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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, claiming more lives annually than cancer and chronic lung disease combined. In 2016, CVD accounted for 840,678 deaths in the United States with 121.5 million American adults having some form of CVD between 2013 and 2016.¹ Despite the continued negative impact CVD has on society, progress has been made in its prevention and treatment. From 2006 to 2016, mortality rates attributable to CVD declined 18.6%. 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 2019 update, approximately 46% of adults in the United States (≥ 20 years of age) had hypertension between 2013 to 2016.¹ This was defined as a systolic blood pressure (SBP) ≥ 130 mm Hg or diastolic blood pressure (DBP) ≥ 80 mm Hg, self-reported antihypertensive use, or having been told previously (at least twice) that one has high blood pressure (BP).¹ This age-adjusted prevalence correlates to an estimated 116.4 million US adults with hypertension. The prevalence of hypertension among the sexes is fairly similar (49% for males and 42.8% for females). With regard to race, African Americans have the highest prevalence of hypertension; 57.6% among males and 53.2% among females. In the United States, over 64% of patients with hypertension were aware of their diagnosis and an estimated 53% were actively using antihypertensive medications in 2013 to 2016. However, only 24.7% of treated patients were appropriately controlled.

The pathophysiology of hypertension is uncertain, but appears to be related to multiple interrelated factors.^2,3 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.³ 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).² In primary hypertension, genetic factors may play an important role; however, no specific genetic trait has been linked to increased BP currently. A minority of patients has an identifiable cause for elevated BP, 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.

When establishing a diagnosis of hypertension, the primary physical finding is an elevated BP. A majority of patients do not exhibit any other signs or symptoms.² A single elevated BP reading is not diagnostic. Instead, an average of 2 or more measurements during 2 or more clinical encounters should be used to diagnose hypertension.⁴ Once a diagnosis is established, a complete medical evaluation of the patient should be undertaken in order to identify potential secondary causes, evaluate other CV risk factors or comorbid conditions that may guide selection of drug therapy, and assess for the presence of target organ damage.² The primary goal of therapy for hypertension is to reduce associated morbidity and mortality including the occurrence of CV events, cerebrovascular events, heart failure (HF), and kidney disease.

Treatment

Lifestyle interventions remain the cornerstone of treatment for patients with hypertension.⁴ Interventions that have been proven to produce small-to-moderate reductions in SBP include weight loss, physical activity, reduced salt intake, moderation of alcohol intake, and implementation of the Dietary Approaches to Stop Hypertension (DASH) diet.² 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. 

American College of Cardiology/American Heart Association Task Force 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults

In 2017, the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Clinical Practice Guidelines released an update to the prevention, detection, evaluation, and management of high BP in adults that offers revised classifications of hypertension (Table 3) and the management approach.⁴ This guideline recommends the use of BP readings in tandem with atherosclerotic cardiovascular (ASCVD) risk calculators in order to determine appropriate treatment for patients with hypertension.

In patients with stage 1 hypertension, it is reasonable to initiate therapy with a single antihypertensive agent. In patients with stage 2 hypertension and an average BP more than 20/10 mm Hg higher than their target, 2 first-line agents of different pharmacological classes should be initiated.⁴ First-line antihypertensive agents include: thiazide diuretics, calcium channel blockers (CCBs), angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) as these agents have been shown to reduce clinical events.

Dosing for primary antihypertensive agents per the guideline is presented in Table 4. Although a variety of other drugs and drug classes for hypertension exist, either evidence is lacking that these agents reduce clinical events to an extent similar to the primary agents, or safety and tolerability may result in these agents being relegated to secondary antihypertensive agent status. Other factors including age, concurrent medications, adherence, drug interactions, costs, and comorbidities should be considered when choosing a patient-specific antihypertensive regimen as well.

Monitoring Parameters

The 2017 guideline also has recommendations with regard to approach to continued monitoring.⁴ Patients with normal BP should be reassessed annually. For those with elevated BP or stage 1 hypertension with an ASCVD risk < 10%, a BP reassessment should occur in 3 to 6 months. If the BP goal is not achieved within 1 month of antihypertensive therapy initiation in patients with stage 1 (ASCVD risk is ≥ 10% or the patient has known CVD, diabetes mellitus [DM], or chronic kidney disease [CKD]) or stage 2 hypertension, patient adherence should be evaluated and optimized and/or intensification of therapy should be considered. Adjustment and optimization of the antihypertensive regimen should continue until the target BP is reached.

Appropriate administration and monitoring of the 4 recommended primary antihypertensive drug classes are essential. The following are general recommendations for their safe use and monitoring:^2,5

Thiazide diuretics

• Chlorthalidone is preferred based on its prolonged half-life and proven CVD reduction in clinical trials.
• Thiazides 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.
• Monitor for hyponatremia and hypokalemia, uric acid, and calcium levels.
• Exercise caution in patients with a history of acute gout unless the patient is receiving appropriate uric acid-lowering therapy.

ACE inhibitors/ARBs

• Can cause hyperkalemia in patients with CKD 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. Patients with a history of angioedema with ACE inhibitor therapy can receive an ARB beginning 6 weeks after ACE inhibitor discontinuation.
• 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.
• Concurrent administration of an ACE inhibitor and ARB in the same patient is not recommended.
• Do not use in combination with a direct renin inhibitor.

CCBs

• Dihydropyridine CCBs cause more reflex tachycardia, dizziness, headache, flushing, and peripheral edema than nondihydropyridines.
• Avoid use of dihydropyridine CCBs in patients with HF and reduced ejection fraction; amlodipine or felodipine may be administered if required.
• Nondihydropyridine CCBs reduce heart rate and may produce heart block. Avoid use with beta-blockers.
• Avoid use of nondihydropyridine CCBs in patients with HF and reduced ejection fraction.
• There are various significant drug interactions with diltiazem and verapamil.
• 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

HF remains a major cardiovascular epidemic. Globally, > 37.7 million individuals are affected by HF, with an estimated 6.2 million adults impacted in the United States alone.^1,6 An accurate estimate of mortality attributable to HF alone is challenging; however, in 2016, 1 in 8 death certificates listed HF as a cause of death.¹ 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%.⁶

HF may arise from any disorder that decreases contractility (systolic dysfunction), restricts ventricular filling (diastolic dysfunction), or both.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, which is now referred to as heart failure with reduced ejection fraction (HFrEF). However, up to 50% of HF patients have presumed diastolic dysfunction with preserved ejection fraction (HFpEF). The most common cause of HFrEF is coronary artery disease (eg, myocardial infarction [MI]) while patients with HFpEF are typically elderly, female, obese, and have a diagnosis of hypertension, atrial fibrillation, or DM. Many medications can also precipitate or exacerbate HF including antiarrhythmics, β-blockers, CCBs, itraconazole, doxorubicin, imatinib, nonsteroidal anti-inflammatory drugs (NSAIDs), rosiglitazone/pioglitazone, glucocorticoids, androgens and estrogens, cyclophosphamide, trastuzumab, ethanol, and amphetamines among others.

The pathophysiology of HFrEF is complex and progressive.⁷ Usually, an initial event, such as a MI, 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 the disease. The pathophysiology of HFpEF is also complex and is thought to be caused by the interplay of multiple impairments in ventricular diastolic and systolic reserve function, heart rate reserve and rhythm, atrial dysfunction, ventricular and vascular stiffening, impaired vasodilation, pulmonary hypertension, endothelial dysfunction, and peripheral abnormalities.⁸

The primary signs and symptoms of both HFrEF and HFpEF are dyspnea, fatigue, and fluid overload.^7,9 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 (ie, 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.

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 CVD or thyroid disease.^7,9 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)/N-terminal pro-B-type natriuretic peptide (NT-proBNP), and hemoglobin A1C. 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.⁹ This was followed by a focused update in 2017.¹⁰ 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 emphasizes 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 from both the 2013 full guideline and 2017 focused update, which was published after approval of ivabradine and the combination of sacubitril and valsartan, are presented in Table 8 and dosing of medications commonly used in HF is presented in Table 9.

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 HF, fatigue, bradycardia, heart block, and hypotension.⁷ Vital signs should be monitored closely during titration of the β-blocker dose. Patients should be initiated on a low dose and titrated upward no more often than every 2 weeks as tolerated. If adverse effects occur, do not continue dose titration until symptoms have resolved. 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 (GI) effects. Ivabridine increases the risk of atrial fibrillation; monitor cardiac rhythm regularly on patients receiving this drug. 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.

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 MI 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 United States. The incidence of VTE increases with age and is slightly higher among men than women. 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

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 of VTE 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. 

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 (ie, 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 health care 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 nonorthopedic 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.

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. Some of these interactions can significantly increase bleeding or clotting risk (See Resource List at the end of this module).

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.²⁴ Based on estimates from the AHA, 100.1 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. 

The primary goal of hyperlipidemia treatment is to reduce the risk of negative cardiovascular outcomes such as MI, angina, HF, ischemic stroke, or peripheral arterial disease.²⁴

Treatment

Therapeutic lifestyle changes should be instituted in all patients prior to considering pharmacologic therapy.^24,25 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).²⁵ 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.^25,26 The expert panel in ATP IV relied heavily on data from randomized controlled trials involving fixed doses of statins in patients at risk for ASCVD. 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 DM and an LDL level of 70 to 189 mg/dL
• Patients 40 to 75 years of age, with an estimated 10-year risk of ASCVD of ≥ 7.5% and an LDL level of 70 to 189 mg/dL

For patients within these subgroups, high-intensity statin therapy is generally recommended.^25,26 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 DM 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.^25,26 These patients include:

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

2018 Guideline on the Management of Blood Cholesterol

As mentioned prior, the 2013 NCEP ATP IV cholesterol guideline undertook a vastly different approach than previous iterations focusing on identifying patients who would most benefit from statin therapy based on clinical trial evidence, rather than achieving a specific target blood cholesterol level.²⁵ However, since publication, the 2013 guideline has been criticized for this approach and failing to consider issues such as practicality, affordability, convenience, and patient preferences.²⁷

In November 2018, the latest update to the guideline was developed and endorsed by 12 professional organizations.^27,28. With this guideline, target LDL-C levels have been re-introduced, with the expert panel acknowledging that LDL-cholesterol targets provide a signpost to trigger a discussion about treatment intensification. In high-risk patients, addition of either ezetimibe or a PCSK9 inhibitor to statin therapy can be considered in certain individuals, with the expert panel recommending ezetimibe over PSCK9 inhibitors due to practical considerations. In patients who are not high risk and where a treatment decision is more equivocal, risk-enhancing factors that are not included in current risk calculators can be considered. These include presence of the metabolic syndrome, CKD, or a chronic inflammatory disorder; history of preeclampsia or premature menopause in women; persistently elevated LDL-C (≥ 160 mg/dL) or triglycerides (≥ 175 mg/dL); elevated C-reactive protein (≥ 2.0 mg/L); elevated coronary artery calcium score (≥ 100 Agatston units); and certain elevated lipid biomarkers such as apoB and Lp(a).

Finally, the new guidelines state that fasting prior to obtaining a lipid profile is no longer required.^27,28 Although patients should avoid eating a high-fat meal for at least 8 hours prior to the test, eating a light breakfast beforehand will not negatively impact results.

Role of Non-Statin Agents

With regard to the role of non-statin agents, the NCEP ATP IV 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.”²⁶ The panel could find no randomized controlled trials that demonstrated a further reduction in ASCVD 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.”²⁵ This broad approach was meant to allow clinician discretion when prescribing these agents; however, the ACC published an initial expert consensus decision pathway on the role of non-statin therapies in 2016 to more specifically address the appropriate use of these agents, followed by a focused update in 2017.^29,30 These documents recommend 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 ASCVD without comorbidities: 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) second if a less than anticipated response occurs on maximally tolerated statin-ezetimibe or non-statin combination therapy.
• Adults, ≥ 21 years of age, with clinically evident ASCVD with comorbidities: consider addition of ezetimibe (may consider bile acid sequestrants if ezetimibe intolerant and triglycerides < 300 mg/dL) or a PCSK9 inhibitor as the initial non-statin agent, and addition of the other agent second if needed.
• Adults, ≥ 21 years of age, with clinically evident ASCVD and baseline 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 as the initial non-statin agent, and addition of the other agent second if needed.
• Adults, ≥ 21 years of age, without clinically evident ASCVD and baseline 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 as the initial non-statin agent, and addition of the other agent second if needed.
• Patients, 40 to 75 years of age, without clinical ASCVD but with DM and a baseline LDL level of 70 to 189 mg/dL: consider addition of ezetimibe (may consider bile acid sequestrants if ezetimibe intolerant and triglycerides < 300 mg/dL).
• Patients, 40 to 75 years of age, without clinical ASCVD or DM with an estimated 10-year risk of ASCVD of ≥ 7.5% and an LDL level of 70 to 189 mg/dL: consider addition of ezetimibe (may consider bile acid sequestrants if ezetimibe intolerant and triglycerides < 300 mg/dL).

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

Monitoring Parameters

Per the 2013 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.²⁵ 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 DM.
• 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 (ie, for transplantation or human immunodeficiency virus [HIV] infection). Significant drug interactions may occur with statin therapy. Many of these interactions are discussed in the March 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.

PERIPHERAL ARTERIAL DISEASE

Overview

Peripheral arterial disease (PAD) is estimated to affect more than 8 million adults in the United States.³¹ 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.^32,33 Risk factors that contribute to an increased prevalence of PAD include current smoking, DM, hypertension, hyperlipidemia, renal function impairment, hyperhomocysteinemia, and African American ethnicity.^32,34 PAD is most commonly due to the progressive occurrence of systemic atherosclerosis in the arterial lumen of lower limb extremities.³² 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.³¹

During early stages of PAD, patients are often asymptomatic.^32,35 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.^32,36 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.^31,32 Pain at rest is generally noted with advanced disease when blood perfusion to the extremity becomes inadequate.³² 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.³⁴

Diagnosis of PAD can be difficult; ruling out other potential neurologic, inflammatory, and vascular conditions is essential.^32,36 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 DM and/or smoking history
• > 65 years of age
• with known vascular disease
• with reduced/abnormal pulses
• with PAD symptoms.³¹

The best diagnostic test currently available for PAD is the ankle-branchial pressure index (ABI).^31,33 A normal ABI value ranges between 1.0 and 1.4. 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.^31,32

The broad goals of therapy for PAD include managing symptoms associated with disease progression and reducing the risk of cardiovascular events.³⁵

Treatment

The ACCF/AHA published practice guidelines on the management of patients with PAD in 2013, which were subsequently update in 2016.^37,38 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.^32,33,37-39 Current or former smokers should be questioned regarding tobacco use at every visit. 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. Patients with PAD should avoid exposure to secondhand smoke. 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 and is recommended per the guideline.³⁸ Additionally, patients with PAD should receive an annual influenza vaccination.

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.

Monitoring Parameters

Appropriate use and monitoring of statins and antihypertensive agents were reviewed earlier in this module. Monitoring parameters for agents for claudication include:⁴⁰

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.

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 BP, 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.⁴¹ The Vaughan Williams system is still most frequently used to classify the majority of antiarrhythmic agents (Table 15).

Treatment

As mentioned, 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.⁴¹ 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.

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%).⁴¹ Mexiletine therapy is associated with a high incidence of neurologic and/or GI 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.

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

STROKE

Overview

In the United States, an estimated 6.6 million individuals are stroke survivors.⁴² Although stroke remains the leading cause of adult disability, progress has been made in stroke management.⁴² In 2016, stroke was the fifth leading cause of death in the United States.¹ This represented an improvement from years past when stroke was consistently the third or fourth leading cause of mortality. From 2006 to 2016, the age-adjusted stroke death rate fell by 16.7% and the actual number of stroke deaths increased by 3.7%. Both racial (African Americans > Caucasians) and geographic (southeastern United States > other regions) disparities exist with regard to stroke rates.⁴²

There are 2 stroke types, ischemic and hemorrhagic.⁴²  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.⁴² 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.

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.⁴²

Treatment and Prevention

The AHA/American Stroke Association (ASA) published guidelines for the early management of patients with acute ischemic stroke in 2013, which were subsequently updated in 2018.^43,44 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 BP 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.^43,44 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 symptom onset or patient last known well or at baseline state.
• tPA (same dose as above) is also recommended for select patients who can be treated in the time period of 3 to 4.5 hours of ischemic stroke symptom onset or patient last known well. 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).
• For otherwise eligible patients with mild stroke presenting in the 3- to 4.5-hour window, treatment with IV tPA may be reasonable. Treatment risks should be weighed against possible benefits.
• In otherwise eligible patients who have had a previously demonstrated small number (1-10) of cerebral microbleeds on MRI, administration of IV tPA is reasonable.
• In otherwise eligible patients who have had a previously demonstrated high burden (> 10) of cerebral microbleeds on MRI, administration of IV tPA may be associated with an increased risk of symptomatic intracerebral hemorrhage, and the benefits of treatment are uncertain.
• Intravenous tPA for adults with acute ischemic stroke with known sickle cell disease can be beneficial.

Beyond tPA, oral aspirin therapy (initial dose: 325 mg) has also been shown to be of benefit in acute ischemic stroke.^42-44 The guidelines recommend aspirin administration within 24 to 48 hours after stroke onset in most patients; however, aspirin administration is generally delayed until 24 hours after tPA administration. A variety of other medications including UFH, LMWHs, direct thrombin inhibitors, ticagrelor, dipyridamole, and glycoprotein IIb/IIIa inhibitors have been evaluated in acute ischemic stroke; however, data from clinical studies have either been negative (i.e., 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.⁴² Recommendations for antiplatelet therapy in secondary prevention of ischemic stroke are presented in Table 20. Of note, the 2018 guidelines also states that in patients presenting with minor stroke, treatment for 21 days with dual antiplatelet therapy (aspirin and clopidogrel) begun within 24 hours can be beneficial for early secondary stroke prevention for a period of up to 90 days from symptom onset.⁴⁴ 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.

Monitoring Parameters

The AHA/ASA guidelines recommend monitoring for potential bleeding complications during and after tPA therapy.^43,44 In addition, appropriate monitoring of tPA includes:

• Performing BP and neurological assessments every 15 minutes during and after IV tPA infusion for 2 hours, then 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.
• Frequency of BP monitoring should be increased if SBP is > 180 mm Hg or if DBP is > 105 mm Hg; administer antihypertensive agents to maintain BP at or below these levels.
• Obtaining a follow-up CT or MRI scan at 24 hours after tPA before starting anticoagulants or antiplatelets, such as aspirin.

Focus Points for Medication Therapy Management in Cardiovascular Disease

MTM 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 2019 American Geriatrics Society (AGS) Beers Criteria for potentially inappropriate medication use in older adults (see Resource List at the end of this module).⁴⁵

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 guidelines and discuss these with the patient.
• Selection of drug therapy should be individualized as needed (ie, ACE inhibitors or ARBs for CKD and hypertension). The guidelines recommend that initial antihypertensive therapy should include a thiazide diuretic, CCB, 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 BP. If that is the case, combination therapy may be instituted to successfully reach the BP 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, DM, 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 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 health care 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 ASCVD. 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 DM 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.

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