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The following common cardiovascular disorders are discussed within this module:

• Hypertension
• Heart failure
• Venous thromboembolism
• Hyperlipidemia
• Peripheral arterial disease
• Arrhythmias
• Stroke

Introduction

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States (US). In 2013, the overall rate of death in the US attributable to CVD was 222.9 per 100,000; rates were highest for black males (356.7 per 100,000) and lowest for Hispanic females (136.4 per 100,000).¹ Despite the continued negative impact CVD has on society, progress has been made in its prevention and treatment. From 2003 to 2013, mortality rates attributable to CVD declined 28.8%. Medication therapy management (MTM) may contribute to an ongoing reduction in CVD-related morbidity and mortality rates.

HYPERTENSION

Overview

According to the American Heart Association (AHA) heart disease and stroke statistics 2016 update, approximately 33% of adults in the US (≥ 20 years of age) have hypertension.^1,2 This correlates to an estimated disease prevalence of 80 million US adults. The prevalence of hypertension among the sexes is similar. With regard to race, African-Americans have the highest prevalence of hypertension globally at 44%. In the US, over 80% of patients with hypertension are aware of their diagnosis and an estimated 75% are actively using antihypertensive medications.  However, only 54% of treated patients are reaching appropriate treatment goals for hypertension.

The pathophysiology of hypertension is uncertain, but appears to be related to multiple interrelated factors.^3,4 Physiological mechanisms that contribute to the development of essential hypertension include cardiac output, peripheral resistance, the renin-angiotensin-aldosterone system (RAAS), the autonomic nervous system, endothelial dysfunction, and vasoactive substances such as bradykinin or atrial natriuretic peptide.⁴ Increased dietary salt intake, obesity, and insulin resistance may also play roles in the pathophysiology of hypertension among other factors.

For the majority (90%) of patients, the etiology of hypertension is unknown (ie., primary or essential hypertension).³ In primary hypertension, genetic factors may play an important role; however, no specific genetic trait has been linked to increased blood pressure currently. A minority of patients has an identifiable cause for elevated blood pressure, which is known as secondary hypertension. The most common secondary cause of hypertension is renal dysfunction from chronic renal disease or renovascular disease. Other causes of secondary hypertension are listed in Table 1.

Table 1. Causes of Secondary Hypertension3
Diseases	Coarctation of the aorta Cushing syndrome Obstructive sleep apnea Parathyroid disease Pheochromocytoma Primary aldosteronism Thyroid disease
Medications	Amphetamines Anti-vascular endothelin growth factors Bupropion Corticosteroids Calcineurin inhibitors Ergot alkaloids Erythropoiesis stimulating agents Estrogen-containing oral contraceptives Nasal decongestants NSAIDs Venlafaxine/desvenlafaxine
Food substances	Ethanol Licorice Sodium
NSAIDs = nonsteroidal anti-inflammatory drugs.

When establishing a diagnosis of hypertension, the primary physical finding is an elevated blood pressure. A majority of patients do not exhibit any other signs or symptoms.³ A single elevated blood pressure reading is not diagnostic. Instead, an average of 2 or more measurements during 2 or more clinical encounters should be used to diagnose hypertension. Once a diagnosis is established, a complete medical evaluation of the patient should be undertaken in order to identify potential secondary causes, evaluate other cardiovascular risk factors or comorbid conditions that may guide selection of drug therapy, and assess for the presence of target organ damage. The primary goal of therapy for hypertension is to reduce associated morbidity and mortality including the occurrence of cardiovascular events, cerebrovascular events, heart failure, and kidney disease.

Treatment

Lifestyle interventions remain the cornerstone of treatment for patients with hypertension.⁵  Interventions that have been proven to produce small to moderate reductions in systolic blood pressure (SBP) include weight loss, physical activity, reduced salt intake, moderation of alcohol intake, and implementation of the Dietary Approaches to Stop Hypertension (DASH) diet.³ The DASH diet emphasizes vegetables, fruits, and fat-free or low-fat dairy products, includes whole grains, fish, poultry, beans, seeds, nuts, and vegetable oils, and limits sodium, sugary beverages, and red meats. The diet is also low in saturated and trans fats, rich in potassium, calcium, magnesium, fiber, and protein, and emphasizes a reduced amount of sodium intake. The daily nutrient goals evaluated in the DASH studies are presented in Table 2. 

Table 2. Daily Nutrient Goals for the DASH Diet3*
Nutrient	Daily Goal
Total fat	27% of calories
Saturated fat	6% of calories
Protein	18% of calories
Carbohydrate	55% of calories
Cholesterol	150 mg
Sodium	2300 mg
Potassium	4700 mg
Calcium	1250 mg
Magnesium	500 mg
Fiber	30 g
*Based on a 2000 calorie eating plan. A sodium reduction to 1500 mg was even more effective at lowering blood pressure including among those with existing hypertension, African Americans, and middle-aged and older adults.

JNC 8 Guidelines

In December 2013, the Eighth Joint National Committee (JNC 8) released the 2014 evidence-based guideline for the management of high blood pressure in adults.⁵ The recommendations within the JNC 8 report differed from the prior guidelines (JNC 7) in several key aspects. In JNC 7, prehypertension and hypertension were specifically defined; however, JNC 8 does not address definitions of prehypertension and hypertension. Instead, these guidelines define thresholds for pharmacologic treatment (Table 3).

Table 3. JNC 8 Recommendations for Hypertension Management5
Population	Recommendation
General population ≥ 60 years of age	Start pharmacologic therapy to reduce blood pressure at SBP ≥ 150 mmHg or DBP ≥ 90 mmHg and treat to a goal of SBP < 150 mmHg and DBP < 90 mmHg If pharmacologic therapy results in lower SBP (ie., < 140 mmHg) and therapy is well tolerated, treatment does not need to be adjusted (Corollary Recommendation)
General population < 60 years of age	Start pharmacologic therapy to reduce blood pressure at DBP ≥ 90 mmHg and treat to a goal of DBP < 90 mmHg Start pharmacologic therapy to reduce blood pressure at SBP ≥ 140 mmHg and treat to a goal of SBP < 140 mmHg
Population ≥ 18 years of age with chronic kidney disease	Start pharmacologic therapy to reduce blood pressure at SBP ≥ 140 mmHg or DBP ≥ 90 mmHg and treat to a goal of SBP < 140 mmHg and DBP < 90 mmHg
Population ≥ 18 years of age with diabetes	Start pharmacologic therapy to reduce blood pressure at SBP ≥ 140 mmHg or DBP ≥ 90 mmHg and treat to a goal of SBP < 140 mmHg and DBP < 90 mmHg
DBP = diastolic blood pressure; SBP = systolic blood pressure.

With regard to pharmacologic therapy, JNC 8 recommends that initial antihypertensive therapy should include a thiazide diuretic, calcium channel blocker, angiotensin-converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) in the general, non-African American population, including those with diabetes.⁵ The panel did not recommend β-blockers or a-blockers for the initial treatment of hypertension based on data from randomized controlled trials. No randomized controlled trials of fair or good quality were available for carvedilol, vasodilating β-blocking agents (ie., nebivolol), central a₂-adrenergic agonists (ie., clonidine), direct vasodilators (ie., hydralazine), aldosterone receptor antagonists (ie., spironolactone), peripherally acting adrenergic antagonists (ie., reserpine), and loop diuretics; therefore, none of these agents is recommended as a first line treatment option. Dosing for common antihypertensive agents is presented in Table 4. Many patients with hypertension require more than one antihypertensive agent to achieve blood pressure control and any of the 4 drug classes recommended as initial treatment are appropriate choices for add-on therapy.

Table 4. JNC 8 Dosing Recommendations for Antihypertensive Medications5
Medication	Initial daily dose	Target dose	Number of doses each day
ACE inhibitors
Captopril	50 mg	150 to 200 mg	2
Enalapril	5 mg	20 mg	1 to 2
Lisinopril	10 mg	40 mg	1
Angiotensin receptor blockers
Eprosartan	400 mg	600 to 800 mg	1 to 2
Candesartan	4 mg	12 to 32 mg	1
Losartan	50 mg	100 mg	1 to 2
Valsartan	40 to 80 mg	160 to 320 mg	1
Irbesartan	75 mg	300 mg	1
Calcium channel blockers
Amlodipine	2.5 mg	10 mg	1
Diltiazem XR	120 to 180 mg	360 mg	1
Thiazide diuretics
Chlorthalidone	12.5 mg	12.5 to 25 mg	1
Hydrocholorothiazide	12.5 to 25 mg	25 to 100 mg*	1 to 2
β-blockers
Atenolol	25 to 50 mg	100 mg	1
Metoprolol	50 mg	100 to 200 mg	1 to 2
*Current evidence suggests that a dose of 25 to 50 mg daily balances efficacy and safety. ACE = angiotensin converting enzyme; XR = extended release.

Although JNC 7 recommended specific antihypertensive agents for compelling indications (ie., diabetes, chronic kidney disease, heart failure, myocardial infarction, stroke, and high cardiovascular disease risk), JNC 8 only recommends specific drug therapy for racial, chronic kidney disease, and diabetic subgroups based on an evidence review.⁵ In the general black population, including patients with diabetes, JNC 8 recommends initial antihypertensive therapy with a thiazide diuretic or calcium channel blocker. For adults with chronic kidney disease and hypertension, an ACE inhibitor or ARB is recommended as initial or add-on antihypertensive treatment regardless of race or diabetes status. Although this is the recommendation, the panel noted areas where clinical data remain questionable including black patients with chronic kidney disease and those > 75 years of age. For hypertensive black patients with chronic kidney disease and proteinuria, an ACE inhibitor or ARB is recommended to slow progression to end stage renal disease. However, for black patients with chronic kidney disease without proteinuria, choice of initial therapy may include an ACE inhibitor, ARB, calcium channel blocker, or thiazide diuretic. For patients > 75 years of age with chronic kidney disease and hypertension, there are no data to support the use of ACE inhibitors or ARBs although treatment with these agents may be beneficial. The panel suggested ACE inhibitors, ARBs, calcium channel blockers, or thiazide diuretics as options for this age group.

Monitoring Parameters

JNC 8 also made recommendations with regard to approach to continued antihypertensive therapy.⁵ If the blood pressure goal is not achieved within one month of therapy initiation, either the dose should be increased or a second antihypertensive should be added (thiazide diuretic, ACE inhibitor, ARB, or calcium channel blocker). Adjustment of the antihypertensive regimen should continue until the target blood pressure is reached. Addition of a third drug from the prior list is recommended if hypertension remains resistant with an appropriately adjusted 2-drug regimen. Concurrent administration of an ACE inhibitor and ARB in the same patient is not recommended. If there are contraindications to the recommended antihypertensive agents or there is a need to use more than 3 drugs, medications from other classes may be used. Another dosing strategy discussed in JNC 8 is beginning antihypertensive therapy with 2 drugs at the same time, either as separate pills or as a single pill combination. This strategy may also be an acceptable approach; no one strategy has been proven superior to any other. An algorithm for appropriate management of hypertension is available in the JNC 8 guidelines (see Resource List at the end of this module).

Appropriate administration and monitoring of the 4 recommended initial antihypertensive drug classes are essential. The following are general recommendations for their safe use and monitoring:³

Thiazide diuretics

• Should be dosed in the morning to avoid nocturnal diuresis.
• Normal doses should be administered to avoid negative metabolic effects.
• May have additional benefits in osteoporosis.
• May require additional monitoring in patients with a history of gout or hyponatremia.

ACE inhibitors/ARBs

• Can cause hyperkalemia in patients with chronic kidney disease or patients receiving other medications that increase potassium levels.
• May cause acute renal failure in patients with severe bilateral renal artery stenosis or severe stenosis in an artery to a solitary kidney; monitor renal function.
• Avoid use in pregnancy.
• Do not use in patients with a history of angioedema (ACE inhibitors only).
• May cause a cough due to bradykinin accumulation (ACE inhibitors only).
• The initial dose should be reduced in patients who are elderly, on a diuretic, or are volume depleted.

Calcium channel blockers

• Dihydropyridine calcium channel blockers cause more reflex tachycardia, dizziness, headache, flushing, and peripheral edema than nondihydropyridines.
• Nondihydropyridine calcium channel blockers reduce heart rate and may produce heart block.
• Many of the extended-release products have different release mechanisms and bioavailability parameters; therefore, use caution when switching patients from one agent to another.

HEART FAILURE

Overview

Heart failure (HF) remains a major cardiovascular epidemic. Globally, > 37.7 million individuals are affected by HF, with an estimated 5.7 million in the US alone.⁶ An accurate estimate of mortality attributable to HF alone is challenging; however, in 2011, 1 in 9 death certificates listed HF as a cause of death. Although a HF diagnosis is linked to increased mortality and a reduction in quality of life, treatment advances have substantially improved patient outcomes. From 1979 to 2000, the absolute 5-year survival rate for HF increased by 9%.        

Heart failure may arise from any disorder that decreases contractility (systolic dysfunction) or restricts ventricular filling (diastolic dysfunction).⁷ Table 5 lists causes of systolic and diastolic HF. The classic presentation of HF is systolic dysfunction with a reduced left ventricular ejection fraction (LVEF); however, up to 50% of HF patients have presumed diastolic dysfunction with preserved LVEF. The most common cause of systolic dysfunction is myocardial infarction. Many medications can also precipitate or exacerbate HF including antiarrhythmics, β-blockers, calcium channel blockers, doxorubicin, nonsteroidal anti-inflammatory drugs (NSAIDs), rosiglitazone/pioglitazone, saxagliptin/alogliptin, glucocorticoids, androgens and estrogens, cyclophosphamide, trastuzumab, ethanol, and amphetamines.

Table 5. Causes of Systolic and Diastolic HF7
Systolic dysfunction	Diastolic dysfunction
Myocardial infarction Dilated cardiomyopathies Ventricular hypertrophy Pressure overload Volume overload	Increased ventricular stiffness Ventricular hypertrophy Infiltrative myocardial diseases Myocardial ischemia and infarction Mitral or tricuspid valve stenosis Pericardial disease

The pathophysiology of HF is complex and progressive.⁷ Usually, an initial event, such as a myocardial infarction, causes an injury to the heart resulting in impairment in contractility and/or relaxation. This reduction in the pumping capacity of the heart leads to the development of compensatory mechanisms in order to maintain adequate cardiac output. These compensatory mechanisms include tachycardia and increased contractility, increased preload and afterload, and ventricular hypertrophy and remodeling. Although these mechanisms may have some initial beneficial effects, they are also believed to play an essential role in the downward trend of HF.

The primary signs and symptoms of HF are dyspnea, fatigue, and fluid overload.^7,8 Dyspnea and fatigue can have a significant effect on exercise tolerance. Fluid overload may lead to pulmonary and/or peripheral edema. The presence or absence of these signs and symptoms may vary from patient to patient (i.e. one patient may have significant fluid overload with no dyspnea while another patient may have dyspnea with no signs of fluid overload). The spectrum of HF presentation may range from asymptomatic to cardiogenic shock.⁷ Table 6 details potential signs and symptoms of HF.

Table 6. Signs and Symptoms of HF7
Signs	Symptoms
Pulmonary rales Pulmonary edema S3 gallop Cool extremities Pleural effusion Cheyne-Stokes respiration Tachycardia Narrow pulse pressure Cardiomegaly Peripheral edema Jugular vein distention Hepatojugular reflux Hepatomegaly	Dyspnea Orthopnea Paroxysmal nocturnal dyspnea Exercise intolerance Tachypnea Cough Fatigue Nocturia Hemoptysis Abdominal pain Anorexia Nausea Bloating Poor appetite Ascites Mental status changes

There is no one specific test that confirms the presence of HF.⁷ Generally, diagnosis involves a full history and physical examination with particular attention paid to the aforementioned signs and symptoms as well as potential underlying causes such as cardiovascular disease or thyroid disease.^7,8 In addition, the initial laboratory evaluation should include a complete blood count, serum electrolytes (including calcium and magnesium), urinalysis, renal and hepatic function tests, thyroid function tests, lipid profile, B-type natriuretic peptide (BNP), and glucose. An electrocardiogram (ECG) and chest X-ray should also be performed. An echocardiogram is extremely useful in evaluating potential structural and functional abnormalities of the heart. The main goals of HF therapy include relieving or reducing symptoms, improving quality of life, minimizing or preventing hospitalizations, slowing disease progression, and prolonging life.⁷

Treatment

Lifestyle interventions are important in the management of HF.⁷ Historically, patients with HF were discouraged from exercising; however, exercise training programs are currently encouraged in stable patients with HF to improve clinical status. In addition, dietary sodium and fluid restriction is recommended since HF patients often experience sodium and water retention. Patients should restrict sodium intake to < 3 (mild) or < 2 (moderate) grams per day and weigh themselves daily in order to minimize fluid retention and allow for the administration of lower and safer diuretic doses.

ACCF/AHA treatment recommendations

In 2013, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) published guidelines for the management of HF.⁸ The ACCF/AHA disease classification scheme focuses on the development and progression of disease. This approach differs from the New York Heart Association (NYHA) classification system, which focuses on exercise capacity and symptomatic status. Table 7 compares the ACCF/AHA and NYHA HF classification schemes. Pharmacologic treatment recommendations for ACCF/AHA stages A to D are presented in Table 8 and dosing of medications commonly used in HF is presented in Table 9. Of note, ivabradine and the combination of sacubitril, a neprilysin inhibitor, and valsartan, an ARB, were approved in 2015 after publication of the 2013 ACCF/AHA guidelines. Ivabradine is indicated to reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with a LVEF ≤ 35%, who are in sinus rhythm with a resting heart rate ≥ 70 beats/minute and either are on maximally tolerated doses of β-blockers or have a contraindication to beta-blocker use.⁹ Sacubitril/neprilysin is indicated to reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic HF (NYHA II to IV) and reduced ejection fraction.¹⁰ It is usually administered with other HF therapies, in place of an ACE inhibitor or other ARB.

Table 7. Comparison of the ACCF/AHA and NYHA HF Classifications8
ACCF/AHA stages of HF	NYHA functional classification
A: At high risk for HF but without structural heart disease or symptoms of HF	I: No limitation of physical activity; ordinary physical activity does not cause symptoms of HF
B: Structural heart disease but without signs or symptoms of HF	II: Slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in HF symptoms
C: Structural heart disease with prior or current symptoms of HF	III: Marked limitation of physical activity; comfortable at rest, but less than ordinary activity causes HF symptoms
D: Refractory HF requiring specialized interventions	IV: Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest
HF = heart failure.

Table 8. Selected Pharmacologic Treatment Recommendations for ACCF/AHA Stages8
ACCF/AHA stage	Recommendations
A	Hypertension and lipid disorders should be treated per guidelines in order to lower the risk of HF. Other conditions that may contribute to the development of HF such as obesity, diabetes, smoking, and known cardiotoxic agents should be controlled or avoided.
B	In patients with a history of MI or ACS with reduced EF, ACE inhibitors should be administered. If a patient cannot tolerate an ACE inhibitor, an ARB is an appropriate alternative agent. In patients with a history of MI or ACS with reduced EF, β-blocker therapy should be administered. In patients with a history of MI or ACS with reduced EF, statin therapy should be administered. ACE inhibitors and β-blockers should be administered to all patients with a reduced EF for prevention of symptomatic HF regardless of whether or not there is a history of MI. In patients with structural cardiac abnormalities but no history of MI or ACS, hypertension should be treated per guidelines in order to prevent symptomatic HF.
C	All of the above measures listed for stages A and B are recommended where appropriate for patients in stage C. Diuretics should be administered to patients with HF and reduced or preserved EF who have evidence of fluid retention. Addition of an ARB may be considered in a persistently symptomatic patient with HF and reduced EF who is currently receiving an ACE inhibitor and β-blocker, but has a contraindication to an aldosterone antagonist. Use of an aldosterone receptor antagonist is recommended in certain stage C patients. Use of hydralazine/isosorbide dinitrate is recommended in African Americans with NYHA class III to IV HF and reduced EF who have optimized ACE inhibitor and β-blocker therapy; this combination may be useful as well in patients who cannot be given an ACE inhibitor or ARB. Digoxin may be useful in patients with HF and reduced EF to reduce hospitalizations. Patients with chronic HF with atrial fibrillation and an additional risk factor for cardioembolic stroke should receive chronic anticoagulant therapy; chronic anticoagulation may also be reasonable for patients with chronic HF and atrial fibrillation only. Omega-3 polyunsaturated fatty acid supplementation is reasonable to use as adjunctive therapy in patients with NYHA class II to IV symptoms and HF with reduced or preserved EF. ARBs might be considered to decrease hospitalizations in patients with HF and preserved EF.
D	Intravenous inotropic support is reasonable for certain patients in stage D.
ACE = angiotensin converting enzyme; ACS = acute coronary syndrome; ARB = angiotensin receptor blocker; EF = ejection fraction; HF = heart failure; MI = myocardial infarction; NYHA = New York Heart Association.

Table 9. Recommended Dosing for Medications Commonly Used in HF8-11
Medication	Initial oral daily dose	Comments
Diuretics
Bumetanide	0.5 to 1 mg once or twice daily	Maximum total daily dose: 10 mg
Furosemide	20 to 40 mg once or twice daily	Maximum total daily dose: 600 mg
Torsemide	10 to 20 mg once daily	Maximum total daily dose: 200 mg
Chlorothiazide	250 to 500 mg once or twice daily	Maximum total daily dose: 1000 mg
Chlorthalidone	12.5 to 25 mg once daily	Maximum total daily dose: 100 mg
Hydrochlorothiazide	25 mg once or twice daily	Maximum total daily dose: 200 mg
Amiloride	5 mg once daily	Maximum total daily dose: 20 mg
Triamterene	50 to 75 mg twice daily	Maximum total daily dose: 200 mg
ACE inhibitors
Captopril	6.25 mg 3 times daily	Maximum dose: 50 mg 3 times daily
Enalapril	2.5 mg twice daily	Maximum dose: 10 to 20 mg twice daily
Lisinopril	2.5 to 5 mg once daily	Maximum dose: 20 to 40 mg once daily
Quinapril	5 mg twice daily	Maximum dose: 20 mg twice daily
Ramipril	1.25 to 2.5 mg once daily	Maximum dose: 10 mg once daily
Trandolapril	1 mg once daily	Target dose: 4 mg once daily
ARBs
Candesartan	4 to 8 mg once daily	Maximum dose: 32 mg once daily
Losartan	25 to 50 mg once daily	Maximum dose: 50 to 150 mg once daily
Valsartan	20 to 40 mg twice daily	Maximum dose: 160 mg twice daily
Sacubitril/valsartan	49/51 mg twice daily	Target dose: 97/103 mg twice daily
Aldosterone antagonists
Spironolactone	12.5 to 25 mg once daily	Maximum dose: 25 mg once or twice daily
Eplerenone	25 mg once daily	Maximum dose: 50 mg once daily
β-blockers
Bisoprolol	1.25 mg once daily	Maximum dose: 10 mg once daily
Carvedilol	3.125 mg twice daily	Maximum dose: 50 mg twice daily
Carvedilol CR	10 mg once daily	Maximum dose: 80 mg once daily
Metoprolol succinate CR/XL	12.5 to 25 mg once daily	Maximum dose: 200 mg once daily
Hydralazine/isosorbide dinitrate
Fixed-dose combination	37.5 mg hydralazine/     20 mg isosorbide dinitrate 3 times daily	Maximum dose: 75 mg hydralazine/40 mg isosorbide dinitrate 3 times daily
Hydralazine and isosorbide dinitrate	Hydralazine: 25 to 50 mg 3 or 4 times daily and isosorbide dinitrate 20 to 30 mg 3 or 4 times daily	Maximum doses: 300 mg daily in divided doses of hydralazine and 120 mg daily in divided doses of isosorbide dinitrate
Hyperpolarization-activated cyclic nucleotide-gated channel blocker
Ivabradine	5 mg twice daily; after 2 weeks of treatment, adjust dose based on heart rate	Maximum dose: 7.5 mg twice daily
ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; CR = controlled release; XL = extended release.

Monitoring Parameters

The majority of medications for HF should be titrated to doses found to be of benefit in cardiovascular studies. Appropriate administration and monitoring of ACE inhibitors and ARBs should be undertaken as previously described (see Hypertension). Common adverse effects with β-blocker therapy include fluid retention, worsening heart failure, fatigue, bradycardia, heart block, and hypotension.⁷ Vital signs should be monitored closely during titration of the β-blocker dose. If adverse effects occur, do not continue dose titration until symptoms have resolved. Fluid retention caused by therapy may be resolved with a diuretic. A reduction in dose should occur if a patient presents with bradycardia associated with dizziness, lightheadedness, or second- or third-degree heart block. Separate the administration of β-blockers from other antihypertensive agents if hypotension occurs and continue therapy even if it appears that HF symptoms are not improving. Aldosterone antagonists should not be initiated if a patient's baseline serum creatinine is > 2.5 mg/dL in men or > 2 mg/dL in women, or their estimated glomerular filtration rate (eGFR) is ≤ 30 mL/min, or potassium is ≥ 5 mEq/L. If a patient is receiving concurrent potassium supplements, the dose of the supplement should be reduced or the product discontinued. Potassium and renal function should be measured within 2 to 3 days of therapy initiation, then on day 7, then at least monthly for the first 3 months, then every 3 months, and when clinically indicated. If potassium levels increase to > 5.5 mEq/L or renal function worsens, the dose of the aldosterone antagonist should be reduced or discontinued. Common adverse effects with hydralazine/isosorbide dinitrate include headache, dizziness, and gastrointestinal effects. Ivabridine increases the risk of atrial fibrillation; monitor cardiac rhythm regularly on patients receiving this drug.⁹ Discontinue therapy if atrial fibrillation develops. The most common adverse effects with ivabridine include bradycardia, hypertension, atrial fibrillation, and luminous phenomena. Common adverse reactions with use of sacubitril/valsartan include hypotension, hyperkalemia, cough, dizziness, and renal failure.¹⁰

VENOUS THROMBOEMBOLISM

Overview

Globally, venous thromboembolic disease [deep vein thrombosis (DVT) and pulmonary embolism (PE)] has a significant impact on morbidity and mortality.¹² After myocardial infarction and stroke, venous thromboembolism (VTE) is the third most commonly occurring cardiovascular disorder.¹³ Since a substantial portion of patients with VTE are estimated to have clinically silent disease, the exact incidence in the general population is unknown.¹⁴ However, it is approximated that up to 1 million VTE cases occur annually in the US.¹¹ The incidence of VTE increases with age and is slightly higher among men than women.¹⁴ With regard to race, African Americans appear to be at highest risk for VTE development, followed by Caucasians, Hispanic Americans, and Asian Americans/Pacific Islanders.¹⁵

There are a variety of risk factors for VTE, which may be classified as acquired or inherent, transient or persistent.^14,16 Table 10 lists some of these risk factors. A single patient may have multiple risk factors thereby significantly increasing the overall risk for VTE development. No identifiable cause of VTE is found in up to 25% of patients.¹⁶

Table 10. Risk Factors for VTE16
Acquired risk factors	Inherent risk factors
Immobilization Surgery Trauma Female hormone treatments Age Pregnancy Puerperium Malignancy Myeloproliferative disorders Anti-phospholipid syndrome Inflammatory bowel disease	Protein C and S deficiency Antithrombin deficiency Dysfibrinogenemia Heterozygous factor V Leiden mutation Prothrombin 20210A mutation Hyperhomocysteinemia

For many patients with VTE, signs and symptoms are either not present or lack specificity.^14,15  Most DVTs form in the lower extremities. Symptoms may include:

• unilateral leg pain and swelling
• tenderness
• redness
• increased leg temperature
• pain deep in the calf or thigh
• pleuritic pain
• dyspnea
• tachypnea
• tachycardia
• hemoptysis
• syncope
• palpitations

Even though a thorough history and physical examination alone may be inadequate to definitively diagnose VTE, this clinical assessment can be useful in developing a pretest probability of disease that allows for stratification of patients based on probability of risk (ie., low vs. high).¹⁶ The D-dimer assay reflects the level of clotting activity in the blood and is another useful diagnostic tool in the initial evaluation of a patient with a suspected VTE. Although an increase in D-dimer may occur in a variety of other situations including surgery and acute injury, the test has a sensitive association with acute VTE and a high negative predictive value.^15,16  Diagnostic imaging may also be utilized including venous ultrasound and computed tomography (CT) pulmonary angiography.

Treatment and Prevention

The most recent full CHEST guidelines on the treatment and prevention of VTE were published in 2012, with an update on specific topics published in 2016.^17,18 A summary of Food and Drug Administration (FDA)-approved treatment options for acute VTE is presented in Table 11. 

Table 11. Approved Treatment Options for Acute VTE17,19-22
Medication	Dosage regimen(s)
Unfractionated heparin	IV: 80 units/kg bolus and then 18 units/kg/hour infusion (dosage adjustments per institution nomogram) SC: 333 U/kg and then 250 U/kg twice daily
Enoxaparin	SC: 1 mg/kg twice daily or 1.5 mg/kg once daily Use with caution if CrCl < 30 mL/min
Dalteparin	SC: 200 units/kg once daily Use with caution if CrCl < 30 mL/min
Fondaparinux	SC (weight-based): < 50 kg = 5 mg once daily 50 to 100 kg = 7.5 mg once daily           > 100 kg = 10 mg once daily Contraindicated if CrCl < 30 mL/min
Warfarin	Oral: 5 mg once daily titrated to an INR goal of 2 to 3 (typical initial dose) Reduce initial dose in the elderly and in patients with poor nutritional status, liver disease, or those administered medications that decrease metabolism of warfarin
Rivaroxaban	Oral: 15 mg twice daily for 21 days and then 20 mg once daily Avoid if CrCl < 30 mL/min
Dabigatran	Oral: 150 mg twice daily after 5 to 10 days of parenteral anticoagulation (for patients with CrCl > 30 mL/min)
Edoxaban	Oral: 60 mg once daily after 5 to 10 days of parenteral anticoagulation Reduce dose to 30 mg once daily for CrCl 15 to 50 mL/min or body weight ≤ 60 kg or if the patient uses certain P-glycoprotein inhibitors
Apixaban	Oral: 10 mg twice daily for 7 days, followed by 5 mg twice daily
CrCl = creatinine clearance; INR = international normalized ratio; IV = intravenous; SC = subcutaneous. Specific pharmacologic therapy recommendations from the 2012 CHEST guidelines, and 2016 update, for the treatment of VTE include:17,18

2012 recommendations¹⁷

• Either a low molecular weight heparin (LMWH) or fondaparinux is preferable to unfractionated heparin (UFH) for patients being bridged to warfarin.
• LMWH is preferable to intravenous (IV) or subcutaneous (SC) UFH in patients with acute lower extremity DVT with or without PE.
• LMWH therapy should overlap initiation of warfarin for a minimum of 5 days or until the international normalized ratio (INR) exceeds 2.0 for at least 24 hours.
• Once daily LMWH administration is preferred to twice daily SC injections. The CHEST guidelines specifically recommend enoxaparin 2 mg/kg once daily or dalteparin 200 units/kg once daily; however, many prescribers administer enoxaparin 1.5 mg/kg once daily (the FDA-approved dosage regimen).
• Fondaparinux is preferable to IV or SC UFH for patients with acute VTE.
• Early initiation of warfarin therapy is preferred over delayed initiation.
• For stable outpatients, the CHEST guidelines suggest initiating therapy with warfarin 10 mg for the first 2 days followed by maintenance dosing based on INR measurements rather than an estimated maintenance dose.     
• For patients on warfarin with consistently stable INR values, INR testing may be extended to every 12 weeks.
• For patients previously stable on warfarin who have one "out of range" INR value, continue on the present dose and recheck the INR within 1 to 2 weeks.
• For competent patients with stable INR values, home monitoring of INR may be an option.
• Concurrent administration of warfarin with NSAIDs and/or antiplatelet medications should be avoided unless specifically indicated.

2016 update recommendations¹⁸

• In patients with DVT of the leg or PE and no cancer, dabigatran, rivaroxaban, apixaban, or edoxaban is recommended over warfarin as long-term (initial 3 months) anticoagulant therapy.
• In patients with DVT of the leg or PE and cancer, LMWH is recommended over warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban as long-term (initial 3 months) anticoagulant therapy.
• In patients with DVT of the leg or PE who receive extended therapy, there is no need to change anticoagulant therapy after the initial 3 months.
• In patients who have recurrent VTE on warfarin or on dabigatran, rivaroxaban, apixaban, or edoxaban, it is recommended to switch to a LMWH at least temporarily.
• In patients who have recurrent VTE on long-term LMWH therapy, it is recommended to increase the LMWH dose by about 25% to 33%.

An acute DVT in a stable patient without a significant bleeding risk may be treated in an outpatient setting per the guidelines.^17,19 Certain patients with PE may also receive outpatient treatment. These include patients who are hemodynamically and clinically stable, are adherent to therapy, and have access to quality medical care and a strong support system.¹⁹ The guidelines recommend a treatment duration of 3 months in the setting of a provoked VTE (i.e., surgery).^17,19 In situations where the VTE was unprovoked, duration of therapy depends on the bleeding risk of the patient. For low to moderate risk patients, extended anticoagulation therapy is recommended. For patients at high risk for bleeding, therapy may be discontinued at 3 months.

Prevention of VTE remains a high priority for healthcare providers and institutions. Table 12 contains prophylactic dosing regimens for various indications. For acutely ill general medical patients, LMWH, low-dose UFH, or fondaparinux should be continued throughout hospitalization as a prophylactic measure per the CHEST guidelines.¹⁷ For non-orthopedic surgical patients, decisions regarding pharmacologic or mechanical prophylaxis often depend on patient-specific VTE risk and bleeding propensity.¹⁹ The guidelines recommend LMWH administration for VTE prophylaxis in orthopedic surgical patients. Additionally, dabigatran, apixaban, and rivaroxaban have an approved indication for the reduction in risk of recurrence of DVT and PE in patients who have been previously treated.

Table 12. Prophylactic VTE Dosing Regimens19-21
Medication	Acutely ill general medical patients	Nonorthopedic surgery	Orthopedic surgery (total hip or knee replacement)
Enoxaparin	40 mg SC once daily	40 mg SC once daily	30 mg SC twice daily initiated ≥ 12 hours before or after surgery and continued for ≥ 10 to 14 days (potentially up to 35 days)
Dalteparin	5000 units SC once daily	2500 units SC once daily (low risk) 2500 units SC for 12 hours after surgery and then 5000 units SC once daily (high risk)	2500 units SC initiated ≥ 12 hours after surgery and then 5000 units once daily continued for ≥ 10 to 14 days (potentially up to 35 days)
Fondaparinux	2.5 mg SC once daily	2.5 mg SC once daily for up to 10 days	2.5 mg SC once daily and continued for ≥ 10 to 14 days (potentially up to 35 days) If CrCl is 30 to 50 mL/min: 1.5 mg SC once daily
Warfarin	Not recommended	Not recommended	Adjusted warfarin to a goal INR of 2 to 3 for ≥ 10 to 14 days (potentially up to 35 days)
Apixaban	No approved dose	No approved dose	2.5 mg orally twice daily initiated 12 to 14 hours after surgery and continued for 12 days (knee) and 35 days (hip)
Rivaroxaban	No approved dose	No approved dose	10 mg orally once daily for 12 days (knee) and 35 days (hips)
Dabigatran	No approved dose	No approved dose	110 mg orally first day, then 220 mg once daily for patients with CrCl > 30 mL/min (hip)
Unfractionated heparin	5000 U SC 3 times daily in cancer patients	5000 U 2 or 3 times daily until fully ambulatory	5000 U 2 or 3 times daily until fully ambulatory. Continue for ≥ 10 to 14 days (potentially up to 35 days).
CrCl = creatinine clearance; INR = international normalized ratio; LMWH = low molecular weight heparin; SC = subcutaneous; VTE = venous thromboembolism.

Monitoring Parameters

The primary concerns with medications administered for the treatment and prevention of VTE are bleeding due to excessive anticoagulation or clotting due to medication underdosing. Unfractionated heparin therapy is associated with the development of heparin-induced thrombocytopenia (HIT).¹⁹ This risk may be as high as 5% in certain patient populations. Per the CHEST guidelines, platelet count monitoring should occur every 2 to 3 days from day 4 to 14 during heparin administration in patients with a risk of HIT of ≥ 1%. The risk of HIT is much lower with LMWHs, and insignificant with fondaparinux; therefore, platelet count monitoring is not indicated for these agents. The most intensive monitoring is required with warfarin therapy. Warfarin interacts with a variety of medications, diseases, and foods. A comprehensive listing of warfarin interactions can be found on the Anticoagulation Europe website (See Resource List at the end of this module). Some of these interactions can significantly increase bleeding or clotting risk.

If a patient on warfarin therapy presents with an INR value of 4.5 to 10 with no bleeding, the CHEST guidelines do not recommend the routine use of vitamin K as a "reversal agent".¹⁹ For patients with an INR > 10 without bleeding, oral vitamin K at a dose of 1 to 2 mg may be administered. If major bleeding occurs, a combination of parenteral vitamin K and prothrombin complex concentrates is recommended.

HYPERLIPIDEMIA

Overview

Total and low-density lipoprotein (LDL) cholesterol levels generally increase throughout life in both men and women, particularly among those who partake in a typical Western-style diet.²³ Based on estimates from the AHA, 98.9 million adults > 20 years of age have total serum cholesterol levels ≥ 200 mg/dL. A majority of patients at borderline high-risk for negative cardiovascular outcomes are unaware of their high cholesterol levels and < 50% of those at highest risk receive lipid-lowering treatment. Hyperlipidemia may arise from a primary genetic defect; however, there are a number of secondary causes of lipoprotein abnormalities. Table 13 lists secondary causes of hypercholesterolemia. 

Table 13. Secondary Causes of Hypercholesterolemia24

Inappropriate diet Hypothyroidism Biliary obstruction Nephrotic syndrome Pregnancy Anorexia nervosa Medications (ie., diuretics, cyclosporine, glucocorticoids, amiodarone)

The primary goal of hyperlipidemia treatment is to reduce the risk of negative cardiovascular outcomes such as myocardial infarction, angina, HF, ischemic stroke, or peripheral arterial disease.²³

Treatment

Therapeutic lifestyle changes should be instituted in all patients prior to the administration of pharmacologic therapy.^23,24 These changes include decreasing intake of saturated fats and cholesterol, increasing intake of plant stanols and sterols and soluble fiber, weight loss, and increased physical activity.

NCEP ATP IV Treatment Recommendations

In November 2013, the American College of Cardiology-American Heart Association (ACC-AHA) Task Force on Practice Guidelines (NCEP) released fully revised guidelines for the treatment of high blood cholesterol in adults (ATP IV), which are freely available (see Resource List at the end of this module).²⁴ In contrast to the previous ATP III guidelines, which focused on patient-specific lipid-level goals based on risk level, the new guidelines undertook a vastly different approach.^24,25 The expert panel in ATP IV relied heavily on data from randomized controlled trials involving fixed doses of statins in patients at risk for atherosclerotic cardiovascular disease. Utilizing this approach, the expert panel identified 4 subgroups for which the benefits of statin therapy outweigh the risk (although some patients who do not fall into these 4 categories may also benefit from statins). These 4 subgroups include:

• Adults, ≥ 21 years of age, with clinically evident atherosclerotic disease
• Adults, ≥ 21 years of age, with LDL cholesterol levels ≥ 190 mg/dL (not due to secondary modifiable causes)
• Patients, 40 to 75 years of age, with diabetes and an LDL level of 70 to 189 mg/dL
• Patients 40 to 75 years of age, with an estimated 10-year risk of atherosclerotic cardiovascular disease of ≥ 7.5% and an LDL level of 70 to 189 mg/dL
  (A cardiovascular risk calculator is available at AHA website; see Resource List at the end of this module)

For patients within these subgroups, high-intensity statin therapy is generally recommended.^24,25 According to the guidelines, high-intensity statin therapy reduces LDL levels by ≥ 50% on average. The expert panel recommends atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg once daily as appropriate agents for high-intensity therapy. In patients who cannot tolerate high-intensity therapy or those with diabetes and a 10-year risk of atherosclerotic disease < 7.5%, moderate-intensity statin therapy is recommended. Moderate-intensity therapy reduces LDL levels by approximately 30% to < 50% on average. Recommended statin dosage regimens for moderate-intensity therapy include atorvastatin 10 to 20 mg, rosuvastatin 5 to 10 mg, simvastatin 20 to 40 mg, pravastatin 40 to 80 mg, lovastatin 40 mg, extended-release fluvastatin 80 mg, fluvastatin 40 mg, and pitavastatin 2 to 4 mg. All recommended moderate-intensity dosage regimens should be given once daily except for immediate-release fluvastatin, which is administered twice daily.

The new guidelines also identify patients for whom current clinical data do not support the use of statin therapy and for whom no treatment recommendation is made.^24,25 These patients include:

• those on hemodialysis
• those > 75 years of age, unless atherosclerotic cardiovascular disease is present
• those with NYHA class II to IV HF

Finally, the expert panel stated that there is no clinical evidence "to support the use of non-statin cholesterol-lowering drugs, either combined with statin therapy or in statin-intolerant patients."²⁵ The panel could find no randomized controlled trials that demonstrated a further reduction in atherosclerotic cardiovascular disease events in these situations and recommended that "clinicians treating high-risk patients who have a less than anticipated response to statins, who are unable to tolerate a less than recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of a non-statin cholesterol-lowering therapy."²⁴ This broad approach was meant to allow clinician discretion when prescribing these agents; however, the ACC recently convened an expert panel to more specifically address the appropriate use of non-statin therapies.²⁶ In summary, the document recommends the following non-statin pharmacologic approaches for each of the 4 subgroups mentioned previously if an appropriate response is not achieved on maximally tolerated statin therapy:

• Adults, ≥ 21 years of age, with clinically evident atherosclerotic disease: consider addition of ezetimibe first (may consider bile acid sequestrants if ezetimibe intolerant and triglycerides < 300 mg/dL); consider adding or replacing with a PCSK9 inhibitor (alirocumab or evolocumab) if a less than anticipated response occurs on maximally tolerated statin-ezetimibe or non-statin combination therapy.
• Adults, ≥ 21 years of age, with LDL cholesterol levels ≥ 190 mg/dL (not due to secondary modifiable causes): consider addition of ezetimibe (may consider bile acid sequestrants if ezetimibe intolerant and triglycerides < 300 mg/dL) or a PCSK9 inhibitor. If the response is still inadequate, consider the addition of a second-nonstatin agent.
• Patients, 40 to 75 years of age, with diabetes and an LDL level of 70 to 189 mg/dL: consider addition of ezetimibe first and bile-acid sequestrants as second-line therapy.
• Patients 40 to 75 years of age, with an estimated 10-year risk of atherosclerotic cardiovascular disease of ≥ 7.5% and an LDL level of 70 to 189 mg/dL: consider addition of ezetimibe first and bile-acid sequestrants as second-line therapy.

Additional information regarding the appropriate use of non-statin therapies, including safety concerns, may be found in the full expert consensus document (see Resource List at the end of this module).

Monitoring Parameters

Per the NCEP guidelines, all patients should have an initial fasting lipid panel with a follow-up panel 4 to 12 weeks after starting statin therapy to assess adherence.²⁴ With continued therapy, lipid assessments should be undertaken every 3 to 12 months as clinically indicated. Specific statin safety recommendations within the NCEP guidelines include:

• A baseline creatine kinase (CK) level should not be routinely measured in patients administered statin therapy.
• Measurement of a CK level is reasonable for patients exhibiting symptoms of muscle adverse events while receiving statin therapy (ie., pain, tenderness, cramping, weakness, stiffness, or generalized fatigue).
• All patients administered statin therapy should have a baseline alanine aminotransferase (ALT) performed; if a patient develops hepatotoxicity during treatment, measurement of hepatic function is reasonable.
• If 2 consecutive LDL levels are < 40 mg/dL, a reduction in statin dose may be considered.
• Patients administered statin therapy should be screened for new-onset diabetes mellitus.
• Close monitoring of statin therapy should be undertaken in patients who are > 75 years of age as well as those taking concurrent medications that change drug metabolism or those who are receiving multiple medications (i.e., for transplantation or human immunodeficiency virus [HIV] infection). Significant drug interactions may occur with statin therapy. Many of these interactions are discussed in the February 2016 Pharmacist's Letter (see Resource List at the end of this module).
• If mild to moderate muscle symptoms occur during statin therapy, discontinue treatment immediately. These patients should be evaluated for other disease states that may contribute to symptoms. If muscle symptoms resolve, the patients should receive the original or a lower dose of the initial statin in order to establish a causal relationship. If such a relationship is found, the original statin should be discontinued and a low dose of a different statin should be prescribed once muscle symptoms have resolved. If the low dose is tolerated, gradually increase as permitted.
• If severe muscle symptoms occur, discontinue statin therapy and evaluate the patient for possible rhabdomyolysis.

Patient Case #1 JS is a 55-year-old African-American male with established diagnoses of hyperlipidemia, hypertension, and chronic kidney disease with proteinuria. He has a history of a myocardial infarction 2 years ago. His last LDL level was 200 mg/dL and his blood pressure today is 170/95 mmHg. Previously, he was prescribed pravastatin 40 mg once daily, chlorthalidone 25 mg once daily, and aspirin 81 mg daily; however, he admits that adherence has been an issue in the past. He presents to the clinic with new complaints of dyspnea on exertion and fatigue. Upon physical examination, JS is found to have peripheral edema and jugular vein distention. A chest X-ray reveals cardiomegaly and pleural effusion; an echocardiogram has been scheduled. Based on signs and symptoms, the physician suspects new onset Stage C HF in this patient. What are appropriate initial pharmacologic interventions for JS's HF? Per the ACCF/AHA guidelines for Stage C HF, JS should be initiated on ACE inhibitor and β-blocker therapy. High-intensity statin therapy is also recommended for JS. Pravastatin, his current statin, is not a high intensity statin. Since JS has peripheral edema, diuretic therapy is also recommended. He is currently receiving chlorthalidone 25 mg once daily; however, he admits that he has been noncompliant with this therapy. JS's hypertension also needs to be controlled as part of his HF management plan. What would be an appropriate treatment option for control of JS's hypertension? For hypertensive African-American patients with chronic kidney disease and proteinuria, an ACE inhibitor or ARB is recommended. Titrating his ACE inhibitor therapy to an appropriate dose for his HF should also aid in controlling his blood pressure. What would be an appropriate treatment choice to manage JS's increased LDL? Since JS's most recent LDL level was > 190 mg/dL, JS is a candidate for high intensity statin therapy. Appropriate initial choices would be atorvastatin 40 mg once daily or rosuvastatin 20 mg once daily.  Over time, JS's ACE inhibitor and β-blocker therapy are optimized; however, he still has HF symptoms. What may be another treatment option for JS? Another option for JS, an African-American male with advanced HF, may be hydralazine/isosorbide dinitrate.

PERIPHERAL ARTERIAL DISEASE

Overview

Peripheral arterial disease (PAD) is estimated to affect more than 8 million adults in the US.²⁷ Disease prevalence is highly dependent on age with an overall prevalence of 3% to 10% at all ages and an increase to 15% to 20% among patients > 70 years of age.^28,29 Risk factors that contribute to an increased prevalence of PAD include current smoking, diabetes, hypertension, hyperlipidemia, renal function impairment, hyperhomocysteinemia, and African American ethnicity.^28,30 Peripheral arterial disease is most commonly due to the progressive occurrence of systemic atherosclerosis in the arterial lumen of lower limb extremities.²⁸ Other more rare causes of PAD include embolism, degenerative diseases (ie., Marfan syndrome and Ehlers-Danlos syndrome), dysplastic disease, vasculitis, Buerger's disease, inherited thrombophilias, and Entrapment syndromes.²⁷

During early stages of PAD, patients are often asymptomatic.^28,31 The 2 most common signs/symptoms that occur with PAD progression are intermittent claudication (the primary symptomatic indicator of the disease) and pain at rest in the lower extremities.^28,32 Intermittent claudication is generally described as reproducible pain, cramping, discomfort, or numbness in the affected extremity that is provoked by exertion and abates within 10 minutes of rest.^27,28 Pain at rest is generally noted with advanced disease when blood perfusion to the extremity becomes inadequate.²⁸ Nonspecific signs of reduced blood supply may include cool skin temperature, shiny skin, thickened toe nails, absence of hair on the feet/calves, and sores or ulcers. A significant reduction in circulation can result in infection, poorly controlled pain, and eventually amputation.³⁰

Diagnosis of PAD can be difficult; ruling out other potential neurologic, inflammatory, and vascular conditions is essential.^28,32 Patients considered to be at high risk for PAD include:  

• < 50 years of age with an additional atherosclerotic risk factor
• ≥ 50 years of age with diabetes and/or smoking history
• > 65 years of age
• with known vascular disease
• with reduced/abnormal pulses
• with PAD symptoms.²⁷

The best diagnostic test currently available for PAD is the ankle-branchial pressure index (ABI).^27,29 A normal ABI value ranges between 1.0 and 1.4.²⁷  Ankle-branchial pressure index values for mild, moderate, and severe PAD are 0.7 to 0.9, 0.4 to 0.7, and < 0.4, respectively.^27,28

The broad goals of therapy for PAD include managing symptoms associated with disease progression and reducing the risk of cardiovascular events.³¹

Treatment

In 2013, the ACCF/AHA published practice guidelines on the management of patients with PAD.³³ These guidelines discuss both nonpharmacologic and pharmacologic treatment recommendations. Key lifestyle modifications that result in a significant benefit in PAD include smoking cessation and exercise.^28,29,33,34 Per the ACCF/AHA guidelines, current or former smokers should be questioned regarding tobacco use at every visit.³³ Patients who continue to smoke should be offered a smoking cessation plan that includes counseling and potentially 1 or more of the following pharmacologic agents: varenicline, bupropion, and nicotine replacement. Supervised exercise training has been proven to increase walking duration and distance, decrease pain when walking, and delay the onset of intermittent claudication in PAD.²⁸ The ACCF/AHA guidelines recommend supervised exercise training for a minimum of 30 to 45 minutes at least 3 times weekly for a minimum of 12 weeks.³³

The ACCF/AHA guidelines discuss multiple pharmacologic treatment recommendations for PAD. Many of these recommendations focus on cardiovascular risk reduction. Recommendations are summarized in Table 14.

Table 14. ACCF/AHA Recommendations for the Management of PAD33
Medication class	Recommendation(s)
Lipid-lowering drugs	Statin therapy is indicated for all patients with PAD to achieve a LDL goal of < 100 mg/dL. Patients with lower extremity PAD at very high risk for cardiovascular events may be treated to a LDL goal < 70 mg/dL. Fibric acid derivatives may be useful in PAD for patients with low HDL, normal LDL, and high triglyceride levels.
Antihypertensive drugs	Antihypertensive therapy should be initiated in hypertensive patients with lower extremity PAD to achieve goals per the JNC 8 guidelines. Agents specifically mentioned in the PAD guidelines include β-blockers, calcium channel blockers, and ACE inhibitors.
Diabetes medications	Administration of appropriate medications to reduce A1C levels to < 7% is recommended in PAD.
Homocysteine-lowering drugs	Administration of homocysteine-lowering agents (ie., folic acid and vitamin B12) in PAD is not well established.
Antiplatelet and antithrombotic medications	Aspirin 75 to 325 mg daily is recommended for the reduction of negative cardiovascular outcomes in patients with symptomatic atherosclerotic lower extremity PAD. Clopidogrel 75 mg daily is a recommended alternative to aspirin in these patients. The combination of aspirin and clopidogrel may also be considered in symptomatic, high risk patients who are not at an increased risk for bleeding. In asymptomatic patients with an ABI ≤ 0.9, antiplatelet therapy can be useful for cardiovascular risk reduction.
Agents for claudication	Cilostazol 100 mg orally twice daily should be considered in all patients with claudication that limits life activities. Pentoxifylline 400 mg 3 times daily may be an alternative to cilostazol.
A1C = glycosylated hemoglobin; ABI = ankle-brachial pressure index; ACE = angiotensin converting enzyme; HDL = high-density lipoprotein; LDL = low-density lipoprotein; PAD = peripheral arterial disease.

Monitoring Parameters

Appropriate use and monitoring of statins and antihypertensive agents were reviewed earlier in this module. Monitoring parameters for agents for claudication include:³⁵

Cilostazol

• Should not be prescribed to any patient with HF regardless of severity.
• Use with caution in severe renal impairment (creatinine clearance < 25 mL/min).
• Monitor blood counts; rare cases of thrombocytopenia and leukopenia leading to agranulocytosis have been reported.
• Exercise caution when cilostazol is administered with CYP3A4 and CYP2C19 inhibitors. Consider reducing the dose of cilostazol.

Pentoxifylline

• Patients on concurrent warfarin should receive more frequent monitoring of prothrombin times while receiving pentoxifylline.
• Patients with other risk factors complicated by hemorrhage (ie., recent surgery, cerebral and/or retinal bleeding) should have periodic bleeding examinations including hematocrit and/or hemoglobin.

ARRHYTHMIAS

Overview

Arrhythmia refers to a condition in which the heart beats irregularly or abnormally.

There are numerous potential causes of arrhythmias including: stress, medications, drug abuse, ischemic heart disease, smoking, high blood pressure, and electrical shock. Although a variety of medications are FDA-approved for cardiac conduction abnormalities, the overall usage of antiarrhythmic agents has declined significantly since 1989 due to drug toxicity and the introduction of effective nonpharmacologic treatments.³⁶ The Vaughan Williams system is still most frequently used to classify the majority of antiarrhythmic agents (Table 15).

Table 15. Vaughan Williams Classification of Antiarrhythmic Medications36
Class	Drug	Conduction velocity	Refractory period	Automaticity	Ion block
Ia	Quinidine Procainamide Disopyramide	Decreases	Increases	Decreases	Sodium (intermediate) Potassium
Ib	Lidocaine Mexiletine	No effect/Decreases	Decreases	Decreases	Sodium (fast on-off)
Ic	Flecainide Propafenone	Decreases	No effect	Decreases	Sodium (slow on-off)
IIc	β-blockers	Decreases	Increases	Decreases	Calcium (Indirect)
III	Amiodarone Dofetilide Dronedarone Sotalol Ibutilide	No effect	Increases	No effect	Potassium
IVc	Verapamil Diltiazem	Decreases	Increases	Decreases	Calcium

Treatment

As mentioned prior, the administration of antiarrhythmic agents has declined precipitously. Currently, amiodarone is the initial antiarrhythmic prescribed for many arrhythmias including chronic and acute supraventricular and ventricular arrhythmias.³⁶ Amiodarone is unique in many aspects including an extremely long elimination half-life (> 50 days) and large volume of distribution that contributes to a delayed onset of action (days to weeks for the oral formulation) and persistent effects for months after discontinuation. Recommended maintenance doses for certain oral antiarrhythmic medications, including amiodarone, are presented in Table 16. Dose adjustments may be needed for renal and/or hepatic dysfunction for most agents.

Table 16. Recommended Oral Antiarrhythmic Maintenance Doses36
Medication	Dose
Disopyramide	100 to 500 mg every 6 hours 200 to 300 mg every 12 hours (SR form)
Quinidine	200 to 300 mg sulfate salt every 6 hours 324 to 648 gluconate salt every 8 to 12 hours
Mexiletine	200 to 300 mg every 8 hours
Flecainide	50 to 200 mg every 12 hours
Propafenone	150 to 300 mg every 8 hours 225 to 425 mg every 12 hours (SR form)
Amiodarone	400 mg 2 to 3 times daily until 10 grams total, then 200 to 400 mg daily Usual maintenance dose for atrial fibrillation is 200 mg/day; can decrease to 100 mg/day if patient is clinically stable. Usual maintenance dose for ventricular arrhythmias is 300 to 400 mg/day.
Dofetilide	500 mcg every 12 hours
Dronedarone	400 mg twice daily
Sotalol	80 to 160 mg every 12 hours
SR = sustained release.

Monitoring Parameters

Antiarrhythmic agents can produce multiple adverse effects (Table 17). Many patients cannot continue with chronic antiarrhythmic therapy due to these effects. Of note, disopyramide may cause anticholinergic effects (ie., dry mouth, urinary retention, constipation, blurred vision) in a significant percentage of patients (up to 70%).³⁶ Mexiletine therapy is associated with a high incidence of neurologic and/or gastrointestinal effects. In addition, flecainide, propafenone, and disopyramide can cause HF in many patients with existing left ventricular dysfunction and should be avoided in this patient population. Finally, many antiarrhythmic agents can precipitate new, life-threatening arrhythmias. Patients should be monitored closely for the development of this adverse effect.

Table 17. Adverse Effects of Oral Antiarrhythmic Medications36
Medications	Adverse effects
Disopyramide	Anticholinergic symptoms, nausea, anorexia, torsades de pointes, HF, conduction disturbances, ventricular arrhythmias
Quinidine	Cinchonism, diarrhea, abdominal cramps, nausea, vomiting, hypotension, torsades de pointes, worsening HF, conduction disturbances, ventricular arrhythmias, fever, hepatitis, thrombocytopenia, hemolytic anemia
Mexiletine	Dizziness, sedation, anxiety, confusion, paresthesia, tremor, ataxia, blurred vision, nausea, vomiting, anorexia, conduction disturbances, ventricular arrhythmias
Flecainide	Blurred vision, dizziness, dyspnea, headache, tremor, nausea, worsening HF, conduction disturbances, ventricular arrhythmias
Propafenone	Dizziness, fatigue, bronchospasm, headache, taste disturbances, nausea, vomiting, bradycardia or AV block, worsening HF, ventricular arrhythmias
Amiodarone	Tremor, ataxia, paresthesia, insomnia, corneal microdeposits, optic neuropathy/neuritis, nausea, vomiting, anorexia, constipation, torsades de pointes, bradycardia or AV block, pulmonary fibrosis, liver function test abnormalities, hepatitis, hypothyroidism, hyperthyroidism, photosensitivity, blue-gray skin discoloration
Dofetilide	Headache, dizziness, torsades de pointes
Dronedarone	Nausea, vomiting, diarrhea, increases in serum creatinine, bradycardia, torsades de pointes
Sotalol	Dizziness, weakness, fatigue, nausea, vomiting, diarrhea, bradycardia or AV block, torsades de pointes, bronchospasm, worsening HF
AV = atrioventricular; HF = heart failure.

There are multiple monitoring parameters for amiodarone. Table 18 discusses monitoring and adverse effect management recommendations for this agent.

Table 18. Monitoring and Management Recommendations for Amiodarone36
Adverse effect	Monitoring recommendations	Management
Pulmonary fibrosis	Chest radiograph at baseline and every 12 months PFT (if symptomatic)	Discontinue amiodarone immediately; initiate corticosteroid therapy
Hypothyroidism	TFTs at baseline and every 6 months	Thyroid hormone supplementation
Hyperthyroidism	TFTs at baseline and every 6 months	Antithyroid medications (ie., methimazole)
Optic neuritis/neuropathy	Ophthalmologic examination (at baseline if significant visual abnormalities are present, otherwise only if symptoms develop)	Discontinue amiodarone immediately
Corneal microdeposits	Slit-lamp examination	No treatment is needed
Hepatotoxicity	LFTs at baseline and every 6 months	Reduce dose or discontinue amiodarone if LFTs > 3X ULN
Bradycardia/heart block	ECG at baseline and every 3 to 6 months	Reduce the dose, if possible, or discontinue amiodarone if severe
Tremor, ataxia, peripheral neuropathy	History and physical examination at each visit	Reduce the dose, if possible, or discontinue amiodarone if severe
Photosensitivity/blue-gray skin discoloration	History and physical examination at each visit	Patients should wear sunblock while outside
ECG = electrocardiogram; LFT = liver function test; PFT = pulmonary function test; TFT = thyroid function test; ULN = upper limit of normal.

STROKE

Overview

In the US, an estimated 6.5 million individuals are stroke survivors.³⁷ Although stroke remains the leading cause of adult disability, progress has been made in stroke management.^37,38 In 2013, stroke became the fifth leading cause of death in the U.S.¹ This represented an improvement from years past when stroke was consistently the third or fourth leading cause of mortality. From 2003 to 2013, the relative rate of stroke mortality fell by 33.7% and the actual number of stroke deaths declined by 18.2%. Both racial (African Americans > Caucasians) and geographic (southeastern U.S. > other regions) disparities exist with regard to stroke rates.³⁷

There are 2 stroke types, ischemic and hemorrhagic.³⁷  Ischemic stroke is by far the more common (87%) stroke type. The majority of ischemic strokes occur due to local thrombus formation or embolism resulting in cerebral artery occlusion. Thrombus formation is primarily a result of atherosclerosis of the cerebral vasculature; however, 30% of ischemic strokes are cryptogenic. Subarachnoid hemorrhage, intracerebral hemorrhage, and subdural hematomas are all classified as hemorrhagic strokes. Often hemorrhagic strokes occur due to uncontrolled hypertension, trauma, or, less frequently, antithrombotic or thrombolytic therapy.

A patient who has had a stroke may not be able to reliably discuss signs and symptoms due to cognitive or language deficits.³⁷ Signs and symptoms of stroke may include: weakness on one side of the body, loss of vision, vertigo, falling, headache (very severe with hemorrhagic stroke), aphasia, dysarthria, and altered levels of consciousness. There are a variety of diagnostic tests that should be completed emergently in patients who are suspected to have an acute ischemic stroke. Table 19 provides a listing of these examinations.

Table 19. Diagnostic Tests for Suspected Acute Ischemic Stroke38
All patients should receive: Noncontrast brain CT or MRI Blood glucose Oxygen saturation Serum electrolytes/renal function Complete blood count including platelets Markers of cardiac ischemia Prothrombin time/INR ECT	Selected patients should receive: TT and/or ECT if it is suspected that the patient is taking direct thrombin inhibitors or direct factor Xa inhibitors Hepatic function tests Toxicology screen Blood alcohol level Pregnancy test Arterial blood gas (if hypoxia is suspected) Chest radiography (if lung disease is suspected) Lumbar puncture (if subarachnoid hemorrhage is suspected and CT scan is negative for blood) EEG (if seizures are suspected)
CT = computed tomography; ECT = ecarin clotting time; EEG = electroencephalogram; INR = international normalized ratio; MRI = magnetic resonance imaging; TT = thrombin time.

The goals of therapy of acute stroke include prevention of stroke recurrence, decreasing ongoing neurologic injury, mortality, and chronic disability, and preventing complications related to immobility and neurologic dysfunction.³⁷

Treatment and Prevention

In 2013, the AHA/American Stroke Association (ASA) published guidelines for the early management of patients with acute ischemic stroke.³⁸ Initially, patients should be supported from a respiratory and cardiac standpoint. This may include administration of supplemental oxygen, continuous cardiac monitoring, normalization of body temperature, and blood pressure and blood glucose control.

The administration of IV tissue plasminogen activator (tPA, alteplase) is widely recommended for the treatment of acute ischemic stroke in selected patients.³⁸ The benefit of therapy decreases over time; therefore, the earlier the treatment is given, the greater the potential benefit. Per the AHA/ASA guidelines:

• tPA 0.9 mg/kg (maximum dose 90 mg) IV over 60 minutes, with 10% of the dose administered as a bolus over 1 minute, is recommended for select patients who may be treated within 3 hours of ischemic stroke onset.
• For tPA-eligible patients, the benefit of therapy is time dependent, and treatment should be initiated as soon as possible. The door-to-needle time (ie., time to bolus tPA administration) should be within 60 minutes from hospital arrival.
• tPA (same dose as above) is recommended for select patients who can be treated in the time period of 3 to 4.5 hours after stroke onset. Eligibility criteria for the administration of tPA in both the 3-hour and 3- to 4.5-hour treatment windows are addressed in the AHA/ASA stroke guidelines (see Resource List at the end of this module).
• Intravenous tPA remains a reasonable option for patients whose hypertension can be safely lowered (< 185/110 mmHg) and stabilized with antihypertensive agents.

Beyond tPA, oral aspirin therapy (initial dose: 325 mg) has also been shown to be of benefit in acute ischemic stroke.^37,38 The guidelines recommend aspirin administration within 24 to 48 hours after stroke onset in most patients; however, aspirin should never be administered within 24 hours of tPA administration due to an increased bleeding risk. A variety of other medications including UFH, LMWHs, direct thrombin inhibitors, clopidogrel, dipyridamole, and glycoprotein IIb/IIIa inhibitors have been evaluated in acute ischemic stroke; however, data from clinical studies have either been negative (ie., an increased risk of serious bleeding) or limited.

All patients who have experienced an acute ischemic stroke should receive long-term antithrombotic therapy for secondary prevention.³⁷ Recommendations for antiplatelet therapy in secondary prevention of ischemic stroke are presented in Table 20. Beyond these agents, patients who have experienced an acute ischemic stroke should receive treatment for hypertension and hyperlipidemia (ie., statins) as warranted to reduce the risk of stroke recurrence.

Table 20. Recommendations for Antiplatelet Therapy in Secondary Prevention of Ischemic Stroke37*
Type of ischemic stroke	Antiplatelet agent(s)
Noncardioembolic	Aspirin 50 to 325 mg daily Clopidogrel 75 mg daily Aspirin 25 mg + extended-release dipyridamole 200 mg twice daily
Cardioembolic (especially atrial fibrillation)	Warfarin dosing to achieve an INR = 2.5 Dabigatran 150 mg twice daily
INR = international normalized ratio. *Other novel oral anticoagulants have more recently been approved to reduce the risk of stroke in patients with atrial fibrillation including rivaroxaban, edoxaban, and apixaban. Please refer to the product labeling of these agents for specific recommended dosage regimens.

Monitoring Parameters

The 2013 AHA/ASA guidelines recommend monitoring for potential bleeding complications during and after tPA therapy.³⁸ In addition, appropriate monitoring of tPA includes:

• Performing neurological assessments every 15 minutes during infusion and every 30 minutes thereafter for the next 6 hours, then hourly until 24 hours after treatment.
• Discontinuing tPA infusion and obtaining an emergency CT scan if severe headache, acute hypertension, nausea, or vomiting occurs.
• Measuring blood pressure every 15 minutes for the first 2 hours after initiation, then every 30 minutes for the next 6 hours, then hourly until 24 hours after initiation of tPA. Frequency of monitoring should be increased if SBP is ≥ 180 mmHg or if DBP is ≥ 105 mmHg.
• Obtaining a follow-up CT scan at 24 hours before starting anticoagulants or antiplatelets, such as aspirin.

Focus Points for Medication Therapy Management in Cardiovascular Disease

Medication therapy management should initially include a thorough patient medication history including prior agents prescribed, appropriateness of current dosage regimens, any adverse effects, potential drug interactions, adherence issues, and cost considerations. Of note, many cardiovascular agents are listed within the 2015 American Geriatrics Society (AGS) Beers Criteria for potentially inappropriate medication use in older adults (see Resource List at the end of this module).³⁹

Hypertension

• Lifestyle modifications such as weight loss, physical activity, reducing salt intake, moderation of alcohol intake, and implementation of the DASH diet can lower SBP and should be strongly encouraged.
• Be aware of thresholds for pharmacologic treatment per JNC 8 guidelines and discuss these with the patient.
• Selection of drug therapy should be individualized as needed (ie., ACE inhibitors or ARBs for chronic kidney disease and hypertension). The JNC 8 guidelines recommend that initial antihypertensive therapy should include a thiazide diuretic, calcium channel blocker, ACE inhibitor, or ARB. Explain why a certain drug therapy is being chosen for the patient.
• Inform the patient that sometimes only one appropriately dosed medication may not be enough to control blood pressure. If that is the case, combination therapy may be instituted to successfully reach the blood pressure goal.

Heart Failure

• Hypertension and dyslipidemia increase the risk of HF in patients at high risk. These conditions should be appropriately treated per guidelines in order to reduce HF risk.
• Obesity, diabetes, and smoking can also contribute to development of HF. Patients should be counseled regarding this risk and treated appropriately if needed.
• Patients with stages B and C HF should be treated per the most recent ACCF/AHA treatment guidelines. These recommendations include the use of ACE inhibitors, β-blockers, and statins for most patients. Diuretics, aldosterone receptor antagonists, hydralazine/isosorbide dinitrate, and anticoagulant therapy may be needed in certain situations. Evaluate each patient individually to select the most appropriate drug therapy for their stage of HF and symptoms.
• Medications for HF should be titrated to the dose found to have the most beneficial effects in clinical studies. Advise the patient that initiating therapy, particularly β-blockers, may require multiple visits in order to reach the target medication dose safely.

Venous Thromboembolism

• Educate the patient on VTE risk factors, if applicable (ie., recent surgery or oral contraceptive use).
• Treatment or prophylaxis of VTE should generally be guided by the 2012 CHEST guidelines. Evaluate each patient individually to determine which therapeutic agent may be the best option.
• If SC LMWH or UFH is chosen for treatment or prevention of VTE, demonstrate appropriate SC medication administration technique to the patient. Have the patient demonstrate appropriate SC technique prior to the end of the MTM appointment.
• Warfarin therapy is monitored through regular INR levels. Many drugs, foods, and disease states can interact with warfarin and affect appropriate anticoagulation. Educate the patient regarding these risks.
• Educate the patient regarding the signs and symptoms of bleeding. Advise the patient to contact his/her healthcare provider if any of these signs and symptoms occur during VTE therapy.

Hyperlipidemia

• Reducing saturated fat and cholesterol intake, increasing intake of plant stanols/sterols and soluble fiber, weight loss, and physical activity should be strongly encouraged.
• High-intensity statin therapy is recommended in 4 patient subgroups per the NCEP ATP IV guidelines in order to reduce atherosclerotic CVD. Recommend this therapy for patients who are within these subgroups.
• Discuss the cardiovascular risk calculator with patients and explain what the results of the risk calculator mean.
• Explain significant drug interactions with statin therapy.
• Educate the patients regarding signs and symptoms of statin-related muscle toxicity.

Peripheral Arterial Disease

• Smoking cessation and exercise have a significant benefit in PAD. Patients should have a smoking cessation plan that includes counseling and/or pharmacologic treatment.
• Treatment guidelines for PAD focus on cardiovascular risk reduction. Patients with concurrent hyperlipidemia, hypertension, and diabetes should be appropriately treated per guidelines.
• Patients with symptomatic lower extremity PAD should receive aspirin if no contraindications exist. Counsel patients on the benefits and risks of aspirin therapy.
• If intermittent claudication is present, cilostazol is a recommended therapy. Patients should be counseled on the benefits and risks.

Arrhythmias

• Amiodarone is the most frequently prescribed antiarrhythmic therapy. Patients should be monitored closely for pulmonary, hepatic, thyroid, and visual issues. Counsel patients on these potential adverse effects.
• All antiarrhythmics have adverse effects that make adherence to chronic therapy difficult. Educate patients regarding the potential for adverse effects.

Stroke

• Patients who have had an acute ischemic stroke often have hypertension and hyperlipidemia. These conditions should be appropriately treated per guidelines.
• Educate patients regarding the importance of long-term antithrombotic therapy for the secondary prevention of stroke.

Resource List for Cardiovascular MTM JNC 8 Guidelines 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults. Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). Available for free download at: http://jama.jamanetwork.com/article.aspx?articleid=1791497. NCEP ATP IV Guidelines 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Available at: http://circ.ahajournals.org/content/129/25_suppl_2/S1. Role of Non-Statin Therapies 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk. Available at: http://content.onlinejacc.org/article.aspx?articleid=2510936&_ga=1.218335897.1889383793.1460578240#tab1. Common Interactions with Warfarin Available at: AnticoagulationEurope.org, under Publications tab: (http://www.anticoagulationeurope.org/publications/common-interactions-with-warfarin) Heart Risk Calculator American Heart Association/American College of Cardiology.  Heart risk calculator. Available at: http://www.cvriskcalculator.com/. Clinically Significant Statin Drug Interactions Pharmacist's Letter. 2016; 32(3):320303. Updated February 2016. AHA/ASA Stroke 2013 Guidelines American Heart Association/American Stroke Association guidelines for the early management of patients with acute ischemic stroke. Available at: http://stroke.ahajournals.org/content/44/3/870.full.pdf+html.   AGS Beers Criteria 2015 American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (2015). Available for free at: http://geriatricscareonline.org/toc/american-geriatrics-society-updated-beers-criteria-for-potentially-inappropriate-medication-use-in-older-adults/CL001.

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