AS. This trial of 155 adults with calcific AS showed that, although atorvastatin 80 mg daily, more than halved serum LDL cholesterol concentrations, there was no difference in the rate of increase in aortic jet velocity or of progression of aortic valve calcification as measured by Doppler echocardiography or helical computed tomography [46]. The prospective open-label RAAVE study (The Rosuvas‐ tatin Affecting Aortic Valve Endothelium) comprised of 121 consecutive patients with moderate to severe AS. Treatment with rosuvastatin 20 mg was given when LDL-cholesterol was greater than 130 mg/dL and no statin therapy was given when LDL-cholesterol was less than 130 mg/dL. Patients treated with rosuvastatin had significantly attenuated rates of deterioration in mean aortic valve area and aortic jet velocity compared to patients who did not receive rosuvastatin [47]. The prospective and placebo controlled SEAS trial sought the effect of statins on calcific AS. In this study, 1873 adults (mean age 68) with mild-to-moderate AS were enrolled and randomly assigned to treatment with simvastatin plus ezetimibe or placebo [48]. At median follow-up of 52 months there were no differences in the peak aortic jet velocity or valve area noted between the 2 groups. There was also no difference in CV death, aortic valve replacement, non-fatal myocardial infarction, hospitalized unstable angina pectoris, and heart failure due to progression of AS, coronary artery bypass grafting, percu‐ taneous coronary interventions, or non-hemorrhagic stroke. Although there were fewer ischemic events in the treatment group, this difference was only due to a lower rate of coronary bypass grafting at the time of aortic valve surgery so the clinical relevance of this finding is unclear. SEAS study results show that the effect of statin therapy on disease process does not provide convincing evidence [48]. The investigators of SEAS study recently reported the results of simvastatin plus ezetimibe on new-onset AF in 1421 patients with asymptomatic mild-to-moderate AS [6]. The rate of new-onset AF was similar in the simvastatin plus ezetimibe group compared to placebo group. Aortic Stenosis Progression Observation (ASTRONOMER) is the most recently published trial regarding effect of statins on AS. This double-blind prospective trial randomized 269 younger asymptomatic patients with mild tomoderate AS with no indications for lipid-lowering agents to rosuvastatin 40 mg daily (134 patients) or placebo (135 patients). Unlike earlier trials in which bicuspid aortic valve was rare, a bicuspid valve was present in nearly half of the subjects in this study. After a mean followup of 3.5 years, there were no significant differences in the transaortic gradient or aortic valve area in the rosuvastatin group compared to placebo [49].

type 1 receptor in the cardiomyocytes and therefore decrease systolic and diastolic dysfunction in patients with left ventricular hypertrophy and AS [51]. For these reasons ACE inhibitors may have a role in the management of patients with AS. Two preliminary observational studies examined the effect of ACE inhibitors in patients with AS in preventing further changes in the valve leaflets. Rosenhek et al showed that hemodynamic progression of AS did not occur in 211 patients with moderate AS after at least 6 months of treatment with the ACE inhibitors. Furthermore, the presence of hypertension did not appear to influence the outcome [44]. Another retrospective study by Obrien et al of 123 patients evaluated the aortic valve calcium score by electron beam computed tomographic scans. The study showed that ACE inhibitor treatment was associated with a 71% reduction in the progression of aortic valve calcification in 123 patients with AS [52]. At the present, there are no published randomized prospective studies using ACE inhibitors to delay the progression of calcific AS. Some potential targets for therapy in AS such as the pathways involved in inflammation and tissue calcification have not yet been studied. ACE inhibitors have beneficial effects on ventricular systolic and diastolic functions and are well tolerated, increase exercise capacity, and reduce dyspnea in sympto‐ matic patients with mild to moderate AS [6]. ACE inhibitors may provide symptomatic relief when patients with severe AS who are not good candidates for surgery develop symptoms of left heart failure. It should also be kept in mind that ACE inhibitors may increase the trans‐ valvular gradient by reducing afterload or preload and cause sudden clinical deterioration in patients with severe AS. In older adults, ACE inhibitors should be initiated at low doses and gradually increased to avoid hypotension and fall related fractures. Because elderly patients with severe AS generally have extensive atherosclerosis, before initiation of ACE inhibitors

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bilateral renal artery stenosis should be considered and investigated if suspected.

Angiotensin receptor blockers have similar hemodynamic effects like ACE inhibitors. A recently published observational study indicates that both ACE inhibitors and ARBs are associated with lower mortality and CV events in patients with AS [7]. However, prospective and controlled studies are needed to test this finding. Although similar precautions as in ACE inhibitors should be considered when starting and maintaining ARBs, they have some benefits like less incidence of cough. Because compelling evidence does not exist for neither ACE inhibitors nor ARBs for these patients, when RAS blockage is planned ACE inhibitors may be selected in the first step and switching to ARBs may be considered if adverse effects like chronic

Beta blockers are a not part of routine medical treatment. Because beta blockers may aggravate the symptoms of HF, patients with symptoms and signs of HF are not good candidates for this treatment option. Beta blockers may be used in AS patients with angina pectoris or AF with rapid ventricular response. Because older adults are at increased risk for hypotension, bradycardia, conduction disturbances and diabetes, a close follow-up should be performed

when patients with AS are given beta blocker treatment.

*2.10.3. Angiotensin receptor blockers*

cough develop.

*2.10.4. Beta blockers*

At present, if atherosclerotic vascular disease or other indications do not coexist, statin therapy solely for AS cannot be recommended. It should be noted that effect of therapy has not been evaluated in earlier stages of the disease.

#### *2.10.2. Angiotensin converting enzyme inhibitors*

Although expression of angiotensin II has not been shown the in normal valves, sclerotic aortic valve tissues demonstrably express angiotensin II and angiotensin converting enzyme (ACE). Therefore it may contribute to valve inflammation, calcification, and disease progression [50]. It has been shown that ACE inhibitors suppress ventricular fibrosis and inhibit angiotensin II type 1 receptor in the cardiomyocytes and therefore decrease systolic and diastolic dysfunction in patients with left ventricular hypertrophy and AS [51]. For these reasons ACE inhibitors may have a role in the management of patients with AS. Two preliminary observational studies examined the effect of ACE inhibitors in patients with AS in preventing further changes in the valve leaflets. Rosenhek et al showed that hemodynamic progression of AS did not occur in 211 patients with moderate AS after at least 6 months of treatment with the ACE inhibitors. Furthermore, the presence of hypertension did not appear to influence the outcome [44]. Another retrospective study by Obrien et al of 123 patients evaluated the aortic valve calcium score by electron beam computed tomographic scans. The study showed that ACE inhibitor treatment was associated with a 71% reduction in the progression of aortic valve calcification in 123 patients with AS [52]. At the present, there are no published randomized prospective studies using ACE inhibitors to delay the progression of calcific AS. Some potential targets for therapy in AS such as the pathways involved in inflammation and tissue calcification have not yet been studied. ACE inhibitors have beneficial effects on ventricular systolic and diastolic functions and are well tolerated, increase exercise capacity, and reduce dyspnea in sympto‐ matic patients with mild to moderate AS [6]. ACE inhibitors may provide symptomatic relief when patients with severe AS who are not good candidates for surgery develop symptoms of left heart failure. It should also be kept in mind that ACE inhibitors may increase the trans‐ valvular gradient by reducing afterload or preload and cause sudden clinical deterioration in patients with severe AS. In older adults, ACE inhibitors should be initiated at low doses and gradually increased to avoid hypotension and fall related fractures. Because elderly patients with severe AS generally have extensive atherosclerosis, before initiation of ACE inhibitors bilateral renal artery stenosis should be considered and investigated if suspected.

#### *2.10.3. Angiotensin receptor blockers*

Angiotensin receptor blockers have similar hemodynamic effects like ACE inhibitors. A recently published observational study indicates that both ACE inhibitors and ARBs are associated with lower mortality and CV events in patients with AS [7]. However, prospective and controlled studies are needed to test this finding. Although similar precautions as in ACE inhibitors should be considered when starting and maintaining ARBs, they have some benefits like less incidence of cough. Because compelling evidence does not exist for neither ACE inhibitors nor ARBs for these patients, when RAS blockage is planned ACE inhibitors may be selected in the first step and switching to ARBs may be considered if adverse effects like chronic cough develop.

#### *2.10.4. Beta blockers*

and lipid lowering therapy, impact on regression) trial was the first double blind randomized controlled trial of lipid lowering treatment in patients with calcific AS. This trial of 155 adults with calcific AS showed that, although atorvastatin 80 mg daily, more than halved serum LDL cholesterol concentrations, there was no difference in the rate of increase in aortic jet velocity or of progression of aortic valve calcification as measured by Doppler echocardiography or helical computed tomography [46]. The prospective open-label RAAVE study (The Rosuvas‐ tatin Affecting Aortic Valve Endothelium) comprised of 121 consecutive patients with moderate to severe AS. Treatment with rosuvastatin 20 mg was given when LDL-cholesterol was greater than 130 mg/dL and no statin therapy was given when LDL-cholesterol was less than 130 mg/dL. Patients treated with rosuvastatin had significantly attenuated rates of deterioration in mean aortic valve area and aortic jet velocity compared to patients who did not receive rosuvastatin [47]. The prospective and placebo controlled SEAS trial sought the effect of statins on calcific AS. In this study, 1873 adults (mean age 68) with mild-to-moderate AS were enrolled and randomly assigned to treatment with simvastatin plus ezetimibe or placebo [48]. At median follow-up of 52 months there were no differences in the peak aortic jet velocity or valve area noted between the 2 groups. There was also no difference in CV death, aortic valve replacement, non-fatal myocardial infarction, hospitalized unstable angina pectoris, and heart failure due to progression of AS, coronary artery bypass grafting, percu‐ taneous coronary interventions, or non-hemorrhagic stroke. Although there were fewer ischemic events in the treatment group, this difference was only due to a lower rate of coronary bypass grafting at the time of aortic valve surgery so the clinical relevance of this finding is unclear. SEAS study results show that the effect of statin therapy on disease process does not provide convincing evidence [48]. The investigators of SEAS study recently reported the results of simvastatin plus ezetimibe on new-onset AF in 1421 patients with asymptomatic mild-to-moderate AS [6]. The rate of new-onset AF was similar in the simvastatin plus ezetimibe group compared to placebo group. Aortic Stenosis Progression Observation (ASTRONOMER) is the most recently published trial regarding effect of statins on AS. This double-blind prospective trial randomized 269 younger asymptomatic patients with mild tomoderate AS with no indications for lipid-lowering agents to rosuvastatin 40 mg daily (134 patients) or placebo (135 patients). Unlike earlier trials in which bicuspid aortic valve was rare, a bicuspid valve was present in nearly half of the subjects in this study. After a mean followup of 3.5 years, there were no significant differences in the transaortic gradient or aortic valve

area in the rosuvastatin group compared to placebo [49].

evaluated in earlier stages of the disease.

386 Calcific Aortic Valve Disease

*2.10.2. Angiotensin converting enzyme inhibitors*

At present, if atherosclerotic vascular disease or other indications do not coexist, statin therapy solely for AS cannot be recommended. It should be noted that effect of therapy has not been

Although expression of angiotensin II has not been shown the in normal valves, sclerotic aortic valve tissues demonstrably express angiotensin II and angiotensin converting enzyme (ACE). Therefore it may contribute to valve inflammation, calcification, and disease progression [50]. It has been shown that ACE inhibitors suppress ventricular fibrosis and inhibit angiotensin II

Beta blockers are a not part of routine medical treatment. Because beta blockers may aggravate the symptoms of HF, patients with symptoms and signs of HF are not good candidates for this treatment option. Beta blockers may be used in AS patients with angina pectoris or AF with rapid ventricular response. Because older adults are at increased risk for hypotension, bradycardia, conduction disturbances and diabetes, a close follow-up should be performed when patients with AS are given beta blocker treatment.

#### *2.10.5. Diuretics*

Diuretics are not indicated in patients without signs of congestion because of their potential for reducing preload, which may lead to fall in cardiac output and exacerbation in symptoms of HF. Therefore, diuretics are not first-line treatment options in hypertensive patients with severe AS without findings of congestion. Diuretics may improve symptoms of HF by reducing left ventricular end-diastolic pressure in patients with lung congestion, ascites or edema. Older patients may not excrete free water effectively, and they may more easily develop hyponatre‐ mia after diuretic treatment [53]. Thiazide diuretics cause hyponatremia more frequently than loop diuretics [54]. These older patients also have increased tendency to diuretic induced hyponatremia, because concomitant use of other medications like selective serotonin reuptake inhibitors (SSRI), which precipitate hyponatremia, is common. Because of disruption of normal circadian rhythm of antidiuretic hormone, nocturia is frequently seen in elderly patients and may be bothersome and increase the risk of falls when evening or night doses of diuretics are used [55]. Administration of diuretics in earlier hours of the day may be safer. Patients with urgency incontinence may need urinary anti-cholinergics under diuretic treatment to avoid urgency induced falls and significant physical exertion. Diuretics also lead to orthostatic hypotension by inducing volume depletion. Because falls are more frequent and are associated with great morbidity and mortality in these older patients, monitoring of blood pressure at home and avoidance of hypotension is crucial.

mycin, erythromycin, amiodarone, itraconazole, cyclosporine, verapamil, and quinidine can increase serum digoxin concentrations [57]. Digoxin should not be used in patients with severe AS and sinus rhythm. Digoxin may be used to reduce the ventricular rate in patients with AF and a rapid ventricular rate especially when hemodynamic deterioration is present. When these harms are taken into consideration, should be used with caution as an adjunctive agent for heart rate control. Alternatively, beta blockers, which are associated with improved survival in patients with HF and may effectively control heart rate alone, may be used as first line agents in these patients. However, when hypotension and significant HF signs are present,

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Although published data regarding anti-hypertensive drugs in patients with AS is limited, calcium channel blockers like amlodipine do not appear to depress LV function and may be safe to use in patients with AS. Non-dihydropridine agents like diltiazem and verapamil may

Peripheral alpha blocker use may possibly lead to hypotension or syncope, decreased coronary perfusion due to reduced afterload and should generally be avoided. Alpha blockers are listed among the PIMs in the recent Beers criteria and routine use for the treatment of hypertension is not recommended [58]. Alpha blockers are also listed among the PIMs in patients with a

Warfarin treatment is generally recommended in patients with AS and AF to decrease the incidence of stroke and systemic arterial embolism. Assessing the risk of embolism associ‐ ated with AF and bleeding associated with warfarin treatment should be carefully per‐ formed. It is very important to educate the patient and his/her relatives about the benefits and risks of warfarin treatment and the details of follow-up. Integration of the patients' relatives in the treatment plan is crucial especially in older adults with significant cogni‐ tive problems. A meta-analysis which was published in 2007 indicated that aspirin was associated with a 22% reduction in the rate of stroke, while warfarin was associated with 64% reduction [59]. Because warfarin is associated with a significantly lower risk of stroke than aspirin, simply prescribing aspirin without discussing the benefits and risks of war‐ farin treatment with the patients and their relatives would be therapeutic nihilism. Al‐ though there are newer anticoagulant medications like dabigatran which do not require therapeutic monitoring, we need more data especially in the older individuals in order to prescribe them instead of warfarin. For instance, dabigatran is associated with greater risk of bleeding than with warfarin in patients ≥ 75 years and efficacy and safety is not known

influence left ventricular systolic functions and may cause clinical deterioration.

digoxin may be a better agent for symptomatic treatment.

in patients with a creatinine clearance below 30 ml/min [58].

*2.10.8. Calcium channel blockers*

*2.10.9. Alpha blockers*

history of syncope [58].

*2.10.10. Warfarin*

#### *2.10.6. Nitrates*

Nitrates may be used in symptomatic treatment of angina pectoris in patients with severe AS. They should be initiated at low doses and gradually increased to avoid sudden hypotension. Concomitant use of phosphodiesterase inhibitors for erectile dysfunction should be avoided to prevent substantial hypotension.

#### *2.10.7. Digoxin*

Digoxin has a narrow therapeutic index and the risk of adverse events associated with it may be more common in older patients [56]. Digoxin levels may be increased in older patients with impaired kidney functions. Because creatinine levels may be normal or minimally increased in older adults with impaired kidney functions when significant loss of muscle mass (i.e. sarcopenia) is present. It is recommended in the recent ACC/AHA guideline that an initial dose of 0.125 mg daily or every other day is chosen if the patient is older than 70 years old, has impaired kidney function, or has a low lean body mass [57]. Digoxin above 0.125 mg/d is also listed among the potentially inappropriate medications (PIMs) list in the recent Beers criteria [58]. Because digoxin concentrations above 1 ng/ml are not associated with better clinical outcomes and may adversely increase morbidity and mortality, a target digoxin concentration of 0.5-1 ng/ml is recommended despite conventional therapeutic serum concentration is defined as 0.8-2 ng/ml [56, 57]. When there is concomitant hypokalemia, hypomagnesemia or hypothyroidism, digoxin toxicity may occur in lower concentrations [57]. Older patients under digoxin treatment may develop adverse effects like anorexia, nausea, vomiting, confusion, visual problems, and rhythm and conduction disturbances more commonly [56]. Clarithro‐ mycin, erythromycin, amiodarone, itraconazole, cyclosporine, verapamil, and quinidine can increase serum digoxin concentrations [57]. Digoxin should not be used in patients with severe AS and sinus rhythm. Digoxin may be used to reduce the ventricular rate in patients with AF and a rapid ventricular rate especially when hemodynamic deterioration is present. When these harms are taken into consideration, should be used with caution as an adjunctive agent for heart rate control. Alternatively, beta blockers, which are associated with improved survival in patients with HF and may effectively control heart rate alone, may be used as first line agents in these patients. However, when hypotension and significant HF signs are present, digoxin may be a better agent for symptomatic treatment.

#### *2.10.8. Calcium channel blockers*

Although published data regarding anti-hypertensive drugs in patients with AS is limited, calcium channel blockers like amlodipine do not appear to depress LV function and may be safe to use in patients with AS. Non-dihydropridine agents like diltiazem and verapamil may influence left ventricular systolic functions and may cause clinical deterioration.

#### *2.10.9. Alpha blockers*

*2.10.5. Diuretics*

388 Calcific Aortic Valve Disease

*2.10.6. Nitrates*

*2.10.7. Digoxin*

home and avoidance of hypotension is crucial.

to prevent substantial hypotension.

Diuretics are not indicated in patients without signs of congestion because of their potential for reducing preload, which may lead to fall in cardiac output and exacerbation in symptoms of HF. Therefore, diuretics are not first-line treatment options in hypertensive patients with severe AS without findings of congestion. Diuretics may improve symptoms of HF by reducing left ventricular end-diastolic pressure in patients with lung congestion, ascites or edema. Older patients may not excrete free water effectively, and they may more easily develop hyponatre‐ mia after diuretic treatment [53]. Thiazide diuretics cause hyponatremia more frequently than loop diuretics [54]. These older patients also have increased tendency to diuretic induced hyponatremia, because concomitant use of other medications like selective serotonin reuptake inhibitors (SSRI), which precipitate hyponatremia, is common. Because of disruption of normal circadian rhythm of antidiuretic hormone, nocturia is frequently seen in elderly patients and may be bothersome and increase the risk of falls when evening or night doses of diuretics are used [55]. Administration of diuretics in earlier hours of the day may be safer. Patients with urgency incontinence may need urinary anti-cholinergics under diuretic treatment to avoid urgency induced falls and significant physical exertion. Diuretics also lead to orthostatic hypotension by inducing volume depletion. Because falls are more frequent and are associated with great morbidity and mortality in these older patients, monitoring of blood pressure at

Nitrates may be used in symptomatic treatment of angina pectoris in patients with severe AS. They should be initiated at low doses and gradually increased to avoid sudden hypotension. Concomitant use of phosphodiesterase inhibitors for erectile dysfunction should be avoided

Digoxin has a narrow therapeutic index and the risk of adverse events associated with it may be more common in older patients [56]. Digoxin levels may be increased in older patients with impaired kidney functions. Because creatinine levels may be normal or minimally increased in older adults with impaired kidney functions when significant loss of muscle mass (i.e. sarcopenia) is present. It is recommended in the recent ACC/AHA guideline that an initial dose of 0.125 mg daily or every other day is chosen if the patient is older than 70 years old, has impaired kidney function, or has a low lean body mass [57]. Digoxin above 0.125 mg/d is also listed among the potentially inappropriate medications (PIMs) list in the recent Beers criteria [58]. Because digoxin concentrations above 1 ng/ml are not associated with better clinical outcomes and may adversely increase morbidity and mortality, a target digoxin concentration of 0.5-1 ng/ml is recommended despite conventional therapeutic serum concentration is defined as 0.8-2 ng/ml [56, 57]. When there is concomitant hypokalemia, hypomagnesemia or hypothyroidism, digoxin toxicity may occur in lower concentrations [57]. Older patients under digoxin treatment may develop adverse effects like anorexia, nausea, vomiting, confusion, visual problems, and rhythm and conduction disturbances more commonly [56]. Clarithro‐

Peripheral alpha blocker use may possibly lead to hypotension or syncope, decreased coronary perfusion due to reduced afterload and should generally be avoided. Alpha blockers are listed among the PIMs in the recent Beers criteria and routine use for the treatment of hypertension is not recommended [58]. Alpha blockers are also listed among the PIMs in patients with a history of syncope [58].

#### *2.10.10. Warfarin*

Warfarin treatment is generally recommended in patients with AS and AF to decrease the incidence of stroke and systemic arterial embolism. Assessing the risk of embolism associ‐ ated with AF and bleeding associated with warfarin treatment should be carefully per‐ formed. It is very important to educate the patient and his/her relatives about the benefits and risks of warfarin treatment and the details of follow-up. Integration of the patients' relatives in the treatment plan is crucial especially in older adults with significant cogni‐ tive problems. A meta-analysis which was published in 2007 indicated that aspirin was associated with a 22% reduction in the rate of stroke, while warfarin was associated with 64% reduction [59]. Because warfarin is associated with a significantly lower risk of stroke than aspirin, simply prescribing aspirin without discussing the benefits and risks of war‐ farin treatment with the patients and their relatives would be therapeutic nihilism. Al‐ though there are newer anticoagulant medications like dabigatran which do not require therapeutic monitoring, we need more data especially in the older individuals in order to prescribe them instead of warfarin. For instance, dabigatran is associated with greater risk of bleeding than with warfarin in patients ≥ 75 years and efficacy and safety is not known in patients with a creatinine clearance below 30 ml/min [58].

Warfarin is also the drug of choice in patients with AVR with mechanical prostheses. To date there is no alternative for warfarin for these patients and a higher international normalized ratio (2.5-3.5) is targeted. This translates into increased risk of bleeding associated with warfarin especially in the older patients. These patients may also have other bleeding risk factors like concurrent anti-platelet, SSRI or ginkgo biloba use and platelet dysfunction associated with KI or significant AS. Whether warfarin treatment is appropriate for the patient, may even determine if AVR might be performed and if a mechanical prosthesis might be used. Patients, in whom warfarin treatment is planned, should also be carefully assessed about the risk of falls which may lead to significant bleeding, most importantly to intracranial hemor‐ rhage. If warfarin is started, ensuring precautions by educating the patients and their relatives to avoid falls is also crucial.

estimated life expectancy < 12 months, evidence of an acute myocardial infarction within one month, MRI confirmed CVA within six months, ejection fraction < 20 %, heavy calcification in

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Risk Estimation: Accurate estimation of the risk of SAVR performed by an experienced cardiothoracic surgeon and cardiologist is vital to appropriate evaluation of potential candi‐ dates for TAVI. Some risk score algorithms like Ambler score, logistic EuroSCORE and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) are widely used to identify patients at high risk for cardiac surgery. Ambler score was dedicated to predict in-hospital mortality after heart valve surgery [69]. EuroSCORE integrates increased age, female gender, chronic pulmonary disease, extracardiac arteriopathy, neurological dysfunction, previous cardiac surgery, increased serum creatinine, active endocarditis, critical perioperative state, unstable angina, LV dysfunction, recent MI, and pulmonary hypertension as patient and cardiac related factors and some operation related factors like emergency, other than isolated CABG, surgery on thoracic aorta, and postinfarct septal rupture. An online calculator is available in their official website (http://www.euroscore.org/). Logistic EuroSCORE appears to overestimate mortality risk in patients undergoing high-risk aortic valve replacement. The STS-PROM risk scoring which is more complicated integrates age, gender, race, weight, creatinine level, various chronic cardiac and non-cardiac diseases, previous cardiovascular interventions, perioperative cardiac status, hemodynamic status, and operative risk factors. This scoring estimates the rates of postoperative morbidity, mortality, permanent stroke, prolonged ventilation, renal failure, and reoperation. It is updated regularly and calculation can be performed only via the online calculator (http://www.sts.org/). However the STS-PROM model may provide more accurate risk stratification than other scores, more appropriate scoring systems are not currently available. In clinical practice, it seems reasonable that high –risk patients should be evaluated using clinical judgment and a combination of several scores

Stented valves placed either transapically or percutaneously are garnering much attention. In the percutaneous approach, the valve is deployed either antegradely via the transseptal

Transfemoral Approach: The transfemoral approach is simper and quick to access the aortic valve. This route is the first choice of approach in the vast majority of centers performing TAVI procedures. Although surgical cutdown was the technique used for the transfemoral approach at the beginning of the TAVI experience, most centers are now using a fully percutaneous technique. The aortic valve is corossed and a stiff wire is placed in the LV with a large loop. Within these procedures, firstly balloon aortic valvotomy is undertaken and a stented bio‐ prosthesis is then deployed over a balloon intothe aortic annulus. Inflation of the balloon anchors the valve in place in the annulus,effectively achieving AVR. Some specific contrain‐

front of LM, presence of LV thrombus and need for CABG

[70, 71].

**4. Overview of procedure**

**4.1. Approaches used for TAVI**

route,or retrogradely across the native aortic valve.

### **3. Transcathater aortic valve implantation**

Surgical AVR is currently the gold-standard treatment for patients with severe symptomatic AS. Without surgery, the prognosis is extremely poor, with a 3-year survival rate of <30%.How‐ ever, in the huge Euro Heart multinational registry in Europe, 33% of symptomatic patients over the age of 65 years were not referred for surgery [60]. The reasons for not planning surgery were not always the co morbidities. David Bach's series showed the same issue and 33% of symptomatic patients were not referred for surgery, some of whom had a low Euro Score risk [61]. Balloon aortic valvuloplasty, which was described in the 1980s, was the first alternative to surgical therapy [62]. Despite high rates of initial procedural success, restenosis is frequently encountered in the long term. The procedure has generally been abandoned in adult patients except as a palliative procedure often prior to surgical AVR [63]. Trans-catheter aortic valve implantation (TAVI) was first described by Andersen et al in 1992 [64]. They implanted an expandable aortic valve by a catheter technique in a closed chest pig model. The first attempt to use TAVI in man was in 2002 by Cribier et al [65]. A percutaneous bioprosthesis was successfully implanted within the diseased native aortic valve through an antegrade trans‐ septal approach. In more recent years, the technology has developed very rapidly and, to date, more than 40,000 transcathater valves have been implanted worldwide. The results of several large multicenter registries and randomized Placement of Aortic Transcathater Valves (PARTNER) trial, TAVI is now the standard of care for extremely high risk or 'inoperable ' patients and is a valid alternative to surgery for selected high-risk but ' operable ' patients with symptomatic AS [66-68].

Patients might be considered candidates for TAVI if they fulfill the following criteria: symp‐ tomatic severe AS, a life expectancy of >1year, contraindications for surgery, high risk for surgery (clinical judgment plus Euro Score (logistic) >20%; STS Score>10%), and/or porcelain aorta, history of thoracic irradiation, severe thoracic deformity, patent coronary bypass, cachexia, recurrent pulmonary emboli, right ventricular insufficiency and cirrhosis.

Contraindications for TAVI are as follows: an aortic annulus of <18 mm or >27 mm, bicuspid valves or unicuspid or noncalcified valve, severe aortic regurgitation or mitral regurgitation, estimated life expectancy < 12 months, evidence of an acute myocardial infarction within one month, MRI confirmed CVA within six months, ejection fraction < 20 %, heavy calcification in front of LM, presence of LV thrombus and need for CABG

Risk Estimation: Accurate estimation of the risk of SAVR performed by an experienced cardiothoracic surgeon and cardiologist is vital to appropriate evaluation of potential candi‐ dates for TAVI. Some risk score algorithms like Ambler score, logistic EuroSCORE and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) are widely used to identify patients at high risk for cardiac surgery. Ambler score was dedicated to predict in-hospital mortality after heart valve surgery [69]. EuroSCORE integrates increased age, female gender, chronic pulmonary disease, extracardiac arteriopathy, neurological dysfunction, previous cardiac surgery, increased serum creatinine, active endocarditis, critical perioperative state, unstable angina, LV dysfunction, recent MI, and pulmonary hypertension as patient and cardiac related factors and some operation related factors like emergency, other than isolated CABG, surgery on thoracic aorta, and postinfarct septal rupture. An online calculator is available in their official website (http://www.euroscore.org/). Logistic EuroSCORE appears to overestimate mortality risk in patients undergoing high-risk aortic valve replacement. The STS-PROM risk scoring which is more complicated integrates age, gender, race, weight, creatinine level, various chronic cardiac and non-cardiac diseases, previous cardiovascular interventions, perioperative cardiac status, hemodynamic status, and operative risk factors. This scoring estimates the rates of postoperative morbidity, mortality, permanent stroke, prolonged ventilation, renal failure, and reoperation. It is updated regularly and calculation can be performed only via the online calculator (http://www.sts.org/). However the STS-PROM model may provide more accurate risk stratification than other scores, more appropriate scoring systems are not currently available. In clinical practice, it seems reasonable that high –risk patients should be evaluated using clinical judgment and a combination of several scores [70, 71].
